Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([C:9]1[CH:21]=[C:20]([CH3:22])[C:12]([O:13][CH2:14][C:15]([O:17]CC)=O)=[C:11]([CH3:23])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:26]([NH:33][C:15](=[O:17])[CH2:14][O:13][C:12]1[C:11]([CH3:23])=[CH:10][C:9]([C:3]([OH:8])([C:2]([F:24])([F:25])[F:1])[C:4]([F:6])([F:5])[F:7])=[CH:21][C:20]=1[CH3:22])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)COc1c(C)cc(C(O)(C(F)(F)F)C(F)(F)F)cc1C
Reactant: NCc1ccccc1
Product: Cc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(=O)NCc1ccccc1
Temperature: 110 °C

Procedure:
Combine ethyl 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetate (7.0 g=19 mmol) and benzylamine (12.0 g=0.11 mmol). Heat 4 hours at 110° C., allow to cool, and partition between 1.0 N HCl and ether. Dry and concentrate the ether. Recrystallize from ether-hexane and obtain, as a white solid, m.p. 142°-144° C., N-benzyl-2-[4-(hexafluoro-2-hydroxy-2-propyl)-2,6-dimethylphenoxy]acetamide.
Reaction SMILES: Cl.[CH2:2]([N:20](C)[C:21]1[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH2:31](O)C>>[CH2:2]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([NH:27][CH3:31])=[CH:25][CH:26]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCO
Reactant: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CCCCCCCCCCCCCCCCCCNc1ccc(NC)cc1

Procedure:
100 ml 2N hydrochloric acid is added to a solution of which 60.6 g (0.15 mol) N, N-octadecylmethyl- p-nitroaniline is dissolved into 500 ml ethyl alcohol. 52.5 g (0.13 mol) N, N-octadecylmethyl-p-phenylenediamine is obtained after adding 48.8 g (0.75 mol) zinc dust to the solution and heat and reflux it for one hour.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[OH:14].[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@@:22]([NH:44][C:45](=O)[O:46]C2C=CC([N+]([O-])=O)=CC=2)([C:30]2[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][CH:21]=1>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C@@:22]([NH:44][C:45]([NH:8][C@@H:9]2[CH2:13][CH2:12][CH2:11][C@H:10]2[OH:14])=[O:46])([C:30]2[CH:35]=[C:34]([O:36][C:37]([F:42])([F:41])[CH:38]([F:40])[F:39])[CH:33]=[C:32]([F:43])[CH:31]=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:20][CH:21]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: O=C(N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(N[C@@H]1CCC[C@H]1O)N[C@@](Cc1ccccc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.5 %

Procedure:
(1R,2R)-2-aminocyclopentanol TFA salt (107 mg, 0.50 mmol) in DCM (2 mL) was added TEA (140 μL, 1.0 mmol), followed by the addition of crude (S)-4-nitrophenyl 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethylcarbamate (162 mg, 0.27 mmol). The reaction mixture was stirred at room temperature for 18 h, concentrated and purified by ISCO chromatography (12 g column) using hexanes/EtOAc (0-60%) over 30 min to give 1-((S)-1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-3-((1R,2R)-2-hydroxycyclopentyl)urea as a pale yellow solid (110 mg, 73% yield). LCMS RT=3.90 min [M+H] 570.24 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 4 minutes containing 0.1% TFA; 4 mL/min, monitoring at 220 nm). NMR: 400 MHz 1H (CDCl3) 8.24 ppm, 1H, d, J=2.27 Hz; 7.64 ppm, 1H, dd, J=8.59, 2.27 Hz; 7.20 ppm, 1H, m; 7.12 ppm, 6H, m; 6.87 ppm, 1H, d, J=8.59 Hz; 6.62 ppm, 2H, d, J=7.07 Hz; 5.87 ppm, 1H, tt, J=53.02, 2.56 Hz; 4.91 ppm, 1H, d, J=4.04 Hz; 4.40 ppm, 1H, d, J=12.88 Hz; 3.97 ppm, 1H, q, J=6.57 Hz; 3.66 ppm, 1H, m; 3.55 ppm, 1H, d, J=12.63 Hz; 1.99 ppm, 1H, m; 1.66 ppm, 3H, m; 1.30 ppm, 2H, m.
