Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Clc1ccccc1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1ccccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: N1C(C)=CC=CC=1C.C(Cl)Cl.[OH:12][C:13]([CH3:26])([CH3:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].FC(F)(F)S(O[Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])(=O)=O>C(OCC)(=O)C>[Si:33]([O:12][C:13]([CH3:26])([CH3:25])[CH2:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(O)CC(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(CC(=O)OCc1ccccc1)O[Si](C)(C)C(C)(C)C
Reaction time: 2 h

Procedure:
2,6-Lutidine (3.6g) was added to an anhydrous methylene chloride solution of benzyl 3-hydroxy-3-methylbutyrate (3.5g) obtained in the step 1, and stirred with cooling with ice. t-butyldimethylsilyl trifluoromethanesulfonate (3.9mL) was gradually added dropwise thereto, and stirred for 1hour with cooling on ice and then for 2hours at room temperature. The reaction liquid was diluted with ethyl acetate, then washed with water, aqueous saturated ammonium chloride solution and aqueous saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. 4.5g of the residue was purified through silica gel column chromatography to give benzyl 3-(t-butyldimethylsilyloxy)-3-methylbutyrate (2.62g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH2:6][NH:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:2].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.[CH3:32][N:33]([CH2:41][CH2:42][CH2:43][NH:44][CH3:45])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:36]([O:35][C:34]([N:33]([CH3:32])[CH2:41][CH2:42][CH2:43][N:44]([CH3:45])[C:12]([C:11]1[CH:10]=[CH:9][C:8]([NH:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])=[CH:16][CH:15]=1)=[O:14])=[O:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: CCOC(=O)CCNc1ccc(C(=O)O)cc1
Reactant: CNCCCN(C)C(=O)OC(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)CCNc1ccc(C(=O)N(C)CCCN(C)C(=O)OC(C)(C)C)cc1
Reaction time: 0.25 h
Yield: 89 %

Procedure:
4-[(3-Ethoxy-3-oxopropyl)amino]benzoic acid (200 mg, 0.84 mmol) (U.S. Pat. No. 5,977,101 A1) was dissolved in methylene chloride (6 mL), triethylamine (0.14 mL, 1.01 mmol) and pivaloyl chloride (0.10 mL, 0.84 mmol) were added under ice cooling, and the mixture was stirred at the same temperature under a nitrogen atmosphere for 15 minutes. Subsequently, a solution of tert-butyl methyl[3-(methylamino)propyl]carbamate (179 mg, 0.89 mmol) in methylene chloride (2 mL) was added under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 16 hours. After the reaction was completed, a saturated aqueous sodium hydrogencarbonate solution was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by NH silica gel column chromatography (hexane:ethyl acetate, 1:9, v/v) to give the title compound (315 mg; yield, 89%) as a light yellow oily substance.
Reaction SMILES: Cl.Cl.[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1.[CH2:27]([S:29](Cl)(=[O:31])=[O:30])[CH3:28]>>[O:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:29]([CH2:27][CH3:28])(=[O:31])=[O:30])[CH2:24][CH2:25]4)[CH2:14][CH2:13]3)[C:6]=2[CH2:5][CH2:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Product: CCS(=O)(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3CCO4)CC2)CC1

