Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:2]=1[NH2:1]
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)ccc1N
Temperature: 25 °C

Procedure:
To a stirred solution of 2-amino-5-chloro-benzoic acid (50 g, 291 mmol) in methanol (300 mL) was added thionyl chloride (45 mL, 605 mmol) dropwise at 0° C. Then the mixture solution was refluxed for 12 hours before cooling to room temperature. Then the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (500 mL), washed with saturated aqueous sodium bicarbonate solution (3×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-amino-5-chloro-benzoic acid methyl ester (54 g, quant.) as a pale-white solid: LC/MS m/e calcd for C8H8ClNO2 (M+H)+: 186.61, observed: 185.9.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:21][NH:22]C(OC(C)(C)C)=O)=[O:20])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[ClH:30]>O1CCOCC1>[ClH:30].[ClH:30].[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:19]([NH:21][NH2:22])=[O:20])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1ncc2c(NC3CCOCC3)c(C(=O)NNC(=O)OC(C)(C)C)cnc21
Agent: Cl
Solvent: C1COCCO1
Product: CCn1ncc2c(NC3CCOCC3)c(C(=O)NN)cnc21
Reaction time: 1 h

Procedure:
Intermediate 18 (1.39 g) was treated with a 4M solution of hydrochloric acid in dioxane (8 ml) and the mixture stirred under nitrogen for 1 h. Concentration in vacuo afforded Intermediate 19 as a white solid (1.17 g). LCMS showed MH+=305; TRET=2.04 min.
Reaction SMILES: C(O)(=O)C.O.[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:30]([F:33])([F:32])[F:31])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23]([N+:25]([O-])=O)[CH:24]=3)[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1>[Fe].C(O)C>[Cl:6][C:7]1[CH:8]=[C:9]([C:14]2([C:30]([F:32])([F:31])[F:33])[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([CH2:28][CH3:29])=[C:23]([CH:24]=3)[NH2:25])[CH2:15]2)[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: CCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
An iron powder (4.33 g) was added to a mixture of acetic acid (0.5 ml), water (22 ml) and ethanol (34 ml) at room temperature, and thereto was added 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-ethylnitrobenzene (5.60 g) obtained by Reference Production Example 29 at 75° C., and the mixture was stirred at the same temperature for 3 hours. After cooling to room temperature, the reaction mixture was filtrated and washed with ethyl acetate. To the filtrate was added an aqueous saturated sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 5-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-ethylaniline (5.20 g).
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=1[F:45])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:32]([F:35])([F:34])[F:33])=[N:19][C:20]([C:21]([N:23]3[CH2:28][CH2:27][N:26]([C:29](=[O:31])[CH3:30])[CH2:25][CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:47]>C(OCC)(=O)C>[ClH:47].[C:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21]([C:20]2[N:19]=[C:18]([C:32]([F:34])([F:33])[F:35])[N:15]3[CH2:16][CH2:17][N:12]([C:10](=[O:11])[CH2:9][C@H:8]([NH2:7])[CH2:36][C:37]4[CH:42]=[C:41]([F:43])[C:40]([F:44])=[CH:39][C:38]=4[F:45])[CH2:13][C:14]=23)=[O:22])[CH2:24][CH2:25]1)(=[O:31])[CH3:30]
Reactant: CC(=O)N1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(=O)N1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@H](N)Cc2cc(F)c(F)cc2F)CC3)CC1
Yield: 98 %

Procedure:
(R)-[3-[1-(4-Acetyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 17a (0.08 g, 0.12 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 2 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-1-[1-(4-acetyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-amino-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 17 (70 mg, yield 98%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]3[S:19][C:20]([CH3:37])=[C:21]([C:22]4[CH:23]=[C:24]([CH2:28][NH:29]C(=O)OC(C)(C)C)[CH:25]=[CH:26][CH:27]=4)[C:13]=23)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][CH2:28][C:24]1[CH:23]=[C:22]([C:21]2[C:13]3[C:14](=[N:15][C:16]([CH3:18])=[CH:17][C:12]=3[NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])[S:19][C:20]=2[CH3:37])[CH:27]=[CH:26][CH:25]=1
Reactant: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(CNC(=O)OC(C)(C)C)c3)c(C)sc2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(NS(=O)(=O)c2cccc(Cl)c2)c2c(-c3cccc(CN)c3)c(C)sc2n1
Reaction time: 1 h
Yield: 8.5 %

