Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:34]=[CH:33][C:6]([CH2:7][NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)=[N:18][C:17]([Cl:32])=[CH:16][CH:15]=3)=[O:10])=[CH:5][CH:4]=1.Cl[C:36](OCC)=[O:37]>>[Cl:32][C:17]1[CH:16]=[CH:15][C:14]2[N:13]=[CH:12][C:11]3[C:9](=[O:10])[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:34][CH:33]=4)[C:36](=[O:37])[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:30])[F:31])[CH:23]=4)[C:20]=3[C:19]=2[N:18]=1
Reactant: COc1ccc(CNC(=O)c2cnc3ccc(Cl)nc3c2Nc2cccc(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)Cl
Product: COc1ccc(Cn2c(=O)c3cnc4ccc(Cl)nc4c3n(-c3cccc(C(F)(F)F)c3)c2=O)cc1
Reaction time: 120 h

Procedure:
N-(4-methoxybenzyl)-6-chloro-4-(3-(trifluoromethyl)phenylamino)-1,5-naphthyridine-3-carboxamide (4.5 g, 9.2 mmol) is suspended in ethyl chloroformate (50 mL). The resulting mixture was added to 90° C., stirred for 120 hrs, rotary-evaporated to remove the volatile substance, and separated by silicagel column chromatography (EtOAc/PE=0-1/4) to obtain a yellow oil of 9-chloro-3-(4-methoxybenzyl)-1-(3-(trifluoromethyl)phenyl)pyrimido[5,4-c][1,5]naphthyridine-2,4(1H,3H)-dione (700 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:10]([CH2:11][C:12]([OH:14])=[O:13])[N:9]=[N:8][N:7]=2)=[CH:2]1.[CH2:15](O)[CH2:16][CH2:17][CH2:18][OH:19].C1(N=C=NC2CCCCC2)CCCCC1.C(O)(=O)C>CN(C)C=O>[OH:19][CH2:18][CH2:17][CH2:16][CH2:15][O:13][C:12](=[O:14])[CH2:11][N:10]1[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[N:7][N:8]=[N:9]1
Reactant: OCCCCO
Reactant: O=C(O)Cn1nnnc1-c1ccsc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(Cn1nnnc1-c1ccsc1)OCCCCO
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a solution of 1 g (4.76 mM) of [5-(3-thienyl)tetrazol-1-yl] acetic acid and 514 mg (5.71 mM) of 1,4-butanediol in 10 ml of N,N-dimethylformamide was added 1.08 g (5.23 mM) of dicyclohexylcarbodiimide at room temperature. After the mixture was stirred at room temperature for 30 min, a small amount of acetic acid was added to the mixture and then was stirred for 30 min. The mixture was poured into ice-water. The precipitated crystal was filtered off and washed with water. The filtrate was extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/ethyl alcohol=30/1) for separation and purification, to give 810 mg (yield 60.3%) of [5-(3-thienyl)tetrazol-1-yl] acetic acid 4-hydroxybutyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](F)=[N:6][C:5]=1[F:11].[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:6][C:5]=1[F:11]
Reactant: COC(=O)c1ccc(F)nc1F
Reactant: NCc1ccc(Cl)cc1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NCc2ccc(Cl)cc2)nc1F
Reaction time: 2 h

Procedure:
To 2,6-difluoro-nicotinic acid methyl ester (60, 2.00 g, 0.0116 mol) in N,N-dimethylformamide (20.0 mL), under an atmosphere of nitrogen at −40° C., was added p-chlorobenzylamine (61, 2.60 mL, 0.0214 mol). The reaction was stirred at −40° C. to −20° C. for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to give compound (62, 2.0 g, 58.7%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[C:16]3[C:12]=2[CH2:13][CH2:14][CH2:15]3)=[CH:6][C:3]=1[CH:4]=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl>CN(C)C=O>[CH2:30]([O:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[C:19]([CH3:20])=[CH:18][C:17]([N+:21]([O-:23])=[O:22])=[C:16]3[C:12]=2[CH2:13][CH2:14][CH2:15]3)=[CH:6][C:3]=1[CH:4]=[O:5])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(O)c(C=O)c1)CCC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=O)c1)CCC2