Procedure:
The title compound, white solid (41 mg, 39%), MS (ISP) m/z=421.2 [(M+H)+], mp 131° C., was prepared in accordance with the general method of example 47 from trans-4-{2-[4-(2,3-dihydro-benzofuran-4-yl)-piperidin-1-yl]-ethyl}-cyclohexylamine dihydrochloride (intermediate B) (100 mg, 0.25 mmol) and ethanesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:54]([CH3:56])[CH3:55])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]1[NH:18][C:17]2[C:19]3[C:24]([CH:25]=[CH:26][C:16]=2[N:15]=1)=[CH:23][C:22]([C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[CH:33]=[C:32]([C:37]1[NH:41][C:40]([C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[C:47]([O:49]C(C)(C)C)=O)=[N:39][CH:38]=1)[CH:31]=[CH:30]2)=[CH:21][CH:20]=3)=[O:8])=[O:4].Cl.[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)C(O)=O)=[O:61].CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[CH3:58][O:59][C:60]([NH:62][C@H:63]([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)[C:47]([N:43]1[CH2:44][CH2:45][CH2:46][C@H:42]1[C:40]1[NH:41][C:37]([C:32]2[CH:33]=[C:34]3[C:29](=[CH:30][CH:31]=2)[CH:28]=[C:27]([C:22]2[CH:23]=[C:24]4[C:19](=[CH:20][CH:21]=2)[C:17]2[NH:18][C:14]([C@@H:10]5[CH2:11][CH2:12][CH2:13][N:9]5[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:54]([CH3:55])[CH3:56])=[N:15][C:16]=2[CH:26]=[CH:25]4)[CH:36]=[CH:35]3)=[CH:38][N:39]=1)=[O:49])=[O:61]
Reactant: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)C(C)C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
(S)-tert-butyl 2-(5-(6-(2-((S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2-d]imidazol-7-yl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (88 mg, 0.116 mmol) was dissolved in DCM (5 mL) and HCl (4M in dioxane, 1 mL) was added. After stirring for 1 h, the reaction mixture was concentrated and the residue was treated with (R)-2-(methoxycarbonylamino)-2-phenylacetic acid (24 mg, 0.116 mmol), COMU (50 mg, 0.116 mmol) and DMF (3 mL). DIPEA (0.101 mL, 0.58 mmol) was added and the mixture was stirred for 13 min before being quenched with H2O and purified by HPLC to afford the title compound (61 mg, 62%). MS: (ESI) m/z 847 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[CH:14][NH:13][N:12]=1.[C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[CH:17]([CH3:19])[CH3:18].C(=O)([O-])O.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:16]([CH:17]([CH3:19])[CH3:18])[NH:10][C:11]2=[N:12][NH:13][CH:14]=[C:15]12
Reactant: CCOC(=O)CC(=O)C(C)C
Reactant: O=Cc1ccccc1Cl
Reactant: Nc1cc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(C(C)C)Nc2n[nH]cc2C1c1ccccc1Cl
Yield: 3.3 %

Procedure:
2-Chlorobenzaldehyde (1.41 g), 3-aminopyrazole (0.83 g) and ethyl isobutyrylacetate (1.58 g) were stirred in acetic acid (10 ml) at 80° C. for 2 hours. Under ice-cooling, a saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture. The insoluble material was filtered off, and the mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The extract was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (1:1)). The purified product was crystallized from hexane-ethyl acetate to give the title compound (115 mg) as white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:27])[CH:8]=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2].C1C(=O)N([Br:35])C(=O)C1.O>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:27])[C:8]([Br:35])=[C:9]([C:25]#[N:26])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)cn1C
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1c(-c2ccc(OCc3ccccc3)cc2)c(C#N)c(Br)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
A solution of 3-(4-benzyloxy-phenyl)-4-cyano-1-methyl-1H-pyrrole-2-carboxylic acid ethyl ester. (184.73 g, 0.512 mol, prepared in example E-6a or E-6b) in anhydrous THF (2,000 mL) is treated with NBS (109.47 g, 0.615 mol). The resulting reaction mixture is allowed to stir at room temperature overnight. The reaction mixture is poured into water (2,000 mL). The resulting solution is divided into 2 equal parts, and each is extracted with EtOAc (3×800 mL each). The combined organics are dried over anhydrous MgSO4, filtered, then concentrated in vacuo to afford a yellow solid. The yellow solid is purified by column chromatography (silica gel, EtOAc/Hexanes 1/3) to afford the title compound (133.99 g, ˜60% yield) as a white solid: 1H NMR (500 MHz; CDCl3) δ 7.46-7.44 (m, 2H), 7.41-7.38 (m, 2H), 7.36-7.32 (m, 1H), 7.29-7.26 (m, 2H), 7.01-6.99 (m, 2H), 5.10 (s, 2H), 4.11 (q, 2H), 3.98 (s, 3H), 1.02 (t, 31); MS(ES): m/z 438.9.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20]O)[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Br)([Br:39])=O>ClCCl>[CH2:1]([N:8]1[C:12]2[C:13](=[O:24])[N:14]([CH2:22][CH3:23])[C:15]3[N:16]([N:17]=[C:18]([CH2:20][Br:39])[N:19]=3)[C:11]=2[N:10]=[C:9]1[CH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Br)Br
Reactant: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CO)nc12
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1c(=O)c2c(nc(C3CCCC3)n2Cc2ccccc2)n2nc(CBr)nc12

