Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N.COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)N[P:43]([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:44].C(N(CC)CC)C.C(Cl)(Cl)(Cl)[Cl:74]>C(Cl)Cl>[CH2:45]([P:43]([Cl:74])([CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)=[O:44])[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@H](CCSC)NP(=O)(Cc1ccccc1)Cc1ccccc1
Reactant: ClC(Cl)(Cl)Cl
Agent: COC(=O)[C@@H]1CCCN1C(=O)[C@@H]1CCCN1C(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=P(Cl)(Cc1ccccc1)Cc1ccccc1
Temperature: -30 °C

Procedure:
Dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester L-methionyl-L-prolyl-L-proline methylester hydrochloride (2.0 g, 5.1 m mole) was dissolved in methylene chloride (20 ml), and triethyl amine (1.54 g, 15.2 m mole) was added thereto. The solution was cooled at -30° C., and to the cooled solution, a carbon tetrachloride solution (10 ml) of dibenzylphosphorylchloride produced from dibenzylhydrogen phosphite (1.41 g, 5.1 m mole) was added dropwise, and the mixture was further stirred overnight at room temperature. To the reaction solution, methylene chloride (100 ml) was added, and the mixture was washed with 1N hydrochloric acid, water, 5% sodium bicarbonate and water in this order. The mixture was dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain a candy-like residue (3.23 g). The residue was purified by column chromatography (silica gel, developing solvent; ethyl acetate:methanol=20:1) to obtain dibenzylphosphoryl-L-methionyl-L-prolyl-L-proline methylester (1.87 g, yield: 59.6%). A single spot with Rf =0.1 was obtained by thin layer chromatography (developing solvent, ethyl acetate:methanol32 20:1, Colour forming method, spraying of 25% hydrobromic acid and 0.1 ninhydrin, and heating).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)[C:5]([Cl:17])=[CH:4][N:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[C:25]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)[CH2:29][CH2:28]2)[CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:17][C:5]1[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][CH:9]=2)=[N:7][C:2]([NH:22][C:21]2[CH:23]=[CH:24][C:25]([N:27]3[CH2:32][CH2:31][CH:30]([N:33]4[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]4)[CH2:29][CH2:28]3)=[CH:26][C:20]=2[O:19][CH3:18])=[N:3][CH:4]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1

Procedure:
Starting materials: 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) and 2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)aniline (INTERMEDIATE 27).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=S)[NH:10][CH:11]2[CH2:19][CH:18]3[CH:13]4[CH2:14][CH:15]5[CH:17]3[CH:16]5[CH:12]24)=[CH:4][CH:3]=1.[NH3:21]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[NH:21])[NH:10][CH:11]2[CH2:19][CH:18]3[CH:13]4[CH2:14][CH:15]5[CH:17]3[CH:16]5[CH:12]24)=[CH:4][CH:3]=1
Reactant: N
Reactant: S=C(Nc1ccc(Cl)cc1)NC1CC2C3CC4C2C4C13
Solvent: CCO
Product: N=C(Nc1ccc(Cl)cc1)NC1CC2C3CC4C2C4C13
Reaction time: 0.25 h

Procedure:
8-[3-(p-Chlorophenyl)thioureido]tetracyclo[4,3,0,02,4,03,7 ]nonane (0.30 g.) was dissolved in ethanol saturated with ammonia (100 ml.) at room temperature and stirred with yellow mercuric oxide (0.43 g.) for 6 hours. The mixture was then boiled for 15 minutes to remove excess ammonia, filtered and the filtrate evaporated to dryness. The solid residue was recrystallised from toluene/cyclohexane (1:2 v/v) to give 8-[3-(p-chlorophenyl)guanidino]tetracyclo[4,3,0,02,4,03,7 ]nonane, m.p. 170°-171°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10](=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:16]C1CC(C(C)C)CCC1=O>>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([Br:16])[C:10](=[O:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCN(Cc2ccccc2)C1
Reactant: CC(C)C1CCC(=O)C(Br)C1
Product: O=C1CN(Cc2ccccc2)CCCC1Br