Procedure:
A suspension of 2-hydroxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde (3.20 g) and potassium carbonate (1.55 g) in N,N-dimethylformamide (25 mL) was stirred under ice-cooling. After adding dropwise benzyl bromide (1.34 mL), the mixture was stirred at room temperature for 24 hours. The reaction mixture was acidified with diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (3.30 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:41])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]6[N:31](COCC[Si](C)(C)C)[C:30]([CH3:40])=[N:29][C:26]6=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.Cl>CO>[CH3:1][C:2]1([CH3:41])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]6[NH:31][C:30]([CH3:40])=[N:29][C:26]6=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1
Reactant: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2n1COCC[Si](C)(C)C
Agent: Cl
Solvent: CO
Product: Cc1nc2ncc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cc2[nH]1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
A solution of 4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-7-[2-methyl-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazo[4,5-b]pyridin-6-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.54 g, 0.95 mmol) in a mixture of methanol (30 mL) and concentrated hydrochloric acid (1 mL) was stirred at reflux for 16 hours. On cooling to room temperature the solution was concentrated and the pH was adjusted to ˜9 by the addition of 50% aqueous sodium hydroxide and diluted with ethyl acetate (100 mL). The organic layer was washed with 2M aqueous sodium hydroxide (20 mL) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The precipitating white solid was collected by filtration and washed with hexane to provide 4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-7-(2-methyl-1H-imidazo[4,5-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (0.28 g, 67%). 1H NMR (400 MHz, d6-DMSO): 8.53 (d, 1H), 8.38 (s, 1H), 8.03 (d, 1H), 7.70 (d, 1H), 7.54 (dd, 1H), 7.05 (d, 1H), 4.63 (s, 2H), 4.33 (m, 2H), 3.85 (m, 2H), 2.72 (m, 2H), 2.58 (s, 3H), 2.47 (s, 2H), 1.60 (m, 2H), 0.86 (s, 6H); MS (EI) for C26H28N6O: 441 (MH+).
Reaction SMILES: [Al](C)(C)C.C(O[C:8]([C:10]1[C:15]([NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=[C:12]([CH:23]2[CH2:25][CH2:24]2)[N:11]=1)=[O:9])C.[NH2:26][C:27]1[S:28][CH:29]=[C:30]([CH3:32])[N:31]=1>>[CH3:32][C:30]1[N:31]=[C:27]([NH:26][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH:23]3[CH2:24][CH2:25]3)[N:11]=2)=[O:9])[S:28][CH:29]=1
Reactant: Cc1csc(N)n1
Reactant: CCOC(=O)c1nc(C2CC2)ccc1Nc1cccnc1
Agent: C[Al](C)C
Product: Cc1csc(NC(=O)c2nc(C3CC3)ccc2Nc2cccnc2)n1

Procedure:
The Al(Me)3-catalyzed reaction of 6-Cyclopropyl-3-(pyridin-3-ylamino)-pyridine-2-carboxylic acid ethyl ester and 2-Amino-4-methyl-thiazole in accordance with the general method of Example 78, step 2 yielded the title compound as a yellow cristalline solid, MS (ISP): m/e=352.1 (M+H+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][CH:24]1[O:29][CH2:28][CH2:27][NH:26][CH2:25]1>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:26]3[CH2:27][CH2:28][O:29][CH:24]([CH2:23][CH2:22][NH:21][CH3:20])[CH2:25]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CNCCC1CNCCO1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CCNC)C3)c(F)c21

Procedure:
By the use of 1-ethyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid and 2-(2-methylaminoethyl)morpholine, the reaction is similarly carried out as Example 1 to give 1-ethyl-6,8-difluoro-1,4-dihydro-7-[2-(2-methylaminoethyl)morpholino]-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[C:12]=2[F:30])[CH:9]=1)[C:5]#[N:6].O.NN>CO>[NH2:19][CH2:18][C:13]1[C:12]([F:30])=[C:11]([O:10][C:8]2[CH:7]=[C:4]([CH:3]=[C:2]([Cl:1])[CH:9]=2)[C:5]#[N:6])[C:16]([Cl:17])=[CH:15][CH:14]=1
Reactant: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN3C(=O)c4ccccc4C3=O)c2F)c1
Agent: NN
Solvent: O
Solvent: CO
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CN)c2F)c1
Reaction time: 2 h
Yield: 822.2 %

Procedure:
3-Chloro-5-({6-chloro-3-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-2-fluorophenyl}oxy)benzonitrile (1.9 g, 4.3 mmol) was dissolved in MeOH (50 mL) and hydrazine monohydrate (0.63 mL, 12.9 mmol) was added. The reaction mixture was placed in an oil bath at 60° C. and stirred for 2 h. Another portion of hydrazine monohydrate (0.63 mL, 12.9 mmol) was added and the reaction was stirred for 1 h. Purification was accomplished by column chromatography (CH2Cl2/MeOH) to afford the title compound (11 g, 82%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9](=[O:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:17]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C@H:9]([OH:12])[C:8]2[N:13]([CH3:16])[CH:14]=[CH:15][C:7]=2[C:6]1=[O:17]
Reactant: Cn1ccc2c1C(=O)CCN(CCCCl)C2=O
Solvent: C1CCOC1
Product: Cn1ccc2c1[C@@H](O)CCN(CCCCl)C2=O
Temperature: -8 °C
Reaction time: 3 h
Yield: 239.9 %

