Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10].CCCCCC.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]([OH:26])[C:3]2[C:2]([NH:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:12])[CH3:11])=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ncccc1C(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of N-(pyridin-2-yl)pivalamide (1.84 g, 10 mmol) in tetrahydrofurane (100 mL) was added at −78° C. under an atmosphere of nitrogen 1.6 M butyl lithium in hexane (13.1 mL, 21 mmol). The reaction is slighly exothermic and a yellow color appears. The reaction is warmed to 0° C. within 15 minutes and stirred at 0° C. for 2 hours. A white suspension is formed. The reaction is cooled to −78° C. and 4-fluorobenzaldehyde (1.52 g, 1.29 mL, 12.0 mmol) was added in tetrahydrofurane (6.55 mL). The reaction was warmed to room temperature over night to yield an orange suspension. Saturated aqueous ammonium chloride solution was added and the reaction was extracted twice with ethyl acetate and once with methylene chloride. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure. The title compound was obtained as a yellow viscous oil (1.058 g, 35%) after purification by column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent. MS ISP (m/e): 303.1 (100) [(M+H)+].
Reaction SMILES: C[O:2][C:3]([CH:5]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=2[O:18][CH3:19])[N:7]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH:6]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:4].[OH-].[Na+:37]>CO>[CH3:19][O:18][C:11]1[CH:12]=[C:13]([O:16][CH3:17])[CH:14]=[CH:15][C:10]=1[CH:8]1[N:7]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[CH:6]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:5]([C:3]([O-:4])=[O:2])[O:9]1.[Na+:37]
Reactant: COC(=O)C1OC(c2ccc(OC)cc2OC)N(Sc2ccccc2[N+](=O)[O-])C1c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C2OC(C(=O)[O-])C(c3ccccc3)N2Sc2ccccc2[N+](=O)[O-])c(OC)c1

Procedure:
A solution of 5 g of 2-(2,4-dimethoxyphenyl)-3-(2-nitrobenzenesulfenyl)-4-phenyl-5-oxazolidinecarboxylic acid methyl ester in 150 ml of methanol are added with 22 ml of 2% sodium hydroxide. The mixture is refluxed for 1 hour. The solvent is distilled off and the residue is dried at 40° C. under vacuum overnight.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=2)[C:5]2[C:6]3[N:7]([C:26]([C:29](=[O:38])NC4C=CN=CC=4F)=[CH:27][N:28]=3)[N:8]=[C:9]([NH:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]3)[CH:10]=2)[CH2:3][CH2:2]1.[OH-:48].[Na+].Cl>CO>[C:21]([O:20][C:19]([NH:18][C@H:15]1[CH2:14][CH2:13][C@H:12]([NH:11][C:9]2[CH:10]=[C:5]([N:4]([CH:1]3[CH2:3][CH2:2]3)[CH2:39][C:40]3[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=3)[C:6]3[N:7]([C:26]([C:29]([OH:48])=[O:38])=[CH:27][N:28]=3)[N:8]=2)[CH2:17][CH2:16]1)=[O:25])([CH3:22])([CH3:24])[CH3:23]
Reactant: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nn3c(C(=O)Nc4ccncc4F)cnc23)C2CC2)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CN(c2cc(N[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)nn3c(C(=O)O)cnc23)C2CC2)cc1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
83B (19 mg, 0.029 mmol) was dissolved in MeOH (1 mL). 0.5 mL of 1N NaOH was added, and the cloudy reaction mixture was stirred at 65° C. After 2 hrs, the reaction mixture was cooled to room temperature, the pH adjusted to pH 7 with 1N HCl, and the solid was collected via Buchner filtration to afford 6-((trans)-4-(tert-butoxycarbonylamino)cyclohexylamino)-8-(cyclopropyl(4-methoxybenzyl)amino)imidazo[1,2-b]pyridazine-3-carboxylic acid as a white solid (10.6 mg, 0.019 mmol, 65.3% yield). LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=2.1 minutes. [M+H]=551.36.
Reaction SMILES: [O:1]1[C@H:3]2[C@H:4]([OH:28])[CH2:5][C:6]3[C@:25]([CH3:26])([C@@H:2]12)[C@@H:24]1[C:9]([C@H:10]2[C@:21]([CH3:27])([CH2:22][CH2:23]1)[C@@H:13]([CH:14]([CH3:20])[CH:15]([O:18][CH3:19])[O:16][CH3:17])[CH2:12][CH2:11]2)=[CH:8][CH:7]=3.CC1(C)COC(C([C@@H]2[C@]3(C)[C@H](C4[C@H](CC3)[C@]3(C)C(C[C@@H](O)[C@@H]5O[C@@H]53)=CC=4)CC2)C)OC1>>[CH3:19][O:18][CH:15]([O:16][CH3:17])[CH:14]([CH3:20])[C@@H:13]1[C@:21]2([CH3:27])[C@H:10]([C:9]3[C@H:24]([CH2:23][CH2:22]2)[C@:25]2([CH3:26])[C:6]([CH2:5][C@@H:4]([OH:28])[CH2:3][C@@H:2]2[OH:1])=[CH:7][CH:8]=3)[CH2:11][CH2:12]1
Reactant: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Product: COC(OC)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 76.1 %