Reaction SMILES: [C:1]([C:4]1[N:5]=[N:6][N:7]([C:9]2[CH:10]=[C:11]([CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30])[CH:26]=2)[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:8]=1)(=O)[CH3:2].[CH3:35][C:36]([S:39]([NH2:41])=[O:40])([CH3:38])[CH3:37].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[C:36]([S:39](/[N:41]=[C:1](/[C:4]1[N:5]=[N:6][N:7]([C:9]2[CH:10]=[C:11]([CH:24]=[C:25]([N:27]([S:31]([CH3:34])(=[O:33])=[O:32])[CH2:28][CH2:29][CH3:30])[CH:26]=2)[C:12]([NH:14][C@@H:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH3:16])=[O:13])[CH:8]=1)\[CH3:2])=[O:40])([CH3:38])([CH3:37])[CH3:35]
Reactant: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(C(C)=O)nn2)c1)S(C)(=O)=O
Reactant: CC(C)(C)S(N)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(c1cc(C(=O)N[C@H](C)c2ccc(F)cc2)cc(-n2cc(/C(C)=N/S(=O)C(C)(C)C)nn2)c1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.3 %

Procedure:
To a solution of 0.135 g (0.28 mmol) 3-(4-acetyl-1H-1,2,3-triazol-1-yl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide in 1 mL THF was added 0.18 mL (0.83 mmol) Ti(OEt)4 and 0.04 g (0.33 mmol) 2-methyl-2-propanesulfinamide. The mixture was stirred at rt for 1 hr then heated to reflux for 7 hours whereupon 40 mg more racemic 2-methyl-2-propanesulfinamide and 0.15 mL Ti(OEt)4 and were added and the mixture heated 2 more hr before cooling in an ice bath. To this was added 1 mL brine and 10 mL EtOAc and the mixture was stirred vigorously, breaking up clumps with a spatula. The mixture was filtered through celite and rinsed w. 50 mL EtOAc. The filtrate washed with 50 mL brine, dried over MgSO4, filtered, and concentrated to give 0.07 g 3-{4-[(1E)-N-(tert-butylsulfinyl)ethanimidoyl]-1H-1,2,3-triazol-1-yl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[(methylsulfonyl)(propyl)amino]benzamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.14 (s, 1H), 7.96 (s, 1H), 7.87 (s, 1H), 7.39 (m, 2H) 7.07 (m, 2H), 6.51 (br d, J=7.33 Hz, 1H), 5.31 (quint, J=7.14 Hz, 1H), 3.74 (t, J=6.78 Hz, 2H), 2.94 (s, 3H), 2.92 (s, 3H), 1.65 (d, J=6.96 Hz, 3H), 1.54 (m, 2H), 1.33 (s, 9H), 0.93 (t, J=7.32 Hz, 3H). LCMS [M+H]+=591.2
Reaction SMILES: [OH:1][C:2]([CH2:10][CH2:11][CH3:12])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].N1C=CN=C1.[CH3:18][Si:19]([CH3:22])([CH3:21])Cl.CCOCC>CN(C)C=O.O>[CH3:18][Si:19]([CH3:22])([CH3:21])[O:1][C:2]([CH2:10][CH2:11][CH3:12])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5]
Reactant: C#CCC(O)(CCC)CCCC
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C#CCC(CCC)(CCCC)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.8 Grams of 4-hydroxy-4-n-propyl-1-octyne is dissolved in 100 ml of dimethylformamide and treated with 8 g of imidazole and then with 12 g of trimethylchlorosilane. The reaction mixture was stirred at room temperature for 1 hour and then poured into a mixture of ether and water. The organic layer was washed with water 3-4 times, dried over sodium sulfate, and stripped of solvent. Distillation of the residue gave the title product as a colorless liquid.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][C@@H:6]([C:8]([OH:10])=[O:9])[C@@H:5]([NH:11][C:12](=[O:28])[CH2:13][NH:14][C:15](=[O:27])[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=2)[CH2:4][CH2:3]1.C(Cl)Cl.[BH-](OC(C)=O)(OC(C)=O)O[C:34](C)=O.[Na+].C=O.[CH3:48][C:49]([CH3:51])=O>C(O)(=O)C>[C:23]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][C:19]=1[OH:22])[C:15]([NH:14][CH2:13][C:12]([NH:11][C@H:5]1[CH2:4][CH2:3][C@@H:2]([N:1]([CH:49]([CH3:51])[CH3:48])[CH3:34])[CH2:7][C@H:6]1[C:8]([OH:10])=[O:9])=[O:28])=[O:27])([CH3:24])([CH3:25])[CH3:26]
