Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:12]Br>C(Cl)(Cl)(Cl)Cl>[Br:12][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1]([OH:11])=[CH:2][CH:3]=1
Reactant: Oc1cccc2c1CCCC2
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc(Br)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a solution of 37 grams (0.25 mole) of 5,6,7,8-tetrahydronaphthol in 150 ml of carbon tetrachloride was added dropwise with stirring a solution of 44 grams (0.25 mole) of bromine in 50 ml of carbon tetrachloride. When the addition was complete the mixture was stirred for 30 minutes at room temperature and then evaporated in vacuo to a residue which after two recrystallizations from hexane provided 13 grams (22.9 percent) of product, m.p. 83°-85°C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:17]([O-:20])(=O)=[O:18])[CH:11]=[CH:10]2.O>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH:13]=[C:12]([S:17]([Cl:3])(=[O:20])=[O:18])[CH:11]=[CH:10]2
Reactant: O=S(Cl)Cl
Reactant: COc1ccc2cc(S(=O)(=O)[O-])ccc2c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide (0.7 g) was added to a solution of sodium 6-hydroxynapthalene-2-sulfonate (9 mmol) in water (20 ml). Dimethyl sulfate (1.1 eq.) was added to this solution at 50-55° C. over 1 h, followed by sodium chloride (3.3 g). The solid that was formed was filtered off, washed with saturated NaCl solution and toluene and dried. Yield: 75% 2. Thionyl chloride (0.25 ml) was added to a cooled solution of 6-methoxynaphthalene-2-sulfonate (2 mmol) in dry DMF (1 ml) under N2. The reaction mixture was stirred for 3 h at 0° C. Iced water (20 ml) was added to the mixture, the solid was filtered off and washed with iced water. The solid was taken up in DCM (25 ml), the solution dried over Na2SO4, filtered and concentrated under reduced pressure. Yield: 75%
Reaction SMILES: [H-].[Na+].[CH2:3]([C@H:6]1[CH2:10][NH:9][C:8](=[O:11])[CH2:7]1)[CH2:4][CH3:5].[CH3:12][O:13][C:14](=[O:20])[C:15](C)(Br)[CH2:16][CH3:17]>O1CCCC1.O>[CH3:12][O:13][C:14](=[O:20])[CH:15]([N:9]1[CH2:10][C@H:6]([CH2:3][CH2:4][CH3:5])[CH2:7][C:8]1=[O:11])[CH2:16][CH3:17]
Reactant: CCC(C)(Br)C(=O)OC
Reactant: CCC[C@H]1CNC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCC[C@@H]1CC(=O)N(C(CC)C(=O)OC)C1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 84.1 %

Procedure:
A slurry of 60% sodium hydride suspension in mineral oil (0.94 g, 23.4 mmol) in tetrahydrofuran (30 mL) is cooled at 0° C. under a nitrogen atmosphere. A solution of substantially optically pure (R)-4-propyl-pyrrolidin-2-one (IIIa) (2 g, 15.7 mmol) in tetrahydrofuran (2 mL) is added over a 15 minutes period. The reaction mixture is stirred 10 min at 0° C. then a solution of methyl-2-bromo-butyric acid methyl ester (V) (3.69 g, 20.4 mmol) in tetrahydrofuran (2 mL) was added over a 20 minutes period. The reaction mixture is stirred at 0° C. until maximum conversion of starting material and the reaction mixture is then allowed to warm to room temperature and diluted with water (20 mL). Tetrahydrofuran is removed by evaporation and the residue is extracted with isopropyl acetate (20 ml+10 mL). The combined organic layers are dried on anhydrous magnesium sulfate and evaporated to afford 3 g (13.2 mmol, 86%) of a mixture of epimers of compound (VIa), as a mixture respectively of epimer (VIaa) and epimer (VIab).
Reaction SMILES: C(O)C.C([O:6][C:7](=O)[CH2:8][CH2:9][N:10]([C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[CH:11]1[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]1)C>C(O)(=O)C>[Cl:24][C:19]1[N:20]=[CH:21][C:22]2[NH:23][C:7](=[O:6])[CH2:8][CH2:9][N:10]([CH:11]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12]3)[C:17]=2[N:18]=1
Reactant: CCOC(=O)CCN(c1nc(Cl)ncc1N)C1CCC(C)C1
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CCC(N2CCC(=O)Nc3cnc(Cl)nc32)C1
Yield: 80.6 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 2.6 g of the (rac)-3-[(5-amino-2-chloro-pyrimidin-4-yl)-(3-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (V-58) prepared in the previous step was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, and then water and dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure to the crude product. Trituration of the residue with ether, provided 1.8 g of (rac)-2-chloro-9-(3-methyl-cyclopentyl)-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-58).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:14]=[C:13](Cl)[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[N:10]=1>CN(C=O)C>[Cl:8][C:9]1[CH:14]=[C:13]([N:1]2[CH:5]=[CH:4][CH:3]=[N:2]2)[CH:12]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[N:10]=1
Reactant: c1cn[nH]c1
Reactant: CC(C)Oc1ccc(-c2cc(Cl)cc(Cl)n2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2cc(-n3cccn3)cc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.2 %

