Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:11]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=[C:12]=[O:13]>C(N(CC)CC)C>[CH2:21]([O:20][C:18]([C:17]1[CH:23]=[CH:24][C:14]([NH:11][C:12]2[O:13][CH2:2][C:3](=[O:10])[C:4]=2[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:15][CH:16]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1=C(Nc2ccc(C(=O)OCC)cc2)OCC1=O
Reaction time: 1 h

Procedure:
Triethylamine (9.87 ml) was added dropwise, over a period of 1 hour to a cooled (ice bath) solution of ethyl 4-chloroacetoacetate (9.87 g, 60 mmol) and ethyl p-isocyanatobenzoate (14.34 g, 75 mmol) in 60 ml of petroleum ether-ethyl acetate (10:1 by volume), under nitrogen atmosphere. The reaction mixture was stirred at 0°-5° C. for 1 hour. The resulting ethyl 2-[[4-(ethoxycarbonyl)phenyl]-amino]-4,5-dihydro-4-oxo-3-furancarboxylate was filtered and then washed sequentially with petroleum ether, 1 N hydrochloric acid and water. Yield 13.0 g Mp 152°-153° C. (isopropanol).
Reaction SMILES: [CH3:1][N:2](C)C=O.Cl[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH3:17])[N:8]=1>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:17][C:9]1[N:8]=[C:7]([C:1]#[N:2])[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1cc(C(F)(F)F)cc(C#N)n1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To 10 ml of N,N-dimethylformamide were added 1 g of 2-chloro-6-methyl-4-trifluoromethylpyridine, 1.2 g of zinc cyanide and 0.24 g of tetrakistriphenylphosphinepalladium, and the mixture was stirred at 90° C. for 10 hours. After allowing to cool, the reaction solution was poured into water, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.8 g of 6-methyl-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH2:14])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F:15][C:16]([F:31])([F:30])[C:17]1[C:25]2[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=2[N:19]([CH2:26][C:27](O)=[O:28])[N:18]=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>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C@@H:6]([NH:14][C:27](=[O:28])[CH2:26][N:19]1[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C:25]=2[C:17]([C:16]([F:30])([F:15])[F:31])=[N:18]1)[CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cn1nc(C(F)(F)F)c2c1CCCC2)N[C@@H](Cc1ccccc1)c1ncc[nH]1
Reaction time: 0.25 h

