Azzindani/Open_Reaction_Data huggingface dataset:
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: O
Solvent: CO
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: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20]C)=[O:19])=[N:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][C:14]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([OH:20])=[O:19])=[N:13][N:12]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1-c1nnc(-c2ccc(C(C)(C)C)cc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(-c2nnc(-c3ccccc3C(=O)O)o2)cc1
Yield: 87.7 %

Procedure:
A mixture of methyl 2-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoate (1.50 g), 1 M aqueous sodium hydroxide solution (9.0 ml), tetrahydrofuran (18 ml) and methanol (9 ml) was heated under reflux for 1 hr. After cooling, 1 M hydrochloric acid was added to acidify the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-[5-(4-t-butylphenyl)-1,3,4-oxadiazol-2-yl]benzoic acid (1.26 g, yield 87%) as a colorless amorphous solid. NMR (CDCl3) δ: 1.35 (9H, s), 7.52 (2H, d, J=8.8 Hz), 7.67–7.76 (4H, m), 7.96–8.04 (3H, m), 8.15–8.20 (1H, m).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[CH2:32][C:33]#[N:34])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][C:12]=3[F:24])[C:3]=12.[CH:36]([C@@H:38]1[CH2:42][CH2:41][CH2:40][N:39]1[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=O.N1CCCCC1>C(O)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:25][C@H:26]3[CH2:30][CH2:29][CH2:28][N:27]3[C:31](=[O:35])[C:32]([C:33]#[N:34])=[CH:36][C@@H:38]3[CH2:42][CH2:41][CH2:40][N:39]3[C:43]([O:45][C:46]([CH3:47])([CH3:49])[CH3:48])=[O:44])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[CH:13][C:12]=3[F:24])[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C=C(C#N)C(=O)N1CCC[C@@H]1Cn1nc(-c2ccc(Oc3ccccc3)cc2F)c2c(N)ncnc21
Temperature: 100 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a sealed tube was added 3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-3-oxo-propanenitrile (507 mg, 1.07 mmol), tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (0.2, mL, 1.1 mmol), piperidine (0.05 mL, 0.54 mmol) and ethanol (3 mL). The tube was capped and heated to 100° C. for 16 hrs. The reaction was not complete so an additional amount of tert-butyl (2S)-2-formylpyrrolidine-1-carboxylate (732 mg, 3 eq) was added and heating was continued for 4 hrs at 110° C. The reaction was cooled and concentrated then dissolved in DCM (50 mL) and washed with water (50 mL) and brine. The organic layer was dried (MgSO4), filtered and concentrated. The resulting material was purified by Isolera (250 g column; 2%-3% MeOH/DCM) to provide 403 mg (57%) of tert-butyl (2S)-2-[3-[(2R)-2-[[4-amino-3-(2-fluoro-4-phenoxy-phenyl)pyrazolo[3,4-d]pyrimidin-1-yl]methyl]pyrrolidin-1-yl]-2-cyano-3-oxo-prop-1-enyl]pyrrolidine-1-carboxylate as a solid.
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=N[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1.[CH2:24](O)C>[C].[Pd]>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][C:14]2[C:9](=[O:8])[NH:10][CH:11]=[CH:12][CH:24]=2)=[CH:21][CH:20]=1
Reactant: CCO
Reactant: COc1ccc(Cc2nccnc2OCc2ccccc2)cc1
Agent: [Pd]
Product: COc1ccc(Cc2ccc[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of n-butyllithium (1.57 mol/L solution in tetrahydrofuran, 2.0 mL) in tetrahydrofuran (23 mL) was added 2,2,6,6-tetramethylpyridine (0.57 mL) at −78° C. The temperature was raised to 0° C., and the mixture was stirred for 30 minutes. After the reaction mixture was cooled to −78° C., 2-chloropyrazine (0.22 mL) was added to the reaction mixture, and the mixture was stirred for 1 hour at the same temperature. To the reaction mixture was added 4-methoxybezaldehyde (0.35 mL), and the mixture was stirred for additionally 1.5 hours. To the reaction-mixture were added concentrated hydrochloric acid (1.2 mL), ethanol (1.2 mL) and tetrahydrofuran (4.8 mL), and the temperature was raised to room temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. After the residue was extracted with dichloromethane, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/2) to give 2-chloropyrazin-3-yl 4-methoxyphenyl methanol (0.31 g). To a suspension of the obtained 2-chloropyrazin-3-yl 4-methoxyphenyl methanol(0.13 g), sodium hydroxide (0.12 g) and potassium carbonate (0.072 g) in toluene (1 mL) were added benzyl alcohol (0.080 mL) and tris-[2-(2-methoxyethoxy)ethyl]amine (0.017 mL), and the mixture was stirred for 2,hours at 120° C. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/1) to give 2-benzyloxy-3-(4-methoxybenzyl)pyrazine (0.026 g). To a solution of the obtained 2-benzyloxy-3-(4-methoxybenzyl)-pyrazine (0.025 g) in ethanol (1 mL) was added 10% palladium carbon powder (0.0099 g), and the mixture was stirred for 2 hours at room temperature under a hydrogen atmosphere. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography on silica gel (developing solvent: hexane/ethyl acetate=1/3) to give 3-(4-methoxybenzyl)-1H-pyridin-2-one (0.0055 g).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:22][C:23]1[O:27][C:26]([CH:28]=O)=[CH:25][CH:24]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(O)C>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]#[N:16])=[CH:17][CH:18]=1)[CH2:28][C:26]1[O:27][C:23]([CH3:22])=[CH:24][CH:25]=1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)CCCCNCc1ccc(C#N)cc1
Reactant: Cc1ccc(C=O)o1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCCN(CCC)CCCCN(Cc1ccc(C#N)cc1)Cc1ccc(C)o1
Temperature: 0 °C
Reaction time: 19 h
Yield: 99.3 %