Procedure:
To a dry 2 dram vial equipped with a stir bar was added 1H-pyrazole (16 mg, 0.23 mmol), then DMF (1 mL). To the solution was added sodium hydride (60% disp. in oil, 11 mg, 0.27 mmol) upon which effervesence was immediately observed. The mixture was stirred at room temperature for 15 minutes. To the solution was added 2,4-dichloro-6-(4-isopropoxyphenyl)pyridine (60 mg, 0.21 mmol) as a solution in DMF (0.2 mL). The solution was stirred at room temperature for 3 hours and then at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature and then directly purified via C18 chromatography (water:MeOH w/0.1% TFA) to afford 2-chloro-6-(4-isopropoxyphenyl)-4-(1H-pyrazol-1-yl)pyridine as an off-white solid (41 mg, 62%). 1H-NMR (400 MHz, CDCl3) δ 8.05 (d, J=2.5 Hz, 1H), 7.99 (d, J=9.0 Hz, 2H), 7.96 (d, J=1.8 Hz, 1H), 7.81 (d, J=1.5 Hz, 1H), 7.50 (d, J=1.5 Hz, 1H), 6.97 (d, J=8.8 Hz, 2H), 6.56 (dd, J=2.5, 1.8 Hz, 1H), 4.64 (dquin, J=12.2, 6.0 Hz, 1H), 1.40-1.35 (m, 6H); MS: MS m/z 314.2 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[C:13](I)[C:5]([NH:6][CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:16])[CH:3]=1.[CH2:17]([OH:20])[C:18]#[CH:19]>CCN(CC)CC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:14]=[C:13]2[C:5](=[C:4]([F:16])[CH:3]=1)[N:6]([CH2:7][CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:18]([CH2:17][OH:20])=[CH:19]2
Reactant: CS(=O)(=O)CCNc1c(F)cc(Cl)cc1I
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCn1c(CO)cc2cc(Cl)cc(F)c21
Yield: 95.4 %

Procedure:
A mixture of 4-chloro-2-fluoro-6-iodo-N-(2-(methylsulfonyl)ethyl)aniline (450 mg, 1.2 mmol) and prop-2-yn-1-ol (135 mg, 2.4 mmol) in Et3N (20 ml) was degassed and refluxed under N2 atmosphere. PdCl2(PPh3)2 (90 mg, 0.12 mmol) and CuI (45 mg, 0.24 mmol) were added successively to the reaction mixture. After being stirred under reflux overnight, the mixture was concentrated in vacuo and the residue was poured into water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo. The residue was purified by preparative-TLC (PE: EtOAc=5:1) to give {5-chloro-7-fluoro-1-[2-(methylsulfonyl)ethyl]-1H-indol-2-yl}methanol as a yellow solid (350 mg, yield: 95%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]=[C:9]([N:18]3[CH2:24][C:23]4[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=4[S:21](=[O:30])(=[O:29])[CH2:20][CH2:19]3)[CH:8]=2)[CH2:4][C@H:3]1[OH:31].C([O-])(=O)C.[Na+].[N:37]#[C:38]Br>CO>[O:29]=[S:21]1(=[O:30])[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[CH2:24][N:18]([C:9]2[CH:8]=[C:7]([N:5]3[CH2:4][C@H:3]4[C@H:2]([N:1]=[C:38]([NH2:37])[O:31]4)[CH2:6]3)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH3:17])[CH:15]=3)[N:10]=2)[CH2:19][CH2:20]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H](O)[C@@H](N)C3)c2c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N3C[C@@H]4OC(N)=N[C@@H]4C3)c2c1
Reaction time: 8 h

