Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[S:6][C:7]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:8]=2[N:9]=1.[CH2:15]([N:17]=[C:18]=[O:19])[CH3:16]>C(O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:7]2[S:6][C:5]([S:4][CH2:3][CH2:2][NH:1][C:18]([NH:17][CH2:15][CH3:16])=[O:19])=[N:9][C:8]=2[CH:10]=1
Reactant: CCN=C=O
Reactant: NCCSc1nc2cc(Cl)ccc2s1
Solvent: CCO
Product: CCNC(=O)NCCSc1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 89 %

Procedure:
Dissolved in 10 ml of ethanol was 1.00 g (4.09 mmol) of 2-(2-aminoethylthio)-5-chlorobenzothiazole, and 0.36 ml (4.55 mmol) of ethyl isocyanate were added to the solution, which was stirred at room temperature for 15 minutes. The precipitated white crystals were then filtered out to obtain 1.15 g of the title compound (89% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>N1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH:12][C:16]([NH:15][CH2:13][CH3:14])=[O:17])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1
Reactant: CCN=C=O
Reactant: Nc1ccc2ncc(Cl)nc2n1
Solvent: c1ccncc1
Product: CCNC(=O)Nc1ccc2ncc(Cl)nc2n1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
100 mg of 3-chloropyrido[2,3-b]pyrazin-6-ylamine (0.55 mmol) were initially charged in 5 ml of pyridine and 44 μl of ethyl isocyanate (0.55 mmol) were added at room temperature. The mixture was left to stir at 75° C. for 3 h and then another 132 μl in total of ethyl isocyanate (1.65 mmol) were added to the reaction mixture is small portions over 18 h. The solvent was then removed under reduced pressure. The resulting solid was purified by means of column chromatography on silica gel (dichloromethane/methanol eluent). This gave a bright yellow solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[CH:3]=[CH:2]1.[C:13]([NH:16][NH2:17])(=[O:15])[CH3:14]>>[C:13]([NH:16][NH:17][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[CH:3][C:4]=2[CH:9]=1)=[O:12])(=[O:15])[CH3:14]
Reactant: O=C(O)c1ccc2occc2c1
Reactant: CC(=O)NN
Product: CC(=O)NNC(=O)c1ccc2occc2c1
Yield: 85 %

Procedure:
In the same manner as in Reference Example 5 and using 1-benzofuran-5-carboxylic acid instead of benzothiazole-6-carboxylic acid and acetohydrazide instead of 3-[3-(trifluoromethyl)phenyl]propanohydrazide, the title compound (yield 85%) was obtained as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH2:4][NH2:5].CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.[C:30](Cl)(Cl)=[O:31].C1(C)C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:3]=1[CH2:4][N:5]=[C:30]=[O:31]
Reactant: O=C(Cl)Cl
Reactant: NCc1cc(C(F)(F)F)ccc1F
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C=NCc1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a methylene chloride solution of commercially available 2-fluoro-5-trifluoromethyl benzyl amine(5.23 mmol) at 0° C. was added solid Proton sponge (5.23 mmol) then a 20% solution of phosgene in toluene (5.23 mmol). The solution was stirred at 25° C. for 1 hour and then washed with 1N HCl (40 mL). The methylene chloride was then dried with sodium sulfate and evaporated to provide the title compound. 1H-NMR (CDCl3): 7.7 ppm (t, 1H); 7.60 ppm (m, 1H); 7.2 ppm (m, 1H); 4.64 ppm (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C[Si]([C:17]#[N:18])(C)C>[I-].[Zn+2].[I-]>[OH:10][CH:9]([C:8]1[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:12][CH:11]=1)[C:17]#[N:18]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)Cc1ccc(C=O)cc1
Agent: [I-]
Agent: [Zn+2]
Product: CC(C)Cc1ccc(C(O)C#N)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 107.5 %