Procedure:
The procedure of Example 24 was repeated except that 3.4 mg (0. 00887 mmole) of 1α,2α-epoxy-21,21-dimethoxy-20-methylpregna-5,7-dien-3β-ol was used in lieu of 3.8 mg of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α -epoxypregna-5,7-dien-3β-ol to give 2.6 mg of 21,21-dimethoxy-20-methylpregna-5,7-diene-1α,3β-diol (yield: ca. 75%).
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:12][CH:13]([OH:26])[C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>C(O)C>[C:33]1([C:11]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:10]3[CH:15]([CH2:16][NH:8][CH2:9]3)[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH3:25])([OH:17])[CH:13]([OH:26])[CH2:12]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC21
Solvent: CCO
Product: COc1ccccc1C1(O)C(O)CC(c2ccccc2)(c2ccccc2)C2CNCC21
Temperature: 65 °C
Yield: 88.2 %

Procedure:
A mixture of 2 g of (3aRS,4RS,5RS,7aRS)-2-benzyl-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindole-4,5-diol and 50 cm3 of ethanol is heated at 65° C., while stirring; 0.65 g of 20% strength palladium hydroxide-on-charcoal is added and the reaction mixture is then hydrogenated at a temperature of 65° C. and under atmospheric pressure, while stirring. After a reaction time of 1 hour, the theoretical volume of hydrogen was absorbed; the reaction mixture is filtered and then concentrated to dryness under reduced pressure (2.7 kPa). The residue is crystallized from 10 cm3 of isopropyl ether. 1.45 g of (3aRS,4RS,5RS,7aRS)-7,7-diphenyl-4-(2-methoxyphenyl)perhydroisoindole-4,5-diol which melts at 230° C. are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([S:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]O.C(OCC)(=O)C>S(=O)(=O)(O)O.C1(C)C=CC=CC=1>[F:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][O:20][C:19](=[O:21])[CH2:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: OCc1cccc(F)c1
Reactant: O=C(O)CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(CSc1ccc(C(=O)Nc2ccc(F)cc2)cn1)OCc1cccc(F)c1
Yield: 26.5 %

Procedure:
A solution of [5-(4-fluorophenylcarbamoyl)pyridin-2-ylsulfanyl]acetic acid (0.030 g, 0.10 mmole), 3-fluorobenzyl alcohol (0.10 mL, 1.0 mmol), and sulfuric acid (1 drop) in toluene (5 mL) was heated at reflux. After 2 h the reaction mixture was poured into ethyl acetate and washed with saturated sodium bicarbonate and dried over sodium sulfate. Removal of the solvents provided a solid. Purification by trituration using ethyl acetate/hexanes gave 0.011 g (27%) of the titled product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 10.36 (s 1H); 8.86 (m, 1H); 8.12 (m, 1H); 7.74 (m, 2H); 7.51 (m, 1H); 7.35 (m, 1H); 7.15 (m, 5H); 5.16 (m, 2H), 4.18 (m, 2H); MS (EI) m/z 413.05 (M−H)−.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35])[CH:28]=[CH:27]2>C(O)C>[Br:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:37]1[CH2:38][CH2:39][N:40]([C:18](=[O:20])[C:17]3[CH:21]=[CH:22][C:14]([C:12]4[N:13]=[C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[NH:10][CH:11]=4)=[CH:15][CH:16]=3)[CH2:41][CH2:42]1)(=[O:35])=[O:36])[CH:28]=[CH:27]2
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc(C(=O)O)cc2)c[nH]1
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)c[nH]1