Procedure:
To a solution of 1,1-dimethylethyl {[3-(4-{[(3-chlorophenyl)sulfonyl]amino}-2,6-dimethylthieno[2,3-b]pyridin-3-yl)phenyl]methyl}carbamate (Example 70) (40 mg, 0.072 mmol) in DCM (2 mL) was added TFA (0.276 mL, 3.58 mmol) and the mixture stirred for 1 h. The mixture was then loaded onto an SCX cartridge and flushed with MeOH (3×5 mL) followed by 2M NH3 in MeOH (3×5 mL). The desired fractions were combined and concentrated and further purified by normal phase chromatography, eluting with a gradient of 0-20% 2M NH3 in MeOH in DCM, to give the title compound (2.8 mg). LCMS (A) m/z: 458 [M+1]+, Rt 0.96 min (basic).
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@H:12]([OH:14])[CH2:11][N:10]2[C:15]([C:17]2([CH3:20])[CH2:19][CH2:18]2)=[O:16])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C.Cl>CN(C)C1C=CN=CC=1.ClCCl.O>[C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:10]([C:15]([C:17]3([CH3:20])[CH2:19][CH2:18]3)=[O:16])[CH2:11][C@@H:12]([O:14][S:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:29])=[O:28])[CH2:13]2)=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: CC1(C(=O)N2C[C@@H](O)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C(=O)N2C[C@@H](OS(=O)(=O)c3ccccc3)C[C@H]2C(=O)NC2(C#N)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.5 %

Procedure:
(2S,4S)-4-Hydroxy-1-(1-methyl-cyclopropanecarbonyl)-pyrrolidine-2-carboxylic acid (1-cyano-cyclopropyl)-amide (62.0 g, 224 mmol) and 4-(dimethylamino)pyridine (98%, 1.5 g, 12.0 mmol) were dissolved in dichloromethane (370 mL), benzenesulfonyl chloride (31.1 mL, 242 mmol), followed by triethylamine (49.8 mL, 358 mmol) were added at room temperature and the mixture was stirred for 16 h. After that, it was diluted with water (140 mL) and acidified by addition of hydrochloric acid (25% m/m, 21.4 mL). The phases were separated and the organic layer was washed with water (160 mL). The combined aqueous phases were extracted with dichloromethane (160 mL), the combined organic extracts were concentrated in vacuo to a volume of 430 mL. The solvent was exchanged via continuous distillation in vacuo (internal temperature 40° C., 670-170 mbar) to ethanol (670 mL added), the overall volume was kept constant (430 mL). The resulting solution was allowed to cool to room temperature and seed crystals (ca. 10 mg) were added to initiate crystallization. After crystallization had started, the suspension was stirred for 30 min at room temperature, heptane (430 mL) was added within 50 min and it was stirred for 12 h. The suspension was then filtered, the precipitate was washed with heptane/ethanol 2:1 (v/v, 321 mL) and heptane (107 mL) and dried in vacuo at 40° C. to yield the title compound as a white crystalline solid (80.0 g, 85%). MS (ESI & APCI): m/z=418.1 [M+H]+. 1H NMR (CDCl3, 600 MHz): δ 0.59-0.64 (m, 1H), 0.65-0.69 (m, 1H), 0.80-0.90 (m, 1H), 0.99-1.05 (m, 1H), 1.12-1.21 (m, 2H), 1.30 (s, 3H), 1.47-1.53 (m, 2H), 2.15 (ddd, J=5.8 Hz, 9.2 Hz, 14.6 Hz, 1H), 2.70 (br d, J=14.0 Hz, 1H), 3.83 (dd, J=3.8 Hz, 12.3 Hz, 1H), 4.08 (dd, J=5.3 Hz, 12.4 Hz, 1H), 4.55 (br s, 1H), 5.04-5.08 (m, 1H), 7.49 (br s, 1H), 7.61 (t, J=7.8 Hz, 2H), 7.70 (t, J=7.5 Hz, 1H), 7.96 (d, J=7.6 Hz, 2H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].FC(F)(F)S(O[C:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:17][CH:18]=1)(=O)=O.[CH3:31][O:32][C:33]1[C:38](B(O)O)=[CH:37][CH:36]=[CH:35][N:34]=1.O>CN(C)C=O.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:31][O:32][C:33]1[C:38]([C:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:17][CH:18]=2)=[CH:37][CH:36]=[CH:35][N:34]=1
Reactant: O=C(OCc1ccccc1)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncccc1C1=CCN(C(=O)OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 72.8 %