Procedure:
17.2 mg (0.03 mmol; 0.3 mol %) of optically active cobalt (II) complex of the formula (VIII) and 2.54 g (10.0 mmol) of 5-(3-chloropropyl)-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]-azepine-4,8-dione were added in a second reactor, then the atmosphere was replaced with a nitrogen gas, and the mixture was dissolved in 100 mL of THF. To this mixture was added the reducing reagent prepared in process (a) dropwise at −8° C. of reaction bath temperature and the reaction mixture was stirred for 3 hours at −8° C. The reaction mixture was washed with a mixed solution of 40 mL of saturated saline solution and 8 mL of water, and further washed with 40 mL of saturated saline solution, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 6.16 g (optical purity: 83.5% e.e.) of (S)-5-(3-chloropropyl)-8-hydroxy-1-methyl-1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one as pale brown crystalline.
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:29]([O:32][CH2:33][CH3:34])(=[O:31])C.C(Cl)(Cl)Cl>O1CCOC1>[C:1]([O:7][CH2:8][C@H:9]1[O:13][C:12](=[O:14])[CH2:11][C@@H:10]1[CH:29]1[O:32][CH2:33][CH2:34][O:31]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OC[C@@H]1C=CC(=O)O1
Reactant: CCOC(C)=O
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: C1COCO1
Product: CC(C)(C)C(=O)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 93 %

Procedure:
A solution containing 29.0 mg (0.146 mmol) compound (2d) and 3.0 mg (0.016 mmol) benzophenone in 20 mL [1,3]-dioxolane was irradiated at 0° C. for 1.5 hours according to the general procedure. Column chromatography (silica gel 15 g, ethyl acetate in hexanes 40%) gave compound (3d) (37 mg. 93%) as a colorless solid, Rf=0.21, [α]25D 23.8°, c 1.0, CHCl3, IR (neat) 1785, 1740, 1210, 740 cm−1; 1H-NMR (400 MHz, CDCl3) δ: 1.21 (s, 9H), 2.57-2.60 (m, 1H), 2.67-2.75 (m, 2H), 3.91-3.93 (m, 2H), 4.01-4.04 (m, 2H), 4.37 (dd, 1H, J=4.2 Hz, J=12.2 Hz), 4.38 (dd, 1H, J=2.9 Hz, J=12.2 Hz), 4.69 (mc, 1H), 4.92 (d, 1H, J=3.6 Hz). 13C-NMR (100.6 MHz, CDCl3, Dept) δ: 27.14 (+), 29.75 (−), 38.70 (+) (quat), 65.26 (−), 65.43 (−), 65.58 (−), 77.37 (+), 103.30 (+), 175.47 (quat), 178.02 (quat). C13H20O6; Exact Mass: 272.13; Mol. Wt.: 272.29; C, 57.34, H, 7.40, O, 35.25.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#N)=[C:4]([CH3:10])[CH:3]=1.CC(C[Al]CC(C)C)C.CO.[OH:22]S(O)(=O)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:22])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1C#N
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al]CC(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(Br)ccc1C=O
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To 4-bromo-2-methylbenzonitrile (2 g, 10.2 mmol) in toluene (60 mL) cooled to 5 C under argon was added Dibal-H (11.2 mL, 1M solution in toluene, 11.2 mmol) dropwise. The reaction was stirred at 5° C. for 30 minutes then MeOH (3 mL) and 2M H2SO4 (10 mL) were added dropwise. The mixture was stirred for ˜19 h then concentrated in vacuo. The residue was re-dissolved in water/EtOAc. The organic layer was dried and concentrated to give the crude title compound as a brown oil (1.81 g) which was used in the next step without further purification. δH (CDCl3, 400 MHz) 10.20 (1H, s), 7.65 (1H, d), 7.50 (1H, dd), 7.43 (1H, m), 2.64 (3H, s).
Reaction SMILES: [CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:4][CH2:3][CH2:2]1.BrC1N(C2CCCCO2)[C:27]2[C:32](N=1)=C(N)N=C(OC1CCCCC1)N=2>>[CH:1]1([O:5][C:6]2[N:14]=[C:13]3[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]3[CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][O:16]3)=[C:8]([NH2:23])[N:7]=2)[CH2:4][CH2:32][CH2:27][CH2:3][CH2:2]1
Reactant: COc1nc2c(N)nc(OC3CCC3)nc2n1C1CCCCO1
Reactant: Nc1nc(OC2CCCCC2)nc2c1nc(Br)n2C1CCCCO1
Product: COc1nc2c(N)nc(OC3CCCCC3)nc2n1C1CCCCO1