Procedure:
To a mixture of cis-4-amino-1-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]pyrrolidin-3-ol (90 mg 0.20 mmol, prepared in analogy to Example 19-3 in Scheme 7 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide and tert-butyl [cis-4-hydroxypyrrolidin-3-yl]carbamate) and sodium acetate (82 mg, 1.0 mmol) in methanol (10 mL) at 0° C. was added cyanogen bromide (105 mg, 1 mmol). The mixture was stirred overnight gradually from 0° C. to room temperature, and then concentrated in vacuo. The residue was purified by preparative HPLC to afford the pure product as a solid. MS obsd. (ESI+) [(M+H)+] 464, 1H NMR (400 MHz, CD3OD) δ ppm 8.09 (d, J=7.33 Hz, 1 H), 7.98 (d, J=7.58 Hz, 1 H), 7.89 (brs, 1 H), 7.79-7.70 (m, 2 H), 7.66-7.56 (m, 2 H), 6.50 (s, 1 H), 5.89-5.84 (m, 1 H), 5.41 (brs, 2 H), 4.97-5.02 (m, 1 H), 4.63 (brs, 2 H), 4.31 (brs, 1 H), 4.12 (brs, 1 H), 3.77 (brs, 2 H), 3.62-3.42 (b, 2 H), 2.54-2.48 (m, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[F:14][C:15]([F:38])([F:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23][C:24]2[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=2[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([NH:6][C:7]([N:22]([C:19]1[CH:18]=[CH:17][C:16]([C:15]([F:14])([F:37])[F:38])=[CH:21][CH:20]=1)[S:23][C:24]1[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=1[C:26]([O:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:27])=[O:8])=[O:5]
Reactant: CCCCOC(=O)c1ccccc1SNc1ccc(C(F)(F)F)cc1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: CCCCOC(=O)c1ccccc1SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(C(F)(F)F)cc1
Reaction time: 18 h
Yield: 88 %

Procedure:
A solution of 2,6-difluorobenzoyl isocyanate (1.1 g) in dry toluene (5.0 ml) was added to a stirred solution of butyl 2-[[[4-(trifluoromethyl)phenyl]amino]thio]benzoate (1.9 g) in the same solvent (7.0 ml) at room temperature. After 18 hours, the reaction mixture was cooled to -5°, and the crystalline precipitate was separated, washing with cold toluene followed by light petroleum. The pure product was obtained as colourless crystals (2.5 g, melting point 79°-81°) after recrystallisation from diethyl ether/light petroleum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:26]([NH:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:27])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:13])([F:15])[F:14]
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Solvent: CCOCC
Product: C[C@@](O)(C(=O)Nc1ccc(NC(=O)Nc2ccccc2)cc1Cl)C(F)(F)F
Reaction time: 22 h

Procedure:
A mixture of (R)-N-[2-chloro-4-aminophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 208) (0.198 g) and phenyl isocyanate (0.09 ml) in diethyl ether (10 ml) was stirred for 22 hours then evaporated to dryness. The residue was partitioned between water (25 ml) and ethyl acetate (50 ml). The organic phase was washed with brine (25 ml), dried and concentrated by evaporation to give the title compound (170 mg) as a foam. NMR: 1.66 (s, 3H), 7.04 (t, 1H), 7.35 (m, 3H), 7.52 (d, 1H), 7.71 (s, 1H), 7.86 (m, 2H), 8.77 (s, 1H), 8.92 (s, 1H), 9.63 (s, 1H); MS (ESP−): 400.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C[NH:15][C:16]([C:18]1[CH:22]=[C:21]([CH2:23][OH:24])[O:20][N:19]=1)=[O:17].N1C=CC=CC=1>ClCCl>[C:2](=[O:3])([O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[O:24][CH2:23][C:21]1[O:20][N:19]=[C:18]([C:16](=[O:17])[NH2:15])[CH:22]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CNC(=O)c1cc(CO)on1
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
2.84 g (14.07 mmoles) of 4-nitrophenyl chloroformate are added in small portions to a solution of 2.0 g (14.07 mmoles) of 3-methylcarbamoyl-isoxazol-5-yl-methanol (commercial), 1.71 ml (21.11 mmoles) of pyridine and 0.17 g (1.41 moles) of N,N-dimethylaminopyridine in 15 ml of dichloromethane, cooled to about 0° C. The medium is maintained with stirring for 1 hr at 0° C. then for 1 hr at ambient temperature. The precipitate formed is filtered off then copiously rinsed with diisopropyl ether. After drying under vacuum at about 60° C., 3.12 g of the expected product are obtained in the form of a white solid used as such in the following stage.
Reaction SMILES: C([N:20]1[CH2:28][C:27]2[C:26]([C:29]#[N:30])=[CH:25][CH:24]=[CH:23][C:22]=2[CH2:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>>[CH2:21]1[C:22]2[CH:23]=[CH:24][CH:25]=[C:26]([C:29]#[N:30])[C:27]=2[CH2:28][NH:20]1
Reactant: N#Cc1cccc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc2c1CNC2

