Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12]([CH2:14][CH2:15][NH:16][C:17]([C:19]3[NH:23][N:22]=[C:21]([C:24]([N:33]4[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]4)=[O:26])[CH:20]=3)=[O:18])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)[nH]n1
Reactant: OCCN1CCNCC1
Product: O=C(NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1)c1cc(C(=O)N2CCN(CCO)CC2)n[nH]1

Procedure:
The title compound was prepared as in Example 1 starting from 5-{2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylcarbamoyl}-1H-pyrazole-3-carboxylic acid and 1-(2-hydroxyethyl)piperazine. The crude product was purified by flash chromatography using CH2Cl2-MeOH as a gradient eluent (100:0-90:10). 1H NMR (400 MHz, DMSO-d6): 2.40-2.44 (6H, m), 2.95 (2H, t), about 3.5-3.7 (6H, m), about 3.82 (2H, m), 4.41 (1H, t), 6.33 (1H, d), 7.01 (1H, d), about 7.05 (1H, broad s), 7.59 (1H, distorted dd), 7.63 (1H, distorted d), 7.84 (1H, d), about 8.59 (1H, broad s), 13.9 (1H, broad s).
Reaction SMILES: [CH3:1][C@@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[CH2:15]=O>C(Cl)Cl>[CH3:1][C@@H:2]1[N:7]([CH3:15])[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[CH2:3]1
Reactant: C=O
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: ClCCl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C

Procedure:
Commercially available 1,1-dimethylethyl (3S)-3-methyl-1-piperazinecarboxylate (3.05 g, 15.23 mmol), formaldehyde (37% in water) (2.13 mL), sodium triacetoxy borohoydride (5.52 g, 26.04 mmol) and DCM (250 mL) were stirred overnight. The solvent was removed, and 1N NaOH was added to the residue. The mixture was extracted with dichloromethane, and the organics were dried (Na2SO4) and concentrated in vacuo to provide 1,1-dimethylethyl (3S)-3,4-dimethyl-1-piperazinecarboxylate as a clear oil (3.15 g. 97%). LCMS: (M+H)+=215.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[CH:12][C:11]([CH2:21][CH2:22][NH2:23])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8].C(N(CC)CC)C.[Si]([N:35]=[C:36]=[O:37])(C)(C)C>CN(C=O)C>[NH2:1][C:2]1[C:3]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20]3)=[CH:12][C:11]([CH2:21][CH2:22][NH:23][C:36]([NH2:35])=[O:37])=[CH:10][C:4]=2[S:5][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: C[Si](C)(C)N=C=O
Reactant: NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(=O)NCCc1cc(OCC2CCCC2)c2c(N)c(C(N)=O)sc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
To a stirred solution of 3-amino-6-(2-amino-ethyl)-4-cyclopentylmethoxy-benzo[b]thiophene-2-carboxylic acid amide (11) (HCl salt form, 0.065 g, 0.18 mmol) and triethylamine (0.07 mL, 0.5 mmol) in DMF (1 mL) at 0° C. was added TMSNCO (1.35 mL, 10.0 mmol). The reaction was allowed to warm to room temperature and stirred for 24 h. It was slowly quenched with water (0.5 mL) and the precipitates were removed by filtration. The filtrate was concentrated and the residue was purified by preparatory thin layer chromatography to afford the title compound (0.010 g, 15%).
Reaction SMILES: C[Si](C)([CH2:9][CH:10]([OH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C1C=CC=CN=1.[F-].[K+].C(=O)([O-])[OH:22].[K+].OO>CO.O>[C:11]1([CH:10]([OH:17])[CH2:9][OH:22])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C([O-])O
Reactant: C[Si](C)(CC(O)c1ccccc1)c1ccccn1
Agent: OO
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: OCC(O)c1ccccc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 95.5 %