Procedure:
Zinc iodide (0.21 g) was added to a mixture of 4-isobutylbenzaldehyde (6.5 g) and trimethylsilylcyanide (5.0 g). The mixture was stirred at room temperature for 3 minutes and partitioned between ethyl acetate and 7% hydrochloric acid. The organic layer was washed with 7% hydrochloric acid and water and dried over magnesium sulfate. The solvent was removed in vacuo to give 2-hydroxy-2-(4-isobutylphenyl)acetonitrile as a yellow oil (8.15 g).
Reaction SMILES: [C:1](=[O:12])([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])OC(C)(C)C.[NH2:13][C@@H:14]([CH3:17])[CH2:15][OH:16].CC(C)(N)CN>O.C(O)(C)(C)C>[C:8]([O:7][C:1]([NH:13][C@@H:14]([CH3:17])[CH2:15][OH:16])=[O:12])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: C[C@H](N)CO
Agent: CC(C)(N)CN
Solvent: CC(C)(C)O
Solvent: O
Product: C[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 16 h

Procedure:
Di-t-butyl carbonate (15.7 g.) was added to a solution of (+-(S)-2-amino-1-propanol (5.0 g.) in water (13.2 ml.) and t-butanol (6.6 ml.) at ambient temperature, and the mixture was stirred for 16 hr. at ambient temperature, 1,1-Dimethylethylenediamine (2 ml.) was added and the mixture was stirred at ambient temperature for 1 hr. The solution was poured into water (200 ml.) and extracted with diethyl ether (3×100 ml.). The ethereal extract was washed successively with 1 M-hydrochloric acid (50 ml.), saturated sodium carbonate solution (50 ml.) and brine (100 ml.), and then dried (MgSO4). The solvent was evaporated to give (S)-2-t-butoxycarbonylamino-1-propanol, m.p. 42°-3°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[CH3:18][C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:21][N:20]=1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:28]2[CH2:29][CH2:30][N:25]([C:23]3[CH:22]=[CH:21][N:20]=[C:19]([CH3:18])[N:24]=3)[CH2:26][CH2:27]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: Cc1nccc(N2CCNCC2)n1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1nccc(N2CCN(CC3CCN(C(=O)OC(C)(C)C)CC3)CC2)n1
Yield: 24.1 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(formyl)piperidine (7.14 g) and 1-(2-methylpyrimidin-4-yl)piperazine dihydrochloride (8.38 g) in methanol/acetic acid (99:1) (150 ml) was added sodium cyanoborohydride (6.32 g) portionwise over 30 minutes and the resultant suspension stirred at arnbient temperature for 3 hours. The suspension was quenched by addition of saturated aqueous sodium bicarbonate solution and the resulting mixture extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography eluting with 5% methanol in dichloromethane to give 1-tert-butoxycarbonyl-4-[1-(2-methylpyrimidin-4-yl)piperazin-4-ylmethyl]piperidine (3.02 g) as a foam.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[CH:16]1([CH2:21]O)[CH2:20][CH2:19][CH2:18][CH2:17]1.N1C=CC=CC=1>C(Cl)Cl>[CH:16]1([CH2:21][O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCC1CCCC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCC1CCCC1)C(F)(F)F
Temperature: -40 °C
Reaction time: 0.75 h

Procedure:
Trifluoromethanesulfonic anhydride (6.72 mL, 39.94 mmol) is dissolved in DCM (40 mL) and cooled to −40° C. To this is added dropwise cyclopentanemethanol (4.00 g, 39.94 mmol) dissolved in DCM (10 mL) and anhydrous pyridine (3.23 mL, 39.94 mmol). The reaction is stirred at −40° C. for 45 min. The reaction is diluted with hexanes (30 mL) and run through a plug of silica using hexanes (300 mL) as the eluent. Concentration without heating gives trifluoromethanesulfonic acid cyclopentylmethyl ester as a clear, colorless oil that is used immediately.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([C:17]1[N:18]=[CH:19][N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:21]=1)([OH:16])[CH:13]([CH3:15])[CH3:14])[CH:6]=[CH:5]2.Br[CH2:42][CH2:43][CH3:44]>>[NH:20]1[CH:21]=[C:17]([C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][CH2:42][CH2:43][CH3:44])[CH:3]=3)[CH:8]=2)([OH:16])[CH:13]([CH3:14])[CH3:15])[N:18]=[CH:19]1
Reactant: CCCBr
Reactant: CC(C)C(O)(c1ccc2cc(O)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: CCCOc1ccc2cc(C(O)(c3c[nH]cn3)C(C)C)ccc2c1