Procedure:
Prepared in analogy to Example A2 (c) from 2-trityl-2,3-dihydro-1H-isoindole-4-carbonitrile and trifluoroacetic acid. Light brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[N+:15]([C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1)([O-:17])=[O:16]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:1][C:2]1[C:3]2[C:10]([C:21]3[CH:22]=[CH:23][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[CH:9][N:8]([CH:12]([CH3:14])[CH3:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(C)n1cc(I)c2c(Cl)ncnc21
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CC(C)n1cc(-c2ccc([N+](=O)[O-])cc2)c2c(Cl)ncnc21

Procedure:
In a similar manner to Example 10 b), 4-chloro-5-iodo-7-isopropylpyrrolo-[2,3-d]pyrimidine (0.57 g), was reacted with 4-nitrophenylboronic acid (0.30 g) using bis(triphenylphosphine)palladium (II) chloride (0.126 g) to give 4-chloro-7-isopropyl-5-(4-nitrophenyl)pyrrolo[2,3-d]pyrimidine which was reduced using a mixture of ammonium chloride (22 mg),iron powder (0.45 g) in water (2 ml) and industrial methylated spirit (10 ml) to give 4-chloro-5-(4-aminophenyl)-7-isopropylpyrrolo[2,3-d]pyrimidine which was reacted with ammonia in 1,4-dioxen in a sealed vessel to give 4-amino-5-(4-aminophenyl)-7-isopropyl-pyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13])[CH2:11][O:10]1.[NH:18]1[CH:22]=[N:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:12]([S:15][CH2:16][CH3:17])([F:14])[F:13]
Reactant: c1nc[nH]n1
Reactant: CCSC(F)(F)C1(c2ccc(F)cc2F)CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-2-[(ethylthio)(difluoro)methyl]oxirane (4.3 g, 0.016 mol) in DMSO (50 ml), 1,2,4-triazole (2.98 g, 0.043 mol) and potassium carbonate (5.96 g, 0.043 mol) were added, followed by stirring at 60° C. for 2 hours. After the completion of the reaction, water was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated saline and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure. The residue so obtained was crystallized from isopropyl ether-ethyl acetate, whereby 2-(2,4-difluorophenyl)-1-(ethylthio)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)-2-propanol (1.5 g, yield: 25%) was obtained as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1Br.[F:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([OH:42])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([S:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:38]1[CH:39]=[C:40]([OH:42])[CH:41]=[C:36]([F:35])[CH:37]=1
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: C[C@H](Nc1ncnc(N)c1Br)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: C[C@H](Nc1ncnc(N)c1-c1cc(O)cc(F)c1)c1nn2ccc(Sc3ccccc3)c2c(=O)n1-c1ccccc1
Yield: 2.4 %

Procedure:
(S)-2-(1-((6-Amino-5-bromopyrimidin-4-yl)amino)ethyl)-3-phenyl-5-(phenylthio)pyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (230 mg, 0.29 mmol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (68 mg, 0.44 mmol), sodium carbonate (2M, 660 μl, 1.32 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (36 mg, 0.04 mmol) according to the method described in Example 3 to give 4 mg (3% yield) of the title compound as a solid. Purity 91%.
Reaction SMILES: Br[CH:2]([F:16])[CH2:3][CH:4]([N+:13]([O-:15])=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1>[OH:17][C:18]1([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=2)[CH2:23][CH2:22][N:21]([CH:2]([F:16])[CH2:3][CH:4]([N+:13]([O-:15])=[O:14])[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:20][CH2:19]1
Reactant: O=C(c1ccccc1)C(CC(F)Br)[N+](=O)[O-]
Reactant: OC1(c2cccc(C(F)(F)F)c2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)C(CC(F)N1CCC(O)(c2cccc(C(F)(F)F)c2)CC1)[N+](=O)[O-]
Yield: 48.6 %

