Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(C(F)(F)F)=O.[NH2:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13].C[CH2:35][N:36](C(C)C)C(C)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O>C1COCC1.C(Cl)Cl>[CH3:35][NH:36][C:1]([NH:8][CH2:9][CH2:10][CH2:11][C@:12]([C@@H:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]1)([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=1)[OH:13])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@](O)(CCCN)c2cccc(Cl)c2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(F)(F)F
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CNC(=O)NCCC[C@@](O)(c1cccc(Cl)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of the TFA salt of (R)-tert-butyl 3-((S)-4-amino-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.0388 g, 0.078 mmol, 1.0 equiv) in THF (5 mL) and CH2Cl2 (5 mL) at rt were added of DIEA (0.7 mL) and p-nitrophenyl chloroformate (0.0350 g, 0.17 mmol, 2.2 equiv). The mixture was stirred at rt for 3 h. One half of the resulting solution was withdrawn and 33 wt % MeNH2 in EtOH (1.5 mL) was added. The resulting mixture was stirred at rt for 1 h. The solvents were removed in vacuo and the residue was purified by reversed-phase preparative HPLC (Phenomenex® Luna 5μ C18(2) 100 A, 250×21.20 mm, 5 micron, 70%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 7 min, flow rate 25 mL/min) to give (R)-tert-butyl 3-((S)-4-(methylamino-carbonylamino)-1-(3-chlorophenyl)-1-hydroxybutyl)piperidine-1-carboxylate (0.0043 g). LC-MS (3 min) tR=1.71 min, m/z 442, 440 (M+H+), 340.
Reaction SMILES: [O:1]=[C:2]1[NH:6][N:5]=[C:4]([CH2:7][S:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[NH:3]1.N.CO>C1COCC1.[Ni]>[NH2:25][CH2:24][C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([CH2:11][S:8]([CH2:7][C:4]3[NH:3][C:2](=[O:1])[NH:6][N:5]=3)(=[O:9])=[O:10])=[CH:13][CH:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: N#Cc1cccc(-c2ccc(CS(=O)(=O)Cc3n[nH]c(=O)[nH]3)cc2)c1
Agent: [Ni]
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cccc(-c2ccc(CS(=O)(=O)Cc3n[nH]c(=O)[nH]3)cc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99 %

Procedure:
A suspension of 4′-({[(5-oxo-4,5-dihydro-1H-1,2,4-triazol-3-yl)methyl]sulfonyl}methyl)biphenyl-3-carbonitrile obtained in Reference Example 110 (0.250 g, 0.705 mmol), Raney-nickel (0.250 g) and 28% aqueous ammonia (5 mL) in THF (5 mL)-methanol (5 mL) was stirred at room temperature for 4 hr under hydrogen atmosphere (1 atm). The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Diethyl ether was added to the residue, and the precipitated solid was collected by filtration to give the title compound as a pale-blue powder (0.250 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([C:41]2[CH:42]=[N:43][C:44]([O:47][CH3:48])=[CH:45][CH:46]=2)[CH:36]=1)=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cn1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Product: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(OCC(F)(F)F)cc3NC(=O)OC(C)(C)C)c2)cn1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (296 mg, 0.79 mmol) and 3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K10) (289 mg, 0.88 mmol) according to the general procedure M. Obtained as an orange foam (402 mg, 81%).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15]Cl)[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7].[C:37]1(=[O:47])[NH:41][C:40](=[O:42])[C:39]2=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]12.[K].[Cl-].[Na+]>CN(C)C=O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH2:15][N:41]2[C:40](=[O:42])[C:39]3=[CH:43][CH:44]=[CH:45][CH:46]=[C:38]3[C:37]2=[O:47])=[O:17])[CH2:10][C@H:9]1[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)=[O:7]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CCl)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Agent: [Cl-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)N1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Temperature: 25 °C
Reaction time: 7 h
Yield: 56.7 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-4-(2-chloroacetyl)-2-(1H-indol-3-yl-methyl)piperazine (730 mg), potassium phthalimide (260 mg) in dimethylformamide (10 ml) was stirred at room temperature for 7 hours and then poured into aqueous sodium chloride solution (100 ml). The resulting precipitate was collected by filtration, washed with water and dried. The crude product was dissolved in toluene (7 ml) and filtered. To the filtrate was added n-hexane (35 ml) and the whole was stirred for 10 minutes. The resulting powder was collected by filtration, washed with ethyl ether and dried to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-yl-methyl)-4-(phthalimidomethylcarbonyl) piperazine (500 mg).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:19])[N:6]=2)[CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:28])C=1>C(Cl)Cl.O>[CH:1]1([CH2:4][C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17]([CH3:18])=[O:28])[N:12]=3)=[CH:9][N:8]=[C:7]([NH2:19])[N:6]=2)[CH2:2][CH2:3]1