Procedure:
The bromination of 1-benzyl-azepan-3-one takes place in a manner similar to that described above for the preparation of 2-bromo-4-isopropyl-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7](OC)=[O:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2].[BH4-].[Li+].CCOC(C)=O>C1COCC1>[C:1]([C:3]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[O:13][CH3:14])#[N:2]
Reactant: COC(=O)c1ccc(C#N)c(OC)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(CO)ccc1C#N
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of the ester from Step D (48.8 g, 255 mmol) in 400 mL of dry THF under argon at room temperature was added lithium borohydride (255 mL, 510 mmol, 2M THF) over 5 minutes. After 1.5 hours, the reaction was warmed to reflux for 0.5 hours, then cooled to room temperature. The solution was poured into EtOAc/1N HCl soln. [CAUTION], and the layers were separated. The organic layer was washed with water, sat Na2CO3 soln. and brine (4×), dried (Na2SO4), and concentrated in vacuo to provide the titled product.
Reaction SMILES: [C:1]([O:9][C@H:10]1[C:14]([F:16])([F:15])[CH:13](OS(C)(=O)=O)[O:12][C@@H:11]1[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[I-:44]>CC(C)=O>[C:1]([O:9][C@H:10]1[C:14]([F:16])([F:15])[CH:13]([I:44])[O:12][C@@H:11]1[CH2:22][O:23][C:24]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OC1O[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H](OC(=O)c2ccccc2)C1(F)F
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(O[C@@H]1[C@@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(I)C1(F)F)c1ccccc1
Temperature: 25 °C
Yield: 79.6 %

Procedure:
(2R,3R)-4,4-difluoro-5-(methylsulfonyloxy)-2-(trityloxymethyl)tetrahydrofuran-3-yl benzoate 9 (2 g, 3.37 mmol), acetone (20 mL), and NaI (5 g, 33.56 mmol) were charged into a round bottom flask. The resulting mixture was refluxed for >6 hours. HPLC indicated that all starting material 9 was consumed. The reaction mixture was cooled to ambient temperature and filtered. The solvent was removed in vacuo. The residue was partitioned between dichloromethane (105 mL) and water (65 mL). The aqueous layer was extracted with dichloromethane (30 mL). The combined dichloromethane layers were washed sequentially with a 5% aqueous solution of NaHSO3 (2×30 mL), a 1:1 mixture of water and brine (20 mL), and brine (2×20 mL). The solution was dried over MgSO4, filtered, and concentrated to give 1.68 g of (2R,3R)-4,4-difluoro-5-iodo-2-(trityloxymethyl)tetrahydrofuran-3-yl benzoate 10. H1 NMR (CDCl3): δ3.44-3.57 (dd, 2H), 4.41 (m, 1H), 5.60-5.65 (dd, 1H), 6.95 (d, 1H), 7.21-8.15 (m, 20H).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:41])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33].[CH3:42][C:43]([CH3:59])([O:45][C:46]([N:48]1[C:52]2[CH:53]=[CH:54][C:55]([CH:57]=O)=[CH:56][C:51]=2[N:50]=[N:49]1)=[O:47])[CH3:44]>O1CCCC1>[CH3:9][O:10][C:11](=[O:41])/[C:12](/[NH:13][C:14](=[O:34])[C:15]1[C:20]([CH3:21])=[CH:19][C:18]([C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([OH:32])[CH:27]=2)=[O:23])=[CH:17][C:16]=1[Cl:33])=[CH:57]/[C:55]1[CH:54]=[CH:53][C:52]2[N:48]([C:46]([O:45][C:43]([CH3:42])([CH3:59])[CH3:44])=[O:47])[N:49]=[N:50][C:51]=2[CH:56]=1
Reactant: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Reactant: CC(C)(C)OC(=O)n1nnc2cc(C=O)ccc21
Agent: CN(C)C(=N)N(C)C
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc2c(c1)nnn2C(=O)OC(C)(C)C)NC(=O)c1c(C)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Temperature: 25 °C
Reaction time: 42 h
Yield: 88 %