Procedure:
To (S)-1-(1H-imidazol-2-yl)-2-phenylethanamine from the previous reaction was added DMF (10 mL), 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (288 mg, 1.18 mmol), and HATU (530 mg, 1.4 mmol). Diisopropylethylamine (452 μL, 2.6 mmol) was added and the reaction was stirred for 15 min. The reaction was partitioned between EtOAc and H2O. The organics were separated, washed with saturated aqueous NaHCO3, and saturated aqueous NaCl. Solvents were removed in vacuo and the residue purified by column chromatography on silica to provide the desired product: MS (m/z) 418.3 [M+H]+.
Reaction SMILES: C(OC([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[O:29][C:30]3[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:31]=3[N:32]=2)[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.[ClH:47].C(OCC)(=O)C.C(OC(C)C)(C)C>O1CCOCC1>[ClH:47].[F:46][C:42]1[CH:41]=[C:40]([CH:23]2[CH:22]([CH2:21][NH:8][C@@H:9]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]=[CH:13][CH:12]=3)[CH3:10])[CH2:27][CH2:26][N:25]([C:28]3[O:29][C:30]4[CH:36]=[CH:35][C:34]([C:37]([OH:39])=[O:38])=[CH:33][C:31]=4[N:32]=3)[CH2:24]2)[CH:45]=[CH:44][CH:43]=1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCN(c2nc3cc(C(=O)O)ccc3o2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@@H](NCC1CCN(c2nc3cc(C(=O)O)ccc3o2)CC1c1cccc(F)c1)c1cccc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 35 mg of 2-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylic acid in 1.0 mL of 1,4-dioxane solution was added 1.00 mL of a 4 M hydrogen chloride/ethyl acetate solution at room temperature, followed by stirring for 1 hour. Diisopropyl ether was added thereto, and the resulting precipitate was collected by filtration, and dried under reduced pressure to obtain 14 mg of 2-[3-(3-fluorophenyl)-4-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)piperidin-1-yl]-1,3-benzoxazole-5-carboxylic acid hydrochloride.
Reaction SMILES: [CH2:1]1[N:9]2[C:4](=[N:5][S:6](=[O:15])(=[O:14])[C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)[CH2:3][CH2:2]1.[N+:16]([O-])([O-:18])=[O:17].[K+]>OS(O)(=O)=O>[N+:16]([C:12]1[CH:11]=[CH:10][C:8]2[N:9]3[CH2:1][CH2:2][CH2:3][C:4]3=[N:5][S:6](=[O:14])(=[O:15])[C:7]=2[CH:13]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])[O-]
Reactant: O=S1(=O)N=C2CCCN2c2ccccc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)N=C1CCCN12
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A stirred solution of 1,2,3,5-tetrahydrobenzo[e]pyrrolo[2,1-c]-1,2,4-thiadiazine-5,5-dioxide (222 mg; 1 mmol) in H2SO4 (2 ml) at 5° C. was added a solution of KNO3 (122 mg; 1.2 mmol) in H2SO4 (2 ml). The reaction mixture was allowed to warm up to rt. and stirred for 2 h. The reaction mixture was poured into ice water, filtered and air dried to give 190 mg (71%) product.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)=O.[C:21](=O)([O-])[O-].[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([C:3]1[N:4]=[C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[S:6][CH:7]=1)#[CH:21]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C=O)cs2)CC1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#Cc1csc(C2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under argon, tert-butyl 4-(4-formyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (600 mg) is dissolved in methanol, and potassium carbonate (839 mg) and dimethyl 1-diazo-2-oxopropylphosphonate (786 mg) are added. The mixture is stirred at room temperature for 3 hours. After aqueous work-up, the mixture is extracted with ethyl acetate and the extracts are dried with sodium sulphate and concentrated under reduced pressure. The residue is purified chromatographically. This gives tert-butyl 4-(4-ethynyl-1,3-thiazol-2-yl)piperidine-1-carboxylate (493 mg).
Reaction SMILES: [CH2:1]([C:4]1([CH3:19])[C:9]2[NH:10][C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3].[H-].[Na+].[O:22]1[CH2:24][CH:23]1[C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:1]([C:4]1([CH3:19])[C:9]2[N:10]([CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=3)[OH:22])[C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][C:16]=3[C:8]=2[CH2:7][N:6]([CH3:18])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: c1cc(C2CO2)ccn1
Reactant: C=CCC1(C)CN(C)Cc2c1[nH]c1ccc(C)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCC1(C)CN(C)Cc2c1n(CC(O)c1ccncc1)c1ccc(C)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.2 %

Procedure:
4-Allyl-2,4,8-trimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.5 g, 9.8 mmol) was dissolved in 18 mL of DMF and stirred for 10 min at RT. Sodium hydride (1.17 g, 29.2 mmol) was added portionwise and stiffing was continued for additional 10 min. This was followed by dropwise addition of 4-oxiranyl-pyridine (2.38 g, 19.6 mmol) as a solution in DMF. The reaction mixture was stirred at RT for 16 h, quenched with ice water and extracted with EtOAc (3×120 mL). The organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was recrystallized in ether to obtain 1 g of 2-(4-allyl-2,4,8-trimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-1-pyridin-4-yl-ethanol.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@@H:21]1[C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1)=[O:19])[CH3:16].[CH3:30][C:31]1[N:32]=[C:33]([C:38]2[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=2)[S:34][C:35]=1[CH:36]=O.C(OCC)(=O)C>ClC(Cl)C.O>[CH2:15]([O:17][C:18]([C@@H:20]1[CH2:22][C@@H:21]1[C:23]1[CH:24]=[CH:25][C:26]([NH:29][CH2:36][C:35]2[S:34][C:33]([C:38]3[CH:39]=[CH:40][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:43]=3)=[N:32][C:31]=2[CH3:30])=[CH:27][CH:28]=1)=[O:19])[CH3:16]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C=O
Reactant: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(Cl)Cl
Product: CCOC(=O)[C@@H]1C[C@@H]1c1ccc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.1 %