Reactant: CSc1nccc(-c2cnc(N)nc2CC2CC2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CS(=O)c1nccc(-c2cnc(N)nc2CC2CC2)n1

Procedure:
To a solution of 4′-(cyclopropylmethyl)-2-(methylthio)-4,5′-bipyrimidin-2′-amine (4a) (2.17 g, 7.14 mmol) in DCM (14.29 ml) was added m-CPBA (1.761 g, 7.14 mmol). Immediately after the addition of m-CPBA, the reaction completion was observed. The reaction mixture was diluted with DCM and water. The organic layer was washed with saturated sodium bicarbonate and brine, dried with sodium sulfate, and concentrated in vacuo. The crude residue was purified by Biotage flash chromatography [100 g SNAP column, eluted with 1-15% MeOH/DCM] to obtain the desired product as a slightly pale yellow solid (1.47 g, 71% yield). MS (ES+): m/z=290.4/291.5 (100/10) [MH+]. HPLC: tR=0.76 min over 3 min. Purity: 100% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: Br[CH:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1.[C:9]1(=[O:15])[NH:13][C:12](=[O:14])[CH2:11][CH2:10]1.[Na].C1(=O)NC(=O)CC1.[H-].[Na+]>O.CN(C=O)C>[CH:2]1([N:13]2[C:9](=[O:15])[CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: O=C1CCC(=O)N1
Reactant: BrC1C=CCCCC1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(=O)N1C1C=CCCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Bromocycloheptene (1.75 g) was added dropwise at room temperature to a DMF suspension (10 ml) of sodium succinimide prepared from succinimide (0.99 g) and 60% sodium hydride (0.40 g). This mixture was stirred at room temperature for 24 hours, poured into water (10 ml) and extracted with ether. The oily product obtained by concentration was purified by chromatography on silica gel to obtain 0.09 g of N-(2-cycloheptenyl)succinimide [Compound (214)].
Reaction SMILES: C[O:2][C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:30])[N:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)[NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:15])=[O:7]>C(O)C.[OH-].[Na+]>[Cl:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]([NH:5][C@H:4]([C:3]([OH:31])=[O:2])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:24](=[O:30])[N:25]([CH3:29])[CH:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccn(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(Cl)c1C(=O)N[C@@H](Cc1ccc(-c2cccn(C)c2=O)cc1)C(=O)O
Temperature: 50 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a suspension of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine methyl ester (118 mg, 0.269 mmol) in ethanol (6 mL) was added IN aqueous sodium hydroxide solution (4 mL) at room temperature. The resulting solution was heated to 50° C. and stirred for 2 h. Then, the ethanol was removed under vacuum and the residue was diluted with water (25 mL). The aqueous solution was washed with diethyl ether (25 mL) to remove any neutral impurities. The aqueous layer was acidified with 1.0 N HCl and the product was extracted into ethyl acetate (2×25 mL). The combined organic extracts were washed with brine solution (50 mL) and were dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration afforded 81 mg (71% yield) of N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1-methyl-2-oxo-3-pyridinyl)-L-phenylalanine as a white solid: mp 204-210° C. FAB-HRMS m/e calcd for C23H21ClN2O4 (M+H) 425.1268, found 425.1267
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].Br[C:11]1[S:12][CH:13]=[C:14]([Br:16])[N:15]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:11]2[S:12][CH:13]=[C:14]([Br:16])[N:15]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Brc1csc(Br)n1
Reactant: CC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2nc(Br)cs2)CC1
Temperature: 65 °C
Reaction time: 6 h
Yield: 54.8 %

Procedure:
To a solution of 1-acetylpiperazine (316 mg, 4.78 mmol) and 2,4-dibromo-1,3-thiazole (900 mg, 3.71 mmol) in N,N-dimethylformamide (8 ml) was added triethylamine (0.78 ml, 5.56 mmol). The reaction mixture was stirred at 50° C. for 14 hrs and at 65° C. for 6 hrs. After cooling to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane:methanol=100:0→98:2) to give 1-acetyl-4-(4-bromo-1,3-thiazol-2-yl)piperazine (590 mg, yield 55%) as a pale-white brown solid.