Procedure:
1,1,3,3-Tetramethylguanidine (60 μL, 0.48 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 132; 109 mg, 0.22 mmol) in tetrahydrofuran (3 mL) at room temperature. 1-(1,1-dimethylethoxycarbonyl)-1H-benzotriazole-5-carboxaldehyde (Example 40; 55 mg, 0.22 mmol) was added and the solution was stirred at room temperature for 42 h. After the solvents were removed under reduced pressure, the residue was partitioned between ethyl acetate (10 mL) and pH 6 phosphate buffer (5 mL). The organic phase was washed with pH 6 phosphate buffer, brine, 10% aqueous sodium bicarbonate solution and brine. Each of the aqueous layers was extracted in turn with ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and evaporated to give crude (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]-6-methylbenzoyl]amino]-3-[1-(1,1-dimethylethoxycarbonyl)-1H-benzotriazol-5-yl]propenoic acid methyl ester (120 mg) which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1.C([O-])(=O)C.[Na+].[I:22]Cl.O>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:16])[NH:4][C:5]1[S:6][C:7]2[C:13]([I:22])=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:8]=2[N:9]=1
Reactant: ClI
Reactant: COC(=O)Nc1nc2c(OC)cccc2s1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2c(OC)ccc(I)c2s1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
(4-Methoxy-benzothiazol-2-yl)-carbamic acid methyl ester (31.0 g, 130 mmol) and sodium acetate (32.3 g, 394 mmol) are dissolved in 400 ml of glacial acetic acid and slowly treated with iodine monochloride (13.5 ml, 264 mmol) at 0° C. The reaction mixture is then slowly warmed to room temperature and stirred for 15 hours. After addition of water (1.3 l), the formed precipitate is filtered off and washed with water. The filter cake is then dissolved in a minimal amount of tetrahydrofurane (about 150 ml) and decolorized with 1M aqueous sodium thiosulfate. The product is precipitated by the addition of water (about 2.0 l), filtered off and dried at 60° C. for 12 hours. 42.3 g (89%) white solid. MS: m/e=364 (M+).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5](=[O:7])[C:4]2([CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][CH2:8]2)[NH:3]1.C(OC(N1CCCCC1=O)=O)C1C=CC=CC=1.[H][H].N1CC(=O)NC1=O>C(O)C.[Pd].C(O)(=O)C>[NH:3]1[C:4]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5](=[O:7])[NH:6][C:2]1=[O:1]
Reactant: O=C1NC(=O)C2(CCN(C(=O)OCc3ccccc3)CC2)N1
Reactant: [H][H]
Agent: [Pd]
Agent: O=C1CCCCN1C(=O)OCc1ccccc1
Agent: O=C1CNC(=O)N1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C1NC(=O)C2(CCNCC2)N1
Temperature: 60 °C

Procedure:
To a solution of 14.6 g (48.1 mmol) benzyl 2,4-dioxo-1,3,8-triaza-spiro[4.5]decan-8-carboxylate (prepared from N-(benzyloxycarbonyl)piperidone by the method from J. Med. Chem. 1995, 38, 3772) in 250 ml dry ethanol were added 500 mg 10% Pd/C, and the mixture was filled into an autoclave. After stirring at 60° C. and 10 atm of hydrogen for 3 h no starting hydantoin could be detected by TLC. A precipitate had been formed which was redissolved by addition of 100 ml acetic acid. The catalyst was removed by filtration and the solution was concentrated in vacuo. Aqueous sodium bicarbonate solution was added until the mixture became a clear solution, and the title compound precipitated in two crops upon concentration in vacuo.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])[N:20]=3)[N:15]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].CN(C(ON1N=[N:55][C:50]2[CH:51]=CC=N[C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)(C)C>CN(C=O)C>[C:1]([CH:3]1[CH2:4][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25](=[O:26])[NH:55][CH:50]([CH3:51])[CH3:49])[CH:23]=4)[N:20]=3)[N:15]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[CH:14]=2)=[O:12])[CH3:9])[CH2:6]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C(=O)O)c3)nc12)C(=O)N1CC(C#N)C1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)N
Solvent: CN(C)C=O
Product: CC(C)NC(=O)c1cccc(-c2cnc3c(n2)c(C(=O)N[C@H](C)C(=O)N2CC(C#N)C2)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.8 %

Procedure:
To a solution of 3-[7-[(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethylcarbamoyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzoic acid (70 mg, 0.13 mmol) and HATU (53.4 mg, 0.14 mmol) in DMF (1.5 mL) was added isopropylamine (44 μL, 0.51 mmol). The reaction mixture was stirred at room temp for 4 h then quenched with water and extracted with EtOAc (2×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was chromatographed with 50% to 100% EtOAc/hexanes to isolate 52 mg (69%) of 2-(3-isopropylcarbamoyl-phenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as an off-white foamy solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH:19]=[O:20])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][Mg]Cl>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@H:14]2[NH:15][C:16](=[O:18])[O:17][C@H:13]2[CH2:12][C@H:11]([CH:19]([OH:20])[CH3:29])[C@H:10]1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(O)[C@H]1C[C@@H]2OC(=O)N[C@@H]2[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h

