Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Cl[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH:8][C:12]2[N:20]=[CH:19][CH:18]=[CH:17][C:13]=2[C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(O)c1cccnc1Cl
Reactant: COc1ccc(CN)cc1
Solvent: c1ccncc1
Product: COc1ccc(CNc2ncccc2C(=O)O)cc1
Yield: 77.2 %

Procedure:
p-Methoxybenzylamine (8.24 mL, 63.5 mmol) was added to a solution of 2-chloronicotinic acid (5 g, 31.7 mmol) in pyridine and refluxed overnight. The pyridine was distilled and the residue was dissolved in 1N NaOH. The solution was diluted with water to adjust the pH to 10 to 11 and washed by dichloromethane. The aqueous phase was neutralized with cold aqueous 10% HCl solution to adjust the pH to 4 to 5. The solids formed were filtered, washed with cold water, and dried in a vacuum oven to yield 6.32 g (77%) of 2-(4-methoxy-benzylamino)-nicotinic acid (11) as white solids. MP: 229° C.; 1H-NMR (DMSO-d6): δ 3.72 (s, 3H), 4.60 (d, J=3.6 Hz, 2H), 6.40 (dd, J=4.9, 7.7 Hz, 1H), 6.62 (d, J=7.6 Hz, 2H), 7.25 (d, J=7.6 Hz, 2H), 8.09 (dd, J=1.8, 7.0 Hz, 1H), 8.26 (dd, J=1.8, 7.0 Hz, 1H), 8.48 (br. s, 1H), 13.11 (s, 1H); EIMS: 259 (M+1), 281 (M+23).
Reaction SMILES: Cl.F[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][N:7]=[C:6]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=1.[N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[NH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:21]1([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][N:7]=[C:6]3[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[CH:15]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[N:23]=[CH:22]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Cc1cccc(Nc2ncnc3ccc(F)cc23)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(Nc2ncnc3ccc(-n4cnc5ccccc54)cc23)c1
Temperature: 150 °C
Yield: 47.5 %

Procedure:
A mixture of 6-fluoro-4-(3-methylanilino)quinazoline hydrochloride salt (0.347 g), benzimidazole (0.33 g), potassium carbonate (0.78 g) and DMF (7 ml) was stirred and heated at 150° C. for 24 hours. The mixture was evaporated and the residue was suspended in a mixture of methylene chloride and methanol. The suspension was filtered and the filtrate was evaporated to give a solid which was washed with ethyl acetate and purified by column chromatography using a 24:1 mixture of methylene chloride and methanol as eluent. The resultant solid was triturated with methylene chloride, filtered and dried to give 6-(1-benzimidazolyl)-4-(3-methylanilino)quinazoline (0.2 g), m.p. 245-246° C.; NMR Spectrum: (CD3SOCD3) 2.35 (s, 3H), 6.96-6.99 (d, 1H), 7.27-7.33 (t, 1H), 7.35-7.42 (m, 2H), 7.64-7.77 (m, 3H), 7.82-7.86 (m, 1H), 7.99-8.03 (d, 1H), 8.15-8.20 (m, 1H), 8.66 (s, 2H), 8.90 (d, 1H), 9.80 (s, 1H);
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][S:5]([C:8]1[CH:46]=[CH:45][C:11]([O:12][C:13]2[C:14]([CH:28]3[CH2:32][CH2:31][CH2:30][N:29]3[C:33]([O:35]C3C=CC([N+]([O-])=O)=CC=3)=O)=[CH:15][C:16]3[NH:20][CH:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[NH:18][C:17]=3[CH:27]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]>O1CCCC1>[CH3:1][N:2]([CH3:3])[C:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:28]1[C:14]1[C:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]([S:5]([CH3:4])(=[O:6])=[O:7])=[CH:46][CH:45]=2)=[CH:27][C:17]2[N:18]=[C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[NH:20][C:16]=2[CH:15]=1)=[O:35]
Reactant: CS(=O)(=O)c1ccc(Oc2cc3c(cc2C2CCCN2C(=O)Oc2ccc([N+](=O)[O-])cc2)NC(c2ccccn2)N3)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)N1CCCC1c1cc2[nH]c(-c3ccccn3)nc2cc1Oc1ccc(S(C)(=O)=O)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
1 ml of dimethylamine (2.0 M tetrahydrofuran solution) was added to a tetrahydrofuran (1 ml) solution of 20 mg of 4-nitrophenyl 2-(6-(4-methanesulfonyl-phenoxy)-2-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-5-yl)-pyrrolidin-1-carboxylate, and the reaction liquid was stirred overnight in a sealed tube at 100° C. The reaction solvent was evaporated away under reduced pressure, and the resulting residue was purified through reversed-phase middle-pressure liquid chromatography [ODS-AS-360-CC (by YMC), mobile phase: water-acetonitrile-0.1% trifluoroacetic acid]. The solvent of the resulting fraction was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate, and dried with anhydrous sodium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].Cl[CH2:14][C:15]([NH2:17])=[O:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:12]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:10](=[O:11])[N:2]1[O:1][CH2:14][C:15]([NH2:17])=[O:16]
Reactant: NC(=O)CCl
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)CON1C(=O)c2ccccc2C1=O