Procedure:
To 129 mg (0.5 mmol) of the (2-hydroxy-2-phenylethyl)(2-pyridyl)silane obtained in Example 6, a solution of 58 mg (1.0 mmol) of potassium fluoride and 100 mg(1.0 mmol) of potassium hydrogencarbonate in methanol(1 ml)tetrahydrofuran(1 ml) was added, followed by 1.71 g (15 mmol) of 30% aqueous hydrogen peroxide. The mixture was continued to be stirred at an inner temperature of 50° C. for 6 hours, and then cooled to room temperature. After addition of 10 ml of water, the mixture was extracted with four portions of 10 ml of diethyl ether. The separated organic layers were combined together and washed with 10 ml of a 15% aqueous sodium thiosulfate solution. After drying over magnesium sulfate, the residue after the evaporation of the solvent was purified with silica gel chromatograph to give 66 mg of phenyl-1,2-ethanediol. Yield: 96%
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[N+:24]([O-])([OH:26])=[O:25]>>[N+:24]([C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=1[CH3:1])([O-:26])=[O:25]
Reactant: Cc1cc(=O)[nH]c(=O)[nH]1
Reactant: O=[N+]([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1[nH]c(=O)[nH]c(=O)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 5 h
Yield: 54 %

Procedure:
50.5 g (0.40 mol) of 6-methyluracil (Merck) are introduced in portions over the course of one hour with stirring at 0 to +5° C. into a solution of 200 ml of 100% nitric acid (fuming) and 50 g of phosphorus pentoxide. When the exothermic reaction is complete, the mixture is stirred at +5° C. for a further 5 hours. The reaction mixture is subsequently poured into 1 kg of ice-water. The resultant precipitate is filtered, washed with water and then dried to constant weight, giving 37 g (54%) of 5-nitro-6-methyluracil, pale-yellow powder, m.p. 281° C. with decomposition.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:19]([NH:27][C:28]([NH:14][C:13]1[C:8]([O:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:1]([CH3:4])([CH3:2])[CH3:3])=[N:9][CH:10]=[CH:11][CH:12]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-(2-tert-Butylphenoxy)-3-aminopyridine (200 mg, 0.82 mmol) and benzoyl isothiocyanate (133 μL, 0.99 mmol, 1.2 eq) in DCM (10 mL) was heated at reflux for 1 h. The mixture was cooled to rt and evaporated to give the crude product. Purification by flash chromatography (silica, 0-50% EtOAc/hexane gradient) provided Example 217a as a white fluffy powder. (M+H)+=406.29.
Reaction SMILES: Br.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH2:18])[S:16][CH:17]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.Cl>N1C=CC=CC=1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:10])([F:12])[F:11])=[CH:5][C:4]=1[C:13]1[N:14]=[C:15]([NH:18][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)(=[O:29])=[O:28])[S:16][CH:17]=1
Reactant: Nc1nc(-c2cc(C(F)(F)F)ccc2F)cs1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: Br
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2nc(-c3cc(C(F)(F)F)ccc3F)cs2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.3 %

