Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([CH:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C@H:21]3[S:20][C:19]([NH2:35])=[C:18]2[CH2:36][C:37]2[S:41][CH:40]=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1>C(N(CC)CC)C>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:34])[C@@H:24]([C:25](=[O:33])[CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:21]3[S:20][CH:19]([NH2:35])[C:18]=2[CH2:36][C:37]2[S:41][CH:40]=[CH:39][CH:38]=2)=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC1=C(Cc2cccs2)C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](C(=O)Cc3ccccc3)[C@H]2S1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: NC1S[C@@H]2[C@H](C(=O)Cc3ccccc3)C(=O)N2C(C(=O)OC(c2ccccc2)c2ccccc2)=C1Cc1cccs1

Procedure:
A solution of 10.2 g of 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester in 130 ml of a 9:1-mixture of pyridine and triethylamine is left to stand in the dark and under nitrogen for 31/2 days at room temperature, then evaporated under reduced pressure. The residue is evaporated several times to dryness with toluene and then triturated with ethyl acetate. The solid residue is recrystallised from ethyl acetate and yields the somewhat impure 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester. The mother liquors of trituration and crystallisation are evaporated to dryness and yield on evaporation a mixture of the 7β-phenylacetylamino-3-(2-thenyl)-ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester and the 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester which is chromatographed on 160 g of silica gel. Elution is performed with methylene chloride containing 2% of ethyl acetate, fractions of 200 ml (of 100 ml from fraction 9) being taken. Fractions 5-8 yield some impure 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester and fractions 9-11 some impure 7β-phenylacetyl-amino-3-(2-thenyl)ceph-2-em-4ξ-carboxylic acid diphenylmethyl ester. The product of fractions 5-8 is crystallised from ethyl acetate and combined with the first crystalline product and chromatographed on 60 g of silica gel. Elution is performed with methylene chloride containing 0.5% of ethyl acetate, fractions of 60 ml being taken. Fractions 7-9 yields the pure 7β-phenylacetyl-amino-3-(2-thenyl)-ceph-3-em-4-carboxylic acid diphenylmethyl ester, which after crystallisation from ethyl acetate melts at 184°C; [α]D20 = -65° ± 1° (c = 0.968 in chloroform): thin-layer chromatogram (silica gel): Rf = 0.46 (system: toluene/ethyl acetate 4:1) and Rf = 0.57 (system: toluene/acetone 9:1); ultraviolet absorption spectrum (in 95% ethanol): λmax = 264μ (ε = 9600); infrared spectrum (in mineral oil); characteristic bands at 2,99μ, 5,59μ, 5,77μ, 5,98μ, 6,10μ and 6,50μ.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5](S(O)(=O)=O)=[CH:4][CH:3]=1.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1.[CH2:18](Br)[C:19]1C=CC=C[CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O(C(OC)(C)C)C>[CH2:12]([O:16][CH2:15][C:14]1[CH:13]=[CH:17][CH:20]=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COC(C)(C)OC
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of compound 23.1 (1.8 g, 5.03 mmol) in DMF (6 mL) and 2,2-dimethoxyl propane (12 mL) was added p-toluenesulfonic acid monohydrate (0.095 g, 0.5 mmol). The resultant mixture was stirred at 65° C. for 3 h. The excess 2,2-dimethoxyl propane was slowly distilled. The reaction mixture was cooled to room temperature and charged with THF (50 mL), benzyl bromide (0.8 mL, 6.73 mmol) and cesium carbonate (2.0 g, 6.13 mmol). The resulted mixture was stirred at 65° C. for 16 h. The reaction was quenched with acetic acid aqueous solution (4%, 100 mL) at 0° C., and extracted with ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to afford desired mono protected compound 23.3 (1.21 g, 49%).
Reaction SMILES: C(O)(=O)C.[C:5]1([N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:12]([N:14]2[CH2:19][CH2:18][NH:17][C@H:16]([C:20]([OH:22])=[O:21])[CH2:15]2)=[O:13])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)C(C)C)(C)C.[CH2:38]([N:43]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:44](Cl)=[O:45])[CH2:39][CH2:40][CH2:41][CH3:42]>CN(C=O)C>[CH2:38]([N:43]([C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:44]([N:17]1[CH2:18][CH2:19][N:14]([C:12](=[O:13])[N:11]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:15][C@H:16]1[C:20]([OH:22])=[O:21])=[O:45])[CH2:39][CH2:40][CH2:41][CH3:42]
Reactant: CCCCCN(C(=O)Cl)c1ccccc1
Reactant: O=C(O)[C@@H]1CN(C(=O)N(c2ccccc2)c2ccccc2)CCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CCCCCN(C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C[C@H]1C(=O)O)c1ccccc1
Temperature: 25 °C