Procedure:
0.485 g (1.69 mmol) of 4-[(4-dipropylaminobutyl)amino]methylbenzonitrile (2a), 9.7 ml of ethanol, and 371 mg (3.37 mmol, 2.0 equivalents) of 5-methyl-2-furaldehyde were charged in a 50 ml recovery flask under a nitrogen stream. The mixture was then cooled to 0° C. After the addition of 0.857 g (4.05 mmol, 2.4 equivalents) of sodium triacetoxyborohydride, the mixture was stirred at room temperature for 19 hours. After confirming the disappearance of the raw material by TLC, the reaction solution was added to 50 ml of a saturated sodium bicarbonate aqueous solution, and extracted twice with 50 ml of chloroform. The chloroform layer was washed with 100 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography (Chromatorex NH, chloroform:n-hexane=11:1), thereby obtaining 0.640 g of 4-{[(4-dipropylaminobutyl)-(5-methylfuran-2-ylmethyl)amino]methyl}benzonitrile (17) as a light yellow oily substance (yield: 99.5%). [HPLC: 98.9% (HPLC measurement conditions B)]
Reaction SMILES: [CH3:1][Si:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22]CC(=O)C[CH2:18]2)[CH:9]=1.NC1N2N=CC=C2N=C(C2C[CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46]C2)C=1.NC1N2N=CC=C2N=C(C2CCC(=O)CC2)C=1>>[CH3:31][Si:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][O:25][CH2:24][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:32])([CH3:33])[CH3:1])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH2:18]2)[CH:9]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(N)n3nccc3n2)CC1
Agent: Nc1cc(C2CCC(=O)CC2)nc2ccnn12
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1

Procedure:
tert-Butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate was synthesized in a manner similar to the synthesis of 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone, but with tert-butyl 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate substituted for 4-(7-aminopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH:13]([OH:29])[CH2:14][NH:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[C:21]([OH:28])[CH:20]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>O1CCOCC1.[Pd]>[C:25]([C:22]1[CH:23]=[CH:24][C:19]([O:18][CH2:17][CH2:16][NH:15][CH2:14][CH:13]([OH:29])[C:12]2[CH:30]=[CH:31][C:9]([OH:8])=[CH:10][CH:11]=2)=[CH:20][C:21]=1[OH:28])(=[O:27])[NH2:26]
Reactant: NC(=O)c1ccc(OCCNCC(O)c2ccc(OCc3ccccc3)cc2)cc1O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: NC(=O)c1ccc(OCCNCC(O)c2ccc(O)cc2)cc1O

