Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[C:27]([CH3:44])=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([CH3:43])([CH3:42])[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])[N:34]=2)[N:31]=1.C(=O)(O)[O-].[Na+]>>[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[C:27]([CH3:44])=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([CH3:42])([CH3:43])[C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1Cl
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc2nc(C(C)(C)C(=O)OC(C)C)cn2nc1NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 58.7 %

Procedure:
1.40 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 0.636 g of isopropyl 2-(6-chloro-7-methylimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 190-200° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (185:15:2). The desired fraction was collected to yield 0.737 g of isopropyl 2-[6-[3-[4-(diphenylmethoxy)piperidino]propylamino]-7-methylimidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate as an oily substance. This oily substance was dissolved in 6 ml of ethanol; 3.15 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 7 hours. After cooling, the mixture was concentrated under reduced pressure; under ice cooling conditions, 1.89 ml of 1 N hydrochloric acid was added; the residue was washed with ethyl acetate. To the water layer, 1.89 ml of 1 N hydrochloric acid was added to saturate with sodium chloride, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure; 1.89 ml of 1 N hydrochloric acid was added to the residue, followed by concentration to dryness under reduced pressure. The residue was crystallized by the addition of ethyl ether, collected by filtration, washed with ethyl ether and dried to yield 0.445 g of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17](Cl)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CN(C)C=O>[CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[C:17]([N:25]6[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]6)[CH:18]=[CH:19][CH:20]=5)[C:15](=[O:23])[N:14]([CH3:24])[C:13]=34)[N:5]=2)[CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: Cn1c(=O)c2c(Cl)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Solvent: CN(C)C=O
Product: Cn1c(=O)c2c(N3CCCCC3)cccc2n2cnc(-c3noc(C4CC4)n3)c12
Yield: 81 %

Procedure:
3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl-5-oxo-6-chloro-4,5-dihydro-imidazo(1,5-a)quinazoline (0.28 g, 0.8 mmol) was heated to 110° C. for 2 1/4 h in a mixture of 20 ml of dimethylformamide and 1 ml of piperidine. The reaction mixture was then evaporated in vacuo and the residue triturated with 5 ml of water, filtered off and dried to give 0.26 g (81%) 3- (5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4-methyl -5-oxo- 6-(1-piperidyl)-4,5-dihydro-imidazo(1,5-a)quinazoline, M.p. 185°-192° C..
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([N+:11]([O-])=O)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14]1([CH3:24])[CH:19]=CC(S(Cl)(=O)=O)=C[CH:15]=1.C(O)(C)(C)C>N1C=CC=CC=1>[NH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([O:6][C:14]([CH3:24])([CH3:19])[CH3:15])=[O:5])=[C:2]([CH3:1])[CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: c1ccncc1
Solvent: CC(C)(C)O
Product: Cc1cc(N)ccc1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 104.4 %

Procedure:
2-Methyl-4-nitrobenzoic acid (700 mg, 3.86 mmol) was dissolved in pyridine (8 mL), p-toluenesulfonyl chloride (1.47 g, 7.74 mmol) was added, then tert-butanol (0.369 mL, 3.86 mmol) was added under ice cooling, and the mixture was stirred at 0° C. for 2 hours and at room temperature for 2 hours. tert-Butanol (0.369 mL, 3.86 mmol) was further added, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, water was added, then the mixture was extracted with ethyl acetate (×3), and the organic layer was washed with 1 N hydrochloric acid, a 1 N aqueous sodium hydroxide solution, water, and saturated sodium chloride solution. The organic layer was dried with anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, a solution of the resulting residue in ethyl acetate (40 mL) was added to 10% palladium-carbon (dry; 222 mg), the atmosphere in the system was replaced with a hydrogen atmosphere, and then the mixture was stirred at room temperature for 2 hours. The atmosphere in the system was replaced with a nitrogen atmosphere, and then the mixture was filtered through celite. The solvent was evaporated under reduced pressure to give the title compound (835 mg; yield, 100%) as a brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([CH3:26])=[N:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20][Br:34])[NH:12][C:11]([C:21]2[S:22][C:23]([CH3:26])=[N:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Yield: 70.4 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(5-methyl-1,3,4-thiadiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.88 g, 2 mmol) was reacted with NBS (0.36 g, 2 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.73 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].Br[C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[CH3:22]>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[N:19]=[C:18]([CH3:21])[CH:17]=[C:16]2[CH3:22]
Reactant: Cc1cc(C)c2cccc(Br)c2n1
Reactant: Cc1cccc(C)c1N
Product: Cc1cc(C)c2cccc(Nc3c(C)cccc3C)c2n1
Yield: 46 %