Procedure:
A stirred solution of 0.383 g (1.00 mmole) of (S)-4-(diphenylcarbamoyl)piperazine-2-carboxylic acid acetate salt (from Step C) and 0.400 g (3.09 mmole) of N,N-diisopropylethylamine in 6 ml of DMF at 0° C. was treated with 0.253 g (1.12 mmole) of N-pentyl-N-phenylcarbamoyl chloride (from Step B) and then was warmed to 25° C. for 16 hours. The DMF was removed in vacuo and the residue was partitioned between 20 ml of 1N HCl and 50 ml of chloroform which was dried over sodium sulfate and concentrated in vacuo to a yellow oil. The oil was flash chromatographed over 100 cc of silica gel with 12×25 ml of chloroform, 10×25 ml of 80:20:2 chloroform-methanol-ammonia water. Fractions 19-26 were combined and concentrated to 0.338 g (ammonium salt) of clear glass which was homogeneous by TLC (80:20:2 chloroform-methanol-ammonia water, Rf =0.4). The product was partitioned between 20 ml. of 1N HCl and 30 ml of chloroform which was dried over sodium sulfate and concentrated in vacuo to 0.337 g (72%) of a clear glass.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH2:25]([NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH2:25]([NH:33][C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[N:8][C:9]=3[NH2:11])[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=2)=[CH:38][CH:37]=1)[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Reactant: O=C(NCCc1ccccc1)c1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C(=O)NCCc5ccccc5)cc4)c4c(N)ncnc43)CC2)CC1
Yield: 23 %

Procedure:
cis-3-Iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (100 mg, 0.226 mmol), 4-[(phenethylamino)carbonyl]phenylboronic acid (60 mg, 0.249 mmol), palladium tetrakistriphenyphosphine (16 mg, 0.014 mmol) and sodium carbonate (58 mg, 0.544 mmol) were mixed with ethylene glycol dimethyl ether (3 mL) and water (1.5 mL). The reaction mixture was heated at reflux overnight. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by preparative thin layer column chromatography using dichloromethane/methanol (80:20) as mobile phase to give cis-N1-phenethyl-4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzamide (28 mg, 23%). 1H NMR (DMSO-d6) δ 1.62 (m, 4H), 2.24 (m, 16H), 2.88 (m, 2H), 3.54 (m, 2H), 4.82 (m, 1H), 7.29 (m, 7H), 8.73 (d, J==8.10 Hz, 2H), 7.99 (d, 8.17 Hz, 1H), 8.67 (m, 1H). LC/MS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 3.5 mL/min.): MH+=539.3, Rt=2.50 min.
Reaction SMILES: CO[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16](=O)C)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[OH-:19].[Na+].BrBr.S([O-])(O)(=O)=O.[Na+].[O:29]1[CH2:34]COCC1>O>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:34]([OH:29])=[O:19])=[CH:8][CH:7]=2)=[CH:14][CH:13]=1
Reactant: [OH-]
Reactant: COc1ccc(-c2ccc(OC(C)=O)cc2)cc1
Reactant: C1COCCO1
Agent: BrBr
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 40 °C
Reaction time: 0.5 h