Procedure:
The requisite 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-t-butyloxycarbonylaminoimidazol-4-yl)benzoyl]piperazine starting material was prepared by a coupling method exactly analogous to that described in Example 1, starting from 4(2-t-butyloxycarbonylaminoimidazol-4-yl)benzoic acid and 1-(6-bromonaphth-2-ylsulphonyl)piperazine, to give 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-t-butyloxycarbonylaminoimidazol-4-yl)benzoyl]piperazine as a colourless solid (after trituration with hot ethanol) (248 mg, 40% yield), m.p. 175-177° C., 1H NMR (d6DMSO) 1.5 ppm (s,9H), 3.0-3.1 ppm (broad s,4H), 3.4-3.7 ppm (broad s,4H), 6.6 ppm (s,2H), 7.3 ppm (d,2H), 7.4 ppm (s,1H), 7.7 ppm (d,2H), 7.8 ppm (t,2H), 8.2 ppm (t,2H), 8.4 ppm (s,1H), 8.45 ppm (s,1H); MS (M+H)+ 640/642 (w), (M+H-56)+ 584/585 (s), loss of C4H8.
Reaction SMILES: C(N(CC)[C:4](=[O:32])[CH:5]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)[C:6]([NH:8][S:9]([C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=1)(=[O:11])=[O:10])=[O:7])C.[CH:35]([NH2:48])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:36]1([CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[NH:48][C:4](=[O:32])[CH:5]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=2)[C:6]([NH:8][S:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=2)(=[O:11])=[O:10])=[O:7])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CCN(CC)C(=O)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Product: O=C(NC(c1ccccc1)c1ccccc1)C(Cc1ccc([N+](=O)[O-])cc1)C(=O)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 31.6 %

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (400 mg) obtained in Example 6 (4) and benzhydrylamine (171 mg). This was purified by silica gel column chromatography to give the title compound (155 mg) as a white powder.
Reaction SMILES: CS(O[CH2:6][CH:7]1[O:12][CH2:11][CH2:10][N:9]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[C:15]([NH:21][C:22]3[N:27]=[C:26]([N:28]([CH:38]4[CH2:40][CH2:39]4)[CH2:29][C:30]4[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=4)[C:25]4=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]4[N:23]=3)[C:14]=2[Cl:46])[CH2:8]1)(=O)=O.[CH3:47][O:48][C:49]1[CH:56]=[CH:55][C:52]([CH2:53][NH2:54])=[CH:51][CH:50]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.C(OCC)(=O)C>[Cl:46][C:14]1[C:13]([N:9]2[CH2:10][CH2:11][O:12][CH:7]([CH2:6][NH:54][CH2:53][C:52]3[CH:55]=[CH:56][C:49]([O:48][CH3:47])=[CH:50][CH:51]=3)[CH2:8]2)=[CH:18][C:17]([C:19]#[N:20])=[CH:16][C:15]=1[NH:21][C:22]1[N:27]=[C:26]([N:28]([CH:38]2[CH2:40][CH2:39]2)[CH2:29][C:30]2[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[C:25]2=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:24]2[N:23]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCOC(COS(C)(=O)=O)C4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Reactant: COc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CNCC2CN(c3cc(C#N)cc(Nc4nc(N(Cc5ccc(OC)cc5)C5CC5)c5ncc(C#N)n5n4)c3Cl)CCO2)cc1
Temperature: 80 °C
Yield: 64.9 %

Procedure:
A vial was charged with (+/−)-(4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)morpholin-2-yl)methyl methanesulfonate (56.5 mg, 0.085 mmol) and 4-methoxybenzylamine (33.3 μl, 0.255 mmol) in acetonitrile (904 μl). Potassium carbonate (58.7 mg, 0.425 mmol) was added and the vial was capped and heated at 80° C. ON. After cooling to room temperature, the reaction mixture was diluted with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. (+/−)-2-((2-Chloro-5-cyano-3-(2-(((4-methoxybenzyl)amino)methyl)morpholino)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (38.9 mg) was isolated as a white solid and used as is in subsequent chemistry.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([N:18]=[N+]=[N-])[CH:13]([OH:21])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C(S)CCS>CO>[CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[CH:13]([OH:21])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=NC1CCCN(C(=O)OCc2ccccc2)CC1O
Agent: SCCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: NC1CCCN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C