Reaction SMILES: Cl.[S:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:17]=2)=[CH:5][N:4]=[CH:3]1.[C:18](Cl)([Cl:20])=[O:19].C1(C)C=CC=CC=1.C(N(CC)CC)C>ClCCl>[S:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[O:16][CH2:15][CH2:14][N:13]([C:18]([Cl:20])=[O:19])[CH2:12][C:11]=3[CH:17]=2)=[CH:5][N:4]=[CH:3]1
Reactant: O=C(Cl)Cl
Reactant: c1ncc(-c2ccc3c(c2)CNCCO3)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)N1CCOc2ccc(-c3cncs3)cc2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of 7-(thiazol-5-yl)-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine hydrochloride as obtained in step 2 in dichloromethane (20 mL) at −20° C. added 20% phosgene in toluene (0.25 mL, 0.50 mmol) followed by addition of triethylamine (0.35 mL, 25 mmol). The reaction was allowed to warm to 25° C. and stand for 18 h. The mixture was then concentrated to give 7-(thiazol-5-yl)-2,3-dihydrobenzo[f][1,4]oxazepine-4(5H)-carbonyl chloride.
Reaction SMILES: II.C(C1C=CC(S(O)(=O)=[O:12])=CC=1)C.ClCl.Cl[C:18]1[C:23]([Cl:24])=[C:22]([CH2:25][CH3:26])[C:21]([Cl:27])=[CH:20][C:19]=1S(O)(=O)=O.[N+:32]([O-])([OH:34])=[O:33]>S(=O)(=O)(O)O.O>[Cl:24][C:23]1[C:22]([CH2:25][CH3:26])=[C:21]([Cl:27])[CH:20]=[C:19]([N+:32]([O-:34])=[O:33])[C:18]=1[OH:12]
Reactant: O=[N+]([O-])O
Reactant: CCc1ccc(S(=O)(=O)O)cc1
Reactant: CCc1c(Cl)cc(S(=O)(=O)O)c(Cl)c1Cl
Agent: ClCl
Agent: II
Agent: O=S(=O)(O)O
Solvent: O
Product: CCc1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Iodine (5 parts) was dissolved in 96% sulfuric acid (1000 parts) and 4-ethylbenzenesulfonic acid (186 parts) was added thereto. Chlorine (about 235 parts) was introduced therein, while being stirred at a temperature of 40° to 60° C. Then, a 2,3,5-trichloro-4-ethylbenzenesulfonic acid content in the reaction mixture reached 78.3%. Successively, water (200 parts) was added to the reaction mixture so as to make a ratio of sulfuric acid to water 8:2, and the reaction mixture was subjected to steam distillation at a temperature of 160° to 200° C., thereby performing desulfonation reaction. Mixed acid consisting of 67% nitric acid (110 parts) and concentrated sulfuric acid (174 parts) was added dropwise to the desulfonation reaction product isolated from water, while being stirred at a temperature of 20° to 40° C., and the mixture was kept at that temperature for 1 to 3 hours. Thereafter, the reaction mixture was poured into water (950 parts) at a temperature of 30° C. or below. The reaction product was separated from water and then washed with water. The crude product of 2,3,5-trichloro-4-ethylnitrobenzene (220 parts) was added to a mixture of methanol (1560 parts), water (200 parts) and potassium hydroxide (240 parts), and the resulting mixture was refluxed for 4 hours. Thereafter, the reaction mixture was cooled to ambient temperature to deposit precipitate. The precipitate separated and washed with methanol and then water was placed in 20 % sulfuric acid (510 parts). The mixture was stirred for 3 hours at a temperature of 70° to 75° C., and then cooled to produce crystals of 2,4-dichloro-3-ethyl-6-nitrophenol. The crystals were collected on a filter, washed with water and then dried to obtain a desired product (141.8 parts). The over-all yield from 4-ethylbenzenesulfonic acid was found to be 60.1 %. The product had a melting point of 45.1° to 