Procedure:
Sodium carbonate (2.0 M in water; 4.0 mL, 8.09 mmol) was added to a solution of benzyl 4-{[(trifluoromethyl)sulfonyl]oxy}-3,6-dihydropyridine-1(2H)-carboxylate (1.26 g, 3.45 mmol) and (2-methoxypyridin-3-yl)boronic acid (0.58 g, 3.79 mmol) in N,N-dimethylformamide (12 mL). Dichloro [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.25 g, 0.345 mmol) was added and the mixture was heated to 70° C. After 2 h, the mixture was cooled to ambient temperature and water was added. The mixture was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and concentrated. Purification by silica gel chromatography (100% hexanes→50% hexanes/ethyl acetate) to give the title compound (0.815 g). MS 325.2 (M+1).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]([F:19])([F:18])[C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.Cl[C:21]1[NH:25][C:24]2[CH:26]=[C:27]([C:30]([F:33])([F:32])[F:31])[CH:28]=[CH:29][C:23]=2[N:22]=1.C(N(CC)C(C)C)(C)C>>[F:33][C:30]([F:31])([F:32])[C:27]1[CH:28]=[CH:29][C:23]2[N:22]=[C:21]([N:15]3[CH2:16][CH2:17][N:12]([C:11]4[CH:10]=[CH:9][N:8]=[CH:7][C:6]=4[C:5]([F:4])([F:18])[F:19])[CH2:13][CH2:14]3)[NH:25][C:24]=2[CH:26]=1
Reactant: FC(F)(F)c1ccc2nc(Cl)[nH]c2c1
Reactant: FC(F)(F)c1cnccc1N1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc2nc(N3CCN(c4ccncc4C(F)(F)F)CC3)[nH]c2c1

Procedure:
The piperazine from step (b) above (0.55 g, 1.81 mmol), 2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.4 g, 1.81 mmol, Example 1c) and N,N-diisopropylethylamine (0.63 mL, 3.62 mmol, Aldrich) reacted under the conditions of Example 3c to give the title compound as a light-yellow solid. M.p. 220-224° C. MS (ESI, pos. ion) m/z: 416 (M+1).
Reaction SMILES: Cl[O-].[Na+].[Cl:4][C:5]1[C:14]([CH:15]=[CH2:16])=[C:13]([Cl:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8].[CH3:18][C:19]([CH3:24])([CH3:23])[CH:20]=[N:21][OH:22].Cl[O-]>ClCCl.O>[Cl:4][C:5]1[C:14]([CH:15]2[O:22][N:21]=[C:20]([C:19]([CH3:24])([CH3:23])[CH3:18])[CH2:16]2)=[C:13]([Cl:17])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: C=Cc1c(Cl)ccc(C(=O)OC)c1Cl
Reactant: CC(C)(C)C=NO
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1ccc(Cl)c(C2CC(C(C)(C)C)=NO2)c1Cl
Reaction time: 12 h

Procedure:
17 ml of a 12% strength aqueous sodium hypochlorite solution were added dropwise at room temperature into a vigorously stirred solution of 2.6 g (10 mmol) of methyl 2,4-dichloro-3-ethenylbenzoate and 1 g (10 mmol) of 2,2-dimethylpropional-doxime in 100 ml of dichloromethane. After the mixture had been stirred for in each case 2 hours, two further portions of 0.5 g (5 mmol) of the oxime and 9 ml of the hypochlorite solution were added. Stirring was continued for 12 hours at room temperature, and the reaction mixture was then stirred into 350 ml of water. After extraction with dichloromethane, drying and removal of the solvent, the residue was chromatographed.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:34])([CH2:28][N:29]1[CH:33]=[N:32][N:31]=[N:30]1)[C:10]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:27]=[CH:26][C:23](C#N)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1)([F:12])[F:11].[Cl:35]C1C=CC(B(O)O)=CC=1>>[Cl:35][C:23]1[CH:26]=[CH:27][C:20]([O:19][C:16]2[CH:15]=[CH:14][C:13]([C:10]([F:12])([F:11])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:34])[CH2:28][N:29]3[CH:33]=[N:32][N:31]=[N:30]3)=[N:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(Oc2ccc(Cl)cc2)cn1