Procedure:
Sodium triacetoxyborohydride (0.297 g, 1.40 mmol) was added to a solution of enantiomerically enriched-(cis)-ethyl-2-(4-aminophenyl)cyclopropanecarboxylate (0.115 g, 0.56 mmol) (III-1c) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carbaldehyde (0.152 g, 0.56 mmol) in 5 mL of dichloroethane. The mixture was stirred at room temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and the solvent evaporated. The residue was purified by chromatography on silica gel with hexane:ethyl acetate to give 0.186 g (72% yield) of (cis)-ethyl-2-{4-[({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)amino]phenyl}cyclopropanecarboxylate (III-2e) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.06 Hz, 2H), 7.63 (d, J=8.24 Hz, 2H), 7.10 (d, J=8.24 Hz, 2H), 6.57 (d, J=8.61 Hz, 2H), 4.43 (s, 2H), 3.91 (br s, 1H), 3.87 (q, J=7.14 Hz, 2H), 2.48 (s, 3H), 2.48 (m, 1H), 2.00 (m, 1H), 1.63 (m, 1H), 1.27 (m, 1H), 1.00 (t, J=7.14 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]1.C(N(CC)CC)C.[C:21](C(CC(N)=O)C(N)=O)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CN(C=O)C>[C:25]1([CH2:24][O:23][C:21]([NH:1][CH2:2][CH:3]2[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4]2)=[O:22])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NC(=O)CC(C(N)=O)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC(CNC(=O)OCc2ccccc2)C1
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of 1,1-dimethylethyl 3-(aminomethyl)-1-azetidinecarboxylate (5.0 g, 26.84 mmole) in DMF (40 mL) was added triethylamine (4.9 mL, 34.9 mmole) and Cbz-succinamide (8.7 g, 34.9 mmole). After 18 hours, the reaction solution was concentrated under vacuum and redissolved in EtOAc (250 mL). The organic solution was washed with H2O (2×150 mL), brine (100 mL) and dried over Na2SO4 and concentrated. The remaining residue was purified on silica (hexanes/EtOAc, 1:1) to give the title compound (5.5 g, 64%) as a light yellow oil: LC-MS (ES) m/e 321 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:32]C(=O)OC(C)(C)C)=[C:5]([C:7](=[O:31])[NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:30])[C:13]=2[C@@H:14]2[CH2:20][CH2:19][C@@H:18]([NH:21]C(OC(C)(C)C)=O)[C@H:17]([F:29])[CH2:16][O:15]2)[N:6]=1.[F:40][C:41]1[C:46]([C:47]([F:50])([F:49])[F:48])=[CH:45][CH:44]=[CH:43][C:42]=1B(O)O>>[NH2:32][C:4]1[S:3][C:2]([C:42]2[CH:43]=[CH:44][CH:45]=[C:46]([C:47]([F:50])([F:49])[F:48])[C:41]=2[F:40])=[N:6][C:5]=1[C:7]([NH:8][C:9]1[CH:10]=[N:11][N:12]([CH3:30])[C:13]=1[C@@H:14]1[CH2:20][CH2:19][C@@H:18]([NH2:21])[C@H:17]([F:29])[CH2:16][O:15]1)=[O:31]
Reactant: Cn1ncc(NC(=O)c2nc(Br)sc2NC(=O)OC(C)(C)C)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: OB(O)c1cccc(C(F)(F)F)c1F
Product: Cn1ncc(NC(=O)c2nc(-c3cccc(C(F)(F)F)c3F)sc2N)c1[C@@H]1CC[C@@H](N)[C@H](F)CO1