Procedure:
A solution of 2-hydroxyisoindoline-1,3-dione (2.4 g, 14.71 mmol), 2-chloroacetamide (1.65 g, 17.65 mmol) and K2CO3 (2.44 g, 17.65 mmol) in 40 mL of DMF was stirred at 90° C. overnight. The solid was removed by filtration and the solution was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with EtOAc/methanol gradient to afford the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, 1H), 7.68-7.64 (m, 2H), 7.45-7.43 (m, 2H), 7.35 (s, 1H), 4.23 (s, 2H). LCMS (method A): [MH]+=221, tR=2.665 min.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][CH:17]=1)[C:14]([NH2:18])=[C:13]1[C:8]([CH2:9][CH2:10][CH2:11][CH2:12]1)=[N:7]2.[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CS(C)=O>[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:18][C:14]1[C:15]2[C:6]([N:7]=[C:8]3[C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9]3)=[CH:5][C:4]([Cl:3])=[CH:17][CH:16]=2
Reactant: Nc1c2c(nc3cc(Cl)ccc13)CCCC2
Reactant: BrCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Clc1ccc2c(NCCCCCCCBr)c3c(nc2c1)CCCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.1 %

Procedure:
Potassium hydroxide (95 mg, 1.7 mmoL) was added to a solution of 6-chloro-1,2,3,4-tetrahydro-acridin-9-ylamine (395 mg, 1.7 mmoL) in dimethylsulfoxide (15 ml) and the mixture was stirred vigorously under nitrogen at room temperature for 2 h. 1,7-Dibromoheptane (438 mg, 1.7 mmoL) was added, and the reaction was continued to stir at room temperature for 12 h. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The combined ethyl acetate extract was dried, filtered and concentrated. The resulting residue was purified by column chromatography on silica gel using hexane/ethyl acetate/triethyl amine (8/2/1) to provide the desired product (244 mg, 0.60 mmoL) in 35% yield.
Reaction SMILES: Br[C:2]1[C:3](CNC2C[C@H](C)O[C@H](C)C2)=[N:4][C:5]2[N:6]([N:25]=[CH:26][C:27]=2[C:28]2[CH:29]=[N:30][C:31]3[C:36]([CH:37]=2)=[CH:35][C:34]([F:38])=[CH:33][CH:32]=3)[C:7]=1[N:8](COCC[Si](C)(C)C)COCC[Si](C)(C)C.O>C(O)(C(F)(F)F)=O>[F:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[N:30]=[CH:29][C:28]([C:27]1[CH:26]=[N:25][N:6]3[C:7]([NH2:8])=[CH:2][CH:3]=[N:4][C:5]=13)=[CH:37]2
Reactant: C[C@@H]1CC(NCc2nc3c(-c4cnc5ccc(F)cc5c4)cnn3c(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c2Br)C[C@H](C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Nc1ccnc2c(-c3cnc4ccc(F)cc4c3)cnn12
Reaction time: 2 h

