Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8](Cl)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[N:24]=[C:25]([CH3:27])[O:26][C:22]=2[CH:21]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([S:8]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[N:24]=[C:25]([CH3:27])[O:26][C:22]=3[CH:21]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: Cc1nc2ccc(N)cc2o1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nc2ccc(NS(=O)(=O)c3cccc(Cl)c3C)cc2o1
Reaction time: 0.08 h
Yield: 65.2 %

Procedure:
To a solution of 3-chloro-2-methylbenzenesulphonyl chloride (163 mg, 0.723 mmol) in dichloromethane (3 mL) was added pyridine (140 μL, 1.72 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylbenzoxazole (102 mg, 0.688 mmol) was added. The resulting mixture was stirred for 1 h at room temperature, then saturated NaHCO3 solution was added (8 mL) and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (151 mg, 65%), single spot at Rf 10.50 (60:40 hexane:ethyl acetate). mp 127.1-127.5° C., HPLC purity 97% (tR 2.05 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 7.85 (1H, dd, J=8.1, 1.1 Hz), 7.53 (1H, dd, J=8.1, 1.3 Hz), 7.45 (1H, d, J=8.4 Hz), 7.27 (1H, d, J=2.2 Hz), 7.17 (1H, t, J=7.9 Hz), 6.93 (1H, s, N—H), 6.86 (1H, dd, J=8.4, 2.2 Hz), 2.71 (3H, s), 2.58 (3H, s). LCMS: 335.14 (M−). FAB-MS (MH+, C15H13ClN2O3S): calcd 337.0413, found 337.0406.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1)=[O:23]>>[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][N:34]([CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[C:7]([O:6][C:5]4[CH:15]=[CH:16][CH:17]=[C:3]([C:2]([F:19])([F:18])[F:1])[CH:4]=4)[CH:8]=3)[CH2:33][CH2:32]2)[CH:26]=1)=[O:23]
Reactant: O=Cc1cccc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc(Oc4cccc(C(F)(F)F)c4)c3)CC2)c1

Procedure:
Prepared by Procedure F and Scheme R using 3-[3-(trifluoromethyl)phenoxy]benzaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 497.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6](=[O:19])[CH2:7][C@@H:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([OH:11])=O)([CH3:4])[CH3:3].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:54][C@H:55]([C:62]([NH:64][C@@H:65]([CH2:73][CH:74]([CH3:76])[CH3:75])[C@H:66]([C:68]1[S:69][CH:70]=[CH:71][N:72]=1)[OH:67])=[O:63])[CH2:56][C:57]1[N:61]=[CH:60][NH:59][CH:58]=1>ClCCl>[C:13]1([CH2:12][C@H:8]([CH2:7][C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:19])[C:9]([NH:54][C@H:55]([C:62]([NH:64][C@@H:65]([CH2:73][CH:74]([CH3:76])[CH3:75])[C@H:66]([C:68]2[S:69][CH:70]=[CH:71][N:72]=2)[OH:67])=[O:63])[CH2:56][C:57]2[N:61]=[CH:60][NH:59][CH:58]=2)=[O:11])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)[C@@H](O)c1nccs1
Reactant: CC(C)(C)NC(=O)C[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H](CC(=O)NC(C)(C)C)Cc1ccccc1)[C@@H](O)c1nccs1
Temperature: -10 °C
Reaction time: 0.03 h
Yield: 111.7 %

Procedure:
To 0.276 g of (R)alpha-[2-[(1,1-dimethylethyl)amino]2-oxoethyl]benzenepropionic acid in one ml of dichloromethane was added 0.014 ml of triethylamine and 0.465 g of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP). After 1.5 minutes, 0.337 g of N-(L-histidyl)-(S)2-amino-4-methyl-(R)1-(2-thiazolyl)pentan-1-ol was added and one ml of dichloromethane. The mixture was stirred 16 hours and the solvent removed. The residue in 5 ml of ethyl acetate was washed with 2 ml of water, three times with 2 ml of 1M sodium bicarbonate with 2 ml of brine. Cooling (-10° C.) gave crystals which were filtered off. The filtrate was concentrated under vacuum to give 0.65 g of an oil. This oil was purified by thick layer chromatography on five 20×20×0.2cm silica gel plates developed with 20% methanol in dichloromethane containing 0.2% triethylamine. The band at RF 0.8 was separated, washed with methanol and the solvent removed. The residue in dichloromethane was filtered and the filtrate concentrated to give 0.3 g of a glass, mp 120°-130° C. [α]D26 -8°±1(c, 1.042, methanol).
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C([N:14]1[CH2:22][CH:21]2[CH:16]([C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:19][C:20]2=[O:23])[CH2:15]1)C1C=CC=CC=1.C(OC(C)C)(C)C>ClCCCl>[C:30]1([C:17]2([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:16]3[CH:21]([CH2:22][N:14]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:15]3)[C:20](=[O:23])[CH2:19][CH2:18]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: C=COC(=O)Cl
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(Cc3ccccc3)CC12
Solvent: ClCCCl
Solvent: CC(C)OC(C)C
Product: C=COC(=O)N1CC2C(=O)CCC(c3ccccc3)(c3ccccc3)C2C1
Reaction time: 0.5 h