Procedure:
Repeat the procedure of Example 1 except use 2,6-dimethylaniline instead of 2,6-diisopropylaniline and 8-bromo-2,4-dimethylquinoline instead of 8-bromoquinoline to give purified (4) in 46% yield.
Reaction SMILES: CO[C:3](=[O:22])[CH2:4][CH2:5][C:6]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21])([C:13]#[N:14])[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10].ClC1C=CC(C(C#N)(CCC(O)=O)CCC(O)=O)=CC=1.O1CCCC1.CC(C)([O-])C.[K+]>C(O)(=O)C>[C:9]([CH:8]1[CH2:7][C:6]([C:13]#[N:14])([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[CH2:5][CH2:4][C:3]1=[O:22])([O:11][CH3:12])=[O:10]
Reactant: COC(=O)CCC(C#N)(CCC(=O)OC)c1ccccc1Cl
Agent: CC(C)(C)[O-]
Agent: N#CC(CCC(=O)O)(CCC(=O)O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)C1CC(C#N)(c2ccccc2Cl)CCC1=O
Yield: 95 %

Procedure:
Following the procedure of Example 1, Part B, but substituting 39.11 gm. (0.121 mole) dimethyl-4-(o-chlorophenyl)-4-cyanopimelate (prepared in Part A, above) for the dimethyl ester of 4-(p-chlorophenyl)-4-cyanopimelic acid, and using 780 ml. of the tetrahydrofuran, 27.4 gm. (0.24 mole) of the potassium tert-butoxide, and 195 ml. of the 2.5 N acetic acid instead of the 700 ml., the 24.4 gm (0.218 mole), and the 175 ml., respectively, there is prepared 33.4 gm. (95% yield) of 2-carbomethoxy-4-cyano-4-(o-chlorophenyl)cyclohexanone as a crystalline solid having a melting range of 113° to 118° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[CH:3]=1.[Li]CCCC.[CH3:17][C:18](OC(C)=O)=[O:19]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:9][O:10][CH3:11])[C:3]=1[C:18](=[O:19])[CH3:17]
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCOc1cccc(Cl)c1C(C)=O
Temperature: -75 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-chloro-3-(methoxymethoxy)benzene (24 g, 136.74 mmol, 1.00 equiv, 98%) in THF (240 mL) was added TMP (21 g, 150.00 mmol, 1.10 equiv). To the above solution was added n-BuLi (61 mL, 1.10 equiv, 2.5 mol/L) dropwise with stirring at −75° C. over 30 min. After stirring for 2 h at −75° C., the resulting mixture was reacted with Ac2O (15.5 g, 148.92 mmol, 1.10 equiv, 98%) via dropwise addition with stirring at −75° C. over 30 min. The mixture was stirred for additional 30 min at room temperature, and then quenched by adding water. The resulting mixture was extracted with 2×300 mL of ethyl acetate. The combined organic layers was washed with H2O, dried over Na2SO4 and concentrated under vacuum to give 1-(2-chloro-6-(methoxymethoxy)phenyl)-ethanone as a yellow oil.
Reaction SMILES: [C:1]([CH:3]1[CH2:5][NH:4]1)#[N:2].[CH2:6]1[O:19][C:18]2[CH:17]=[CH:16][C:10]([C:11]([N:13]=[C:14]=[O:15])=[O:12])=[CH:9][C:8]=2[O:7]1.C1OC2C=CC(C(N)=O)=CC=2O1>C1(C)C=CC=CC=1>[CH2:6]1[O:19][C:18]2[CH:17]=[CH:16][C:10]([C:11]([NH:13][C:14]([N:4]3[CH2:5][CH:3]3[C:1]#[N:2])=[O:15])=[O:12])=[CH:9][C:8]=2[O:7]1
Reactant: N#CC1CN1
Reactant: O=C=NC(=O)c1ccc2c(c1)OCO2
Agent: NC(=O)c1ccc2c(c1)OCO2
Solvent: Cc1ccccc1
Product: N#CC1CN1C(=O)NC(=O)c1ccc2c(c1)OCO2
Temperature: 0 °C