Procedure:
To a 6-bromo-5-(((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ylamino)methyl)-3-(6-fluoroquinolin-3-yl)-N,N-bis((2-(trimethylsilyl)ethoxy)methyl)pyrazolo[1,5-a]pyrimidin-7-amine (69.3 mg, 0.09 mmol) in TFA (2 ml) was added few drops of water and stirring continued for 2 h at room temperature. LC/MS showed no starting material remaining. TFA along with water was rotoevaporated. This crude compound was submitted to the analytical group for purification to afford the desired 6-bromo-5-((2R,6S)-2,6-dimethyltetrahydro-2H-pyran-4-ylamino)methyl)-3-(6-fluoroquinolin-3-yl)pyrazolo[1,5-a]pyrimidin-7-amine. LCMS: 3.157 mins, m/z=499.0 (MH+).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH:23]=[C:22]3[C:17]([CH:18]=[CH:19][C:20]([O:24][CH3:25])=[CH:21]3)=[N:16]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.CO>[Pd].C1COCC1>[CH3:25][O:24][C:20]1[CH:19]=[CH:18][C:17]2[C:22](=[CH:23][N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[N:16]=2)[CH:21]=1
Reactant: COc1ccc2nn(-c3ccc(OCc4ccccc4)cc3)cc2c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2nn(-c3ccc(O)cc3)cc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104 %

Procedure:
Under a hydrogen atmosphere, a mixture of 2-[4-(benzyloxy)phenyl]-5-methoxy-2H-indazole (160 mg), 10% palladium/carbon (containing water (50%), 52 mg), methanol (10 mL) and THF (5 mL) was stirred at room temperature for 1 hr. The catalyst was removed by filtration, and the obtained filtrate was concentrated under reduced pressure to give the title compound (121 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:14]1[S:15][C:16]2[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.C(N(C(C)C)CC)(C)C>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][N:11]([C:14]2[S:15][C:16]3[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCOC(=O)c1cccc2nc(Br)sc12
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cccc2nc(N3CC(NC(=O)OC(C)(C)C)C3)sc12
Yield: 92 %

Procedure:
The same operation as in Example (217a) was performed using 3-tert-butoxycarbonylaminoazetidine (300 mg, 1.74 mmol), ethyl 2-bromo-1,3-benzothiazole-7-carboxylate obtained in Example (1f) (332 mg, 1.16 mmol) and diisopropylethylamine (0.40 mL, 2.32 mmol), to obtain 403 mg of the title compound as a pale yellow solid (92%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23](=[O:34])[NH:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:11][N:10]=1)(C)(C)C.[ClH:36]>CCOC(C)=O>[ClH:36].[CH3:33][O:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][NH:24][C:23]([C:12]2[C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]([CH2:8][NH2:7])=[N:10][CH:11]=2)=[O:34])=[CH:27][CH:28]=1
Reactant: COc1ccc(CNC(=O)c2cnc(CNC(=O)OC(C)(C)C)c3cc(OC)c(OC)cc23)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1ccc(CNC(=O)c2cnc(CN)c3cc(OC)c(OC)cc23)cc1
Yield: 69 %

Procedure:
As described in example 1, a solution of [6,7-dimethoxy-4-(4-methoxy-benzylcarbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (84 mg) was treated with HCl in EtOAc to give 46 mg (69%) of 1-aminomethyl-6,7-dimethoxy-isoquinoline-4-carboxylic acid 4-methoxy-benzylamide hydrochloride: 1H NMR (DMSO-d6) δ 3.71 (s, 3H), 3.80 (s, 3H), 3.98 (s, 3H), 4.45 (d, 2H, J=6.03 Hz), 4.69-4.72 (m, 2H), 6.90 (d, 211, J=8.64 Hz), 7.32 (d, 2H, J=8.53 Hz), 7.44 (s, 1H), 7.61 (s, 1H), 8.46 (s, 1H), 8.59-8.62 (br s, 3H), 9.25 (t, 1H, J=6.53 Hz); MS: APCI (M−H) calc'd for C21H23N3O4 380.2; found 380.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([O:16]C)=[O:15])[C:7]([C:10]([O:12]C)=[O:11])=[N:8][CH:9]=1.[OH-].[Na+]>O>[CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([C:14]([OH:16])=[O:15])[C:7]([C:10]([OH:12])=[O:11])=[N:8][CH:9]=1
Reactant: COCc1cnc(C(=O)OC)c(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1cnc(C(=O)O)c(C(=O)O)c1
Temperature: 10 °C
Yield: 83.9 %

