Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[N:21]=[C:20]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH:29]C(OC(C)(C)C)=O)[C:19]([C:37]#[N:38])=[CH:18][C:14]=3[C:15]([NH2:17])=[O:16])[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1.C([O-])([O-])=[O:40].[K+].[K+].OO.O>CS(C)=O>[N:1]1[N:2]([C:6]2[CH:7]=[C:8]([NH:12][C:13]3[C:14]([C:15]([NH2:17])=[O:16])=[CH:18][C:19]([C:37]([NH2:38])=[O:40])=[C:20]([NH:22][C@@H:23]4[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]4[NH2:29])[N:21]=3)[CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(Nc2cccc(-n3nccn3)c2)c(C(N)=O)cc1C#N
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1cc(C(N)=O)c(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(-n2nccn2)c1
Reaction time: 0.08 h
Yield: 38.3 %

Procedure:
To a solution of 2-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-6-((1R,2S)-2-tert-butyloxycarbonylaminocyclohexylamino)-5-cyanonicotinamide (50 mg, 0.12 mmol) in DMSO (1 mL) was added K2CO3 (200 mg, 1.45 mmol) and H2O2 (50% in H2O, 0.8 mL) at ambient temperature (caution: gas evolution). After stirring for 5 min, it was added water, the resulting precipitate was collected by filtration and was treated with TFA in DCM, 10 min later, the solution was concentrated and purified by preparative HPLC to give 2-(3-(2H-1,2,3-triazol-2-yl)phenylamino)-6-((1R,2S)-2-aminocyclohexylamino)pyridine-3,5-dicarboxamide (20 mg). MS found for C26H33N9O4 as M+H, 436.4. λ=267.6, 312.8 nm.
Reaction SMILES: [CH:1]1([NH2+:7][CH:8]2[CH2:13]CCCC2)CCCCC1.[C:14]([NH:24][C@H:25]([C:35]([O-:37])=[O:36])[CH2:26][CH:27]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O-:30])=[O:29])([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].[CH:38]1([NH2+]C2CCCCC2)CCCCC1.CC(C)(N)CCl>>[CH3:38][N:7]([CH3:1])[CH:8]([O:36][C:35](=[O:37])[C@H:25]([CH2:26][CH:27]([C:31]([CH3:32])([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[NH:24][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH3:13]
Reactant: C1CCC([NH2+]C2CCCCC2)CC1
Reactant: CC(C)(C)C(C[C@H](NC(=O)OCc1ccccc1)C(=O)[O-])C(=O)[O-]
Agent: CC(C)(N)CCl
Product: CC(OC(=O)[C@H](CC(C(=O)O)C(C)(C)C)NC(=O)OCc1ccccc1)N(C)C

Procedure:
that N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-dicyclohexyl-ammonium salt is reacted with dimethyl-aminoethylchloride to form N-carbobenzyloxy-γ-tert.butyl-L-glutamic acid-α-dimethylaminoethyl ester,
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C@H:9]([OH:20])[CH2:10][NH:11][CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.Cl[C:39]([O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)=[O:40]>C(Cl)Cl>[CH2:42]([O:41][C:39](=[O:40])[N:11]([CH2:10][C@@H:9]([OH:20])[C@@H:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:28])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:12][C:13]([CH3:19])([CH3:18])[CH2:14][CH2:15][C:16]#[N:17])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(C)(CCC#N)CNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CCC#N)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Yield: 4.7 %

Procedure:
[(1S,2R)-1-Benzyl-3-(4-cyano-2,2-dimethylbutylamino)-2-hydroxy-propyl]-carbamic acid tert-butyl ester (1.300 g, 3.34 mmol) was dissolved in CH2Cl2 and treated with diisopropylethylamine (1.740 ml, 10.01 mmol) and benzyl chloroformate (0.683 g, 4.00 mmol) at ambient temperature under argon with stirring. After 15 h the reaction mixture was concentrated in vacuo, taken up in EtOAc, washed with sat. aq. NaHCO3, and brine. The organic phase was dried over MgSO4, filtered and solvent removed in vacuo. Purification by column chromatography (10% Et2O in CH2Cl2) gave 0.083 g of a white solid. MS (ES): 524 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=[O:10])=[C:4]([Cl:11])[N:3]=1.C(N(CC)CC)C.[CH3:19][O:20][C:21]1[CH:37]=[CH:36][C:24]([CH2:25][NH:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1.[Cl-].[Na+]>C(Cl)Cl>[NH2:1][C:2]1[N:3]=[C:4]([Cl:11])[C:5]([CH:9]=[O:10])=[C:6]([N:26]([CH2:25][C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:37][CH:36]=2)[CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[N:7]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(N)nc(Cl)c2C=O)cc1
Reaction time: 1.25 h