Procedure:
Vinyl chloroformate (56 cc) is added dropwise in the course of 10 minutes to a solution, cooled to +5° C., of (3aRS,7aRS)-2-benzyl-7,7-diphenylperhydro-4-isoindolone (193 g) in 1,2-dichloroethane (1225 cc). After stirring for 30 minutes at between 10° and 20° C., the reaction mixture is heated to reflux for 90 minutes, cooled and concentrated to dryness under reduced pressure (2.7 kPa then 1 kPa). The crystalline mass obtained is stirred vigorously with cold isopropyl ether (200 cc). The crystals obtained are drained, washed with isopropyl ether (2×100 cc) and dried. (3aRS,7aRS)-7,7-Diphenyl-2-vinyloxycarbonylperhydro-4-isoindolone (177 g), m.p. 178° C. is obtained.
Reaction SMILES: O=[C:2]([CH2:9][CH2:10][CH3:11])[CH2:3][C:4](OCC)=[O:5].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][NH2:21])=[CH:16][CH:15]=1.CCN(CC)CC>CC(O)=O>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:4](=[O:5])[CH2:3][C:2]([CH2:9][CH2:10][CH3:11])=[N:21]2)=[CH:16][CH:15]=1
Reactant: CCCC(=O)CC(=O)OCC
Reactant: COc1ccc(NN)cc1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CCCC1=NN(c2ccc(OC)cc2)C(=O)C1
Temperature: 120 °C
Reaction time: 30 h
Yield: 58.9 %

Procedure:
To a suspension of ethyl 3-oxohexanoate (0.58 mL, 3.62 mmol) and (4-methoxyphenyl)hydrazine (0.50 g, 3.62 mmol) in AcOH (3.5 mL) was added Et3N (0.58 mL, 4.16 mmol). The mixture was stirred at 120° C. for 30 h. The solvent was removed by evaporation, and the residue was dissolved in DCM/EtOAc which was washed with saturated aqueous NaHCO3, followed by water and dried using phase separator. Concentration in vacuo, and purification using silica chromatography (CH2Cl2:Et2O 3:1) gave 1-(4-methoxyphenyl)-3-propyl-1H-pyrazol-5(4H)-one (495 mg, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.S(OC)(O[CH3:14])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].O>C1C=CC=CC=1>[CH3:14][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: COc1ccc(C=O)cc1
Yield: 99.7 %

Procedure:
20 g of p-hydroxybenzaldehyde (0.164 mol) was reacted with 29.0 g of dimethyl sulfate (0.230 mol) and 22.0 g of sodium carbonate (0.20 mol) for 2 hr. at 75°-80° C. A total of 12 ml of water was added in small portions over the last hour. Work-up by addition of water, acidification and benzene extraction yielded 22.27 g of p-methoxybenzaldehyde (99.9%) containing not more than 0.1% p-hydroxybenzaldehyde.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].FC(F)(F)C(O)=O.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1.[NH4+].[OH-]>ClCCl>[NH2:1][C:2]([NH:12][C:13]1[CH:21]=[C:20]2[C:16]([CH2:17][CH2:18][CH:19]2[CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[CH:15][CH:14]=1)=[O:3]
Reactant: [N-]=C=O
Reactant: Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Nc1ccc2c(c1)C(CN1CCC(c3ccc(F)cc3)CC1)CC2
Temperature: 5 °C
Reaction time: 3 h