Procedure:
In 400 ml of dioxane was dissolved 30 g of 4-methoxy-4'-acetoxy biphenyl. To this solution was dropped an aqueous solution composed of 84 g of sodium hydroxide, 400 ml of water and 30 ml of bromine and maintained at 40° C., and the solution was stirred for 30 minutes. Thereafter, 200 g of sodium hydrogen sulfate and 1 l of water were added to the solution, and the resultant reaction solution was concentrated under a reduced pressure, methyl bromide and dioxane were evaporated from the reaction solution, an aqueous concentrated hydrochloric acid solution was added to the solution and the solution was then allowed to stand to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried to obtain 28 g of crude 4-methoxy-4'-biphenylcarboxylic acid. In 1.2 l of acetic acid was dissolved 28 g of this crude 4-methoxy-4'-biphenylcarboxylic acid. Thereafter, 240 ml of hydrogen bromide (48% concentration) was added to this solution and the mixed solution was refluxed for 10 hours. To this solution, 3 l of ice water was added, thereby forming a precipitate. The precipitate was recovered by filtration, washed with water, and then dried. The dried product was dissolved in a mixture of 50 ml of acetic anhydride and 25 ml of pyridine, and the solution was dropped in 200 ml of ice water to form a precipitate. The precipitate was recovered by filtration, washed with water and then dried. Recrystallization of the dried precipitate from acetic acid yielded 18 g of 4-acetoxy-4'-biphenylcarboxylic acid. 18 g of the 4-acetoxy-4'-biphenylcarboxylic acid was reacted with 20 g diazomethane to obtain methyl 4-acetoxy-4'-biphenylcarboxylate. The methyl 4-acetoxy-4'-biphenylcarboxylate was dissolved in 500 ml of tetrahydrofuran and an equimolar amount of a 1N aqueous lithium hydroxide solution was added to the resultant solution thereby to hydrolyze the methyl 4-acetoxy-4'-biphenylcarboxylate. The reaction mixture was extracted with ether to obtain 13 g of methyl 4-hydroxy-4'-biphenylcarboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[N:12]([O-])=O.[Na+]>Cl>[NH:1]([C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1)[NH2:12]
Reactant: O=N[O-]
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Agent: [Na+]
Product: COC(=O)c1ccc(NN)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93853.6 %

Procedure:
To a cold solution of methyl 4-aminobenzoate (15.0 g, 0.099 mol) in conc. HCl was added aq. solution of sodium nitrite (7.5 g, 0.109 mmol) at 0-5° C. The reaction mass was stirred at RT for 1-2 h. The reaction mass was cooled to 0° C. and stannous chloride (0.049 g, 0.210 mmol) was added and further stirred at RT for 2-3 h. The reaction mass was filtered to afford 17.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 3.77 (s, 3H), 7.03 (d, J=8.4 Hz, 2H), 7.82 (d, J=8.4 Hz, 2H), 10.69 (br s, 2H); MS (m/z): 167.28 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][N:3]1[CH3:16])=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:40]#[C:41][C:42]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][CH:43]=1>C1(C)C=CC=CC=1>[Cl:48][C:45]1[CH:46]=[CH:47][C:42]([C:41]#[C:40][N:8]2[C:9]3[C:14](=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)[C:6]3[CH2:5][CH2:4][N:3]([CH3:16])[CH:2]([CH3:1])[C:7]2=3)=[CH:43][CH:44]=1
Reactant: Clc1ccc(C#CBr)cc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CCN(C)C3C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccc(Cl)cc2)C(C)N(C)CC1
Temperature: 80 °C
Yield: 19.2 %

Procedure:
1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (214 mg, μmol) was mixed with CuSO4.5H2O (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), K3PO4 (425 mg, 2 mmol) and 1-(bromoethynyl)-4-chlorobenzene (237 mg, 1.1 mmol) in toluene (8-10 ml). The reaction mixture was flushed with nitrogen and heated at 80° C. for 16 h. The reaction mixture was filtered through Celite, and the Celite bed was rinsed with dichloromethane. Combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100-200 mesh) eluting with 60-80% ethyl acetate in hexane to obtain 9-((4-chlorophenyl)ethynyl)-1,2,6-trimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole (67 mg) as brown semi solid. 1H NMR (CDCl3) FREE BASE 7.42 (d, 2H), 7.38 (d, 2H), 7.30 (m, 2H), 7.10 (d, 1H), 3.90 (m, 1H), 3.20 (m, 1H), 2.90 (m, 2H), 2.62 (m, 1H), 2.58 (s, 3H), 2.42 (s, 3H), 1.30 (d, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])([C:28]([F:31])([F:30])[F:29])[C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][C:3]=1[F:40].[C:41](Cl)(=O)[O:42]C1C=CC([N+]([O-])=O)=CC=1.[NH2:54][C@@H:55]1[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56]1>ClCCl>[Si:33]([O:32][C:23]([C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:41](=[O:42])[NH:54][C@@H:55]4[CH2:59][CH2:58][N:57]([C:60]([O:62][C:63]([CH3:66])([CH3:65])[CH3:64])=[O:61])[CH2:56]4)=[C:3]([F:40])[CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[CH:22][CH:21]=1)([C:24]([F:25])([F:26])[F:27])[C:28]([F:31])([F:29])[F:30])([C:36]([CH3:37])([CH3:39])[CH3:38])([CH3:34])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)OC(c1ccc(CN2CCN(C(=O)c3ccc(N)c(F)c3)CC2)cc1)(C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)Nc2ccc(C(=O)N3CCN(Cc4ccc(C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)cc4)CC3)cc2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.2 %