Procedure:
2-Amino-4,6-dichloro-5-pyrimidine carbaldehyde (0.50 g; 2.60 mmol) was stirred in dry DCM (5 ml). Triethylamine (0.263 g; 2.60 mmol) and di(4-methoxybenzyl)amine (0.669 g; 2.60 mmol) were added and the reaction stirred at r.t for 1.25 h. the reaction was worked up by addition of further DCM (50 ml) and extraction with saturated sodium chloride solution (3×50 ml). The organic layer was washed with water (50 ml), dried (MgSO4) and evaporated yielding a yellow foam (0.957 g; 2.32 mmol; 89.2%).
Reaction SMILES: [CH3:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:4].C(N(CC)CC)C.[Br:26][CH2:27][CH2:28][C:29](Cl)=[O:30]>C1(C)C=CC=CC=1>[Br:26][CH2:27][CH2:28][C:29]([NH:16][C:15]1[CH:14]=[CH:13][C:12]([N:9]2[CH2:10][CH2:11][CH:6]([NH:5][C:3](=[O:4])[CH2:2][CH3:1])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1)=[O:30]
Reactant: CCC(=O)NC1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(Cl)CCBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCC(=O)NC1CCN(c2ccc(NC(=O)CCBr)cc2)CC1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
16 Grams of p-[4-(N-methylacetylamino)-1-piperidyl]aniline was dissolved in 150 ml of toluene then to this solution was added 9.12 ml of triethylamine. Next, 11 g of β-bromopropionyl chloride in 30 ml of toluene solution was added dropwise thereto under stirring at 80° C. The reaction was continued further for 30 minutes, then the resinous materials formed in the reaction mixture were removed, then the remaining liquid was washed with water, dried and the solvent was removed by evaporation to yield 18 g of N-(β-bromopropionyl)-p-[4-(N-methylacetylamino)-1-piperidyl]aniline as in the form of an oily substance.
Reaction SMILES: CN(C)C=O.[F:6][C:7]([F:17])([F:16])[C:8]([N:10]=[C:11]1[NH:15][CH2:14][CH2:13][S:12]1)=[O:9].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[Cl:18][C:19]1[N:20]=[CH:21][C:22]([CH2:25][N:15]2[CH2:14][CH2:13][S:12][C:11]2=[N:10][C:8](=[O:9])[C:7]([F:6])([F:16])[F:17])=[CH:23][CH:24]=1
Reactant: O=C(N=C1NCCS1)C(F)(F)F
Reactant: ClCc1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(N=C1SCCN1Cc1ccc(Cl)nc1)C(F)(F)F
Yield: 86.6 %

Procedure:
Dimethylformamide (2 mL) and tetrahydrofuran (18 mL) were added to 162 mg (0.82 mmol) of 2,2,2-trifluoro-N-(thiazolidin-2-ylidene)acetamide obtained by the above-described method, following which 198 mg of 2-chloro-5-chloromethylpyridine and 150 mg (1.09 mmol) of potassium carbonate were added, and the mixture was refluxed under heating for 20 hours. Following reaction completion, the reaction mixture was returned to room temperature, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The concentrate was purified on a TLC plate (two 0.5 mm plates, developed with 100% ethyl acetate), giving 230 mg of the target compound (yield, 87%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:6][N:7]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(Oc2cccc([N+](=O)[O-])c2)cn1
Temperature: 140 °C
Reaction time: 4 h
Yield: 77.2 %