Procedure:
A solution of potassium isocyanate (1.5 g) dissolved in dichloromethane (20 ml) was cooled to 5° C. and a solution of trifluoroacetic acid (1.9 g) In dichloromethane (20 ml) was added dropwise. To the resulting mixture was added dropwise a solution of 1-(6-aminoindan-1-ylmethyl)-4-(4-fluorophenyl)piperidine, 2a (3 g) in dichloromethane (10 ml). The temperature was allowed to raise to room temperature. After stirring for another 3 hours the mixture was poured on ice (500 g) and diluted aqueous NH4OH was added until pH>9. The organic phase was separated and worked-up as above. The crude title product was purified by column chromatography on silica gel (eluted with 4% triethylamine in ethanol/ethyl acetate 1:3). The purled product (2 g) was dissolved in acetone (20 ml) and added to a solution of fumaric acid (0.6 g) in ethanol (20 ml). The precipitated hemifumarate salt was filtered off and dried. Yield: 1.6 g, mp: 172-174° C. 1H NMR (DMSO-d6): δ 1.65-1.90 (m, 5H); 2.10-2.35 (m, 3H); 2.45-2.90 (m, 5H); 3.10-3.25 (m, 2H); 3.45 (qui, 1H); 6.85 (s, 2H); 6.60 (s, 1H); 7.00-7.15 (m, 4H); 7.30 (dd, 2H); 7.45 (s, 1H); 8.45 (s, 1H).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH:43]=O)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:25][CH2:24]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:47][N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:45][CH3:46])=[C:10]([CH2:19][N:20]([CH2:29][C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][N:51]5[CH2:52][CH2:53][N:48]([CH3:47])[CH2:49][CH2:50]5)[CH:38]=4)[C:33]([CH3:36])=[CH:34][CH:35]=3)[C:21]([C:23]3([C:26]([NH2:28])=[O:27])[CH2:24][CH2:25]3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(C=O)c2)c1)C(=O)C1(C(N)=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN(Cc1ccc(C)c(-c2cccc(CN3CCN(C)CC3)c2)c1)C(=O)C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
A mixture of N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-[(3′-formyl-6-methyl-3-biphenylyl)methyl]-1,1-cyclopropanedicarboxamide (55 mg, 0.088 mmol), 1-methylpiperazine (9.80 μL, 0.088 mmol), sodium triacetoxyborohydride (37.4 mg, 0.177 mmol) and acetic acid (6.07 μL, 0.106 mmol) in DCM (3 mL) was stirred at room temperature overnight. The reaction mixture was quenched with saturated NaHCO3 and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give the crude residue. It was purified by reverse phase hplc with a Gilson HPLC (acidic conditions: 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, washed with saturated NaHCO3 and extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N1-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N1-({6-methyl-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-1,1-cyclopropanedicarboxamide as a solid (29 mg, 46.4%). LC-MS m/z 707 (M+H)+, 0.77 min (ret time).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.O[C@H:32]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH3:33].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][C@@H:32]([CH3:33])[C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)C(=O)[C@H](C)O
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)C(=O)[C@H](C)OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 35.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (2.0 g, 5.0 mmol) dissolved in 25 mL of anhydrous dichloromethane (DCM) was reacted with 0.90 mL (1.31 g, 10 mmol) of oxalyl chloride. Upon completion of the reaction, a solution of 2 mL (1.2 g, 10.0 mmol) of (2S)-2-hydroxy-4-methylpentan-3-one (synthesized following procedures according to Gallop et al., U.S. Pat. No. 6,927,036) and 0.85 mL of pyridine (0.79 g, 10.0 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:9) as eluent to provide 0.9 g (36% yield) of the title compound (30a) as a colorless oil. Rf=0.39 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.05 (s, 3H), 0.10 (s, 3H), 0.94 (s, 9H), 1.09 (s, 6H), 1.12 (d, J=7.2 Hz, 3H), 1.19 (d, J=7.2 Hz, 3H), 1.46 (d, J=7.2 Hz, 3H), 2.32-2.39 (m, 2H), 2.83 (sept., J=7.2 Hz, 1H), 3.31-3.35 (m, 2H), 3.69-3.72 (m, 2H), 4.10-4.13 (m, 3H), 5.24 (q, J=7.2 Hz, 1H) ppm. MS (ESI) m/z 501.09 (M+H)+, 523.03 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [OH-].[Na+].[C:3]([NH:6][C:7]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)(C(OCC)=O)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4].Cl>C(O)C>[C:3]([NH:6][CH:7]([CH2:18][C:19]1[CH:24]=[N:23][CH:22]=[CH:21][N:20]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:5])[CH3:4]
Reactant: CCOC(=O)C(Cc1cnccn1)(NC(C)=O)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C(Cc1cnccn1)NC(C)=O
Temperature: 20 °C
Reaction time: 1 h
Yield: 79.2 %