Procedure:
In a similar manner to that described in Example 31-(i), the reaction of 1-(6-hydroxynaphthalen-2-yl)-2-methyl-1-(1-trityl-1H-imidazol-4-yl)-1-propanol (1.265 g) with 1-bromopropane (0.24 ml) was carried out to give the titled compound (0.711 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[O:8])=[C:5]([NH2:18])[NH:4][N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:25](OC)(=[O:28])[C:26]#[CH:27]>CCO>[NH2:18][C:5]1[C:6]([C:7]([NH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[O:8])=[C:2]2[NH:1][C:25](=[O:28])[CH:26]=[CH:27][N:3]2[N:4]=1
Reactant: COc1ccncc1NC(=O)c1c(N)n[nH]c1N
Reactant: C#CC(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: COc1ccncc1NC(=O)c1c(N)nn2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27 %

Procedure:
To a mixture of 3,5-diamino-N-(4-methoxy-3-pyridyl)-1H-pyrazole-4-carboxamide 9 (300 mg, 1.209 mmol) and Cs2CO3 (591 mg, 1.814 mmol) in EtOH (5 mL) was added methyl prop-2-ynoate (203.3 mg, 215.1 μL, 2.418 mmol), dropwise, over 15 minutes and the reaction mixture was stirred overnight at room temperature. The mixture was filtered and product purified by preparative HPLC. Solvents were evaporated in vacuum to afford the product as a yellow solid (yield 27%). LC-MS (M+H)+=301.1; 1H NMR (500 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.58 (s, 1H), 8.71 (d, 1H), 8.58 (d, 1H), 7.68 (d, 1H), 6.45 (d, 1H), 6.38-6.28 (m, 2H), 4.25 (s, 3H);
Reaction SMILES: [CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13](B(O)O)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1.C(N(CC)CC)C>C(O)C.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>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]3[O:14][C:13]([C:20]4[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=4)=[CH:12][C:11]=3[CH:18]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cc2cc(C3CCCCC3)ccc2o1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2cc3cc(C4CCCCC4)ccc3o2)cc1
Yield: 50.2 %

Procedure:
A mixture of 5-cyclohexylbenzofuran-2-ylboronic acid (75 mg, 0.37 mmol), 4-bromobenzaldehyde (62 mg, 0.34 mmol), triethylamine (1.1 mL, 7.5 mmol) and bis(triphenylphosphine)palladium(II)chloride (13 mg, 0.05 mmol) in ethanol (11 mL) was irradiated in a microwave instrument at 100° C. for 20 min. The reaction mixture was cooled, and the solvent was removed. The residue was purification by silica gel chromatography on ISCO system gave the title compound (52 mg, 46% yield): >95% purity by LCMS, ESI-MS: 305.2 M+H+). 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 8.00 (d, 2H), 7.95 (d, 2H), 7.46 (d, 2H), 7.19 (d, 1H), 7.16 (s, 1H), 2.63-2.58 (m, 1H), 1.94-1.76 (m, 4H), 1.53-1.42 (m, 4H), 1.38-1.25 (m, 2H). MS (ESI) m/z: Calculated: 304.38; Observed: 305.2 (M++1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[CH2:11][C:12]#[N:13])=[CH:2]1.O.[NH2:16][NH2:17]>CCO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH:11]=[C:12]([NH2:13])[NH:16][N:17]=2)=[CH:2]1
Reactant: NN
Reactant: N#CCC(=O)c1c[nH]c2ccccc12
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2c[nH]c3ccccc23)n[nH]1
Temperature: 25 °C
Yield: 43.6 %