Procedure:
0.6 g of 6-benzyl-7-cyclopentyl-4-ethyl-2-hydroxymethyl-imidazo[4,5-e]-s-triazolo[1,5-a]pyrimidin-5-one are taken up in 7 ml of dichloromethane and 0.25 ml of triethylamine are added at ambient temperature with stirring. Then 0.15 ml of thionyl bromide are added. After 2 hours' stirring at constant temperature the reaction is complete. For working up, the mixture is diluted with 20 ml of dichloromethane and washed successively with 15 ml of water and 15 ml of aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and the solvent is distilled off in vacuo. The residue remaining is recrystallised from diethyl ether. 0.45 g of the title compound remain, pure enough to be used in the subsequent reactions.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:34][C:35]([OH:39])([CH3:38])[CH2:36]O.CN(C=O)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH2:34][C:35]([CH3:38])([OH:39])[CH3:36])=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(O)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)O
Temperature: 10 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
N-Benzyloxycarbonyl-L-valine (2.02 g, 8.0 mmol), 4-dimethylaminopyridine (100 mg, 0.8 mmol), and), and dicyclohexylcarbodiimide (2.04 g, 9.9 mmol, in 20 mL CH2Cl2) were added to 2-methyl-1,2-propanediol (12.2 mmol) in 30 mL dry CH2Cl2, with cooling in an ice bath. DMF (5 mL) was added. After stirring for 5 h at 10° C., the reaction mixture was filtered, concentrated, and then redissolved in ethyl acetate. The organic solution was washed with saturated NaCl, dried over anhydrous Na2SO4, and concentrated. Flash column chromatography (silica, 2/1 petroleum ether-ethyl acetate) gave 2.3 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([OH:30])=O)[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:64]([CH2:66][NH2:67])[OH:65]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[CH:24]=[C:25]([C:28]([NH:67][CH2:66][CH2:64][OH:65])=[O:30])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: O=C(O)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1ccc2c(c1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Reaction time: 8 h

Procedure:
A mixture of 2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene-9-carboxylic acid (53 mg), HATU (61 mg) and diisopropylethylamine (0.028 mL) and ethanolamine was stirred in N,N-dimethylformamide (3 ml). The reaction mixture was stirred overnight, and then diluted with ethyl acetate, washed with water, dried (MgSO4) and the solvent removed in vacuo. Purification using flash chromatography yielded 398 (24 mg). NMR: (CDCl3): 2.30 (1H, t, br.), 3.05 (2H, t), 3.51-3.55 (2H, m), 3.7-3.75 (2H, m), 4.31 (2H, t), 6.40 (1H, br.), 6.80 (1H, s), 6.99 (1H, d), 7.05-7.12 (2H, m), 7.42-7.52 (2H, m), 7.90 (1H, s), 8.01 (1H, s). MS. ESI+510 (MH++MeCN)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[CH:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH:28]=[N:27][NH:26][C:25]2=[O:29])=[CH:20][CH:19]=1)([CH3:17])[CH3:16].FC1C=C(F)C=CC=1[C@]1([C@H](O)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:26]1[C:25](=[O:29])[N:24]([C:21]2[CH:22]=[CH:23][C:18]([CH:15]([CH3:17])[CH3:16])=[CH:19][CH:20]=2)[CH:28]=[N:27]1)[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: CC(C)c1ccc(-n2cn[nH]c2=O)cc1
Agent: C[C@@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: CC(C)c1ccc(-n2cnn([C@H](C)[C@@]3(c4ccc(F)cc4F)CO3)c2=O)cc1
Yield: 27.9 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.72 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.68 g of 4-(4-isopropylphenyl)-3(2H,4H)-1,2,4-triazolone, an about 1:1 mixture (0.89 g) of 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]- 4-(4-isopropylphenyl)-3 (2H, 4H)-1,2,4-triazolone and (1R)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@:12]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)([NH2:20])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][C:30]=1[C:37]([F:40])([F:39])[F:38].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[F:28][C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:20][C@@:12]([C:4]2[CH:5]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:7]=[C:2]([F:1])[CH:3]=2)([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:31][C:30]=1[C:37]([F:38])([F:39])[F:40]
Reactant: N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(C(F)(F)F)c1
Reactant: O=Cc1ccc(F)c(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: Fc1ccc([C@@](Cc2ccccc2)(NCc2ccc(F)c(C(F)(F)F)c2)c2cc(F)cc(C(F)(F)F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
(R)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine (21.5 mg, 0.057 mmol) in dichloroethane (0.5 mL) in a two drum vial was added 4-fluoro-3-(trifluoromethyl)benzaldehyde (21.9 mg, 0.114 mmol) followed by a drop of acetic acid. The reaction mixture was shaken for 20 minutes at room temperature before NaBH(OAc)3 (36.3 mg, 0.171 mmol) was added. The reaction was stirred at room temperature overnight. The solvents were removed and the residue was purified by preparative HPLC (phenominex C18 column, 21×100 mm, 5μ) using MeOH/H2O (with 0.1% TFA) to give (R)—N-(4-fluoro-3-(trifluoromethyl)benzyl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(4-fluorophenyl)-2-phenylethanamine as a colorless oil (17.5 mg, 46% yield). LCMS: 4.32 min (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.78-3.91 (m, 4H), 6.60 (d, J=7.47 Hz, 2H), 7.14-7.27 (m, 7H), 7.35-7.48 (m, 6H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:35][NH:36][CH2:37][C:38]([OH:40])=[O:39]>>[F:34][C:2]([F:33])([F:1])[C:3]1[CH:28]=[C:27]([C:29]([F:31])([F:32])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:36]([CH2:37][C:38]([OH:40])=[O:39])[CH3:35])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: CNCC(=O)O
Product: CN(CC(=O)O)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1