Procedure:
A mixture of 9.4 g of γ-bromo-4-fluoro-2-nitrobutyrophenone, 7.1 g of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 4.0 of potassium carbonate, a catalytic amount of potassium iodide and 60 ml of toluene was stirred at room temperature for 10 hours. The resulting mixture was diluted with water and extracted with toluene-ethyl acetate (1:1), and the organic layer was extracted with cold 30% hydrochloric acid. The hydrochloric acid layer was washed with toluene, made alkaline with 20% aqueous sodium hydroxide solution under cooling and extracted with ethyl acetate. The extracts were washed with water, dried over anhydrous sodium sulfate and concentrated to yield 6.4 g of γ-[4-hydroxy-4-(3-trifluoromethylphenyl)piperidino]-4-fluoro-2-nitrobutyrophenone as a residual oil, which was converted into its hydrochloride by a conventional manner. M.P. 200°-209° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.[N+:14]([CH3:17])([O-:16])=[O:15].C([O-])(=O)C.[NH4+]>C(O)(=O)C.O>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:17][N+:14]([O-:16])=[O:15])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])C=Cc1ccc(OC(F)(F)F)cc1
Temperature: 150 °C
Yield: 100.3 %

Procedure:
A solution of 4-trifluoromethoxy benzaldehyde (1 g, 5.26 mmol) and nitromethane (0.96 g, 15.8 mmol) in acetic acid (10.6 mL) is treated with ammonium acetate (1.01 g, 13.2 mmol) is heated under microwave to 150° C. for 15 minutes. The reaction mixture is diluted with water, and extracted three times with DCM (50 mL). The combined extracts are washed sequentially with 2 N sodium hydroxide, water, and brine, dried over sodium sulfate and concentrated. The residue is subjected to silica gel chromatography to yield 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (1.23 g) as a solid. A portion of 4-trifluoromethoxy-(2-nitro-vinyl)-benzene (0.504 g, 2.16 mmol) is hydrogenated with hydrogen in a balloon, 10% Pd/C (115 mg, 5 mol %) in MeOH (22 mL) containing concentrated hydrochloric acid (0.27 mL) at room temperature for 15 hours. The mixture is filtered and filtrate is concentrated to a solid that is washed with diethyl ether to obtain 2-(4-trifluoromethoxy-phenyl)-ethylamine hydrochloride [0.3 g, 57%, Intermediate (12)] as a solid. LC/MS: MS: 206 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)c1ccc(O)c(Br)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1ccc(S(C)(=O)=O)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
To a solution of 2-bromo-4-(methylsulfonyl)phenol (3.2 g, 12.7 mmol) in DMF (35 mL) at 0° C. was added K2CO3 (5.3 g, 38.1 mmol). The reaction was stirred at 0° C. for 0.5 h and to this cold solution was slowly added CH3I (2.7 g, 19.1 mmol) drop wise. The reaction was stirred at r.t. overnight. After the reaction was completed, 80 mL of ice-water was added. The mixture was extracted with EA (60 mL×3). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and evaporation of the solvent, the obtained residue was purified on column chromatography (silica gel, ethyl acetate/petroleum ether=1:4) to give 2-bromo-1-methoxy-4-(methylsulfonyl)benzene (2.12 g, 63.0%) as yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[C:6]([Cl:12])[CH:5]=1)=[O:3].[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([N:11]=[C:13]=[O:14])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:1]
Reactant: CC(=O)c1cc(Cl)c(N)c(Cl)c1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(N=C=O)c(Cl)c1

Procedure:
A mixture of 5 g. of 4-amino-3,5-dichloroacetophenone, 5 ml. of phosgene, and 30 ml. of toluene was heated to 150° C. for 24 hours at a sealed tube. The reaction mixture obtained was cooled and concentrated under a reduced pressure to provide crude 4-acetyl-2,6-dichlorophenyl isocyanate. The crude product was dissolved in 100 ml. of toluene and after adding 10 g. of cyclohexanol to the solution, the mixture was stirred overnight at 100° C. The reaction mixture was cooled and concentrated under reduced pressure. The residue formed was then recrystallized from a mixture of benzene and n-hexane to provide 4.3 g. of 3,5-dichloro-4-cyclohexyloxycarbonylaminoacetophenone having a melting point of 88°-89° C.
Reaction SMILES: P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:2].[NH2:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=O.O>O1CCCC1>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:16](=[S:2])[NH2:15]
Reactant: NC(=O)c1ccccn1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: O
Solvent: C1CCOC1
Product: NC(=S)c1ccccn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 74.8 %

Procedure:
43 g of phosphorus pentasulfide were added slowly to 46.8 g of the amide of Stage A in 700 ml of tetrahydrofuran and the mixture was stirred for 4 hours at ambient temperature. The reaction mixture was poured into water and extracted with ether. The extracts were dried and the solvent was evaporated under reduced pressure. After chromatography on silica (eluant: CH2Cl2 --AcOEt 8-2), 10 g of expected product melting at 137° C. were obtained.