Procedure:
To a solution of 4-azido-3-hydroxy-azepane-1-carboxylic acid benzyl ester (3.3 g, 11.37 mmol) in methanol (50 mL) was added triethylamine (5 mL) and 1,3-propanedithiol (3.42 mL, 35 mmol). The mixture was stirred at ambient temperature until TLC analysis showed complete consumption of the starting material. A white precipitate was removed by filtration and the filtrate was evaporated to dryness. The residue was triturated with a 1:1 hexane/diethyl ether mixture to remove excess dithiol and dried under vacuum to yield 4-amino-3-hydroxy-azepane-1-carboxylic acid benzyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]=[O:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl.C([O-])(O)=O.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH2:13][OH:14])=[N:10][C:9]=2[C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CSc1ccc(-c2nc(C=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CSc1ccc(-c2nc(CO)[nH]c2-c2ccc(F)cc2)cc1
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of compound from step 3 (350 mg, 1 mmol) and NaBH4 (75 mg, 2 eg.) in methanol (10 ml) was stirred for 1 hour at 25° C. The reaction was acidified with 2N HCl (4 ml), stirred for 2 hours and placed on a steam bath for 2 minutes. After cooling, the mixture was neutralized with aqueous NaHCO3 solution, extracted with methylene chloride, dried (MgSO4) and evaporated. The residue was chromatographed on silica gel, eluting with toluene/methanol (90/10). The crude product was recrystallized from ethyl acetate/hexane to give 240 mg (78%) of pure 5-(4-fluorophenyl)-2-hydroxymethyl-4-(4-methylthiophenyl)-1H-imidazole: m.p. 108°-110° C. Anal. Calc'd. for C17H15N20FS: C, 64.95; H, 4.81; N, 8.91; S, 10.20. Found: C, 64.69; H, 4.92; N, 8.79; S, 10.41.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[NH:24][N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].[H-].[Na+].[CH3:43][C:44]1([CH3:55])[O:48][CH:47]([CH2:49]OS(C)(=O)=O)[CH2:46][O:45]1>CN(C=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:40])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:49][CH:47]5[CH2:46][O:45][C:44]([CH3:55])([CH3:43])[O:48]5)[N:23]=4)[N:20]=3)[N:15]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CC1(C)OCC(COS(C)(=O)=O)O1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3n[nH]c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4COC(C)(C)O4)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a round-bottomed flask, 2-(6-chloro-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (see Example 23, 120 mg, 0.21 mmol) was dissolved in DMF (1.3 ml). The reaction mixture was cooled to 0° C. and sodium hydride (60% dispersion in mineral oil, 12 mg, 0.31 mmol) was added. The reaction mixture was stirred at 0° C. for 30 min then a solution of methanesulfonic acid 2,2-dimethyl-[1,3]dioxolan-4-ylmethyl ester (131 mg, 0.62 mmol) in DMF (0.5 ml) was added. The reaction mixture was stirred at 0° C. for 1 h and then at room temperature for 48 h. The reaction mixture was quenched with water and extracted with ethyl acetate (2×). The combined organic layers were washed with water, sat LiCl, and brine then dried over MgSO4 and concentrated to give 2-[6-chloro-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indazol-3-yl]-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 a light brown viscous oil which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:31][CH3:32])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([O:26]CC)=[O:25])=[CH:6][C:7]2[C:8]([CH3:17])([CH3:16])[CH2:9][CH2:10][C:11]([CH3:15])([CH3:14])[C:12]=2[CH:13]=1)[CH3:2].[OH-].[K+].Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:5](/[C:18](/[CH2:31][CH3:32])=[C:19](/[F:30])\[CH:20]=[CH:21]\[C:22](\[CH3:29])=[CH:23]\[C:24]([OH:26])=[O:25])=[CH:6][C:7]2[C:8]([CH3:16])([CH3:17])[CH2:9][CH2:10][C:11]([CH3:14])([CH3:15])[C:12]=2[CH:13]=1)[CH3:2]
Reactant: CCOC(=O)/C=C(C)/C=C/C(F)=C(/CC)c1cc2c(cc1OCC)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1cc2c(cc1/C(CC)=C(F)\C=C\C(C)=C\C(=O)O)C(C)(C)CCC2(C)C
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of ethyl (2E,4E,6E)-7-(3-ethoxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-6-fluoro-3-methylnona-2,4,6-trienoate (Compound 1, 3.55 g, 8.02 mmol) in ethanol (60 mL) was treated with 2 N aqueous potassium hydroxide (20 mL), and the solution was stirred at 60° C. overnight. The solution was cooled to room temperature, and acidified with 1 N HCl, and the products were extracted three times with ethyl acetate. The combined organic layers were washed with water, brine and dried over magnesium sulfate. The solution was filtered through a sintered glass funnel containing a bed of silica gel about 1 inch thick using ethyl acetate as the eluent. The solvent was removed in vacuo, and the residue was recrystalized form acetonitrile to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH2:11][CH2:10][CH:5]([C:6](OC)=[O:7])[CH2:4][CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(=O)(O)[O-].[Na+]>CCCCCC>[CH3:1][N:2]1[CH2:11][CH2:10][CH:5]([CH:6]=[O:7])[CH2:4][CH2:3]1
Reactant: COC(=O)C1CCN(C)CC1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCCCCC
Product: CN1CCC(C=O)CC1
Reaction time: 1.5 h
Yield: 78.6 %