Procedure:
A mixture of dimethyl 5-(methoxymethyl)-2,3-pyridinedicarboxylate (60.0 g, 0.25 mol) and 50% sodium hydroxide solution (50.0 g, 0.63 mol) in water is heated at 90°-110° C. for 2 hours under nitrogen while distilling off methanol and water. The reaction mixture is cooled to 10° C., treated with sulfuric acid to adjust the pH to 2.0 and filtered to obtain a solid. The solid is washed with water and vacuum dried to give the title product as a white solid (44.3 g, mp 161°-162° C.).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[C:16]([NH:28]C(OC(C)(C)C)=O)[C:17]3[N:18]([N:20]=[C:21]([C:23]4[O:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[CH:19]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[O:24]1[CH:25]=[CH:26][CH:27]=[C:23]1[C:21]1[N:22]=[C:17]2[C:16]([NH2:28])=[N:15][C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:19][N:18]2[N:20]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(N2CCN(C(=O)OC(C)(C)C)CC2)cn2nc(-c3ccco3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1nc(N2CCNCC2)cn2nc(-c3ccco3)nc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(8-tert-butoxycarbonylamino-2-furan-2-yl-[1,2,4]triazolo[1,5-a]pyrazin-6-yl)-piperazine-1-carboxylic acid tert-butyl ester (140 mg, 0.29 mmol; see Example 16 (i) above) in methylene chloride (4 mL) was added trifluoroacetic acid (400 μL). The reaction was stirred at room temperature for 2 hours. After the solvent and extra trifluoroacetic acid was evaporated, the residue was dissolved in methylene chloride (4 mL). The title compound in methylene chloride was divided into two portions and used for further reactions (see Example 17 and Example 18 below) without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[P:13](OCC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[P:13]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: COC(=O)c1ccc(CO)cc1
Product: CCOP(OCC)OCc1ccc(C(=O)OC)cc1

Procedure:
contacting the methyl p-(hydroxymethyl)benzoate of step (1) with triethyl phosphite to obtain diethyl p-(methoxycarbonyl)benzyl phosphite;
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][NH:21][CH2:22]3)[C@@H:18]2[C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1.[C:35]1(=O)[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:34][C:3]([F:2])([F:33])[C:4]1[CH:5]=[C:6]([C@H:14]([O:16][C@H:17]2[CH2:25][CH2:24][C@@H:23]3[C@@H:19]([CH2:20][N:21]([C:35]4[CH2:39][CH2:38][C:37](=[O:40])[CH:36]=4)[CH2:22]3)[C@@H:18]2[C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH3:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: C[C@@H](O[C@H]1CC[C@H]2CNC[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Product: C[C@@H](O[C@H]1CC[C@H]2CN(C3=CC(=O)CC3)C[C@H]2[C@@H]1c1ccc(F)cc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
To a solution of 12.3 mg (0.26 mmol) of (3aR,4R,5S,7aR)-5-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy}-4-(4-fluorophenyl)octahydro-1H-isoindole (Example 2) in ˜2 mL dry toluene was added 2.7 mg (0.028 mmol) cyclopentane-1,3-dione and a catalytic amount (˜0.5 mg) of PTSA. The resulting mixture was heated at reflux for 16 hr. The solvent was removed vacuum and the residue was purified by prep TLC eluting with EtOAc/MeOH (95/5) to afford the title compound. 1H-NMR (CDCl3): δ: 7.73 (1H, s), 7.20 (2H, s), 7.03–6.90 (2H, m), 4.98, 4.80 (1H, s), 4.50 (1H, m), 3.62–3.18 (2H, m), 3.30–3.18 (3H, m), 3.15, 2.97 (1H, d, J=11.2 Hz), 2.68 (2H, m), 2.55–2.40 (4H, m), 2.17 (1H, m), 2.20 (1H, m), 2.00 (1H, m), 1.85 (1H, m), 1.62 (1H, m), 1.33 (3H, d, J=6.2 Hz). MS: (MH)+556.0.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[N:11]1[C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[N:13]=[C:12]1Br)(=O)C.[CH:23]1([NH2:26])[CH2:25][CH2:24]1.[OH-].[Na+]>C(O)C>[Cl:20][C:18]1[C:17]([Cl:21])=[CH:16][C:15]2[N:11]([C@@H:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C@H:5]3[OH:4])[C:12]([NH:26][CH:23]3[CH2:25][CH2:24]3)=[N:13][C:14]=2[CH:19]=1
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1n1c(Br)nc2cc(Cl)c(Cl)cc21
Reactant: NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O[C@@H]1CCCC[C@H]1n1c(NC2CC2)nc2cc(Cl)c(Cl)cc21
Yield: 67 %