Procedure:
A mixture of 6-methylpyridin-3-ol (17.6 g, 161 mmol), 1-fluoro-3-nitrobenzene (25.0 g, 177 mmol), potassium carbonate (66.8 g, 483 mmol) and N,N-dimethylformamide (200 mL) was stirred at 90° C. for 13 hr, 120° C. for 5 hr and 140° C. for 4 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was dried to give the title compound (28.6 g, 77%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:16]3[N:17]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:15]=3[CH:14]=[C:13]([C:37](=[NH:40])[NH:38][OH:39])[N:12]=2)[C:5]([N:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[C:41](N1C=CN=C1)(N1C=CN=C1)=[O:42].N1(C2CCCCCCCCCC2)CCCN=CCCCCC1>C(#N)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:11]2[C:16]3[N:17]([CH2:29][C@H:30]4[CH2:35][CH2:34][C@H:33]([CH3:36])[CH2:32][CH2:31]4)[C:18]([N:20]4[CH2:25][CH2:24][O:23][C@@H:22]5[CH2:26][CH2:27][CH2:28][C@@H:21]45)=[N:19][C:15]=3[CH:14]=[C:13]([C:37]3[NH:40][C:41](=[O:42])[O:39][N:38]=3)[N:12]=2)[C:5]([N:8]([CH3:9])[CH3:10])=[N:6][CH:7]=1
Reactant: CN(C)c1ncc(Cl)cc1-c1nc(C(=N)NO)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: C1=NCCCN(C2CCCCCCCCCC2)CCCCC1
Solvent: CC#N
Solvent: ClCCl
Product: CN(C)c1ncc(Cl)cc1-c1nc(-c2noc(=O)[nH]2)cc2nc(N3CCO[C@@H]4CCC[C@H]43)n(C[C@H]3CC[C@H](C)CC3)c12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-N-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (racemic, 22 mg, 0.075 mmol) and 1,1′-carbonyldiimidazole (12 mg, 0.07 mmol) in acetonitrile (1 mL) was added 1,8-diazabicycloundec-7-ene (23 mg, 0.15 mmol). The reaction was stirred at room temperature for 18 hours. The reaction was then diluted with CH2Cl2 and washed with water. The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified on a silica gel column (0 to 10% MeOH/CH2Cl2) to afford 3-{4-[5-chloro-2-(dimethylamino)pyridin-3-yl]-2-[(trans)-hexahydrocyclopenta[b][1,4]oxazin-4(4aH)-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one (racemic). NMR shows 8:2 mixture of rotamers, 1H NMR (400 MHz, CD3OD) (for major rotamer) δ 8.27 (d, J=2.8 Hz, 1H), 8.12 (s, 1H), 7.98 (d, J=2.8 Hz, 1H), 3.76-4.04 (m, 3H), 3.35-3.51 (m, 3H), 3.13 (m, 1H), 2.98 (m, 1H), 2.53 (s, 6H), 2.34 (m, 1H), 1.64-1.77 (m, 3H), 1.44-1.56 (m, 3H), 1.12-1.24 (m, 3H), 0.71-0.84 (m, 7H), 0.50-0.62 (m, 2H). MS ES calc'd. for C30H37ClN8O3 [M+H]+ 593. found 593
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:27]1([C:34](=[NH:36])[NH2:35])[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH2:28]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:36]=[C:34]([C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[CH:28]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CC1=CC=CC(O)(C(=N)N)C1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4cccc(C)c4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 33 mg (0.22 mmol, 1.1 eq.) of 1-hydroxy-3-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 16 mg (18% of theory)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH:16]2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCN(C(C)C)C(C)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C(Cl)Cl>[F:1][C:2]([F:28])([F:29])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][CH:15]2[CH2:19][CH2:18][CH:17]([N:20]([C:41]([N:40]([CH3:44])[CH3:39])=[O:42])[CH3:21])[CH:16]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CNC1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)N(C)C1CCC(OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1c1ccccc1
Yield: 85.4 %

Procedure:
To a solution of 25 mg of amine prepared in Example 11 and 0.05 mL of DIPEA in 0.5 mL of methylene chloride was added 15 mg of dimethylcarbamoyl chloride. After 2 h at 50° C. in a sealed vial, the volatiles were evaporated under a stream of nitrogen and the residue was purified on a 1 mm preparative silica gel plate eluted with ethyl acetate to afford 25 mg of title compound. Mass spec (NH3 /CI): 489 (M+1).
Reaction SMILES: Cl.C(N[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][N:13]=[C:14]([CH3:27])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:10][CH:9]=1)=[O:7])(=O)C.S(=O)(=O)(O)[OH:29]>O>[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([CH2:12][N:13]=[C:14]([CH3:27])[N:15]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])=[CH:10][CH:9]=1)([OH:7])=[O:29]
Reactant: CC(=O)NC(=O)c1ccc2c(c1)N(Cc1ccc(Cl)cc1Cl)C(C)=NC2
Reactant: O=S(=O)(O)O
Agent: Cl
Solvent: O
Product: CC1=NCc2ccc(C(=O)O)cc2N1Cc1ccc(Cl)cc1Cl
Temperature: 70 °C
Yield: 38.5 %