Procedure:
To a deep cold (below -70° C.) solution of methyl 1-methylisonipecotate (15.7 g. 0.1 mol) in 500 mL of hexane was added, dropwise over 1 hr, 100 mL of 1N diisobutylaluminum hydride (DIBAL-H) in hexane. The solution was stirred for 1.5 h, and 20 mL of saturated aqueous ammonium chloride was very slowly added. The reaction mixture was gradually allowed to come to ambient temperature and stirring was continued for an additional hour. To the reaction mixture was added 10 mL of saturated aqueous sodium bicarbonate and the organic layer was decanted. The aqueous layer was extracted with methylene chloride (200 mL×3) and then with ether (200 mL×3). The combined extracts were dried with magnesium sulfate and evaporated to give 10 g (79%) of a pale yellow oil (crude). The crude aldehyde was used for further reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH:9](O)[CH3:10])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C([N:34](CC)CC)C>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:15][CH:14]=2)[CH:9]([NH2:34])[CH3:10])=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(O)C(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(Cl)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CC(N)C(Cc1ccc(C#Cc2ccccc2)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
141 mg of the alcohol compound thus obtained was dissolved in 2 ml of ethyl acetate, and 62 μl of methanesulfonyl chloride and 161 μl of triethylamine were added thereto, followed by stirring at room temperature for 30 minutes. Insoluble precipitates were filtered off from the reaction solution. Then, the filtrate was concentrated under reduced pressure, and the residue was dissolved in 5 ml of dimethylformamide. Then, 255 mg of sodium azide was added thereto, followed by heating at 80° C. for 4 hours. The reaction solution was left to cool to room temperature. Then, ethyl ether and water were added thereto for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was heated and refluxed together with 187 mg of triphenylphosphine in 7 ml of 10%-water containing tetrahydrofuran for one hour. The reaction solution was evaporated to dryness under reduced pressure. Then, the residue was dissolved in ethanol and again evaporated to dryness under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform/methanol=50/1+10/1) to obtain 129 mg (yield: 92%) of (1RS,2SR)-2-(4-chlorophenyl)-1-methyl-3-(4-phenylethynylphenyl)propylamine
Reaction SMILES: [Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[NH:4][C:3]=1[C:9]#[N:10].[C:11](=O)([O-])[O-].[K+].[K+].[I-].FC(F)(F)C1NC(Br)=C(Br)C=1C#N>CC(C)=O.C(COC)OC.O>[Br:1][C:2]1[C:6]([Br:7])=[C:5]([Br:8])[N:4]([CH3:11])[C:3]=1[C:9]#[N:10]
Reactant: N#Cc1[nH]c(Br)c(Br)c1Br
Reactant: O=C([O-])[O-]
Agent: N#Cc1c(C(F)(F)F)[nH]c(Br)c1Br
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: COCCOC
Product: Cn1c(Br)c(Br)c(Br)c1C#N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4,5-Tribromo-pyrrole-2-carbonitrile (1.0 g, 0.003 mo1) is dissolved in a mixture of acetone (20 mL) and dimethoxyethane (10 mL). Potassium carbonate (0.45 g, 0.0033 mol) is added followed by methyl .iodide (0.478 g, 0.0033 mo1). After stirring overnight at room temperature, the mixture is poured into water precipitating a white solid. The solid (0.S g, 80%) has mp 115°-119° C.