Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[N:5]1.[H-].[Na+].[CH3:23][N:24]1[C:28]2=[N:29][CH:30]=[CH:31][CH:32]=[C:27]2[N:26]=[C:25]1S(C)(=O)=O.O>CN(C=O)C>[F:20][CH:2]([F:1])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:25]3[N:24]([CH3:23])[C:28]4=[N:29][CH:30]=[CH:31][CH:32]=[C:27]4[N:26]=3)=[CH:15][CH:14]=2)=[N:5]1
Reactant: Oc1ccc(-c2nn(CC(F)F)c3cccnc23)cc1
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(Oc2ccc(-c3nn(CC(F)F)c4cccnc34)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
To a stirred solution of 4-[1-(2,2-difluoroethyl)-1H-pyrazolo[4,3-b]pyridin-3-yl]phenol (142 mg) in DMF (4 mL) was added NaH (60% in oil, 20.63 mg) at room temperature. The mixture was stirred at room temperature for 30 min and then 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (109 mg) was added. The mixture was exposed to microwave irradiation at 180° C. for 30 min, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane). The product was crystallized from AcOEt/hexane to give the title compound (90 mg)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13](=[O:15])[CH3:14])=[C:6]2Cl.C([O-])([O-])=O.[K+].[K+].[CH:23]([N:26]([CH2:30][CH3:31])[CH:27](C)C)(C)C>O1CCOCC1.CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13](=[O:15])[CH3:14])=[C:6]2[NH:9][C@H:10]1[CH2:11][CH2:12][C@H:3]([CH2:31][CH2:30][N:26]([CH3:23])[CH3:27])[CH2:4][CH2:5]1
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ccc(Br)cc2c1N[C@H]1CC[C@H](CCN(C)C)CC1
Temperature: 25 °C

Procedure:
Following general procedure A-1, tert-butyl (trans-4-(2-(dimethylamino)ethyl)cyclohexyl) carbamate (336 mg, 1.24 mmol) was reacted with 6 N aqueous HCl (2 mL) to afford a viscous colorless oil. The oil was dissolved in dioxane (10 mL) and DMF (5 mL) followed by the addition of 1-(6-bromo-4-chloroquinolin-3-yl)ethanone (285 mg, 1.0 mmol), K2CO3 (0.55 g, 4.0 mmol), and N,N-diisopropylethylamine (1.0 mL, 5.8 mmol) and the resultant suspension was heated at 100° C. for 16 h. The reaction mixture was cooled to room temperature, diluted with satd. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. Purification by column chromatography (silica, 0-20% methanol/dichloromethane) afforded the desired product (227 mg, 54%) as a light yellow-brown solid. ESI MS m/z 418 [C21H28BrN3O+H]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[C:19]([CH2:20]C4C=CC(C#N)=CC=4)=[CH:18][N:17]=[CH:16]3)=[CH:10][C:9]2=[O:29])[CH:5]=[CH:4][CH:3]=1.[C:30]([N:49]1C=C(CC2C=CC(C#N)=CC=2)N=C1)(C1C=CC=CC=1)(C1C=CC=CC=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][C:11]([CH2:14][N:15]3[C:19]([CH2:20][C:33]4[CH:32]=[C:31]([CH:36]=[CH:35][CH:34]=4)[C:30]#[N:49])=[CH:18][N:17]=[CH:16]3)=[CH:10][C:9]2=[O:29])[CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3cccc(Cl)n3)c(=O)c2)cc1
Reactant: N#Cc1ccc(Cc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Product: N#Cc1cccc(Cc2cncn2Cc2ccn(-c3cccc(Cl)n3)c(=O)c2)c1

Procedure:
3-[3-(6'-chloro-2-oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile was prepared in a manner substantially similar to the procedure described above for 4-[3-(6'-chloro-2-oxo-2H-[1,2'] bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile, but substituting 3-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile for 4-(1-trityl-1H-imidazol-4-ylmethyl)-benzonitrile in Step 7.