Procedure:
To a solution of 3-(1H-indol-3-yl)-3-oxo-propionitrile (6.4 g, 34.7 mmol, 1.0 eq), in absolute EtOH (40 mL), hydrazine monohydrate (5.0 mL, 104.1 mmol, 3.0 eq) was added and the reaction was heated at reflux for 24 hours. The reaction mixture was allowed to cool to room temperature; the solid was filtered and washed with Et2O/EtOAc 10/1 to give 3.0 g of title product (yield 74%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=O)[N:13]=1.[NH:19]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[NH2:20]>CN(C)C=O.C(O)(=O)CC>[CH:16]1[CH:17]=[CH:18][C:10]([OH:9])=[C:11]([C:12]2[N:13]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[OH:1])[N:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=3)[N:20]=2)[CH:15]=1
Reactant: O=c1nc(-c2ccccc2O)oc2ccccc12
Reactant: NNc1ccc(C(=O)O)cc1
Solvent: CCC(=O)O
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-n2nc(-c3ccccc3O)nc2-c2ccccc2O)cc1
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 80.7 %

Procedure:
A suspension of 0.7 g (2.92 mmol) of 2-(2-hydroxyphenyl)benz[e][1,3]oxazin-4-one and 0.52 g (3.44 mmol) of 4-hydrazinobenzoic acid in 5 ml of N,N-dimethylformamide and 5 ml of propionic acid is heated up to 150° C. The mixture is maintained at this temperature and stirred for 1.5 hours. After completion of the reaction, the mixture is cooled and poured onto crushed ice. The resulting crystals are aspirated and washed with water. After drying, 0.88 g of raw deferasirox is obtained, i.e. 81% of the theory, with an HPLC purity of 93% and a melting temperature of 255 to 262° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([N+:18]([O-:20])=[O:19])=[C:13]([N:15]=[C:16]=[O:17])[CH:14]=2)[CH:5]=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:16](=[O:17])[NH:15][C:13]1[CH:14]=[C:9]([O:8][C:6]2[CH:5]=[CH:4][C:3]([C:21]([F:22])([F:23])[F:24])=[C:2]([Cl:1])[CH:7]=2)[CH:10]=[CH:11][C:12]=1[N+:18]([O-:20])=[O:19])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C=Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)Nc1cc(Oc2ccc(C(F)(F)F)c(Cl)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A solution of 5-[(2-chloro-α,α,α-trifluoro-p-tolyl)oxy]-2-nitrophenyl isocyanate (107 g, 0.299 mol) in methylene chloride is cooled to 0° C., treated with a mixture of glycine ethyl ester hydrochloride (50.1 g, 0.359 mol) and triethylamine (166 mL, 1.20 mol) in methylene chloride over 10 minutes, refluxed overnight, cooled to room temperature, washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. A solution of the solid in methylene chloride is placed on a silica gel plug, eluted with methylene chloride and concentrated in vacuo to give the title product as a yellow solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[F:34])[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:29][C:28]3[CH:31]=[CH:32][C:33]([F:34])=[C:26]([F:25])[CH:27]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Product: Fc1ccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)cc1F
Yield: 6.6 %

Procedure:
The title compound (0.005 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C; 0.07 g) using 3,4-difluorobenzyl bromide (0.06 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C20H18ClF2N3, 373.12; found, m/z 374.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 7.16-7.10 (m, 1H), 6.98-6.97 (m, 1H), 6.89-6.88 (m, 1H), 5.27 (s, 2H), 3.81 (s, 2H), 3.09-3.06 (m, 2H), 2.80-2.76 (m, 2H), 1.75-1.70 (m, 2H).
Reaction SMILES: [CH:1]1([C:6]2([CH3:19])[CH2:14][C:13]3[C:8](=[C:9]([Cl:17])[C:10]([Cl:16])=[C:11]([OH:15])[CH:12]=3)[C:7]2=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25](=[O:28])[CH2:26]Br)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].O=C1C2C(=CC(OCC(OC(C)(C)C)=O)=C(Cl)C=2Cl)CC1C1CCCC1>O.CN(C)C=O>[O:18]=[C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:15][CH2:26][C:25]([O:24][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:28])=[C:10]([Cl:16])[C:9]=2[Cl:17])[CH2:14][C:6]1([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[CH3:19]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Agent: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C1CCCC1)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Reaction time: 1 h