Procedure:
A solution of (4-amino-3-fluorophenyl)(4-(4-(2-(tert-butyldimethylsilyloxy)-1,1,1,3,3,3-hexafluoropropan-2-yl)benzyl)piperazin-1-yl)methanone (0.674 mmol, 400 mg) and 4-nitrophenyl carbonochloridate (0.674 mmol, 136 mg) in dichloromethane (10 mL) was stirred at room temperature for 30 minutes. (R)-tert-Butyl 3-aminopyrrolidine-1-carboxylate (2.021 mmol, 0.353 mL, 376 mg) was added and the reaction stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane (10 mL) and washed with saturated aqueous sodium hydrogen carbonate solution (10 mL). The organic phase was concentrated and the resulting residue was purified by column chromatography on silica gel (eluting with dichloromethane—5% methanol/95% dichloromethane gradient) to afford the title compound (300 mg).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:16][CH:17]2[CH2:31][CH:20]3[CH2:21][N:22](C(OC(C)(C)C)=O)[CH2:23][CH:19]3[CH2:18]2)=[N:5][C:6]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:15])[CH:14]=2)=[N:7][CH:8]=1)#[N:2].Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl.O>[CH3:15][N:13]1[CH:14]=[C:10]([NH:9][C:6]2[N:5]=[C:4]([NH:16][CH:17]3[CH2:31][CH:20]4[CH2:21][NH:22][CH2:23][CH:19]4[CH2:18]3)[C:3]([C:1]#[N:2])=[CH:8][N:7]=2)[CH:11]=[N:12]1
Reactant: Cn1cc(Nc2ncc(C#N)c(NC3CC4CN(C(=O)OC(C)(C)C)CC4C3)n2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cn1cc(Nc2ncc(C#N)c(NC3CC4CNCC4C3)n2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
To a solution of tert-butyl 5-((5-cyano-2-((1-methyl-1H-pyrazol-4-yl)amino)pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (425 mg, 1.001 mmol) in dichloromethane (30 mL) was added the solution of HCl in EtOAc (10 mL, 40 mmol), and the mixture was stirred at rt for 1 h. The mixture was diluted with water (20 mL) and adjust to pH=8-9 with saturated NaHCO3 solution and then extracted with DCM (30 mL×3). The combined organic phases were washed with brine (50 mL), dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (DCM/MeOH (v/v)=5/1) to give the title product as a white solid (185.2 mg, 57.02%).
Reaction SMILES: [NH:1]([C:5]1[CH:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[C:2]([NH2:4])=[S:3].Cl.[CH2:16](I)[CH3:17]>C(#N)C.O1CCOCC1>[CH2:16]([S:3][C:2](=[NH:4])[NH:1][C:5]1[CH:6]=[C:7]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=1)[CH3:17]
Reactant: CN(C)Cc1cccc(NC(N)=S)c1
Reactant: CCI
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: CCSC(=N)Nc1cccc(CN(C)C)c1
Yield: 18.6 %