Reactant: CC(C)(C)c1cc(C(=O)NCC(=O)N[C@H]2CC[C@@H](N)C[C@H]2C(=O)O)ccc1O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)N(C)[C@@H]1CC[C@H](NC(=O)CNC(=O)c2ccc(O)c(C(C)(C)C)c2)[C@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 29 %

Procedure:
To a solution of (1R,2S,5R)-5-amino-2-(2-(3-tert-butyl-4-hydroxybenzamido)acetamido)cyclohexanecarboxylic acid (67 mg, 0.17 mmol) in anhyd CH2Cl2 (1 mL) and acetone (1 mL) was added acetic acid (0.5 mL) and NaBH(OAc)3 (110 mg, 0.51 mmol) and the reaction mixture was stirred at room temperature for 12 h. The reaction mixture was concentrated in vacuo and the residue was dissolved in CH2Cl2 (1 mL) and CH3CN (1 mL). To this solution was added formaldeyde (4 mL, 37% in water) and NaBH(OAc)3 (200 mg, 0.84 mmol) in five portions over 10 h. The reaction mixture was stirred at room temperature for 12 h and then concentrated in vacuo to dryness. The residue was dissolved in water and purified by semi-preparative HPLC to give (1R,2S,5R)-2-(2-(3-tert-butyl-4-hydroxybenzamido)acetamido)-5-(isopropyl(methyl)amino)cyclohexanecarboxylic acid (22.4 mg, 29% over 3 steps) as a white powder: 1H NMR (300 MHz, CD3OD) δ 7.95 (s, 1H), 7.78 (s, 1H), 7.58-7.54 (m, 1H), 6.80-6.77 (m, 1H), 4.55 (s, 1H), 4.08-3.91 (m, 3H), 3.90-3.71 (m, 1H), 3.69-3.45 (m, 1H), 2.92-2.85 (m, 1H), 2.79 (s, 3H), 2.15-1.55 (m, 7H), 1.41-1.33 (m, 15H); MS found: (M+H)+=448.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39].CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([CH3:1])[C:25]([C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)([C:27]([F:30])([F:28])[F:29])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39]
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (0.24 ml) in dry tetrahydrofuran (8 ml) stirred under argon at 0° C., was added n-butyl lithium (“n-BuLi”) (2.5 M in hexane) (0.74 ml). The solution was stirred at 0° C. for 30 minutes then was cooled to −85° C. To this solution was added a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (made as described in EP 1,731,512) (500 mg) in dry tetrahydrofuran (3 ml). The reaction mixture was stirred at −85° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added methyl iodide (0.14 ml) and the reaction mixture was stirred at −85° C. for 1 hour. More methyl iodide (0.08 ml) was added and the reaction mixture was stirred at −85° C. for a further 30 minutes. Then the reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C. The mixture allowed to warm to ambient temperature and was then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 85:15) to give 4-[5-(3,5-dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a white foam. 1H-NMR (CDCl3, 400 MHz): 7.98-7.92 (m, 1H), 7.58-7.38 (m, 5H) 4.22-4.05 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H), 1.58-1.56 (m, 3H), 0.94-0.92 (m, 3H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:7][NH:6]1)=[O:4].C(N(CC)CC)C.[CH:15]([S:18](Cl)(=[O:20])=[O:19])([CH3:17])[CH3:16]>ClCCl>[CH3:1][O:2][C:3]([CH:5]1[CH2:7][N:6]1[S:18]([CH:15]([CH3:17])[CH3:16])(=[O:20])=[O:19])=[O:4]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COC(=O)C1CN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a stirred solution of aziridine-2-carboxylic acid methyl ester (0.5 g) in dichloromethane (20 ml) at 0° C. were added triethylamine (0.95 g) and isopropylsulfonyl chloride (1.38 g). The mixture was warmed to room temperature and stirred for 3.5 h. The mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and washed with brine. The organic phase was dried (MgSO4), filtered and evaporated to give the crude 1-(propane-2-sulfonyl)-aziridine-2-carboxylic acid methyl ester as a yellow oil.