Procedure:
Following the procedure for Example 101 starting from tert-butyl N-[2-bromo-4-[[5-[(2S,5R,6S)-5-(tert-butoxycarbonylamino)-6-fluoro-oxepan-2-yl]-1-methyl-pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (Intermediate 95), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid gave 156. 1H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1H), 8.56 (t, J=7.7 Hz, 1H), 7.85 (s, 1H), 7.79 (t, J=7.3 Hz, 1H), 7.57 (s, 2H), 7.49 (t, J=7.9 Hz, 1H), 4.91-4.82 (m, 1H), 4.67-4.49 (m, 1H), 4.42-4.26 (m, 1H), 4.21-4.00 (m, 1H), 3.77 (s, 3H), 2.13-2.01 (m, 1H), 1.90-1.67 (m, 4H). LCMS (ES+) m/z 517 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13]([C:15]1[CH:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=2)[CH:16]=1)=[O:14])(C)(C)C.O>ClCCl>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([N:17]2[CH:18]=[CH:19][C:15]([C:13]([OH:14])=[O:12])=[CH:16]2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)c1ccn(-c2ccc(Cl)cn2)c1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1ccn(-c2ccc(Cl)cn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
Trifluoroacetic acid (3 ml) was added to a solution of 1-(5-chloropyridin-2-yl)pyrrole-3-carboxylic acid tert-butyl ester (1.0 g) in dichloromethane (10 ml) and stirred at room temperature for four hours. Water was added to the reaction solution and the precipitated solid was washed with water to give the titled compound (775 mg) as a gray solid.
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1.C(O)(=O)CC>Br>[CH2:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:18][NH:10]1
Reactant: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C2)cc1
Agent: Br
Solvent: CCC(=O)O
Solvent: Oc1ccccc1
Product: c1ccc2c(c1)CNC2
Temperature: 25 °C
Yield: 62.6 %

Procedure:
A solution of 12.0 g (0.044 mol) of 2-(p-tolylsulfonyl) isoindoline, 12.0 g (0.13 mol) of phenol, 90 ml of 48% HBr, and 15 ml (0.201 mol) of propionic acid was refluxed for two hours. The mixture was cooled to room temperature, triturated with diethyl ether, and then added to a solution of 75 gm of sodium hydroxide in 200 ml of cold water. This mixture was extracted with diethyl ether and the combined ether extracts were washed with water. The organic phase was dried over magnesium sulfate, concentrated in vacuo and kugelrohr distilled to give 3.28 g (61%) of a white solid, m.p. 118°-127° C. NMR: (CDCl3) δ 2.2 (1H,s), 4.0 (4H, s), 6.95 (4H, s)
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=2)[N:8]=1)=O.[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[NH:34]N>>[F:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[C:5]([C:7]2[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]3[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=3)[N:8]=2)=[CH:4][CH:3]=[N:2]1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OC(F)(F)F)cc2)ccc1=O
Reactant: NNc1cc(F)ccc1F
Product: O=c1ccn(-c2ccc(OC(F)(F)F)cc2)nc1-c1ccnn1-c1cc(F)ccc1F