Procedure:
A mixture of 0.5 g of 4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide with 0.33 g of 4-methoxy-benzenesulfonyl chloride was stirred overnight with 2 ml of pyridine. The resulting, red colored suspension was poured into 30 ml of 1N hydrochloric acid and the mixture was extracted lo with ethyl acetate. The organic phase was dried with magnesium sulphate and concentrated. The residue was dissolved in a mixture of 30 ml of ethanol and 20 ml of 2N sodium hydroxide solution. After the addition of 0.5 g of active charcoal the mixture was stirred at room temperature for 30 minutes and subsequently the active charcoal was filtered off. The product separated upon neutralization with concentrated hydrochloric acid. Recrystallization from 30 ml of 50% ethanol yielded 0.26 g of N-[4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-yl]-4-methoxy-benzenesulfonamide as colorless crystals.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=1.[Li]CCCC.CON(C)[C:27](=[O:29])[CH3:28]>C(OC)(C)(C)C.O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][O:9][CH2:8][C:6]2[CH:7]=[C:2]([C:27](=[O:29])[CH3:28])[CH:3]=[N:4][CH:5]=2)=[CH:12][CH:13]=1
Reactant: CON(C)C(C)=O
Reactant: COc1ccc(COCc2cncc(Br)c2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc(COCc2cncc(C(C)=O)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
To a solution of 3-bromo-5-{[(4-methoxybenzyl)oxy]methyl}pyridine (4.4 mmol) in methyl t-butyl ether (20 mL) was added n-BuLi (2.5M in hexane, 1.96 mL) dropwise at −78° C. The reaction mixture was allowed to stir for 15 min and then N-methoxy-N-methylacetamide (6.7 mmol) in methyl t-butyl ether (3 mL) was added dropwise. The reaction mixture was allowed to stir for 30 min at −78° C. and then diluted with water and allowed to warm to rt. After stirring for 30 min, the phases were separated and the aqueous solution was extracted with EtOAc. The organic solutions were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 1-(5-{[(4-methoxybenzyl)oxy]methyl}pyridin-3-yl)ethanone (3.1 mmol, 70%) as a white solid. LCMS: (FA) ES+ 272.1.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[C:21]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1>>[C:21]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:1]2[CH:2]([C:11]3[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]2=[O:7])[CH:22]=1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 402.39 g/mol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[F:19][C:20]1([F:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:22]3[CH2:23][CH2:24][CH2:25][C:20]([F:26])([F:19])[CH2:21]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: FC1(F)CCCNC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(I)cc2C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1Cc2ccc(N3CCCC(F)(F)C3)cc2C1

Procedure:
Prepared in analogy to Example A3(d) from 5-iodo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (Example A38(b)) and 3,3-difluoropiperidine hydrochloride. Pink solid. MS (m/e): 339.1 ([M+H]+, 100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1>>[CH3:9][O:10][C:11]([C:12]1[CH:17]=[CH:16][C:15]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)=[O:19]
Reactant: OB(O)c1cccs1
Reactant: COC(=O)c1ccc(Br)cc1
Product: COC(=O)c1ccc(-c2cccs2)cc1
Yield: 64.5 %

Procedure:
2-(4-methoxycarbonylphenyl)thiophene was prepared in the same manner as described in Example 32C from thiophene-2-boronic acid (1.0 g, 7.81 mmol) and methyl-4-bromobenzoate (1.68 g, 7.81 mmol). Purification by column chromatography using 2% ethyl acetate/hexanes gave 1.1 g of 2-(4-methoxycarbonylphenyl)thiophene as a white solid (65% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[CH2:6][CH2:5]2.[CH3:12][CH:13](O)[CH:14]=[CH2:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)(C)C.C1(C)C=CC=CC=1>[CH2:12]([CH:6]1[CH2:5][C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:7]1=[O:11])[CH:13]=[CH:14][CH3:15]
Reactant: C=CC(C)O
Reactant: O=C1CCc2cc(Cl)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2cc(Cl)ccc2C1=O
Yield: 36 %

Procedure:
A solution of 25 g of 5-chloro-1-indanone, 31 ml of 3-buten-2-ol and 250 mg of p-toluenesulfonic acid in 31 ml of 2,2-dimethoxy-propane and 250 ml of anhydrous toluene was boiled under reflux for 17 hours. The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 11.9 g (36%) of (RS)-2-(2-buten-1-yl)-5-chloro-1-indanone were obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[C:35]([C:37]1[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=1)#[CH:36]>C(N(CC)CC)C.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([NH:13][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:36]#[C:35][C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)=[CH:3][C:4]([C:17]3[CH:22]=[N:21][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[CH:5][C:6]=2[N:7]=1)=[O:16])[CH3:15]
Reactant: C#Cc1cncn1C
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C#Cc3cncn3C)c2s1
Temperature: 80 °C