Procedure:
0.26 g. 2-Cyanoaziridine are dissolved in 5 ml. toluene and introduced, while stirring at 0° C., into a solution of 0.73 g. 3,4-methylenedioxybenzoyl isocyanate in 25 ml. toluene. The reaction mixture is further stirred for 1 hour at 0° C. and the precipitated material (0.65 g.) is filtered off with suction at ambient temperature and briefly boiled with isopropanol, 0.2 g. of the desired 1-(N-3,4-methylenedioxybenzoyl-carbamoyl)-2-cyanoaziridine thereby remaining undissolved (m.p. 145°-153° C., at 172° C. a clear melt is obtained). It is contaminated with a little 3,4-methylenedioxybenzamide.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]#[C:24][CH3:25])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].[CH3:26][N:27]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:28](Cl)=[O:29]>>[CH2:22]([O:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([N:7]2[CH2:8][CH2:9][N:10]([C:28]([N:27]([CH3:26])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:29])[CH2:11][CH:6]2[C:4]([O:3][CH2:1][CH3:2])=[O:5])(=[O:13])=[O:14])=[CH:16][CH:17]=1)[C:23]#[C:24][CH3:25]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCNCC2C(=O)OCC)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N2CCN(C(=O)N(C)c3ccccc3)CC2C(=O)OCC)cc1
Yield: 98 %

Procedure:
In the same manner as described in Step 1 of Example 215, the 1-(4but-2-ynyloxy-benzenesulfonyl)-piperazine-2-carboxylic acid ethyl ester (1.0 g, 2.7 mmol) was treated with N-methyl-N-phenylcarbamoyl chloride to provide 1.33 g (98%) of ethyl 1-{[4-(2-butynyloxy)phenyl]sulfonyl}-4-[(methylanilino)carbonyl]-2-piperazine-carboxylate as a brown oil. Electrospray Mass Spec 500.2 (M+H)+.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][NH:13][CH2:14][C:15]1[O:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[O:19]1[CH:18]=[CH:17][CH:16]=[C:15]1[CH2:14][N:13]([CH3:12])[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2
Reactant: CNCc1ccco1
Reactant: O=C1CCc2cc(F)ccc21
Solvent: CCO
Product: CN(Cc1ccco1)c1ccc2c(c1)CCC2=O