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(4-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-8) and 2,5-difluoro-phenylhydrazine according to the method described for example 91. MS: M=435.3 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:18][O:19][C:20](=[O:46])[C@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1)[NH:22][C:23]([C:25]1([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[S:24]>ClCCl.CN(C=O)C.O>[CH3:18][O:19][C:20](=[O:46])[C@H:21]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([NH:45][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[CH:5][C:6]=2[CH3:11])=[O:10])=[CH:41][CH:40]=1)[NH:22][C:23]([C:25]1([CH2:30][CH2:31][CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH2:29][CH2:28][CH2:27][CH2:26]1)=[S:24]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(C)ccnc2C)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To an ice cold solution of 2,4-dimethyl-3-pyridinecarboxylic acid (0.3 mmol, 45 mg) in dichloromethane (2 mL) containing one drop of DMF, was added oxalyl chloride (0.39 mmol, 49.5 mg) at 0° C. The reaction mixture was stirred for 30 min at this temperature, was allowed to warm to room temperature and was stirred for an additional 2 h. The solution was concentrated and the residue was dried under high vacuum. To a mixture of above acid chloride and 4-amino-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (0.2 mmol, 88 mg) in dichloromethane (3 mL) was added diisopropylethylamnine (1 mmol, 0.175 mL) at room temperature. After the solution had stirred for 15 h, TLC analysis of the mixture did not detect any starting material remaining. The solution was diluted with water (20 mL) and dichloromethane (20 mL) and the layers were separated. The aqueous phase was extracted with dichloromethane (10 mL) and the combined organic extracts were washed with brine (300 mL). The dried (MgSO4) solution was filtered and evaporated to dryness and the residual material was purified by RP-HPLC to obtain 74 mg (65%) of 4-[[(2,4-dimethylpyridin-3-yl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester as an amorphous colorless solid. HRMS: Obs. mass, 574.2389. Calcd. mass, 574.2409 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[C:18]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.[OH:38][C@@H:39]([CH2:52][NH2:53])[CH2:40][O:41][C:42]1[C:50]2[NH:49][C:48](=[O:51])[NH:47][C:46]=2[CH:45]=[CH:44][CH:43]=1>>[Cl:16][C:17]1[C:18]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH:2][C:3]3[CH:8]=[CH:7][C:6]([N:9]4[CH2:14][CH2:13][CH:12]([NH:53][CH2:52][C@H:39]([OH:38])[CH2:40][O:41][C:42]5[C:50]6[NH:49][C:48](=[O:51])[NH:47][C:46]=6[CH:45]=[CH:44][CH:43]=5)[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1
Reactant: NC[C@H](O)COc1cccc2[nH]c(=O)[nH]c12
Reactant: O=S(=O)(Cl)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Agent: Cl
Product: O=c1[nH]c2cccc(OC[C@@H](O)CNC3CCN(c4ccc(NS(=O)(=O)c5ccc(Oc6ncc(C(F)(F)F)cc6Cl)cc5)cc4)CC3)c2[nH]1

Procedure:
The title compound was prepared from 1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained in Example 224), 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzenesulfonyl chloride, and (S)-4-[2-hydroxy-3-aminopropoxy]-1,3-dihydro-2H-benzimidazol-2-one (U.S. Pat. No. 5,786,356/1998) according to the procedure of Example 346; MS (ES) m/z: 733.3 (MH+).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:13])=[C:8]([Cl:12])[C:9]=2[CH3:11])[S:4][C:3]=1[C:14]#[N:15].[NH2:16][NH2:17]>CS(C)=O>[Cl:12][C:8]1[C:9]([CH3:11])=[C:10]2[C:2]3[NH:16][N:17]=[C:14]([NH2:15])[C:3]=3[S:4][C:5]2=[N:6][C:7]=1[CH3:13]
Reactant: Cc1nc2sc(C#N)c(Br)c2c(C)c1Cl
Reactant: NN
Solvent: CS(C)=O
Product: Cc1nc2sc3c(N)n[nH]c3c2c(C)c1Cl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
The 3-bromo-5-chloro-4,6-dimethylthieno[2,3-b]pyridine-2-carbonitrile (0.273 g, 0.91 mmol) was added to a microwave reaction vial. The DMSO (4 mL) was added, followed by hydrazine (0.085 mL, 2.72 mmol). The vial was sealed and irradiated at 120 degrees for 10 minutes. LC\MS shows no remaining starting material. The reaction was cooled to RT, then poured into 50 mL of ice-water. The ice was allowed to melt and resulting slurry was poured through filter paper, washing the solid with cold water (3×). The solid was then dried under vacuum at 60° C. to give 220 mg (96%) of the product as a light yellow solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 5.53 (bs, 2H), 2.74 (s, 3H), 2.61 (s, 3H). LC/MS: RT=0.58 min., m/z=253.0 [M+H]+.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-])=O)=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:19]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[C:15]2[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=2)[CH2:9][CH2:8][CH2:7]1)[CH3:20]
Reactant: [H][H]
Reactant: CCN(CC)CCN1CCCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CCN(CC)CCN1CCCc2cc(N)ccc21
Yield: 90.5 %