Reaction SMILES: [C:1]([NH:8][C@@H:9]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:10]([OH:31])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:39]([Si:43]([CH3:46])([CH3:45])Cl)([CH3:42])([CH3:41])[CH3:40].N1C=CN=C1>CN(C=O)C>[C:1]([NH:8][C@@H:9]([CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)[C@@H:10]([O:31][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:46])[CH3:45])[CH2:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:19][CH:18]=1)[C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@H](C[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O)O[Si](C)(C)C(C)(C)C

Procedure:
In analogy with Example 1 j), 28.8 g (54.8 mmol) of 5(S)-(Boc-amino)-4(S)-hydroxy-6-cyclohexyl-2(R)-[(4-benzyloxyphenyl)methyl]hexanoic acid in 288 ml of DMF, are converted into the title compound with 35.8 g (237.6 mmol) of tert-butyldimethylchlorosilane and 30 g (440 mmol) of imidazole. The title compound is purified by column chromatography (SiO2, hexane/ethyl acetate: 4:1 to 1:1); TLC Rf (E)=0.34; tRet (gradient from 75 to 100% (a) in (b) over 20 min)=25.06 min; FAB-MS (M+H+)=526.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9](Cl)=[O:10])[CH2:5][CH2:4]1)#[N:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:35]=[CH:36][CH:37]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]2[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]3[CH2:34][CH2:33]3)=[O:31])[N:28]=2)[CH:25]=1>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]([C:3]1([C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=2)[C:9]([NH:15][C:16]2[CH:37]=[CH:36][CH:35]=[C:18]([O:19][C:20]3[CH:21]=[CH:22][C:23]4[N:24]([N:26]=[C:27]([NH:29][C:30]([CH:32]5[CH2:33][CH2:34]5)=[O:31])[N:28]=4)[CH:25]=3)[CH:17]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: N#CC1(c2cccc(C(=O)Cl)c2)CC1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)nn3c2)c1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)C6CC6)nn5c4)c3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of 3-(1-cyanocyclopropyl)benzoyl chloride synthesized above in N,N-dimethylacetamide (5.0 mL) was added N-[6-(3-aminophenoxy)[1,2,4]triazolo[1,5-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.485 mmol) produced in Example B2(vii), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→0/100), and the obtained oil was triturated with ethyl acetate, toluene and diisopropyl ether to give the title compound (175 mg, 63%) as a colorless powder.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].[F:13][C:14]([F:27])([F:26])[C:15]1[CH:16]=[C:17]([OH:25])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[F:13][C:14]([F:26])([F:27])[C:15]1[CH:16]=[C:17]([CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1)[O:25][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: Oc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCOc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Ethyl 7-bromoheptanoate and 3,5-bis(trifluoromethyl) phenol were added to dimethylformamide (DMF). The solution was added with potassium carbonate and stirred at room temperature. The solution was added with water and extracted twice with ethyl acetate. After the organic layer was washed three times with water and dried over anhydrous magnesium sulfate, the solvent was removed. The residue was purified by silica gel column chromatography to obtain ethyl 7-(3,5-bis (trifluoromethyl)phenoxy)heptanoate.