Procedure:
A solution of 5-fluoro-1-indanone (1.0 g, 6.66 mmol) and N-methylfurfurylamine (2.0 g, 18.0 mmol) in ethanol (10 mL) was heated to about 80° C. for about 2 days. The reaction mixture was concentrated under vacuum and the residue was purified by flash column chromatography on silica gel using hexane/ethyl acetate (2:1) as the mobile phase to provide the desired product. MS (ESI): m/z 242 (M+H)+.
Reaction SMILES: B.[CH3:2][C:3]1([CH3:28])[CH2:12][CH2:11][C:10]([CH3:14])([CH3:13])[C:9]2[CH:8]=[C:7]([C:15]3([CH3:27])[C:19]4[CH:20]=[C:21]([C:24](O)=[O:25])[CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[CH:6]=[CH:5][C:4]1=2.O>C1COCC1>[CH3:2][C:3]1([CH3:28])[CH2:12][CH2:11][C:10]([CH3:13])([CH3:14])[C:9]2[CH:8]=[C:7]([C:15]3([CH3:27])[C:19]4[CH:20]=[C:21]([CH2:24][OH:25])[CH:22]=[CH:23][C:18]=4[O:17][CH2:16]3)[CH:6]=[CH:5][C:4]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(C(=O)O)cc43)ccc21
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(C3(C)COc4ccc(CO)cc43)ccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
7.7 ml of a 1M solution of borane in THF are added dropwise at 0° C. to a solution of 3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-3-methyl-2,3-dihydrobenzofuran-5-carboxylic acid (1.7 g, 4.7 mol) in THF (10 ml). The mixture is stirred for 4 hours at ambient temperature and then 2 ml of a solution of THF and water (1:1) are added. After concentration in vacuo at 40° C. in a rotary evaporator. The mixture is extracted with ethyl acetate. The organic phase is washed with water, dried over anhydrous magnesium sulphate, concentrated in vacuo at 40° C. in a rotary evaporator. The product is purified by flash chromatography on a silica column.
Reaction SMILES: CC(C)[C@H]([NH:6][C@@H:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[CH2:8][CH3:9])CO.CN.I(O)(=O)(=O)=O>CO.O>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C@H:7]([NH2:6])[CH2:8][CH3:9]
Reactant: CC[C@@H](N[C@H](CO)C(C)C)c1ccccn1
Agent: CN
Agent: [O-][I+3]([O-])([O-])O
Solvent: CO
Solvent: O
Product: CC[C@@H](N)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-3-methyl-2-((R)-1-(pyridin-2-yl)propylamino)butan-1-ol (step 2, crude product) (40.8 mmol) in MeOH (250 ml) was added methylamine (60 ml of a 40% aqueous solution) followed by a solution of periodic acid (37.2 g, 163 mmol) in water (70 ml). The mixture was stirred at RT overnight and the resulting white solid precipitate was filtered off. The filtrate was concentrated in vacuo to remove the MeOH. The residual aqueous layer was then extracted with EtOAc. The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with a 0-20% MeOH/DCM gradient affords the title product; [M+H]+ 137.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]3[N:22]=[CH:23][C:24]([C:25](O)=[O:26])=[C:14]3[N:13]=2)[CH:5]=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].[S:28]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])(=[O:30])[NH2:29]>>[S:28]([C:32]1[CH:33]=[C:34]([NH:38][C:25]([C:24]2[CH:23]=[N:22][N:15]3[C:16]([C:18]([F:19])([F:20])[F:21])=[CH:17][C:12]([C:4]4[CH:5]=[CH:6][C:7]([C:8]([F:10])([F:9])[F:11])=[C:2]([Cl:1])[CH:3]=4)=[N:13][C:14]=23)=[O:26])[CH:35]=[CH:36][CH:37]=1)(=[O:30])(=[O:31])[NH2:29]
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)c(Cl)c3)nc12
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3-chloro-4-trifluoromethyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.17) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 562.1 [(M+H)+]; mp 287° C.
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13].N1C=CC=CC=1>ClCCl>[C:12]([O:10][CH2:9][CH2:8][C@H:7]([OH:11])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:14])[CH3:13]
Reactant: OCC[C@H](O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCC[C@H](O)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (S)-1-phenyl-1,3-propanediol (8.0 g, 52.6 mmol) in dichloromethane (80 ml) were added at 0° C. acetic anhydride (5.5 ml) and pyridine (4.7 ml). The mixture was stirred for 6 hours at the same temperature range and for 1.5 hour at room temperature. The reaction mixture was washed with an aqueous solution of sodium hydrogencarbonate, water and a saturated aqueous saline solution, successively. The solvent was distilled off under reduced pressure. The residue was subjected to a silica gel column chromatography to give 4.8 g of (S)-3-hydroxy-3-phenylpropyl acetate. Physico-chemical properties and spectral data of these products are shown in [Table 7].
Reaction SMILES: [C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12.C(N1C=CN=C1)([N:35]1C=CN=C1)=O.CN(C1C=CC=CN=1)C.[OH-].[NH4+]>O1CCCC1>[C:1]1(=[O:32])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([O:25][CH3:26])[CH:12]=2)[CH2:7][C:8]([NH2:35])=[O:9])[C:4](=[O:27])[C:3]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:2]12
Reactant: COc1cc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN(C)c1ccccn1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)ccc1OCc1ccccc1
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
A mixture of 3-phthalimido-3-(4'-benzyloxy-3'-methoxyphenyl)propionic acid (1.00 g, 2.32 mmol), carbonyldiimidazole (0.406 g, 2.50 mmol) and a catalytic amount of dimethylaminopyridine in 20 mL of dry tetrahydrofuran under nitrogen was stirred for 1 hour. To the reaction solution was then added 0.25 mL of concentrated ammonium hydroxide. After 15 minutes, the reaction mixture was concentrated in vacuo to an oil which was diluted with 20 mL of water and stirred overnight. The resulting slurry was filtered and the solid dried to afford 0.645 g (65%) of 3-phthalimido-3-(4'-benzyloxy-3'-methoxyphenyl)propionamide as a white powder: 1H NMR (DMSO-d6) δ 7.84 (m, 4 H, Ar), 7.60-7.25 (m, 5 H), 7.53 (br s, 1 H, CONH), 7.15-6.8 (m, 4 H), 5.67 (t, 1 H, J=7.8 Hz), 5.04 (s, 2 H, OCH2), 3.75 (s, 3 H, OMe), 3.19 (d, 2 H, J=9, 16.5 Hz); 13C NMR (DMSO-d6) δ 171.1, 167.6,148.8, 147.2, 137.0, 134.5, 132.0, 131.2, 128.3, 127.7, 127.6, 123.0, 119.3, 113.2, 111.4, 69.8, 55.5, 50.3, 36.9. Anal. Calcd for C25H22N2O5. Theory: C, 69.76; H, 5.15; N, 6.51. Found: C, 69.54; H, 5.13; N, 6.28.
Reaction SMILES: [CH2:1]([NH:4][C:5]([NH:7][CH2:8][CH:9]=[CH2:10])=S)[CH:2]=[CH2:3].C(N(CC)CC)C.[I-].ClC1C=CC=C[N+]=1C>C(#N)C>[CH2:1]([N:4]=[C:5]=[N:7][CH2:8][CH:9]=[CH2:10])[CH:2]=[CH2:3]
Reactant: C=CCNC(=S)NCC=C
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCN=C=NCC=C