Procedure:
To a solution of the compound (43.5 mg) obtained in Example 40 in acetonitrile (5 ml), a solution of hydrogen chloride in 1,4-dioxane (4N, 0.1 ml) and ethyl iodide (50 mg) were added and heated under reflux for 5 h. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride methanol=5:1) to give 9.2 mg of the titled compound (yield, 19%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O-:10])=O)[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.[NH2:42][CH2:43][C:44]1[CH:52]=[CH:51][CH:50]=[C:49]2[C:45]=1[CH:46]=[N:47][N:48]2[CH:53]1[CH2:58][CH2:57][CH2:56][CH2:55][O:54]1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([NH:42][CH2:43][C:44]2[CH:52]=[CH:51][CH:50]=[C:49]3[C:45]=2[CH:46]=[N:47][N:48]3[CH:53]2[CH2:58][CH2:57][CH2:56][CH2:55][O:54]2)=[O:10])[CH:5]=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: NCc1cccc2c1cnn2C1CCCCO1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1Cl
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2cnn3C2CCCCO2)cc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55.3 %

Procedure:
2-Chloro-1,4-benzenedicarboxylic acid, 1-methyl ester (Example 1; 84.3 mg, 0.393 mmol) was suspended in dichloromethane (1.5 mL) and the mixture was cooled to 0° C. BOP reagent (191 mg, 0.432 mmol) was added in one portion, followed by 4-aminomethyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (Example 12; 91 mg, 0.393 mmol) with a 2×0.25 mL wash of dichloromethane. Diisopropylethylamine (0.21 g, 1.62 mmol) was added over 1 min at ˜0° C. The mixture was stirred at ˜0° C. for 30 min and then at room temperature for 3.5 h. The mixture was concentrated to remove dichloromethane, and ethyl acetate (60 mL) was added. The solution was washed with 1 M HCl, sodium hydrogen carbonate solution, and brine (10 mL each), then dried (MgSO4), filtered, and concentrated. Ethyl acetate/petroleum ether was added and the insoluble material was filtered off to give 2-chloro-4-[[[[1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (93 mg, 55%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[N:4]=[CH:5][N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:15])([CH3:14])[CH3:13])[CH:7]=1.[Li]CCCC.CN([CH:26]=[O:27])C>>[F:17][C:2]([F:16])([F:1])[C:3]1[N:4]=[C:5]([CH:26]=[O:27])[N:6]([CH2:8][O:9][CH2:10][CH2:11][Si:12]([CH3:13])([CH3:14])[CH3:15])[CH:7]=1
Reactant: CN(C)C=O
Reactant: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Agent: [Li]CCCC
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1C=O
Yield: 14.2 %

Procedure:
Reaction of 4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (590 mg, 2.2 mmol), 2.3 M n-BuLi (1.3 mL, 3.0 mmol), and DMF (0.51 mL, 6.6 mmol) followed by purification of the crude material on silica gel (10% EtOAc/hexanes) gave the title compound as a yellow oil (92 mg, 14% over two steps). 1H NMR (CDCl3) □ 0.02 (s, 9H), 0.95 (m, 2H), 3.60 (m, 2H), 5.79 (s, 2H), 7.28 (s, 1H), 7.67 (s, 1H), 9.86 (s, 1H).
Reaction SMILES: ClC1C=CC2SC=C(CN3CCN(C4SC(C(O)=O)=C(C)N=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.[N:50]1[CH:55]=[CH:54][C:53]([CH2:56][NH2:57])=[CH:52][CH:51]=1>>[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:57][CH2:56][C:53]4[CH:54]=[CH:55][N:50]=[CH:51][CH:52]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1
Reactant: NCc1ccncc1
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccncc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyridin-4-ylmethanamine, the title compound was obtained as a colorless solid in 60% yield: mp 146-149° C.; 1H NMR (300 MHz, CDCl3) δ 8.51 (d, J=6.0 Hz, 2H), 7.29-7.24 (m, 4H), 7.07-7.01 (m, 2H), 6.21 (br s, 1H), 4.59 (d, J=6.0 Hz, 2H), 4.45 (s, 2H), 4.08 (t, J=9.0 Hz, 2H), 3.46 (t, J=9.0 Hz, 2H), 2.61 (s, 3H); MS (ES+) m/z 426.3 (M+1).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH:8]1[CH2:13][CH2:12][CH:11]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:10][CH2:9]1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: O=C1CCC(Oc2ccccn2)CC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(Oc3ccccn3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 4-(pyridin-2-yloxy)-cyclohexanone (as prepared in Step A) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in the previous step) using the procedure described in Step D of Example 1.