Reaction SMILES: [Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([NH:10][CH:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:12]2[C:13]([C:20](O)=[O:21])=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=2)[CH:3]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[CH:5]=[C:4]([N:10]2[CH:11]([C:23]3[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=3)[C:12]3[C:13](=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=3)[C:20]2=[O:21])[CH:3]=1
Reactant: CC(C)n1cc(C(Nc2cc(Cl)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C(=O)O)n1
Solvent: ClCCl
Solvent: CO
Product: CC(C)n1cc2c(n1)C(=O)N(c1cc(Cl)c(=O)n(C)c1)C2c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Example 1 using 4-(((5-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)amino)(4-chlorophenyl)methyl)-1-isopropyl-1H-pyrazole-3-carboxylic acid (Step 42.2). tR: 4.25 min (HPLC 1); tR: 0.95 min (LC-MS 2); ESI-MS: 417 [m+H]+(LC-MS 2); Rf=0.51 (CH2Cl2/MeOH 9:1); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39-1.46 (m, 6H) 3.43 (s, 3H) 4.54-4.67 (m, 1H) 6.16 (s, 1H) 7.20-7.27 (m, 2H) 7.32-7.38 (m, 2H) 7.87 (s, 1H) 7.88-7.90 (m, 1H) 7.91-7.93 (m, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.CCCCC.CON(C)[C:19](=[O:51])[C@@H:20]([NH:28][C:29]([CH2:31][N:32]1[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[CH:36][N:35]([C:44](=[O:46])[CH3:45])[CH:34]([CH:47]([CH3:49])[CH3:48])[C:33]1=[O:50])=[O:30])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O1CCCC1>[C:44]([N:35]1[CH:36]=[C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[N:32]([CH2:31][C:29]([NH:28][C@@H:20]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([C:2]2[O:1][CH2:5][CH2:4][CH:3]=2)=[O:51])=[O:30])[C:33](=[O:50])[CH:34]1[CH:47]([CH3:49])[CH3:48])(=[O:46])[CH3:45]
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Reactant: C1=COCC1
Agent: [Cl-]
Agent: [Li]C(C)(C)C
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C2=CCCO2)C(=O)C1C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 2,3-dihydrofuran (80 μl) in anhydrous tetrahydrofuran (2 ml) is cooled to −78° C., a 1.55 N tert-butyllithium/pentane solution (660 μl) is added thereto, and the mixture is stirred for one hour. The mixture is added to a solution of N1-methoxy-N1-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide (295 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (3 ml) cooled at −78° C., and the whole is stirred for two hours. The temperature is raised to 0° C., and the reaction mixture is stirred for 30 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (38.4 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S-:9])[CH:6]=[CH:7][CH:8]=1.[K+].Cl[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([S:9][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: COc1cccc([S-])c1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(Sc2ccc([N+](=O)[O-])cc2)c1
Temperature: 0 °C
Yield: 91.7 %

Procedure:
A solution of potassium 3-methoxybenzenethiolate (6.37 g, 35.7 mmol) and 4-chloronitrobenzene (5.11 g, 32.5 mmol) in dimethylformamide (30 mL) was stirred at room temperature for 4 hours. The reaction mixture was poured into ice water and a yellow solid was collected by filtration. Recrystallization from 90% ethanol yielded the title anisole (7.79 g, 92%) as a yellow solid; mp 81°-83° C. 1H--NMR (250 MHz, d6 --DMSO): 3.80 (s, 3H, OCH3) 7.10-7.19 (m, 3H, aromatic) 7.32 (d, 2H, J=7.1 Hz, aromatic) 7.43-7.49 (m, 1H, aromatic) 8.15 (d, 2H, J=7.0, aromatic). MS (CI, CH4): 262 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.S(Cl)(Cl)=O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:7]
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 87 %

Procedure:
A solution of 14.61 g. (0.079 m.) of 3-fluoro-4-nitrobenzoic acid, 200 ml. of benzene, 10 ml. of thionyl chloride, and 1 ml. of N,N-dimethylformamide was stirred overnight at room temperature under a calcium chloride drying tube. The resulting clear solution was then heated to reflux for one hour, after which time the solution was concentrated to approximately 75% of the original volume by distillation. The mixture was cooled by placing the flask in an ice bath. With additional cooling, 20 g. of aluminum chloride was added in portions through Gooch tubing over a period of about 45 minutes. The resulting dark mixture was stirred and allowed to warm to room temperature overnight. The reaction flask was again cooled in an ice bath as 300 ml. of 1N hydrochloric acid was added dropwise. The mixture was extracted several times with ethyl acetate and the combined extracts were washed with water, a saturated solution of sodium bicarbonate, water, a saturated solution of sodium chloride, and then dried over magnesium sulfate. Filtration and evaporation of the solvent in vacuo provided 16.8 g. (87% yield) of the desired compound as an oil which solidified on scratching. Recrystallization from 95% ethanol afforded yellow needles, m.p. about 77°-79° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([N:14]3C(=O)C4C(=CC=CC=4)C3=O)=[N:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1.O.NN>C(O)C>[F:1][C:2]1[C:7]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH2:14])=[N:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=C1c2ccccc2C(=O)N1c1ccn(Cc2cccnc2F)n1