Procedure:
A solution of 8.7 g of 4-benzyloxy-α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-benzyl alcohol in 100 ml of dioxan is hydrogenated under normal conditions with the addition of 2 g of palladium-on-charcoal catalyst (5%) until 1 equivalent of hydrogen has been taken up. The product which has precipitated is brought into solution after adding 200 ml of methanol, by warming, the catalyst is filtered off and the filtrate is evaporated. Recrystallisation of the residue from isopropanol yields crystalline α-[N-[2-(4-carbamoyl-3-hydroxy-phenoxy)-ethyl]-aminomethyl]-4-hydroxybenzyl alcohol with a melting point of 181°-182°.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]3[CH2:13][CH2:12][CH2:11]C[C:9]=3[C:5]=2[C:4](=O)[NH:3][CH:2]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:4]1[C:5]2[C:9]3[CH2:11][CH2:12][CH2:13][C:8]=3[S:7][C:6]=2[N:1]=[CH:2][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2sc3c(c12)CCCC3
Solvent: CN(C)c1ccccc1
Product: Clc1ncnc2sc3c(c12)CCC3

Procedure:
To 10.56 g 5,6,7,8-tetrahydro[1]benzothieno[2,3-d]pyrimidin-4(3H)-one (0.51 mol) and 10 mL dimethylaniline was added, in one portion, 50 mL POCl3. The mixture was heated to reflux for 5 h under argon, cooled and the excess POCl3 was removed by concentration in vacuo. The residue was poured into 200 g ice and neutralized with satd Na2CO3. The resulting blue-gray gum was filtered, washed with water and crystallized from ethanol to give 7.03 g (0.031 mol) of product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8].[C:22](Cl)(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>CC(N(C)C)=O>[C:22]([NH:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:19])([CH3:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])(=[O:30])[CH2:23][CH2:24][CH2:25][CH2:26][C:27]([NH:1][C:2]1[C:3]([I:21])=[C:4]([C:13]([NH:15][C:16]([CH3:19])([CH3:20])[CH2:17][OH:18])=[O:14])[C:5]([I:12])=[C:6]([C:10]=1[I:11])[C:7]([OH:9])=[O:8])=[O:28]
Reactant: CC(C)(CO)NC(=O)c1c(I)c(N)c(I)c(C(=O)O)c1I
Reactant: O=C(Cl)CCCCC(=O)Cl
Solvent: CC(=O)N(C)C
Product: CC(C)(CO)NC(=O)c1c(I)c(NC(=O)CCCCC(=O)Nc2c(I)c(C(=O)O)c(I)c(C(=O)NC(C)(C)CO)c2I)c(I)c(C(=O)O)c1I

Procedure:
Analogously to Example 10, 5-amino-N-(2-hydroxy-1,1-dimethylethyl)-2,4,6-triiodoisophthalamic acid is reacted with hexanedioic acid dichloride in dimethylacetamide, and the reaction mixture is worked up. The thus-obtained product melts at 280°-281° C., with decomposition.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[C:17]([C:24](O)=[O:25])=[CH:16]2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(OCC)(=O)C.Cl.[F:59][CH2:60][CH2:61][NH2:62]>C(Cl)Cl>[F:59][CH2:60][CH2:61][NH:62][C:24]([C:17]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:23]2[N:15]([CH2:14][C:3]2[C:2]([CH3:1])=[C:7]([O:8][CH2:9][C:10]([F:12])([F:11])[F:13])[CH:6]=[CH:5][N:4]=2)[CH:16]=1)=[O:25]
Reactant: NCCF
Reactant: Cc1c(OCC(F)(F)F)ccnc1Cn1cc(C(=O)O)c2ncccc21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(OCC(F)(F)F)ccnc1Cn1cc(C(=O)NCCF)c2ncccc21
Reaction time: 0.08 h
Yield: 49 %