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (150 mg, 0.27 mmol), copper(I) iodide (5 mg, 0.027 mmol) and 5-ethynyl-1-methyl-1H-imidazole (56 μl, 0.54 mmol) were dissolved in triethylamine (2 mL) and DMF (1 mL) and the mixture deoxygenated by bubbling N2 through the solution for 20 min. Pd(PPh3)2Cl2, (19 mg, 0.027 mmol) was added and the reaction heated to 80° C. for 4 h under a N2 atmosphere, at the end of which time LCMS indicated product formation. The reaction was diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound.
Reaction SMILES: C(O)C.C([O:8][C:9](=O)[CH2:10][CH2:11][N:12]([C:17]1[C:22]([NH2:23])=[CH:21][N:20]=[C:19]([Cl:24])[N:18]=1)[CH2:13][CH2:14][CH2:15][CH3:16])(C)(C)C>C(O)(=O)C>[CH2:13]([N:12]1[CH2:11][CH2:10][C:9](=[O:8])[NH:23][C:22]2[CH:21]=[N:20][C:19]([Cl:24])=[N:18][C:17]1=2)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCN(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCN1CCC(=O)Nc2cnc(Cl)nc21
Yield: 89.4 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 1.3 g of the 3-[(5-amino-2-chloro-pyrimidin-4-yl)-butyl-amino]-propionic acid tert-butyl ester (V-44), prepared in the previous step, was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, water and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 0.90 g of 9-butyl-2-chloro-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-44).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([CH:27]3[CH2:30][CH:29]([CH2:31][OH:32])[CH2:28]3)=[N:9][C:10]=2[C:11]2[CH:20]=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[N+:33]([C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)([O-:35])=[O:34].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N+:33]([C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:32][CH2:31][C@H:29]2[CH2:28][C@@H:27]([C:8]3[N:4]4[CH:5]=[CH:6][N:7]=[C:2]([Cl:1])[C:3]4=[C:10]([C:11]4[CH:20]=[C:19]5[C:14]([CH:15]=[CH:16][C:17]([C:21]6[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=6)=[N:18]5)=[CH:13][CH:12]=4)[N:9]=3)[CH2:30]2)=[O:41])=[CH:43][CH:44]=1)([O-:35])=[O:34]
Reactant: OCC1CC(c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn23)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(OC[C@H]1C[C@@H](c2nc(-c3ccc4ccc(-c5ccccc5)nc4c3)c3c(Cl)nccn32)C1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of {3-[8-chloro-1-(2-phenylquinolin-7-yl)imidazo[1,5-a]pyrazin-3-yl]cyclobutyl}methanol (46.52 g, 105.5 mmol) and 4-nitrobenzoyl chloride (23.55 g, 126.9 mmol) in methylene chloride (260 mL) was added N,N-diisopropylethyl amine (55.17 mL, 316.7 mmol). The mixture was stirred at rt for 15 h. Yellow precipitates were collected by filtration, washed with ethyl acetate, and dried to afford the title compound; 1H NMR (CDCl3, 400 MHz) δ 2.70-2.78 (m, 4H), 2.96-3.02 (m, 1H), 3.81-3.86 (m, 1H), 4.41 (d, J=4.8 Hz, 2H), 7.37 (d, J=5.2 Hz, 1H), 7.44-7.48 (m, 1H), 7.51-7.55 (m, 2H), 7.58 (d, J=5.2 Hz, 1H), 7.88-7.96 (m, 5H), 8.16-8.19 (m, 2H), 8.26-8.29 (m, 2H), 8.33 (d, J=8.8 Hz, 1H), 8.54 (s, 1H); MS (ES+): m/z 590 [MH+]; HPLC: tR=4.37 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4].[CH3:31][C:32]([CH3:34])=O>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([N:28]([CH:32]([CH3:34])[CH3:31])[CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](NC)C3)c(F)c1)C2=O
Reactant: CC(C)=O
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)C(C)C)C3)c(F)c1)C2=O