Procedure:
Compound 7 was prepared in a similar manner to compound 5 from (4-chlorophenyl)boronic acid to afford a solid (50 mg, 0.1 mmol, 35.7%). 1H NMR (500 MHz, CDCl3): δ 8.73 (s, 1H), 8.22 (d, J=2.5 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.46-7.37 (m, 3H), 7.30 (dd, J=3.0, 9.0 Hz, 1H), 7.04-7.00 (m, 2H), 6.80-6.77 (m, 1H), 6.76-6.71 (m, 1H), 5.49 (d, J=14.5 Hz, 1H), 5.16 (d, J=14.5 Hz, 1H). MS(ESI): m/z 479 [M++1]. HPLC: 98.43%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[C@@H:13]2[C@@H:14]([CH3:17])[CH2:15][CH2:16][C@@H:12]2[C:11]([C:18](OC)=[O:19])=[CH:10][O:9]1.[H-].C([Al+]CC(C)C)C(C)C.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.CC(C)=O>[OH:19][CH2:18][C:11]1[C@H:12]2[CH2:16][CH2:15][C@H:14]([CH3:17])[C@H:13]2[C@H:8]([O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[O:9][CH:10]=1
Reactant: COC(=O)C1=CO[C@@H](OC2CCCCO2)[C@H]2[C@@H]1CC[C@@H]2C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CC[C@@H]2C(CO)=CO[C@@H](OC3CCCCO3)[C@@H]21
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Methyl (1S, 4aS, 7S, 7aR)-1,4a,5,6,7,7a-hexahydro-1-(2-tetrahydropyranyloxy)-7-methylcyclopenta[c]pyran-4-carboxylate (1.25 g, 0.0042 mol) obtained in Example 10 was dissolved in 20 ml of anhydrous tetrahydrofuran, and the reaction solution was cooled by ice in the atmosphere of an argon gas. Then, 7 ml of diisobutylaluminum hydride (1.5 mol, toluene solution) was added dropwise. After the reaction mixture was stirred at the same temperature for 2 hours, ml of acetone was added and furthermore, a 3% aqueous sodium hydroxide solution was added dropwise. The reaction mixture solution was stirred for 1 hour. Magnesium sulfate was added to the solution and 20 minutes later, insoluble matters were filtered by a celite and concentrated under a reduced pressure. The resulting colorless oily substance, i.e., (1S, 4aS, 7S, 7aR)-1,4a,5,6,7,7a-hexahydro-4-(hydroxymethyl)-1-(2-tetrahydropyranyloxy)-7-methylcyclopenta[c]pyran (0.95 mg, yield=83.9%) had the following physicochemical properties:
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:33]1([C:36](Cl)=[O:37])[CH2:35][CH2:34]1>N1C=CC=CC=1>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:16]1[CH:17]=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:36]([CH:33]4[CH2:35][CH2:34]4)=[O:37])[S:3][C:4]=3[CH:10]=2)[CH:13]=[CH:14][C:15]=1[CH3:32])=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.9 %

Procedure:
To a solution of N-{5-[(2-amino-1,3-benzothiazol-6-yl)oxy]-2-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.452 mmol) in pyridine (4.0 mL) was added cyclopropanecarbonyl chloride (90 μL, 0.994 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methanol (2.0 mL)/tetrahydrofuran (2.0 mL)/water (2.0 mL). 1N Aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was neutralized with 1N hydrochloric acid, diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), successively, 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=70/30→0/100), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/diisopropyl ether to give the title compound (129 mg, 56%) as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:34])[F:33])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:20]4[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:32]([F:35])([F:33])[F:34])=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:20]4[CH2:21][NH:22][CH2:23][CH2:24][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(=O)N3CCC(c4cc(F)ccc4C(F)(F)F)CC3)c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CNCC2)N1CCC(c2cc(F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 3-(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (45, 120 mg, 0.24 mmol) in CH2Cl2 (2 mL) was added HCl (2N in Et2O, 2 mL). The mixture stirred for 18 h at ambient temperature. Additional HCl (2N in Et2O, 1 mL) was added and the mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with Et2O (20 mL) and the resulting solids were collected by filtration to provide (4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-3-yl)methanone hydrochloride (46) as a white solid (104 mg, 99%): 1H NMR (300 MHz, DMSO-d6) δ 9.54-9.19 (m, 2H), 7.84 (dd, J=9.0, 5.7 Hz, 1H), 7.60-7.51 (m, 1H), 7.32-7.20 (m, 1H), 5.32-5.12 (m, 1H), 4.78-4.60 (m, 1H), 4.29-4.16 (m, 2H), 3.43-3.30 (m, 2H, overlaps with H2O), 3.26-3.06 (m, 2H), 2.95 (t, J=5.4 Hz, 2H), 2.89-2.72 (m, 1H), 1.84-1.65 (m, 4H) missing N—H pyrazole; ESI MS m/z 397 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2([C:14]3[CH:13]=[C:12](Br)[S:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[N:6]=1.[C:18]([C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1)#[N:19].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:1][C:2]1[N:3]([CH3:17])[C:4](=[O:16])[C:5]2([C:14]3[CH:13]=[C:12]([C:24]4[CH:25]=[C:20]([CH:21]=[CH:22][CH:23]=4)[C:18]#[N:19])[S:11][C:10]=3[CH2:9][CH2:8][CH2:7]2)[N:6]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CN1C(=O)C2(CCCc3sc(Br)cc32)N=C1N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CN1C(=O)C2(CCCc3sc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 90 °C
Yield: 10.4 %