Procedure:
Prepared similarly to Intermediate 57 from 8-bromo-2-(cyclohexyloxy)-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[N:19][CH3:20])[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].C1(C)C=CC=CC=1.[H][H]>[Ni].ClC1C=CC=CC=1Cl>[CH3:20][NH:19][C@@H:12]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:18]=2[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11]1
Reactant: [H][H]
Reactant: CN=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: [Ni]
Solvent: Clc1ccccc1Cl
Solvent: Cc1ccccc1
Product: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21

Procedure:
N-[4-(3,4-dichlorophenyl)-3,4-dihydro-1(2H) naphthalenylidene]methanamine (Ketimine) (50 g), toluene (300 ml), Raney Nickel (0.15 g wet basis) and o-dichlorobenzene (25 ml) are charged into a reaction vessel. The mixture is hydrogenated at 5 to 6 kg/cm2 over pressure of hydrogen for 6 to 7 hrs at about 28 to 30° C. The catalyst is removed by filtration and the cake is washed with 50 ml methanol. The cis to trans ratio is 75 to 80/25 to 20. The amount of dehalogenated by product is <0.1%. Sertraline racemate free base thus formed is treated with hydrochloric acid (24 ml, 33%) and predominantly isomer of sertraline HCl racemate is filtered [Cis>95%, trans<5%, dehalogenation product <0.1%, yield 0.80 to 0.82%].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[OH-].[Na+].[CH:13](O)=O>>[NH:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[CH:13]1
Reactant: O=CO
Reactant: N#Cc1ccc(N)c(N)c1
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc2[nH]cnc2c1
Temperature: 100 °C
Yield: 82 %

Procedure:
3,4-Diaminobenzonitrile (1.0 g; 7.5 mmol) was dissolved in formic acid (3 mL) and heated at 100° C. for 1.5 hours. The mixture was cooled, neutralised with 10% sodium hydroxide and the resulting precipitate isolated by filtration and dried in vacuo to yield the title compound as a brown solid (890 mg; 82%). 1H NMR (DMSO-d6) δ 8.50 (1H, s), 8.19 (1H, s), 7.79 (1H, d, J=8.3 Hz), 7.62 (1H, dd, J=8.3, 1.54 Hz). LC/MS (Method C): 144 (M+H)'. HPLC (Method F) Rt=2.14 min (Purity: 99.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[C:21]([O:22][CH3:23])=[C:20]([O:24][CH3:25])[C:19]([O:26][CH3:27])=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(OC)c(OC)c(OC)c1N
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(OC)c(OC)c(OC)c1NC(=O)c1ccc(Cl)cc1

Procedure:
A solution of 20.3 g of 4-chlorobenzoyl chloride in 60 ml of THF was added dropwise to the solution of 25.3 g of methyl 2-amino-3,4,5-trimethoxybenzoate and 16 ml of triethylamine in 100 ml of THF. The mixture was refluxed for 1 hour (h), cooled in an ice bath and filtered. After concentration, a colorless residue remained. Yield: 34.1 g. Melting point (m.p.): 116° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:43])C(=O)C1.O>CN(C)C=O>[CH2:1]([N:8]1[C:12]2[C:13](=[O:35])[N:14]([CH3:34])[C:15]([CH:24]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:11]=2[C:10]([Br:43])=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(Cl)cc2)c2c(Br)cn(Cc3ccccc3)c2c(=O)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.8 %

Procedure:
A solution of methyl 2-(1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (480 mg, 0.974 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was treated with NBS (173 mg, 0.974 mmol) and then stirred at room temperature for 20 minutes. Water was added and then mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-50% ethyl acetate/hexanes) to afford methyl 2-(1-benzyl-3-bromo-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-5-yl)-2-(tert-butoxy)acetate (450 mg, 0.787 mmol, 81% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.45-7.28 (m, 9H), 7.03-7.01 (m, 1H), 5.91-5.76 (m, 2H), 5.09 (s, 1H), 3.77 (s, 3H), 3.65 (s, 3H), 1.00 (s, 9H); LCMS (m/z) ES+=571 (M+1).
Reaction SMILES: [CH3:1][C:2](C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:24])=[O:23])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(I)C>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[CH:17]([CH2:20][CH2:21][CH3:22])[N:16]([CH2:1][CH3:2])[S:15]2(=[O:23])=[O:24])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCCC1C(=O)N(Cc2ccccc2)S(=O)(=O)N1CC
Reaction time: 1 h
Yield: 1139.8 %