Procedure:
6-Butoxy-2-[3-fluoro-4-((R)-3-methylaminopyrrolidin-1-yl)phenyl]-3,4-dihydro-2H-isoquinolin-1-one (hydrochloride) was reductively alkylated with acetone by method J. The product with the molecular weight of 453.61 (C27H36FN3O2) was obtained in this way; MS (ESI): 454 (M+H+).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[NH:10][C:9]2=[O:17])[S:6][CH:7]=1.Br[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].[H-].[Na+]>CN(C=O)C>[CH3:1][S:2][C:3]1[N:4]=[C:5]([N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:9]2=[O:17])[S:6][CH:7]=1
Reactant: CSc1csc(-n2c(=O)[nH]c3ccccc32)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1csc(-n2c(=O)n(CC(=O)OC(C)(C)C)c3ccccc32)n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 1-[4-(methylthio)-1,3-thiazol-2-yl]-1,3-dihydro-2H-benzimidazol-2-one from Step B (710 mg, 2.67 mmol) and tert-butyl bromoacetate (578 mg, 2.97 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (194 mg of a 60% dispersion in mineral oil, 4.85 mmol). The mixture was stirred at 0° C. for 15 min, then quenched with saturated aqueous NaHCO3 and extracted with CH2Cl2 (2×35 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 70:30, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH2:22])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[F:21])=[CH:10][C:9]=1[NH:22][C:27](=[O:26])[CH2:28][C:29](=[O:41])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[CH:40]=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1N
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2cc(F)ccc2F)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1

Procedure:
Prepared from (3-amino-2′,5′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G45) (160 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (130 mg, 0.5 mmol) according to the general procedure K. Obtained as an amorphous off-white substance (129 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:19])[C:10](=[CH:14][NH:15][C:16](=[O:18])[CH3:17])[C:11](=[O:13])[CH3:12])=[CH:4][CH:3]=1.[CH2:20]([O:22][C:23]([O:26][CH2:27][CH3:28])=[CH:24][CH3:25])[CH3:21]>C1(C)C=CC=CC=1>[CH2:20]([O:22][C:23]1([O:26][CH2:27][CH3:28])[C@@H:24]([CH3:25])[C@H:14]([NH:15][C:16](=[O:18])[CH3:17])[C:10]([C:9](=[O:19])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:11]([CH3:12])[O:13]1)[CH3:21]
Reactant: CC=C(OCC)OCC
Reactant: CC(=O)NC=C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CCOC1(OCC)OC(C)=C(C(=O)Nc2ccc(Cl)cc2)[C@@H](NC(C)=O)[C@@H]1C
Temperature: 100 °C

Procedure:
N-(4'-chlorophenyl)-2-(acetylaminomethylene)-3-oxobutanamide (83 g) in toluene (200 ml) was treated with 1,1-diethoxyprop-1-ene (60 ml) and heated at 100° C. for 6 hours. The mixture was evaporated and the residue was triturated with toluene to give trans-2,2-diethoxy-3,6-dimethyl-4-(acetylamino)-5-(4'-chlorophenylcarbamoyl)-3,4-dihydro-2H-pyran (80.5 g) m.p. 199°-201° C.
Reaction SMILES: [CH:1]([S:5]([C:8]1[N:12]=[CH:11][NH:10][N:9]=1)(=[O:7])=[O:6])([CH2:3][CH3:4])[CH3:2].[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17](Cl)=[O:18])[CH2:14][CH3:15].O1CCCC1>C(N(CC)CC)C>[CH2:13]([N:16]([CH2:20][CH2:21][CH3:22])[C:17]([N:10]1[CH:11]=[N:12][C:8]([S:5]([CH:1]([CH2:3][CH3:4])[CH3:2])(=[O:6])=[O:7])=[N:9]1)=[O:18])[CH2:14][CH3:15]
Reactant: CCCN(CCC)C(=O)Cl
Reactant: CCC(C)S(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)n1cnc(S(=O)(=O)C(C)CC)n1

Procedure:
A mixture of 9.5 g. 3-sec.butylsulphonyl-1,2,4-triazole, 8.2 g. dipropylcarbamoyl chloride, 50 ml. dry tetrahydrofuran and 7.5 ml. dry triethylamine was refluxed under anhydrous conditions for 2 hours. The reaction mixture was worked up as described in Example 1 to produce a solid product which was recrystallized from a mixture of toluene and petroleum ether (b.p. 60° - 80°C.) to give 1-dipropylcarbamoyl-3-sec.butylsulphonyl-1,2,4-triazole, m.p. 80° - 81°C. Elemental analysis satisfactory.