46.5° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]=[O:43])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:50][CH2:49][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:52]N1CCCCC1CO.C[Zn]C>C1(C)C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH:42]([OH:43])[CH3:52])[C:38]2=[N:44][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:51])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:48])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:47])=[C:28]([F:46])[C:29]=2[C:30]2[CH:45]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:49][CH2:50]1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Reactant: CN1CCCCC1CO
Agent: C[Zn]C
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Reaction time: 1 h

Procedure:
Methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (0.017 g, 0.024 mmol, 1.0 equiv) and (1-methylpiperidin-2-yl)methanol (3.12 mg, 0.024 mmol, 1.0 equiv) were mixed in 1 mL toluene and concentrated to remove water. Then the mixture was re-dissolved in toluene (1.2 mL). To this solution was added 1 M dimethyl zinc (0.097 mL, 4.0 equiv) and stirred for 1 hour. It was quenched by 1 mL methanol. After concentration, the residue was used as is for the next reaction. LCMS (ESI, M+1): 720.4.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13]1([CH2:19][C:20](OC)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[O:21]=[C:20]([CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: COP(C)(=O)OC
Reactant: COC(=O)Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)Cc1ccccc1)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of dimethyl methylphosphonate (2.16 mL, 20 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 13.75 mL, 22 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl phenylacetate (1.40 mL, 10 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH: CH2Cl2=2:98) to give the product (1.50 g) with colorless oil in 62% yield. 1HNMR (CDCl3, ppm) δ 3.074 (d, J=21 Hz, 2H), 3.760 (s, 3H), 3.762 (s, 3H), 3.86 (s, 2H), 7.31 (m, 5H).
Reaction SMILES: C1COCC1.[Cl:6][C:7]1[C:11]([CH3:12])=[CH:10][S:9][C:8]=1[C:13]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1.O.[NH2:22][NH2:23].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Cl:6][C:7]1[C:11]([CH3:12])=[CH:10][S:9][C:8]=1[C:13]1([C:18]([NH:22][NH2:23])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NN
Reactant: Cc1csc(C2(C(=O)Cl)CCCC2)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1csc(C2(C(=O)NN)CCCC2)c1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
DMF (a catalytic amount) was added to a thionyl chloride (15 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarboxylic acid (1.59 g), followed by stirring at 75° C. for 30 minutes. The reaction solution was subjected to evaporation under reduced pressure to obtain 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbonyl chloride. A THF (20 ml) solution of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbonyl chloride was added dropwise to a THF (20 ml) solution of hydrazine monohydrate (12.6 ml) at 0° C., followed by stirring at 0° C. for 3 hours. After the reaction solution and chloroform were added to a saturated aqueous sodium hydrogen carbonate solution, the organic layer was separated. The organic layer washed with brine and, after drying over anhydrous sodium sulfate and filtration, the solvent was removed by evaporation under reduced pressure to obtain 1.65 g of 1-(3-chloro-4-methyl-2-thienyl)cyclopentanecarbohydrazide (pale yellow solid).