Procedure:
To a solution of the above crude 3 (1.4 g, 3.6 mmol) in THF (10 mL) was added methylmagnesium chloride (7.0 mL, 2.5M in THF, 17.5 mmol) at −78° C. After 1 hour, the reaction mixture was quenched with saturated aqueous NH4Cl (20 mL) and extracted with DCM (4×50 mL). The combined organic layer was dried over anhydrous MgSO4 and concentrated in vacuo to give a residue, which was purified by a silica gel column, eluted with 10% MeOH in DCM to give 4 as a white solid (1.0 g, 68% in two steps, the ratio of diastereomers is 1:3 by 1H NMR). (ES, m/z): [M+H]+ 397.9; 1H NMR (300 MHz, CDCl3) δ 7.30-7.45 (m, 10H), 4.91-4.96 (m, 2H), 4.70-4.87 (m, 2H), 4.50-4.69 (m, 2H), 3.74-3.79 (m, 2H), 3.47-3.58 (m, 2H), 1.50-1.76 (m, 2H), 1.15 (d, J=6.6 Hz, 3H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22](I)=[CH:21][C:20]=3[F:26])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.C[Si]([C:33]#[CH:34])(C)C.C(N(CC)CC)C>C1COCC1.[Cu](I)I>[OH:1][C@@H:2]([CH2:27][OH:28])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:33]#[CH:34])=[CH:21][C:20]=3[F:26])=[C:12]([CH3:17])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: Cc1c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@@H](O)CO)cnc2n(C)c1=O
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#Cc1ccc(Nc2c(C)c(=O)n(C)c3ncn(C[C@@H](O)CO)c(=O)c23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.7 %

Procedure:
(R)-3-(2,3 Dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-6,8-dimethylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (200 mg, 0.4 mmol, Example 8), trimethylsilyl acetylene (66 μL, 0.6 mmol), triethylamine (84 μL, 0.6 mmol), copper iodide (14 mg, cat) and dichlorobis(triphenylphoshine) palladium(II) (14 mg, 0.02 mmol) were mixed in THF (2 mL). The mixture was subjected to microwave irradiation at 120° C. for 20 minutes. The solvent was removed in vacuo and the residue dissolved in methanol. Potassium carbonate (50 mg) was added and the solution stirred at RT for 1 hour. After filtration and evaporation the residue was purified by HPLC to give 119 mg of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.79 (s, 3 H) 3.11 (s, 1 H) 3.54-3.66 (m, 3 H) 3.82-3.90 (m, 1 H) 3.94-4.02 (m, 1 H) 4.30 (dd, J=14.15, 3.79 Hz, 1 H) 6.67 (t, J=8.46 Hz, 1 H) 7.19 (dd, J=8.21, 0.88 Hz, 1 H) 7.21-7.25 (m, 1 H) 8.27 (s, 1 H) [M+H] calc'd for C20H19FN4O4, 399; found, 399.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8](=[O:11])[NH:9][N:10]=2)[N:7]=1.[C:12]1([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH2:29])[CH2:22][CH2:21]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)C(C)C)C>C(O)CCC>[C:30]1([CH:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][CH2:28][NH:29][C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8](=[O:11])[NH:9][N:10]=4)[N:7]=3)[CH2:22][CH2:21]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=c1[nH]nc2ccc(Cl)nn12
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Yield: 28.1 %

Procedure:
0.512 g of 6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was dissolved in 15 ml of n-butanol; 0.88 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.04 ml of N-ethyldiisopropylamine were added, followed by refluxing under heating in an oil bath for 5 hours. After cooling, the n-butanol was mostly distilled off under reduced pressure; to the residue, an aqueous solution of sodium hydrogen carbonate was added; the reaction mixture was extracted with ethyl acetate; the extract was washed with saturated saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (85:15:1). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.35 g of the title compound.
Reaction SMILES: [C:1]1([C:7]2([C:10]([OH:12])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:13]C1C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>CO>[C:1]1([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1(c2ccccc2)CC1
Yield: 147.5 %