Procedure:
({5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-methyl-amino)-acetic acid I was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and N-Methyl Glycine following General Procedure C.
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[CH:29]=[CH:30][C:31]([O:50][CH3:51])=[C:32]([CH:49]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:27][C:28]2[CH:29]=[CH:30][C:31]([O:50][CH3:51])=[C:32]([O:33][C:34]3[CH:35]=[CH:36][C:37]4[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]5[CH2:48][CH2:47]5)=[O:45])[N:42]=4)[N:39]=3)[CH:49]=2)=[O:12])[CH2:4][CH2:5][CH2:6]1)#[N:2]
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2cccc(C3(C#N)CCC3)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 72.3 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (43 mg, 0.21 mmol), oxalyl chloride (23 μL, 0.27 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (2.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (60 mg, 0.18 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (68 mg, 74%) was obtained as a white powder.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[CH:28](=[O:33])[CH2:29][CH:30]([CH3:32])[CH3:31]>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[C:16]([CH:28]([OH:33])[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccccc2)on1
Agent: [Li]CCCC
Product: CC(C)CC(O)c1c(OCCNC(=O)OC(C)(C)C)noc1-c1ccccc1
Yield: 77 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-phenylisoxazole (0.2 g), butyllithium (1.6M hexane solution, 0.9 ml) and isovaleraldehyde (0.09 ml) were subjected to reaction and post-treatment in a similar manner to that described in Example 44(a) to obtain the title compound (0.2 g, 77%) as a colorless oil.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([CH2:21][N:22]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[C:23]3=[O:26])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1.N[C:37]1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.CC1C=CC=CC=1N=C=S>>[CH3:33][CH:32]([CH3:34])[C@H:27]([N:22]1[CH2:21][C:20]2[C:24](=[CH:25][C:17]([C:14]3[CH:15]=[CH:16][C:11]([NH:10][C:9]([NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:37])=[S:35])=[CH:12][CH:13]=3)=[CH:18][CH:19]=2)[C:23]1=[O:26])[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)cc2C1=O
Agent: Cc1ccccc1N=C=S
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=S)Nc4ccccc4C)cc3)cc2C1=O

Procedure:
The compound of example 71 was prepared analogous to compound of example 51 by reaction of compound of example 6 with 2-methyl phenyl isothiocyanate. The compound of example 71 was used directly without isolation for the preparation of compound of example 72.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].C(Cl)Cl.C(N(CC)CC)C.[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([C:27](Cl)=[O:28])=[CH:23][CH:22]=1>O>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=1)=[O:28])(=[O:9])[NH2:10]
Reactant: NC(=O)c1ccccc1N
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(C(=O)Nc2ccccc2C(N)=O)cc1
Yield: 88.2 %

Procedure:
To a well stirred mixture of anthranilamide (34.05 g; 0.25 mol), methylene chloride (650 ml) and triethylamine (~30 ml) is added p-toluoyl chloride (33 ml; 0.25 mol) dropwise over 25 minutes (a slight exotherm is noted). On completion of the addition, the reaction mixture is stirred for one hour, diluted with water (1000 ml). The mixture is stirred vigorously, filtered, the product washed with water and dried to afford 56.08 g solid, mp 206°-208° C.