Procedure:
(±)trans-2-(2-Bromo-5,6-dichloro-1H-benzimidazol-1-yl)cyclohexyl acetate (Example 45, part c, 1.00 g, 2.46 mmol) and cyclopropylamine (5.0 ml) were refluxed in absolute ethanol (15 ml) for 3 days. The solution was cooled and 1 N sodium hydroxide (2.4 ml) was added. The residual solid was crystallized from ethanol-water to provide title compound as off-white powder (0.56 g, 67%), m.p. 149-151° C.; 1H-NMR (DMSO-d6, 200 MHz) δ: 7.55, 7.39 (both s, each 1, 2 aromatic CH), 6.90 (m, 1, NH), 4.73 (d, J=5.2 Hz, 1, OH), 4.1-3.8 (m, 2, OCH and NCH), 2.8-2.65 (m, 1, CHNH), 2.2-1.9 and 1.8-1.2 (m, 8, 4 CH2), 0.75-0.45 (m, 4, 2 cyclopropyl CH2).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15](=[O:19])OCC)=[N:5]2.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([NH:14][C:15]([N:30]1[CH2:31][CH2:32][N:27]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:28][CH2:29]1)=[O:19])=[N:5]2
Reactant: Cc1ccccc1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Product: COc1nc2ccc(F)cc2nc1NC(=O)N1CCN(c2ccccc2C)CC1
Yield: 73 %

Procedure:
Ethyl N-(6-fluoro-2-methoxyquinoxalin-3-yl)carbamate and 1-(2-methylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound (yield, 73%). 1H NMR (200 MHz, CDCl3): δ 2.35 (s, 3H), 2.98-3.03 (m, 4H), 3.73-3.78 (m, 3H), 4.10-4.14 (m, 4H), 7.02-7.17 (m, 2H), 7.19-7.29 (m, 2H), 7.36 (s, 1H), 7.48-7.60 (m, 1H), 7.67-7.74 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:17](O)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([CH3:23])([CH3:24])[CH3:22])[C:17]([NH:28][C:29]3[CH:41]=[CH:40][C:32]([C:33]([O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[O:34])=[CH:31][CH:30]=3)=[O:18])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC(C)(C)C)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC(C)(C)C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Reaction time: 0.58 h

Procedure:
110 mg (283 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4-dimethylpentanoic acid (racemate), 65.6 mg (339 μmol) of tert-butyl 4-aminobenzoate, 129 mg (339 μmol) of HATU and 148 μl (849 μmol) of N,N-diisopropylethylamine in 9 ml of dimethylformamide were reacted according to General Method 5A. The solvent was removed and the residue was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 100 mg (62% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])=[CH:5][C:4]=1[CH2:15][CH2:16][CH3:17].[CH2:18]([O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:33]2[C:28](=[C:29](O)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:18]([O:20][C:21](=[O:35])[CH2:22][O:23][C:24]1[C:33]2[C:28](=[C:29]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:15][CH2:16][CH3:17])[CH:5]=3)[CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH3:19]
Reactant: CCCc1cc(CCCCCO)ccc1OC
Reactant: CCOC(=O)COc1cccc2c(O)cccc12
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1cc(CCCCCOc2cccc3c(OCC(=O)OCC)cccc23)ccc1OC
Yield: 79.5 %