Procedure:
2′-amino-2-bromo-1′-methyl-6,7-dihydro-5H-spiro[benzo[b]thiophene-4,4′-imidazol]-5′(1′H)-one (0.127 g, 0.4 mmol), 3-cyanophenyl boronic acid (59 mg, 0.4 mmol) and Pd(dppf)Cl2 (33 mg, 0.04 mmol), were suspended in DMF (1.5 mL). Cs2CO3 (0.35 mL, 3.7 M aq. solution, 1.29 mmol) was added and the solution was degassed under a stream of nitrogen for 10 min. The mixture was heated at 90° C. for 2 hr. The reaction was cooled and solvent was removed in vacuo. The crude residue was purified using preparative HPLC to give the title compound as off-white solid (14 mg, 11%). 1H NMR δ (ppm)(DMSO-d6): 8.11 (1H, s), 7.86 (1H, d, J=8.18 Hz), 7.71 (1H, d, J=7.72 Hz), 7.57 (1H, t, J=7.85 Hz), 7.14 (1H, s), 6.41 (2H, br s), 3.02 (3H, s), 2.84-2.76 (2H, m), 2.11 (1H, d, J=13.56 Hz), 1.91 (2H, s), 1.70 (1H, s). HPLC (Method c) Rt 9.2 (min) m/z 337 (MH+).
Reaction SMILES: [F:1]C1N=CC=CC=1C(NC(C1C=CC=CC=1)CN1CCOCC1)=O.[ClH:25].Cl.[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([O:36][C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]4[N:59]=[CH:58][CH:57]=[CH:56][C:45]=4[C:46]([NH:48][C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=4[CH3:55])=[O:47])=[CH:39][C:38]=3[F:60])=[C:30]2[CH:29]=[CH:28]1>>[ClH:25].[NH:27]1[C:31]2=[N:32][CH:33]=[CH:34][C:35]([O:36][C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]4[N:59]=[CH:58][CH:57]=[CH:56][C:45]=4[C:46]([NH:48][CH2:49][C:54]4[CH:53]=[CH:52][C:51]([F:1])=[CH:50][CH:55]=4)=[O:47])=[CH:39][C:38]=3[F:60])=[C:30]2[CH:29]=[CH:28]1
Reactant: Cc1ccccc1NC(=O)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: O=C(NC(CN1CCOCC1)c1ccccc1)c1cccnc1F
Agent: Cl
Product: O=C(NCc1ccc(F)cc1)c1cccnc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Yield: 13 %

Procedure:
2-Fluoro-N-(2-morpholino-1-phenylethyl)nicotinamide (0.096 g, 0.29 mmol) was converted to the title compound (0.022 g, 13%) in a manner similar to the preparation of 2-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-o-tolylnicotinamide (Step B of Example 8). 1H NMR (DMSO-d6) δ 12.53 (s, 1H), 10.93-11.05 (m, 2H), 9.73 (d, 1H, J=7.8 Hz), 8.59 (dd, 1H, J=7.9, 1.3 Hz), 8.35 (dd, 1H, J=4.7, 1.4 Hz), 8.20 (d, 1H, J=6.2 Hz), 8.06-8.15 (m, 1H), 7.45-7.55 (m, 3H), 7.23-7.40 (m, 4H), 6.90-6.99 (m, 1H), 6.60 (d, 1H, J=6.2 Hz), 6.38-6.45 (m, 1H), 5.53-5.64 (m, 1H), 3.10-4.00 (m, 10H); HRMS(ESI+), 553.2363 (M+H)+ calc, 553.2368 (M+H)+ found.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5].[OH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CO>[F:1][C:2]1[CH:9]=[C:8]([N:16]2[CH2:17][CH2:18][CH:13]([OH:12])[CH2:14][CH2:15]2)[CH:7]=[C:6]([F:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: OC1CCNCC1
Solvent: CO
Product: N#Cc1c(F)cc(N2CCC(O)CC2)cc1F
Temperature: 65 °C
Yield: 21.3 %

Procedure:
To a solution of 1.0 g (6.4 mmol) of 2,4,6-trifluorobenzonitrile in MeOH (35 mL) was added 0.65 g (6.4 mmol) of 4-hydroxypiperidine and 1.2 mL (6.7 mmol) of N,N-diiisopropylethylamine. The mixture was heated to 65° C. for 4 h then cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography to provide 0.325 g (21%) of 2,6-difluoro-4-(4-hydroxy-piperidin-1-yl)-benzonitrile as a white solid.