Procedure:
12 cm3 of 6N sodium hydroxide are added dropwise to a solution of 14 g of diethyl 2-acetylamino-2-(2-pyrazinylmethyl)malonate in 240 cm3 of ethanol and the mixture is then stirred at a temperature in the region of 20° C. After 1 hour, the reaction medium is neutralized with 6 cm3 of 12N hydrochloric acid. After stirring for 2 hours at a temperature in the region of 20° C., the reaction medium is filtered and the filtrates are then concentrated under reduced pressure (1 kPa) at a temperature in the region of 40° C. The residue is taken up in 200 cm3 of dioxane, refluxed for 2 hours and concentrated as above. 8.5 g of ethyl (2RS)-2-acetylamino-3-(2-pyrazinyl)propanoate are obtained in the form of a cream-colored solid [1H NMR spectrum (300 MHz, (CD3)2SO-d6 δ in ppm): 1.13 (t, J=7 Hz: 3H); 1.80 (s: 3H); 3.12 (dd, J=14 and 8.5 Hz: 1H); 3.22 (dd, J=14 and 6 Hz: 1H); 4.07 (q, J=7 Hz: 2H); 4.71 (mt: 1H); 8.36 (d, J=8 Hz: 1H); 8.52 (d, J=2.5 Hz: 1H); from 8.55 to 8.65 (mt: 2H]).
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([NH2:28])=[CH:25][CH:26]=2)[CH:21]=[N:20]1>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([NH:28][C:2]3[CH:17]=[C:6]4[C:7]5[C:12]([CH2:13][CH2:14][N:5]4[C:4](=[O:18])[N:3]=3)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=5)=[CH:25][CH:26]=2)[CH:21]=[N:20]1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: Nc1ccc2[nH]ncc2c1
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2ccc3[nH]ncc3c2)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 1H-indazol-5-ylamine as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 13.00 (br, 1H), 9.60 (s, 1H), 8.36 (br, 1H), 8.06 (s, 1H), 7.69 (d, 1H), 7.51 (m, 2H), 7.10-6.95 (2H), 6.35 (s, 1H), 3.99 (t, 2H), 3.84 (s, 3H) and 2.97 (t, 2H); MS (ESI) (M+H)+ 360.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>>[F:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([F:9])[CH:4]=1
Reactant: Fc1ccccc1CBr
Reactant: Oc1ccc(Br)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(OCc2ccccc2F)ccc1Br
Yield: 108.5 %