Procedure:
1.56 g of N,N'-bis(allyl)thiourea, 2.4 g of triethylamine and 3.07 g of 2-chloro-1-methylpyridinium iodide are reacted in 40 ml of acetonitrile and the reaction mixture is worked up as described in Example 4. The product is obtained as a faintly yellowish oil.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:16]=1)[CH3:2].[CH3:25][CH2:26]O>S(=O)(=O)(O)O>[CH2:25]([O:23][C:22](=[O:24])[CH2:21][C:17]1[CH:16]=[C:15]([C:6]2[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:12])[F:14])=[CH:10][C:5]=2[CH2:4][NH:3][CH2:1][CH3:2])[CH:20]=[CH:19][CH:18]=1)[CH3:26]
Reactant: CCO
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cccc(CC(=O)OCC)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (0.34 mmol) in EtOH (7 mL) was added sulfuric acid (3-4 drops), and the reaction was stirred at 50° C. overnight. Once no starting material was seen by analytical LCMS, the mixture was filtered over a pad of Celite and rinsed with EtOH. The filtrate was concentrated to give the title compound.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][C@@H:13]([CH:23]=O)[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Br-].[N+:26]([C:29]1[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=1[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>COCCOC>[Si:1]([O:8][CH2:9][C@H:10]1[N:15]([C:16]([O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:17])[CH2:14][C@@H:13](/[CH:23]=[CH:31]/[C:30]2[CH:51]=[CH:52][CH:53]=[CH:54][C:29]=2[N+:26]([O-:28])=[O:27])[O:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C=O)OC[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=[N+]([O-])c1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1C[C@@H](/C=C/c2ccccc2[N+](=O)[O-])OC[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To tert-butyl (2S,5S)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-formylmorpholine-4-carboxylate (1 eq.) in DME (0.2 M) at rt were added (2-nitrobenzyl)(triphenyl)phosphonium bromide (1.1 eq.), potassium carbonate (2 eq.) and 18-C-6 (0.1 eq.). The reaction mixture was stirred at rt for 12 hrs, filtered on celite and the filtrate was concentrated under reduced pressure. The crude product was purified by automated SiO2 flash chromatography system using solvent gradient of 10% to 60% EtOAc/Hex to afford the desired compound
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)NNC(=O)c1ccccc1
Reactant: O=C(O)CCc1cccc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1cccc(Br)c1
Yield: 67.2 %

Procedure:
A solution of (3-(3-bromophenyl)propionic acid (257 mg, 1.12 mmoles) and benzoic acid N′-isopropyl-hydrazide (200 mg, 1.12 mmoles) in DMF (6 mL) was treated with triethylamine (0.47 mL, 3.36 mmoles), HOBT (182 mg, 1.34 mmoles) and EDCI (2.58 mg, 1.34 mmoles) at room temperature for 18 h. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a solid (293 mg, 67%).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([OH:24])[C:9]2[C:17]3[C:12](=NC=[C:15]([C:18]4[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=4)[CH:16]=3)[NH:11][CH:10]=2)=[C:6]([F:25])[CH:5]=[CH:4][C:3]=1[OH:26].O.[CH3:28][N:29](C)C=O>O1CCCC1>[F:1][C:2]1[C:3]([OH:26])=[CH:4][CH:5]=[C:6]([F:25])[C:7]=1[C:8]([C:9]1[C:28]2[N:29]=[C:15]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:16]=[CH:17][C:12]=2[NH:11][CH:10]=1)=[O:24]
Reactant: CN(C)C=O
Reactant: Oc1ccc(F)c(C(O)c2c[nH]c3ncc(-c4cccnc4)cc23)c1F
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1c(F)ccc(O)c1F)c1c[nH]c2ccc(-c3cccnc3)nc12
Temperature: 25 °C
Reaction time: 50 h

Procedure:
To 2,4-difluoro-3-[hydroxy-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-methyl]-phenol (P-0009, 45.0 mg, 1.27 mmol) in tetrahydrofuran (15 mL) and N,N-dimethylformamide (5 mL) was added dichlorodicyanoquinone (87 mg, 3.8 mmol). The reaction was stirred at room temperature for 50 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The desired compound was isolated by silica eel column chromatography eluting with 5% methanol in methylene chloride to give a white solid (P-0066, 7 mg, 15.6%). MS(ESI) [M+H+]+=352.1.