Procedure:
See FIG. 18(d). 1-((3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl)methyl)-1H-pyrrolo[3,2-b]pyridine-3-carboxylic acid (100 mg, 0.27 mmol) was taken in DCM (10 mL) to get a clear solution. Triethyl amine (0.190 mL, 1.37 mmol) was added followed by the addition of 1-Propanephosphonic acid cyclic anhydride solution in ethyl acetate (0.326 mL, 0.55 mmol) and stirred the reaction mass for 5 minutes. 2-Fluoroethylamine hydrochloride (54.5 mg, 0.55 mmol) was added and stirred the reaction mass for 3 h. After completion of the reaction, diluted with DCM and then washed with water and brine solution. The organic layer was separated, dried, evaporated and the crude compound was purified by silica gel chromatography using methanol and dichloromethane as eluent. Yield-49%. ES+MS m/z: 411 (M+1). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.25 (s, 3 H ) 3.67 (q, J=5.21 Hz, 1 H ) 3.76 (q, J=5.21 Hz, 1 H ) 4.50 (t, J=4.99 Hz, 1 H ) 4.66 (t, J=4.90 Hz, 1 H ) 4.90 (q, J=8.85 Hz, 2 H ) 5.68 (s, 2 H ) 7.06 (d, J=5.84 Hz, 1 H ) 7.24 (dd, J=8.38, 4.62 Hz, 1 H ) 7.93 (d, J=7.35 Hz, 1 H ) 8.17 (d, J=5.65 Hz, 1 H ) 8.24 (s, 1 H ) 8.48 (d, J=3.77 Hz, 1 H ) 8.94 (t, J=5.75 Hz, 1 H ).
Reaction SMILES: C[Sn]([N:5]=[N+:6]=[N-:7])(C)C.[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:38]=[CH:37][C:24]4[O:25][CH2:26][C:27]5[CH:34]=[C:33]([C:35]#[N:36])[CH:32]=[CH:31][C:28]=5[C:29](=[O:30])[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1.Cl.[OH-].[Na+]>C1(C)C(C)=CC=CC=1>[Cl:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][C:15]([CH2:19][O:20][C:21]3[CH:38]=[CH:37][C:24]4[O:25][CH2:26][C:27]5[CH:34]=[C:33]([C:35]6[NH:36][N:7]=[N:6][N:5]=6)[CH:32]=[CH:31][C:28]=5[C:29](=[O:30])[C:23]=4[CH:22]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: N#Cc1ccc2c(c1)COc1ccc(OCc3ccc4ccc(Cl)cc4n3)cc1C2=O
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1C
Product: O=C1c2ccc(-c3nnn[nH]3)cc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Yield: 106.1 %

Procedure:
1.03 g of trimethyltin azide was added to 1.07 g of 2-(7-chloroquinolin-2-yl)methoxy-8-cyano-11-oxo-6,11-dihydrodibenz[b,e]oxepine obtained by the same method as in Reference example 34 suspended in 30 ml of xylene and the mixture was refluxed under heating for 13 hours. 1 ml of conc. hydrochloric acid was added to the reaction mixture, the mixture was adjusted to about pH 4 with a 1N-sodium hydroxide aqueous solution and crystals precipitated were collected by filtration. The crystals were dissolved in a chloroform-methanol mixed solution and the organic layer was washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The residue obtained by removing the solvent was applied to silica gel column chromatography to obtain 1.25 g of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:2]=1.C(O)(=O)C.[O:16]=[CH:17][C:18](=[CH2:20])[CH3:19]>C1COCC1>[CH3:19][CH:18]([CH2:20][N:10]1[CH:11]=[C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[N:8]=[CH:9]1)[CH:17]=[O:16]
Reactant: c1cncc(-c2c[nH]cn2)c1
Reactant: C=C(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C=O)Cn1cnc(-c2cccnc2)c1