Procedure:
A solution of 4-bromo-3-fluorophenol (5 g, 25 mmol), 2-fluorobenzylbromide (4.94 g, 26 mmol) and potassium carbonate (5.39 g, 39 mmol) was stirred at room temperature for 6 h. The solvent was evaporated, the residue taken up in water and extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure, affording the title compound (8.11 g) as a white solid; Rt (HPLC) 6.31 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([OH:15])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH3:26].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([O:15][CH2:25][CH3:26])=[CH:10][C:9]=1[CH3:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCBr
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(C)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C)c(NC(=O)OC(C)(C)C)cc1C
Temperature: 60 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of compound 35 (4 mmol, 948 mg) in 5 mL DMF, potassium carbonate (K2CO3, 8 mmol, 1.1 g) and bromoethane (4.8 mmol, 523 mg) were added. The reaction was stirred overnight at 60° C. Water (2 mL) was added to dissolve the unreacted potassium carbonate, and the reaction mixture was then extracted with ethyl acetate (3×10 mL). The organic layers were combined and dried over Na2SO4. After removal of the solvent, the crude product was purified by using flash chromatography (0-30% ethyl acetate/hexane) to give the title product 36 (90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[CH:15]([OH:26])[C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[N:19]2>C(Cl)Cl.O=[Mn]=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[C:15]([C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[CH:21][CH:20]=[N:19]2)=[O:26]
Reactant: CC(C)(C)C(=O)Nc1ccc(F)c(C(O)c2ccc3nccnc3c2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ccc(F)c(C(=O)c2ccc3nccnc3c2)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To the solution of N-(4-fluoro-3-(hydroxy(quinoxalin-6-yl)methyl)phenyl)pivalamide (5.16 g, 14.6 mmol, 1.0 eq.) in DCM (50 mL) was added MnO2 (6.4 g, 73 mmol, 5.0 eq.). The resulting mixture was stirred at 50° C. overnight. The solid was removed by filtration and the filtrate was concentrated. The resulting residue was purified by flash column chromatography (PE/EA=2/1, v/v) to afford N-(4-fluoro-3-(quinoxaline-6-carbonyl)phenyl)pivalamide as a yellow foam (4.7 g, 92%).
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:12]2[O:11][CH2:10][CH2:9][C:8]=2[CH:7]=[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=1>C(O)(=O)C.[Fe]>[Br:1][C:5]1[C:6]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:8]2[CH2:9][CH2:10][O:11][C:12]=2[C:4]=1[Br:3]
Reactant: BrBr
Reactant: CCOC(=O)CCc1cc(Br)c2c(c1)CCO2
Agent: [Fe]
Solvent: CC(=O)O
Product: CCOC(=O)CCc1cc2c(c(Br)c1Br)OCC2
Temperature: 50 °C
Reaction time: 5 h
Yield: 53.1 %

Procedure:
Bromine (0.80 g, 5.01 mmol) was added dropwise to a mixture of ethyl 3-(7-bromo-2,3-dihydrobenzofuran-5-yl)propionate (1.0 g, 3.34 mmol) and iron (10 mg) in acetic acid (10 ml) and the reaction mixture was stirred at 50° C. for 5 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Water was added to the residue and the organic matter was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium bicarbonate solution, a saturated aqueous sodium chloride solution and water and then dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:3) to give 0.67 g (yield: 53%) of the target compound.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:11]=3[N:10]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:9]2=[O:29])[CH2:4][CH2:3]1.[CH3:30][N:31]=[C:32]=[O:33]>ClCCl>[Cl:28][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[O:26][CH3:27])[CH2:19][N:10]1[C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][C:12]=2[N:8]([C@H:5]2[CH2:6][CH2:7][C@H:2]([NH:1][C:32]([NH:31][CH3:30])=[O:33])[CH2:3][CH2:4]2)[C:9]1=[O:29]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CC[C@H](N)CC3)c3ccc(C#N)cc32)cc1Cl
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)N[C@H]1CC[C@H](n2c(=O)n(Cc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc32)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A mixture of 1-(trans-4-aminocyclohexyl)-3-(3-chloro-4-methoxybenzyl)-5-cyano-2,3-dihydro-1H-benzimidazol-2-one (100 mg) and methyl isocyanate (17 mg) in dichloromethane (3 mL) was stirred at 0° C. for 2 hours under nitrogen atmosphere. The mixture was partitioned between water and a mixture of chloroform and methanol (5:1). The separated organic layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue was subjected to a preparative thin-layer chromatography eluting with a mixture of chloroform and methanol (10:1). The obtained substance was triturated with diethyl ether to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[trans-4-(3-methylureido)cyclohexyl]-2,3-dihydro-1H-benzimidazol-2-one (69 mg) as colorless powders.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[C:11]([C:13]3[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][C:14]=3[N+:22]([O-])=O)[O:10][N:9]=2)=[CH:4][CH:3]=1.O1CCCC1>[Pd].C(OCC)(=O)C>[NH2:22][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:13]=1[C:11]1[O:10][N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:12]=1)[C:17]([OH:19])=[O:18]
Reactant: O=C(O)c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1cc(C(=O)O)ccc1-c1nc(-c2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
A mixture of 4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]-3-nitrobenzoic acid (0.600 g), 5% palladium on carbon (0.600 g), tetrahydrofuran (30 ml) and ethyl acetate (30 ml) was stirred under a hydrogen atmosphere at room temperature and normal pressure for 30 min. Palladium on carbon was filtered off, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1, volume ratio) to give 3-amino-4-[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]benzoic acid (0.15 g, yield 28%). Recrystallization from hexane-tetrahydrofuran gave yellow prism crystals. melting point: 294–296° C. (decomposition).