Procedure:
To a solution of 1-phenylcyclopropanecarboxylic acid (25 g, 0.15 mol) in CH3OH (200 mL) was added TsOH (3 g, 0.1 mol) at room temperature. The mixture was refluxed overnight. The solvent was evaporated under reduced pressure to give crude product, which was dissolved into EtOAc. The EtOAc layer was washed with aq. sat, NaHCO3. The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to give methyl 1-phenylcyclopropanecarboxylate (26 g, 96%), which was used directly in the next step. 1H NMR (400 MHz, CDCl3) δ 7.37-7.26 (m, 5H), 3.63 (s, 3H), 1.63-1.60 (m, 2H), 1.22-1.19 (m, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[O:18][C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:16][C:15]=1[CH:25]([OH:27])[CH3:26].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:37]=[O:38])[CH:33]=[CH:34][C:35]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:34][C:35]=1[O:27][CH:25]([C:15]1[N:16]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:18][C:14]=1[CH3:13])[CH3:26])[CH:37]=[O:38]
Reactant: Cc1oc(-c2ccccc2)nc1C(C)O
Reactant: COc1cc(C=O)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1OC(C)c1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
Diethyl azodicarboxylate (DEAD) (4.71 g) was added dropwise, under ice-cooling, to a mixture of 1-(5-methyl-2-phenyl-4-oxazolyl)ethanol (5.0 g), vanilline (3.75 g), triphenylphosphine (Ph3P) (7.1 g) and tetrahydrofuran (THF) (80 ml). The reaction mixture was stirred for 8 hours at room temperature and concentrated under reduced pressure. The residue was subjected to column chromatography on silica gel. From the fraction eluted with ethyl acetate-hexane (1:4, v/v), was obtained 3-methoxy-4-[1-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzaldehyde (4.48 g, 54%), which was recrystallized from ethyl acetate-hexane to give colorless needles, m.p.104-105° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=[O:5].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:3]=1[CH:4]=[O:5]
Reactant: CCCCCCCCCBr
Reactant: O=Cc1c(O)cccc1Cl
Product: CCCCCCCCCOc1cccc(Cl)c1C=O

Procedure:
2-chloro-6-hydroxy-benzaldehyde was alkylated with 1-bromononane as in Example 1 to give 2-chloro-6-nonyloxy benzaldehyde. Reduction with sodium borohydroxide as in Example 1 gave 2-chloro-6-nonyloxy benzyl alcohol which on treatment with triphenylphosphine hydrobromide in acetonitrile as in Example 1 yielded [[2-chloro-6-nonyl-oxy]phenyl]methyl]triphenyl phosphonium bromide. Condensation with 7-formyl-3-methyl-2,4,6-octatrienoic acid ethyl ester as described in Example 3 produced (All E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid ethyl ester. The ester was subjected to hydrolysis, as in Example 5, to produce (All-E)-9-[2-chloro-6-(nonyloxy)phenyl]-3,7-dimethyl-2,4,6,8-nonatetraenoic acid mp 129°-131° (from ethyl acetate/hexane mixture).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)C(C)C)(C)C.Cl[CH2:26][O:27][CH3:28]>C(Cl)Cl>[Cl:1][C:2]1[N:3]([CH2:10][C@:11]([OH:15])([CH3:14])[CH2:12][O:13][CH2:26][O:27][CH3:28])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: COCCl
Reactant: C[C@](O)(CO)Cn1cc([N+](=O)[O-])nc1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOC[C@](C)(O)Cn1cc([N+](=O)[O-])nc1Cl
Temperature: 25 °C
Reaction time: 46 h
Yield: 69.2 %

Procedure:
(R)-2-Chloro-1-(2,3-dihydroxy-2-methylpropyl)-4-nitroimidazole prepared in Example 10 (7.4 g, 31 mmol) was dissolved in methylene chloride (120 ml). N,N-diisopropylethylamine (13.1 ml, 74 mmol) and chloromethylmethyl ether (7.1 ml, 74 mmol) were added to the solution followed by stirring at room temperature for 46 hours. The reaction mixture was washed with water, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate=9/1) to afford (R)-2-chloro-1-(2-hydroxy-3-methoxymethoxy-2-methylpropyl)-4-nitroimidazole (6.0 g, yield 69%) as a light yellow oil.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(CC)CC)C.Br.[Br:17][C:18]1[CH:19]=[C:20]([CH2:25]Br)[C:21]([NH2:24])=[N:22][CH:23]=1>CN(C)C=O>[NH2:24][C:21]1[C:20]([CH2:25][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8])=[CH:19][C:18]([Br:17])=[CH:23][N:22]=1
Reactant: CCOC(=O)CN
Reactant: Nc1ncc(Br)cc1CBr
Agent: Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNCc1cc(Br)cnc1N
Reaction time: 8 h

Procedure:
Glycine ethyl ester hydrochloride (805 mg, 5.7 mmol) and triethylamine (2.6 mL, 18.46 mmol) were successively added to a solution of 5-bromo-3-(bromomethyl)pyridin-2-amine hydrobromide (2, 5.7 mmol) in dimethylformamide (65 mL) at room temperature. The reaction mixture was stirred overnight then partitioned between ethyl acetate (70 ml) and water (100 mL). The aqueous phase was separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were washed with a saturated solution of sodium chloride (3×40 mL), dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography on silica gel, using dichloromethane/methanol (10:0 to 95:5) as eluent. The title product was obtained as a yellow solid (1.1 g, 68%).