Procedure:
A suspension of N,N-diethyl-2-(6-nitro-3,4-dihydroquinolin-1(2H)-yl)ethanamine (0.85 g, 3.06 mmol) and palladium on charcoal, 10% wt (0.163 g, 0.153 mmol) in ethanol (30 mL) was stirred at room temperature under a balloon of hydrogen overnight. The mixture was filtered through a pad of celite. The celite pad was rinsed with 20 mL of methanol. The filtrate was concentrated and the residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in methanol/95% CH2Cl2 to give a dark brown residue (685 mg, 90%). 1H-NMR (CDCl3) δ 6.63-6.32 (m, 3H), 3.37-3.23 (m, 4H), 2.74-2.56 (m, 8H), 1.93 (t, J=5.7 Hz, 2H), 1.08 (t, J=7.2 Hz, 6H). MS (ESI): 248.2 (M+1).
Reaction SMILES: [N:1]1([C:6]2[C:11](B(O)O)=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=2)=[C:18]([F:29])[CH:17]=1>>[F:29][C:18]1[CH:17]=[C:16]([C:11]2[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:7][CH:8]=[CH:9][CH:10]=2)[CH:21]=[CH:20][C:19]=1[C:22]1[N:23]=[CH:24][C:25]([NH2:28])=[N:26][CH:27]=1
Reactant: OB(O)c1cccnc1N1CCCC1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: Nc1cnc(-c2ccc(-c3cccnc3N3CCCC3)cc2F)cn1

Procedure:
Title compound was prepared using methods analogous to those described in Example 377 using (2-(pyrrolidin-1-yl)pyridine-3-yl)boronic acid and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C19H18FN5, 335.15; m/z found, 336.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.56 (m, 1H), 8.22-8.17 (m, 1H), 8.12 (s, 1H), 7.97-7.88 (m, 1H), 7.45-7.38 (m, 1H), 7.29-7.23 (m, 1H), 7.21-7.14 (m, 1H), 6.75-6.67 (m, 1H), 4.67 (s, 2H), 3.28-3.10 (m, 4H), 1.87-1.73 (m, 4H).
Reaction SMILES: [Br:1]Br.[F:3][CH2:4][C:5]([CH2:10][F:11])([CH3:9])[C:6](=[O:8])[CH3:7]>C(Cl)Cl>[F:3][CH2:4][C:5]([CH2:10][F:11])([CH3:9])[C:6](=[O:8])[CH2:7][Br:1]
Reactant: BrBr
Reactant: CC(=O)C(C)(CF)CF
Solvent: ClCCl
Product: CC(CF)(CF)C(=O)CBr

Procedure:
51 ml (1 mol) of bromine were added dropwise to 136 g (1 mol) of 3,3-bisfluoromethylbutane-2-one in 700 ml of methylene chloride such that decoloration was continuous. The solvent was then distilled off under a water pump vacuum. An almost quantitative yield of crude 3,3-bisfluoromethyl-1-bromo-butan-2-one was obtained as an oil, which could be further reacted directly.