Procedure:
A mixture of 2-cyclopentyl-2-methyl-5-hydroxy-6,7-dichloro-1-indanone (2.98 g., 0.01 mole), tert.-butylbromoacetate (2.15 g., 0.011 mole), potassium carbonate (2.76 g., 0.02 mole) and dimethylformamide (15 ml.) is stirred at 25° for 1 hour then poured into water (50 ml.) the tert.-butyl (1-oxo-2-cyclopentyl-6,7-dichloro-5-indanyloxy)acetate which separates is filtered, rinsed with water and dried.
Reaction SMILES: O=[C:2]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1.[ClH:29].Cl.[NH2:31][CH2:32][CH2:33][O:34][NH2:35].N1C=CC=CC=1>C(O)C>[ClH:28].[ClH:29].[NH2:31][CH2:32][CH2:33][O:34][N:35]=[C:2]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1
Reactant: NCCON
Reactant: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 105.3 %

Procedure:
A mixture of 1-{1-[4-oxo-4-(4-chlorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2-benzimidazolone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.35 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. The solvent was evaporated, and the residue was taken up in hot 2-propanol and chilled. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 2.1 g (53%) of product, mp 140°-145° C. (dec).
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[F:32][C:33]([F:37])([F:36])[CH2:34][SH:35]>O>[F:32][C:33]([F:37])([F:36])[CH2:34][S:35][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1
Reactant: FC(F)(F)CS
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)CSc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 85.3 %

Procedure:
To a mixture of 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 0.50 g of potassium carbonate and 2 ml of DMF, 0.15 g of 2,2,2-trifluoroethanethiol was added. The reaction mixture was stirred at room temperature for 1.2 hours. Water was added to reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.32 g of 2-[3-(2,2,2-trifluoroethylthio)pyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 46”).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32](OC)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1.O>CCOCC>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:23]3[CH:24]=[C:25]4[C@:30]([C:32]([C:2]5[S:3][CH:4]=[CH:5][N:6]=5)=[O:33])([CH2:31][C:22]=3[CH:21]=[N:20]2)[CH2:29][N:28]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:27][CH2:26]4)=[CH:15][CH:14]=1
Reactant: Brc1nccs1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(C(=O)OC(C)(C)C)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(C(=O)c2nccs2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 87.5 %

Procedure:
2-Bromothiazole (0.643 mL, 7.14 mmol) in dry ether (7 mL) was added to n-butyllithium (2.5 M in Hexanes) (2.92 mL, 7.31 mmol) in dry ether (5 mL) at −78° C. The reaction mixture was stirred at −78° C. for 45 minutes. A solution of (R)-6-tert-butyl 4a-methyl 1-(4-fluorophenyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-4a,6(4H)-dicarboxylate (1.0 g, 2.339 mmol) in dry ether (15 mL) was added dropwise and the reaction mixture was stirred for 0.5 hour at −78° C. Water (60 mL) was added and the reaction mixture was stirred at room temperature for 10 minutes. The aqueous layer was extracted with dichloromethane (3×75 mL). The combined organic extracts were washed with brine (100 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil. The crude product was purified by column chromatography on silica gel (gradient: 0-40% ethyl acetate in isohexane) to afford (R)-tert-butyl 1-(4-fluorophenyl)-4a-(thiazole-2-carbonyl)-4a,5,7,8-tetrahydro-1H-pyrazolo[3,4-g]isoquinoline-6(4H)-carboxylate as an off-white solid (984 mg). LCMS (Method F, ES-API): RT 2.64 min, m+H=480.9; 1H NMR (400 MHz, CDCl3): δ 8.06 (1H, d, J=3.0 Hz), 7.64 (1H, s), 7.48-7.43 (2H, m), 7.31 (1H, s), 7.20-7.14 (2H, m), 6.55 (1H, s), 5.60 (1H, br s), 4.49 (1H, d, J=15.0 Hz), 4.21 (1H, br s), 3.28-3.25 (1H, m), 2.86-2.81 (3H, m), 2.49 (1H, d, J=14.5 Hz), 1.55 (9H, s).