Procedure:
To a stirred suspension of 5-(4-methoxy-3-propylphenyl)pentanol (2.48 g), ethyl(5-hydroxy-1-naphthalenyloxy)acetate (2 g), and triphenylphosphine (3.2 g) in dry tetrahydrofuran (30 ml) under nitrogen was added diethyl azodicarboxylate (1.65 ml) slowly so that the temperature did not rise above 50°. After 3 hours the solution was evaporated, and the residue was chromatographed on silica with a mixture of dichloromethane and light petroleum (bp 40°-60°) (4:6) to give the sub-title ester (3 g), mp 70° (from ethanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][NH:19][CH2:20][CH2:21][NH:22][CH3:23].C([O-])([O-])=O.[K+].[K+]>O>[CH3:18][N:19]([CH2:20][CH2:21][NH:22][CH3:23])[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: CNCCNC
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CNCCN(C)c1nc(C)[nH]c2cc(-c3ccccc3)nc1-2
Yield: 21.6 %

Procedure:
This compound was prepared according to the method described in Example 2 by employing 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (70 mg, 0.29 mmol), N,N′-dimethylethylenediamine (Aldrich Chemical Company) (0.15 mL, 1.44 mmol) and K2CO3 (0.40 g, 2.87 mmol) in H2O (2 mL). The crude material was purified by flash chromatography on silica gel with 9:1 CHCl3:MeOH as eluant to give 18.5 mg (22%) of the title compound as an off-white solid. An analytical sample was obtained by recrystallization from EtOH. 1H NMR (CDCl3; 400 MHz): δ 2.60 (s, 6), 3.04 (t, 2, J=4.5), 3.15 (s, 3), 3.75 (t, 2, J=4.5), 6.76 (s, 1), 7.31-7.42 (m, 3), 7.70 (d, 2, J=7.4). MS m/z: 296 (M+1), 294 (M−1). HRMS: Calcd for M+H: 296.1875. Found: 296.1884.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[C:7]([O:23][CH3:24])[CH:8]=2)[N:3]=1.NC(N)=[S:29]>C(O)C>[CH2:16]([O:15][C:13]([CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:25][CH3:26])=[C:7]([O:23][CH3:24])[CH:8]=2)[N:3]=[C:2]([SH:29])[N:11]=1)=[O:14])[CH3:17]
Reactant: NC(N)=S
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(Cl)nc2cc(OC)c(OC)cc12
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1nc(S)nc2cc(OC)c(OC)cc12

Procedure:
The resultant product (600 mg) of (166-1) and thiourea (250 mg) were dissolved in ethanol (100 mL), and the mixture was heated under reflux for 48 hrs. The yellow solid precipitated in the reaction mixture was collected by filtration and washed with water and ethyl acetate to give the title compound (500 mg) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:5])[CH3:4].[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:18]Cl>O1CCCC1>[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH3:18])([CH3:5])[CH3:4]
Reactant: CC(C)c1ccccc1O
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCOc1ccccc1C(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
In dry tetrahydrofuran (60 mL) was suspended 4.80 g (120 mmol) of 60% sodium hydride, and a dry tetrahydrofuran (80 mL) solution containing 13.6 g (100 mmol) of 2-isopropylphenol was added dropwise to the suspension at 0° C. After stirring at 0° C. for 10 minutes, a dry tetrahydrofuran (80 mL) solution containing 14.9 g (119 mmol) of 2-methoxyethoxymethyl chloride was added dropwise thereto. The reaction mixture was stirred in an ice bath for 2 hours, poured into ice-cold water (250 mL), and extracted with ethyl acetate. The organic layers were combined, washed successively with 1 mol/L aqueous sodium hydroxide solution and brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=50:1) to obtain 18.1 g (80.8 mmol, Yield: 80.8%) of 1-isopropyl-2-[(2-methoxyethoxy)methoxy]benzene.