Reaction SMILES: [NH2:1][C:2]1([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH2:7][CH2:6][CH2:5][N:4]([CH3:8])[CH2:3]1.[CH2:14]([C:22]1[O:26][C:25]([C:27](ON2C(=O)CCC2=O)=[O:28])=[CH:24][CH:23]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C.C(OCC)C>CN(C=O)C>[CH3:8][N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH2:9][C:10]([O:12][CH3:13])=[O:11])([NH:1][C:27]([C:25]2[O:26][C:22]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:23][CH:24]=2)=[O:28])[CH2:3]1
Reactant: O=C(ON1C(=O)CCC1=O)c1ccc(CCc2ccccc2)o1
Reactant: COC(=O)CC1(N)CCCN(C)C1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC1(NC(=O)c2ccc(CCc3ccccc3)o2)CCCN(C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of methyl 2-(3-amino-1-methylpiperidin-3-yl)acetate (37 mg, 0.2 mmol) and 2,5-dioxopyrrolidin-1-yl 5-phenethylfuran-2-carboxylate (75 mg, 0.24 mmol) in DMF (1 mL) was treated with triethylamine (0.11 μL, 0.8 mmol) and stirred at room temperature for 18 h. Diethyl ether (20 mL) was added and the resulting white precipitate was collected and purified by silica gel chromatography (elution 5% MeOH/CH2Cl2 to 10% MeOH/CH2Cl2) to give the title compound as a white powder (69 mg, 87%). MS ESI 385.2 [M+H]+, calcd for [C22H28N2O4+H] 385.20.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16](Cl)(=[O:18])=[O:17].[OH-].[Na+]>>[CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[O:18])=[O:17]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: CNc1ccccc1
Product: CN(c1ccccc1)S(=O)(=O)c1ccccc1Br

Procedure:
Freshly distilled N-methylaniline (b.p. 196° C.) is prepared. To 1.07 g (0.01 mole) of the N-methylaniline is added 2.56 g (0.01 mole) of 2-bromobenzenesulfonyl chloride (98 w/w %). The mixture is stirred until hot. Ten percent sodium hydroxide is then added dropwise with stirring until the solution is slightly alkaline, and 2-bromo-N-methylbenzene-sulfonanilide is formed as a viscous red-brown liquid. It is washed with water several times until the wash water is neutral to litmus paper. A viscous red-brown liquid is extracted with ether, and the ether layer is dried over magnesium sulfate, filtered and the solvent removed by evaporation. The yield of red-brown oil is 2.30 g (70% yield). 1H NMR (deuterioacetone): δ7.1-8 (m, 9 ArH), 3.3 (s, 3H, N--CH3).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][N:10]([CH2:18][C:19]([O:21]CC)=O)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]N)[CH3:26].C([N:37](C(C)C)CC)(C)C.C(N)(C)C>C(Cl)(Cl)Cl.CCOCC>[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:8]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]([CH2:18][C:19]([NH2:37])=[O:21])[N:9]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CN(C)CCCCCCN
Reactant: CCOC(=O)Cn1ncc(-c2ccccc2)c1-c1ccccc1
Solvent: CC(C)N
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: CN(C)CCCCCCc1nn(CC(N)=O)c(-c2ccccc2)c1-c1ccccc1
Reaction time: 18 h

Procedure:
A mixture of 8 g (0.026 mol) of ethyl 4,5-diphenyl-1H-pyrazole-1-acetate of Example 1, 4.1 g (0.028 mol) of dimethylaminohexylamine and 33.3 mL (0.19 mol) of diisopropylethylamine was stirred on a steam bath under nitrogen for 18 hours. Thin layer chromatography on silica gel with 5% isopropylamine in chloroform showed incomplete reaction. Another 1 mL of dimethylaminohexylamine was added and stirring continued on a steam bath for an additional 24 hours. The reaction was stripped in vacuo, taken up in 200 mL of ether, washed two times with water, washed once with half saturated sodium bicarbonate solution, washed with water again, washed with saturated sodium chloride solution, dried over magnesium sulfate, treated with decolorizing carbon, filtered and stripped. The residue was taken up in ether and treated with a slight excess of hydrochloric acid. The hydrochloride salt was extracted into water and washed three times with ether; the water layer was chilled, and made basic with solid sodium carbonate and extracted two times with ether. The ether extracts were combined, washed once with saturated sodium chloride, dried over magnesium sulfate, treated with decolorizing carbon, filtered and stripped. The resulting residue was triturated in pentane to yield 4.14 g of N([6-(dimethylamino)hexyl]-4,5-diphenyl-1H-pyrazole-1-acetamide, mp 60°-63° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20](Cl)=[O:21])[CH:15]=1.CCOC(C)=O>C1COCC1>[Cl:13][C:14]1[N:19]=[CH:18][N:17]=[C:16]([C:20]([N:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:4]([CH3:3])=[CH:5]2)=[O:21])[CH:15]=1
Reactant: Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cn(C(=O)c2cc(Cl)ncn2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Under a nitrogen atmosphere 120 mg (3.00 mmol) sodium hydride (60% in mineral oil) were added batchwise to 380 mg (2.90 mmol) 3-methylindole in 15 mL THF and the mixture was stirred for 30 min at RT. 500 mg (2.83 mmol) 6-chloropyrimidine-4-carboxylic acid chloride were added batchwise and then the reaction mixture was stirred for 2 h at RT. Then 50 mL EtOAc were added and the mixture was washed with 50 mL saturated sodium hydrogen carbonate solution (1×), 30 mL water and with 50 mL 1 M hydrochloric acid. The organic phase was dried on sodium sulphate, filtered and then evaporated down i. vac. The product was used in the next step without further purification.
Reaction SMILES: [N:1](=[C:3]1[C:8]([CH3:10])([CH3:9])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)[OH:2].O1CCOCC1.[CH3:18][N:19]([S:23][C:24]([Cl:27])([Cl:26])[Cl:25])[C:20](F)=[O:21].C(N(CC)CC)C>O>[CH3:18][N:19]([S:23][C:24]([Cl:27])([Cl:26])[Cl:25])[C:20]([O:2][N:1]=[C:3]1[C:8]([CH3:9])([CH3:10])[NH:7][C:6](=[O:11])[CH2:5][S:4]1)=[O:21]
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Reactant: CC1(C)NC(=O)CSC1=NO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CN(SC(Cl)(Cl)Cl)C(=O)ON=C1SCC(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.7 %

Procedure:
A mixture of 3.5 g of 2-oximino-3,3-dimethyltetrahydro-1,4-thiazin-5-one, dioxane and N-methyl-N-(trichloromethylthio)carbamoyl fluoride (4.5 g) was charged to a stirred flask and 2.1 g of triethylamine was added dropwise at 30° C, over a 2-minute period. The reaction mixture was stirred overnight at room temperature. The reaction mixture was then added to cold water and stirred for 10 minutes. The crystalline solid was filtered, washed thoroughly with water and dried overnight. After drying the crude product was recrystallized from isopropanol to yield 3 g of 2-[O-(N-methyl-N-trichloromethanesulfenylcarbamoyl)oximino]-3,3-dimethyltetrahydro-1,4-thiazin-5-one, m.p. 189°-190° C. The nmr spectrum of this material was consistent with its proposed structure.