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccn(Cc2cccnc2F)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of Intermediate 46 (180 mg, 0.558 mmol) and hydrazine monohydrate (FLUKA, 0.035 mL, 1.117 mmol) in ethanol (10 mL) was stirred at room temperature for 4 h. Precipitate was filtered and washed with DCM. Filtrate was evaporated to dryness. Residue was purified by silica column chromatography using a linear gradient of DCM/MeOH as eluents to yield the title compound (102 mg, 0.53 mmol, 95% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm: 8.15 (m, 1H), 7.57-7.62 (m, 1H), 7.45 (d, 1H), 7.29-7.33 (m, 1H), 5.41 (d, 1H), 5.08 (s, 2H), 4.62 (br s, 2H). [ES+MS] m/z 193 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=[O:26])[N:21]([CH:23]([CH3:25])[CH3:24])[CH2:22][C:9]=23)=[CH:4][CH:3]=1.I[CH3:28]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])[N:11]=[C:10]3[C:20](=[O:26])[N:21]([CH:23]([CH3:24])[CH3:25])[CH:22]([CH3:28])[C:9]=23)=[CH:4][CH:3]=1
Reactant: CC(C)N1Cc2c(nn(-c3ccccc3Cl)c2-c2ccc(Cl)cc2)C1=O
Reactant: CI
Solvent: C1CCOC1
Product: CC(C)N1C(=O)c2nn(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2C1C
Reaction time: 0.17 h
Yield: 16 %

Procedure:
To a solution of 3-(4-chloro-phenyl)-2-(2-chloro-phenyl)-5-isopropyl-4,5-dihydro-2H-pyrrolo[3,4-c]pyrazol-6-one 3A-1 (19 mg, 0.05 mmol) in THF (0.5 ml) at −78° C. was added LiHMDSi (55 μl, 0.055 mmol). A deep blue-black solution was formed. The reaction mixture was stirred for 0.17 hour and then iodomethane (4.4 μl, 0.07 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 0.25 h (until a yellow color formed) and at room temperature for 2 hours, quenched with sat'd aq NH4Cl, and extracted with EtOAc. The organic solution was washed with sat'd aq NaCl, dried, and concentrated in vacuo. The residue was purified on 1 mm chromatotron plates using a 1:1 EtOAc/hexane solution to give 6A-1 as a white solid (3.2 mg, 14%); +ES MS (M+1) 400.3; 1H NMR (CDCl3): δ 7.4–7.3 (m, 4H), 7.28–7.24 (m, 2H), 7.1-7.06 (m, 2H), 4.84–4.77 (m, 1H), 4.37–4.27 (m, 1H), 1.48–1.4 (m, 9H).
Reaction SMILES: [OH:1][C@@:2]1([CH2:22][CH:23]=[CH2:24])[C@@H:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.[H-].[Na+].[CH3:27]N(C=O)C>>[Si:8]([O:7][C@H:6]1[CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][C@:2]1([O:1][CH3:27])[CH2:22][CH:23]=[CH2:24])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]
Reactant: C=CC[C@@]1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: C=CC[C@@]1(OC)CN(C(=O)OC(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-hydroxy-4-(tert-butyldimethylsilyl)oxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate (550 mg) in DMF (10 mL) was added iodemethane (2.2 g) at 0° C. After 10 min, 60% NaH in oil (62 mg) was added, and the mixture was stirred for 1 hour at room temperature. The reaction was quenched with saturated aqueous NH4Cl and the mixture was extracted with Et2O. The extract was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified with silica gel column chromatography (eluent: hexane/EtOAc=1/0˜50/50) to give tert-butyl (3R,4S)-4-(tert-butyldimethylsilyl)oxy-3-methoxy-3-(prop-2-en-1-yl)pyrrolidine-1-carboxylate as a pale yellow foam.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][O:26][C:27](=[O:32])[NH:28][C:29](=[NH:31])[NH2:30])[C:20]=3[F:33])[CH2:15][CH2:14]2)=[CH:9][N:8]=1)=[O:6].C1COCC1.Cl>CO>[C:29]([NH:28][C:27]([O:26][CH2:25][C:21]1[C:20]([F:33])=[C:19]([N:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([C:5]([OH:6])=[O:4])=[N:8][CH:9]=3)[CH2:14][CH2:15]2)[CH:24]=[CH:23][CH:22]=1)=[O:32])(=[NH:30])[NH2:31]
Reactant: COC(=O)c1ccc(N2CCN(c3cccc(COC(=O)NC(=N)N)c3F)CC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N=C(N)NC(=O)OCc1cccc(N2CCN(c3ccc(C(=O)O)nc3)CC2)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A 1M aqueous NaOH solution (1.14 ml) was added to a mixture of 5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylate methyl ester (326 mg), THF (9 ml), and MeOH (3 ml), followed by stirring at room temperature overnight. 1M hydrochloric acid (1.14 ml) was added to the reaction mixture, followed by stirring at room temperature for 1 hour. The generated solid was collected by filtration, washed with water, and then dried at 50° C. under reduced pressure to obtain 5-[4-(3-{[(carbamimidoylcarbamoyl)oxy]methyl}-2-fluorophenyl)piperazin-1-yl]pyridine-2-carboxylic acid (293 mg).