Procedure:
To 7-(acetylcarbamoyl)-1-(2,4-dichlorobenzyl)-1,4-dihydro-2-methylquinazoline hydrochloride (0.46 g) were added water (1.2 g) and concentrated sulfuric acid (1.0 g) and the mixture was heated at 70° C. for 90 min. After cooling, ice was added and the precipitated solid was collected by filtration. The precipitate was washed with water and 2-propanol and dried to give the objective compound (0.145 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=2)[C:4]1=[O:16].[C:17]([C:19]1[CH:32]=[CH:31][C:22]([CH2:23][N:24]2[C:28]([CH:29]=O)=[CH:27][N:26]=[CH:25]2)=[CH:21][C:20]=1[F:33])#[N:18].C(N(CC)C(C)C)(C)C.[BH3-]C#N.[Na+]>CO>[F:33][C:20]1[CH:21]=[C:22]([CH2:23][N:24]2[C:28]([CH2:29][NH:2][C@@H:3]3[CH2:7][CH2:6][N:5]([CH2:8][C:9]4[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=4)[C:4]3=[O:16])=[CH:27][N:26]=[CH:25]2)[CH:31]=[CH:32][C:19]=1[C:17]#[N:18]
Reactant: N[C@@H]1CCN(Cc2cccc(O)c2)C1=O
Reactant: N#Cc1ccc(Cn2cncc2C=O)cc1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: N#Cc1ccc(Cn2cncc2CN[C@@H]2CCN(Cc3cccc(O)c3)C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3-Amino-1-(3-hydroxybenzyl)-2-oxopyrrolidine hydrochloride, as described above in Step N, (200 mg, 0.82 mmol) and 1-(4-cyano-3-fluorobenzyl)-5-imidazolecarboxaldehyde, as described above in Step G, (197 mg, 0.86 mmol), were stirred in MeOH (7 mL) and N,N-diisopropylethylamine was added dropwise to adjust the mixture to ca. pH 5, as judged by wetted pH paper. The mixture was stirred for 1 hour at ambient temperature, then NaCNBH3 (54 mg, 0.86 mmol) was added and stirring was continued for 18 hours. The reaction was quenched with saturated aqueous NaHCO3 (2 mL) and most of the MeOH was removed under reduced pressure. The residual solution was partitioned between saturated aqueous NaHCO3 (3 mL) and CH2Cl2 (10 mL). The aqueous layer was extracted further with CH2Cl2 (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with two column volumes of EtOAc—10% MeOH, then two column volumes of CHCl3—4% MeOH, then CHCl3—4% MeOH—0.4% NH4OH to yield the titled product as a colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].I[C:27]1[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][CH:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:27]3[S:31][C:30]([NH:32][C:33](=[O:35])[CH3:34])=[N:29][CH:28]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CC(=O)Nc1ncc(I)s1
Product: CC(=O)Nc1ncc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)s1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and N-(5-iodo-thiazol-2-yl)-acetamide [CAS-No. 252662-43-4] (268 mg, 1.0 mmol) according to general procedure II. Obtained as an orange solid (240 mg, 48%). MS (EI) 495.1 [(M)+]; mp 302° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[N:11]1([CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: [H][H]
Reactant: O=c1[nH]c2ccccc2n1CCN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1CCN1CCNCC1

Procedure:
A mixture of 79 parts of 1,3-dihydro-1-{2-[4-(phenylmethyl)-1-piperazinyl]ethyl}-2H-benzimidazol-2-one and 320 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is alkalized with ammonium hydroxide and a small amount of water is added. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue solidifies on triturating in 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1,3-dihydro-1-[2-(1-piperazinyl)ethyl]-2H-benzimidazol-2-one; mp. 122.6° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[S:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36](=O)[O:37]C2C=CC=CC=2)[N:32]([C:45]2[CH:46]=[C:47]([CH3:51])[CH:48]=[CH:49][CH:50]=2)[N:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:34]=[C:33]([NH:35][C:36]([NH:22][C:21]2[CH:23]=[CH:24][CH:25]=[C:19]([S:18][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:20]=2)=[O:37])[N:32]([C:45]2[CH:46]=[C:47]([CH3:51])[CH:48]=[CH:49][CH:50]=2)[N:31]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: COCCOc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: Cc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)c1
Product: COCCOc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(C)c4)c3)c2cc1OC
Yield: 88.9 %