Reaction SMILES: [NH:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:14][C:15]([F:50])([F:49])[C:16]1[CH:17]=[C:18]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:19][N:20]1[CH2:25][C:24]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=2)([CH2:26][CH2:27]OS(C)(=O)=O)[CH2:23][O:22][C:21]1=[O:41].C(=O)([O-])[O-].[K+].[K+].[ClH:57]>C(#N)C.CCOCC.O>[OH2:22].[ClH:39].[ClH:57].[NH:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:27][CH2:26][C:24]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=3)[CH2:23][O:22][C:21](=[O:41])[N:20]([CH2:19][C:18]3[CH:17]=[C:16]([C:15]([F:49])([F:50])[F:14])[CH:44]=[C:43]([C:45]([F:47])([F:46])[F:48])[CH:42]=3)[CH2:25]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(NC2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)COC(=O)N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC#N
Product: O=C1OCC(CCN2CCC(Nc3ccccc3)CC2)(c2ccc(Cl)c(Cl)c2)CN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
A mixture of 0.3 g of 4-anilinopiperidine, 0.8 g of the compound obtained in step C of EXAMPLE 4 and 0.69 g of potassium carbonate in 5 ml of acetonitrile is heated at 5°-60° C. for 5 hours. The reaction mixture is poured into water and extracted with AcOEt, the organic phase is washed twice with water and with saturated NaCl solution and dried over MgSO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica H using DCM and then a DCM/MeOH mixture (96/4; v/v) as the eluent. The product obtained is taken up with a saturated solution of gaseous HCl in ether and the precipitate formed is wrung to give 0.12 g of the expected product. M.p.=158° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:16]([OH:18])=O)[CH:14]=3)[N:9]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:8]=2)=[CH:3][CH:2]=1.[C:38]1([N:44]2[CH2:49][CH2:48][CH2:47][C@@H:46]([NH2:50])[CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:38]1([N:44]2[CH2:49][CH2:48][CH2:47][C@@H:46]([NH:50][C:16]([C:13]3[CH:14]=[C:15]4[C:10](=[CH:11][CH:12]=3)[N:9]([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:8]=[C:7]4[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[O:18])[CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H]1CCCN(c2ccccc2)C1
Reactant: O=C(O)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(N[C@@H]1CCCN(c2ccccc2)C1)c1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of 3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (97 mg, 0.20 mmol), (3R)-1-phenylpiperidin-3-amine (120 mg, 0.48 mmol), EDC (0.08 g, 0.4 mmol), HOBt (0.07 g, 0.5 mmol) and DIPEA (400 μl, 2.3 mmol) in DMF (2 ml) was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to provide crude N-[(3R)-1-phenylpiperidin-3-yl]-3-(pyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, which was used as-is without further purification. LCMS calc'd for C43H38N5O [M+H]+=640; found 640.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][CH2:24][CH2:25][NH:26][CH2:27][CH2:28][O:29][CH3:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:26]([CH2:27][CH2:28][O:29][CH3:30])[CH2:25][CH2:24][O:23][CH3:22])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: COCCNCCOC
Product: COCCN(CCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCOC

Procedure:
According to the method in example 5, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and bis(2-methoxyethyl)amine were converted to yield [3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl]-bis-(2-methoxy-ethyl)-amine as orange oil, MS: 479 (MH+, 1Br).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([OH:17])=O)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([C:15]([Cl:20])=[O:17])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cn(-c2ccc(F)cc2)nc1C(=O)O
Product: COc1cn(-c2ccc(F)cc2)nc1C(=O)Cl

Procedure:
E2 (100 mg, 0.42 mmol, 1.0 eq.) was heated in thionyl chloride (1 mL) for 4 h under reflux. Solvent was removed in vacuo and the crude material was resolved in dry toluene and evaporated under reduced pressure again to yield E3. The crude material was used in the next step without further purification.