Reaction SMILES: [ClH:1].C(OC(=O)[N:8](C1C=CC(C#N)=CC=1)[CH2:9][C:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)(C)(C)C.O1[CH2:41][CH2:40]OCC1>>[ClH:1].[NH2:8][CH:9]([C:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=1)[C:41]1[CH:40]=[CH:14][C:10]([C:9]#[N:8])=[CH:11][CH:12]=1
Reactant: CC(C)(C)OC(=O)N(CC1=C(Nc2cccc(C(F)(F)F)c2)CCC1=O)c1ccc(C#N)cc1
Reactant: C1COCCO1
Agent: Cl
Product: N#Cc1ccc(C(N)C2=C(Nc3cccc(C(F)(F)F)c3)CCC2=O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydrogen chloride in 1,4-dioxane (4 M, 29.3 mL, 117 mmol) is added to a mixture of tert-butyl(4-cyanophenyl)(5-oxo-2-(3-(trifluoromethyl)phenylamino)cyclopent-1-enyl)methylcarbamate (intermediate 12, 6.92 g, 14.7 mmol) in 1,4-dioxane (30 mL), and the mixture is stirred at room temperature for 2 h. All volatiles are removed under reduced pressure, and the residue is treated with tert-butyl methyl ether (50 mL). The precipitate is filtered, washed with tert-butyl methyl ether and dried. Yield: 6.10 g. ESI mass spectrum: [M+H]+=372; Retention time HPLC: 0.62 min (X011_S02).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=O)=[CH:3][CH:2]=1.[ClH:21].[NH2:22][OH:23].N1C=CC=CC=1>CO>[ClH:21].[ClH:21].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][C:9]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[C:10]([CH3:14])[C:11]=2[CH:12]=[N:22][OH:23])=[CH:3][CH:2]=1
Reactant: NO
Reactant: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=O
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(-c2ccncc2)sc(-c2ccncc2)c1C=NO
Yield: 42.5 %

Procedure:
A mixture of 2,5-di(4-pyridyl)-4-methylthiophene-3-carbaldehyde (0.14 g), hydroxylamine hydrochloride (0.04 g), and pyridine (0.04 mL) in MeOH (3 mL) was heated at reflux temperature for 16 hours. After cooling, the volatiles were removed by evaporation. The resulting residue was dissolved in 10% methanolic HCl (5 mL) and the solution was concentrated in vacuo again. The resulting solid was washed with water (50 mL) and CH2CI2 (30 mL) to provide the title compound (0.045 g).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]([F:36])([C:32]([F:35])([F:34])[F:33])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][O:30][CH3:31])[CH:22]=1)=O.O>C1COCC1>[F:17][C:18]([F:36])([C:32]([F:33])([F:34])[F:35])[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][O:28][CH2:29][O:30][CH3:31])[CH:22]=1)=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COCOCc1cccc(C(=O)C(F)(F)C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=C(c1cccc(COCOC)c1)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (481 mg) in THF (15 mL) was added ethyl diethylphosphonoacetate (2.55 mL) at 0° C., and the mixture was stirred at room temperature for 5 min. To the obtained colorless solution was added 2,2,3,3,3-pentafluoro-1-(3-((methoxymethoxy)methyl)phenyl)propan-1-one (1.28 g) at room temperature, and the mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.37 g) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.Cl>CO>[ClH:1].[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][CH:15]=3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Nc1ccc(C=O)cc1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: Cl
Solvent: CO
Product: O=Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