Procedure:
Potassium t-butoxide (2.3 g, 2.05 mmol) was added to a solution of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5 g, 1.56 mmol) in 100 ml of THF at 0° C. and the mixture was stirred at this temperature for 1 hour. To the mixture was added ethyl iodide (11.64 g, 7.46 mmol) at 0° C. and the resulting mixture was allowed to stir at room temperature for 40 hours. The resulting mixture was quenched with brine, extracted with ethyl acetate (150 ml) and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 5.27 g of 2-phenylmethyl-4-propyl-5-ethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =H; R2 =propyl; R3 =ethyl) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].[CH2:13]([N:17]=[C:18]=[O:19])[CH2:14][CH2:15][CH3:16]>CCOCC>[CH2:13]([NH:17][C:18]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN=C=O
Reactant: NCCCCCCCCCCN
Solvent: CCOCC
Product: CCCCNC(=O)NCCCCCCCCCCN
Reaction time: 1 h
Yield: 82.5 %

Procedure:
In a 500 ml flask protected with a soda lime tube is placed 10 g (0.058 mole) 1,10-diamino decane and 150 ml ether. A solution of 2.5 g (0.025 mole)n-butyl isocyanate in 25 ml ether is added and the reaction mixture stirred 1 hour. The precipitate is filtered, washed with ether, and dried to 15 g weight. Recrystallization from a mixture of 200 ml alcohol and 100 ml water gives 5.6 g white solids. An analytical sample recrystallized from acetonitrile melts at 83°-84.5°C.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][S:13](/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:15])=[O:14])[CH:7]=1.CO>>[C:18]1(/[CH:17]=[CH:16]/[S:13]([NH:12][C:8]2[CH:7]=[C:6]([CH:5]=[CH:4][C:3]([OH:24])=[O:2])[CH:11]=[CH:10][CH:9]=2)(=[O:15])=[O:14])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1
Solvent: CO
Product: O=C(O)C=Cc1cccc(NS(=O)(=O)/C=C/c2ccccc2)c1

Procedure:
To a suspension of 3-{3-[(E)-2-phenylethenesulfonylamino]phenyl}acrylic acid methyl ester (25a) (0.30 g, 0.87 mmol) in methanol (4 ml) 1N NaOH solution (2.62 ml, 2.62 mmol) was added and the resultant mixture was stirred at ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was acidified with 2N HCl solution and extracted with ethyl acetate. The extract was washed with saturated NaCl and dried (Na2SO4). The solvent was evaporated and the residue was dried in desiccator over P2O5. The title compound was obtained as a white solid (0.26 g, 90%). 1H NMR (DMSO-d6, HMDSO) δ: 6.41 (1H, d, J=16.0 Hz); 7.12-7.51 (9H, m); 7.55-7.81 (3H, m); 10.16 (1H, br s), 12.32 (1H, br s).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH3:15])C(OCC)=O)=[O:5])[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH3:17][C:12]([CH3:16])([CH2:13][CH2:14][CH3:15])[CH2:6][C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCCC(C)(C)C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCC(C)(C)CC(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 64.4 %

Procedure:
To a solution of ethyl 2-ethoxycarbonyl-3,3-dimethylhexanoate (24.5 g, 100 mmol) in ethanol (150 ml), was added aqueous sodium hydroxide solution (1N, 180 ml, 180 mmol) and the mixture was stirred at room temperature for 24 hours and then at 40° C. for additional 2 hours. Aqueous hydrogen chloride (3N, 60 ml, 180 mmol) was added to the reaction mixture and the resulting mixture was then concentrated to 150 ml. The mixture was extracted with ethyl acetate (200 ml) and the aqueous layer was further extracted with ethyl acetate (50 ml×2). The combined organic layers were washed with water (100 ml) and with brine (100 ml), and dried over anhydrous magnesium sulfate. The resulting solution was concentrated and the residue was stirred at 180° C. for 2.5 hours. Ether (30 ml) was added to the reaction mixture. The resulting mixture was then treated with diazomethane. After removing off ether, the residue was further distilled under reduced pressure to give oily product, ethyl 3,3-dimethylhexanoate (11.07 g, 64.4 mmol), 64.4%, b.p.: 87°-94° C./22 mmHg). The structure was identified by the following data.