Procedure:
The title compound was prepared from 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-ylthio)aniline (94 mg, 0.27 mmol) and phenyl 3-tert-butyl-1-m-tolyl-1H-pyrazol-5-ylcarbamate (115 mg, 0.33 mmol) using the procedure in Example 115C to give the title compound (145 mg, 0.24 mmol, 88%). 1H NMR (300 MHz, DMSO-d6) δ 9.25 (s, 1H), 8.67 (s, 1H), 8.45 (s, 1H), 7.81 (s, 1H), 7.48-7.21 (m, 9H), 6.37 (s, 1H), 4.32 (t, 2H), 3.99 (s, 3H), 3.76 (t, 2H), 3.36 (s, 3H), 2.38 (s, 3H), 1.27 (s, 9H); LC-MS (ESI) m/z 613 (M+H)+.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][C:5]1[C:6]2[O:28][CH:27]=[CH:26][C:7]=2[C:8]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]3[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]3)[CH2:13][CH2:12]2)=[N:9][CH:10]=1.[CH3:29][O:30][CH2:31][CH2:32][C:33](O)=[O:34]>>[CH3:29][O:30][CH2:31][CH2:32][C:33]([NH:25][C@H:22]1[CH2:21][CH2:20][C@H:19]([CH2:18][CH2:17][N:14]2[CH2:13][CH2:12][N:11]([C:8]3[C:7]4[CH:26]=[CH:27][O:28][C:6]=4[C:5]([CH3:4])=[CH:10][N:9]=3)[CH2:16][CH2:15]2)[CH2:24][CH2:23]1)=[O:34]
Reactant: Cc1cnc(N2CCN(CC[C@H]3CC[C@H](N)CC3)CC2)c2ccoc12
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3ncc(C)c4occc34)CC2)CC1

Procedure:
The title compound, white solid (79 mg, 61%), MS (ISP) m/z=429.4 [(M+H)+], mp 177° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(7-methyl-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate F) (136 mg, 0.3 mmol) and 3-methoxypropionic acid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:20][N:19]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:20][N:19]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc2cccnc2[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.56 mmol) 3H-Imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester were dissolved in 3 mL DMF. 22.6 mg (0.56 mmol) sodium hydride (60% in mineral oil) were added and the mixture was stirred 30 minutes at room temperature. 157.2 mg (0.56 mmol) 3-Bromomethyl-5-(5-Chloro-thiophen-2-yl)-isoxazole were added and the resulting mixture was stirred for 1 h at 80° C. The reaction mixture was cooled to room temperature and after the addition of a few drops of water concentrated under reduced pressure. HPLC-MS-analysis showed the presence of another isomer (ratio of isomers≈7:1). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester as a brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:24]([CH2:25][S:26][CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[N:30]3)=[CH:23][CH:22]=2)[N:18]=1.ClC1C=C(C(OO)=[O:44])C=CC=1>ClCCl.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[CH:4][C:3]=1/[CH:12]=[CH:13]/[C:14]1[O:15][CH:16]=[C:17]([CH2:19][O:20][C:21]2[CH:35]=[CH:34][C:24]([CH2:25][S:26]([CH2:27][CH2:28][N:29]3[CH:33]=[CH:32][N:31]=[N:30]3)=[O:44])=[CH:23][CH:22]=2)[N:18]=1
Reactant: Fc1cc(C(F)(F)F)ccc1/C=C/c1nc(COc2ccc(CSCCn3ccnn3)cc2)co1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3F)n2)cc1
Temperature: 30 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To a solution of 101 mg (0.20 mmol) 1-[2-(4-{2-[2-(E)-(2-fluoro-4-trifluoromethylphenyl)-vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 8 ml dichloromethane at −30° C. were added drop by drop during 20 min 54 mg (0.24 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 2 ml ethyl acetate. After 1 hour stirring at 30° C. the mixture was allowed to warm up over night, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 9:1 furnished 73 mg (71%) title compound as white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:10]=1)=[N:7][O:8][N:9]=2.Br[C:12]1[CH:13]=[C:14]([NH:18][CH3:19])[CH:15]=[CH:16][CH:17]=1>>[N:9]1[O:8][N:7]=[C:6]2[C:10]([C:12]3[CH:13]=[C:14]([NH:18][CH3:19])[CH:15]=[CH:16][CH:17]=3)=[CH:2][CH:3]=[CH:4][C:5]=12
Reactant: Clc1ccc2nonc2c1
Reactant: CNc1cccc(Br)c1
Product: CNc1cccc(-c2cccc3nonc23)c1

Procedure:
Starting from 5-chloro-benzo[1,2,5]oxadiazole and (3-bromo-phenyl)-methyl-amine. Yellow powder. MS(ES+): 226 (M+1).