4,7-Dichloroquinoline (50 g, 252 mmol) and 4-aminobenzaldehyde (30.6 g, 252 mmol) are stirred in 300 mL of methanol and treated with 126 mL of 2 N HCl. The mixture is boiled on a hot plate and after ~15 minutes, a thick yellow precipitate forms. The heating is continued at a low setting for 3 hours at which point the mixture is allowed to cool to room temperature. The yellow solid is filtered, washed with cold methanol, then ether and dried in vacuo at 60° C. for three days affording 64.65 g (203 mmol, 80% yield) of product: 1H NMR (Me2SO-d6, 300 MHz) δ11.4 (br s, 1H), 10.06 (s, 1H), 8.95 (d,J=9.2 Hz, 1H), 8.65 (d,J=6.9 Hz, 1H), 8.24 (d,J=2.1 Hz, 1H), 8.09 (d,J=8.5 Hz, 2H), 7.92 (d of d,J=2.0, 9.2 Hz, 1H), 7.76 (d,J=8.5 Hz, 2H), 7.13 (d,J=7.0 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[C:7]#[N:8].[C:14]([N:16]=[C:17]([NH2:19])[NH2:18])#[N:15].[OH-].[K+]>COCCO.O>[NH2:15][C:14]1[N:16]=[C:17]([NH2:19])[N:18]=[C:7]([C:6]2[CH:9]=[CH:10][CH:11]=[C:4]([S:3][C:2]([F:12])([F:1])[F:13])[CH:5]=2)[N:8]=1
Reactant: N#CN=C(N)N
Reactant: N#Cc1cccc(SC(F)(F)F)c1
Agent: [K+]
Agent: [OH-]
Solvent: COCCO
Solvent: O
Product: Nc1nc(N)nc(-c2cccc(SC(F)(F)F)c2)n1

Procedure:
2.9 g of m-trifluoromethylthiobenzonitrile (b.p. 86°-88° C./40 mm Hg) and 1.4 g of dicyanodiamide are dissolved in 3 ml of methylcellosolve and the mixture is then combined with 0.3 g of caustic potash and refluxed for 5 hours. After cooling, the mixture is diluted with water and extracted with ether, and the extract, after evaporation, is recrystallized from methanol. Melting point of the obtained material: 172°-174° C.; yield: 2.4 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16][CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[CH:4][CH:3]=1.C([O-])(O)=[O:28].[Na+].OOS([O-])=O.[K+].O>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]2[S:16]([CH2:17][C:18]2[C:23]([F:24])=[CH:22][CH:21]=[C:20]([F:25])[C:19]=2[F:26])=[O:28])=[CH:4][CH:3]=1
Reactant: O=C([O-])O
Reactant: O=C(O)c1cnc(SCc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Agent: O=S([O-])OO
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cnc(S(=O)Cc2c(F)ccc(F)c2F)n1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)thio)-1H-imidazole-5-carboxylic acid (11) (261 mg, 0.68 mmol) in acetone (7 mL) was added 0.2 M NaHCO3 (7 mL) and Oxone (1.05 g, 1.71 mmol) and stirred at room temperature for 2 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to obtain 1-(4-fluorophenyl)-2-((2,3,6-trifluorobenzyl)sulfinyl)-1H-imidazole-5-carboxylic acid (20) as a white solid.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[NH:16][C:17]([CH:20]([C:28]3[CH:33]=[CH:32][C:31]([S:34]([CH:37]4[CH2:39][CH2:38]4)(=[O:36])=[O:35])=[CH:30][CH:29]=3)[CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:18][CH:19]=2)=[N:13][CH:14]=1)C1C=CC=CC=1.C(O)C>[C].[Pd].O1CCCC1>[CH:37]1([S:34]([C:31]2[CH:32]=[CH:33][C:28]([CH:20]([C:17]3[NH:16][C:15]([C:12]4[N:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)=[CH:19][CH:18]=3)[CH2:21][CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH2:39][CH2:38]1
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(OCc4ccccc4)cn3)[nH]2)cc1)C1CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(O)cn3)[nH]2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.6 %

Procedure:
To a solution of 5-(benzyloxy)-2-(5-[1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl]-1H-pyrrol-2-yl)pyridine (1.97 g) in a mixed solvent of ethanol (30 mL) and tetrahydrofuran (30 mL) was added 10% palladium carbon (200 mg), and the mixture was stirred at room temperature for 16 hr under a hydrogen atmosphere. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=20:80-80:20, volume ratio) to give the title compound (1.62 g, yield 99%) as a yellow amorphous solid. MS: 453 (MH+).