Procedure:
To a solution of 4-pyridin-3-yl-imidazole (8.5 g) in THF (293 mL) was added acetic acid (16.8 mL) and methacrolein (9.7 mL) and the resulting solution was heated under gentle reflux for 24 hours. Another 9.7 mL methacrolein was added and the solution was heated under reflux for another 24 hours. THF was then removed in vacuo and the residue was purified on a Flash 75 long column eluting with MeOH—CH2Cl2 to give the title compound as slightly yellow oil.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[N:8]=[C:7]([CH:16]=O)[N:6]=1)([CH3:4])[CH3:3].C([O-])(=O)C.[Na+].[NH2:23][N:24]1[C:28](=[O:29])[CH2:27][S:26][C:25]1=[S:30]>C(O)(=O)C.C(O)C.O>[CH3:1][C:2]([C:5]1[C:10]([OH:11])=[C:9]([C:12]([CH3:14])([CH3:15])[CH3:13])[N:8]=[C:7]([CH:16]=[C:27]2[S:26][C:25](=[S:30])[N:24]([NH2:23])[C:28]2=[O:29])[N:6]=1)([CH3:3])[CH3:4]
Reactant: NN1C(=O)CSC1=S
Reactant: CC(C)(C)c1nc(C=O)nc(C(C)(C)C)c1O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: CC(C)(C)c1nc(C=C2SC(=S)N(N)C2=O)nc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A mixture of 4,6-bis(1,1-dimethylethyl)-5-hydroxy-2-pyrimidine carboxaldehyde (1.00 g, 4.23 mmol), sodium acetate (1.36 g, 16.6 mmol), and 3-aminorhodanine (0.63 g, 4.3 mmol) in glacial acetic acid (15 mL), under nitrogen atmosphere, is warmed to reflux and refluxed 7 hours. This mixture is then cooled to room temperature and stirred 16 hours. After stirring, the reaction mixture is diluted with a 1:2 mixture of ethanol and water and extracted with ethyl acetate. The combined organic extracts are washed with water, aqueous 0.2N hydrochloric acid solution, and brine. The organic phase is dried over magnesium sulfate, concentrated, and purified by flash chromatography (SiO2, 20% ethyl acetate/hexane) followed by recrystallization from methanol and water to give 0.42 g (27%) of the title compound, mp 194°-196° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:25][CH:24]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N+:59]([C:62]1[CH:70]=[CH:69][C:65]([C:66](O)=[O:67])=[CH:64][CH:63]=1)([O-:61])=[O:60].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:66](=[O:67])[C:65]2[CH:64]=[CH:63][C:62]([N+:59]([O-:61])=[O:60])=[CH:70][CH:69]=2)[C@H:10]([CH2:15][O:16][C:17]2[N:18]=[N:19][C:20]([CH2:36][CH2:37][CH2:38][CH3:39])=[C:21]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:27][CH:28]=3)[CH:22]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCc1nnc(OC[C@@H]2CN(C(=O)OC(C)(C)C)CC[C@H]2OC(=O)c2ccc([N+](=O)[O-])cc2)cc1-c1ccc(OC2CCCCC2)cc1
Yield: 77.5 %

Procedure:
To a stirred mixture of (±)-cis-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (Example 43, 1.18 mmol, 0.64 g), PPh3 (1.43 mmol, 0.375 g) and p-nitrobenzoic acid (1.5 mmol, 0.251 g) in anhydrous THF (15 mL) at −60° C. was added DIAD (1.43 mmol. 0.289 mL) over 10 min. The stirring was continued and let the reaction slowly attain room temperature over 3 h. The reaction mixture was diluted with ether (300 mL), washed with water (100 mL) followed by saturated sodium bicarbonate (100 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel flash column chromatography by eluating with 20% ethyl acetate in hexanes to provide (±)-trans-3-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yloxymethyl]-4-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester (0.63 g).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[C:13](OCC)=[O:14])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8](/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)/C=C/c1ccc(C(C)(C)C)c([N+](=O)[O-])c1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(/C=C/CO)cc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
A solution of 9.24 g (33.4 mmol) of 2-t-butyl-5-[(E)-2-ethoxycarbonylethenyl]-1-nitrobenzene [prepared as described in step (ii) above] in 200 ml of tetrahydrofuran was cooled to -70° C. in a dry ice-acetone bath, and 100 ml (100 mmol) of a 1 M solution of diisobutylaluminum hydride in tetrahydrofuran were added dropwise thereto over a period of 45 minutes. The resulting mixture was then stirred for a further 30 minutes. At the end of this time, the reaction temperature was allowed to rise to 0° C., and the reaction was quenched by adding dropwise a mixture of 4 ml of methanol and 20 ml of tetrahydrofuran. The reaction mixture was then poured into 2 N aqueous hydrochloric acid-ice, after which it was extracted with ethyl acetate. The extract was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 300 g of silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 7.06 g (yield 90%) of the title compound as an oily substance.