Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].F[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10](C)(C)[NH:9]2.C(N(CC)CC)C>C1COCC1>[C:1]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:6][CH:7]=2)[NH:12][C:11](=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CC(=O)Nc2ccccc21
Reaction time: 1 h

Procedure:
Acetyl chloride (0.36 ml) is added to 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.676 g) and triethylamine (0.76 ml) in THF (8 ml) at 0°. After stirring for 1 hr, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The layers are separated, the organic phase is filtered through sodium sulfate and concentrated. The concentrate is crystallized from methanomethylene chloride/hexane to give the title compound, mp 164°-165°; NMR (CDCl3) 2.28, 4.54, 7.00, 7.11, 7.21 and 9.19 δ.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[C:17]([CH2:19][C:20]([NH2:22])=[O:21])#[N:18].N1CCCCC1>C(O)C>[C:17]([C:19]1[C:20](=[O:21])[NH:22][C:1]([CH3:2])=[C:4]2[C:5]=1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH2:9]2)#[N:18]
Reactant: N#CCC(N)=O
Reactant: CC(=O)C1CC(c2ccncc2)CCC1=O
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(=O)c(C#N)c2c1CC(c1ccncc1)CC2
Yield: 34.7 %

Procedure:
2-Acetyl-4-(4-pyridyl)cyclohexanone (1.65 g) and cyanoacetamide (0.64 g) were dissolved in ethanol, and a small amount of piperidine was added. The reaction mixture was heated under reflux for 7 hours. After the reaction was completed, deposited crystals were filtered out to obtain 0.7 g of 4-cyano-2,3,5,6,7,8-hexahydro-1-methyl-3-oxo-7-(4-pyridyl)isoquinoline.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][C:9]=3[S:8][CH:7]=2)=[CH:2]1.C(OCC)(=O)C.Cl>C(OCC)(=O)C>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[C:15]3[O:14][CH2:13][CH2:12][NH:11][CH2:10][C:9]=3[S:8][CH:7]=2)=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(-c3ccoc3)csc2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc(-c2csc3c2OCCNC3)co1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
tert-Butyl 8-(furan-3-yl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (51.0 mg) was dissolved in ethyl acetate (2 ml,), and 4N hydrogen chloride-ethyl acetate solution (2 mL) was added. The mixture was stirred at room temperature for 1 hr, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of MeOH and Et2O to give 8-(furan-3-yl)-2,3,4,5-tetrahydrothieno[2,3-f][1,4]oxazepine 1 hydrochloride (30.6 mg, 74.8%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7][CH2:6]2.CN([CH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([CH2:16][C:17]1[C:25]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)[CH2:7][CH2:6]2
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: COc1ccc2c(c1)CCNC2
Solvent: Cc1ccccc1
Product: COc1ccc2c(c1)CCN(Cc1c[nH]c3ncccc13)C2
Yield: 32 %

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydroisoquinoline (prepared by the method of Helfer, Helv. Chim. Acta, 1924, 7, 945) (0.55 g, 3.36 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.59 g, 3.36 mmol) in toluene (3 ml) was heated at reflux under nitrogen for 18 h. The mixture was allowed to cool and the crystallised product collected. Recrystallisation from toluene afforded the title compound (0.31 g, 32%), m.p. 144°-146° C.; (Found: C, 73.04; H, 6.43; N, 14.10. C18H19N3O.0.1H2O requires C, 73.24; H, 6.55; N, 14.23%); δH (DMSO-d6) 2.67 (2H, br s, CH2), 2.76 (2H, t, J 5.4 Hz, CH2), 3.49 (2H, s, CH2), 3.69 (3H, s, OCH3), 3.78 (2H, s, CH2), 6.65 (2H, m, ArH), 6.89 (1H, d, 9 Hz, ArH), 7.01 (1H, dd, J 7.9, 4.7 Hz, 5-H), 7.40 (1H, d, J 2.2 Hz, ArH), 8.03 (1H, dd, J 7.7, 1.3 Hz, 4-H), 8.19 (1H, dd, J 4.6, 1.4 Hz, 6-H), and 11.47 (1H, br s, NH); m/z (CI+, NH3) 294 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[CH:3]=1.C(N(C(C)C)CC)(C)C.[Cl:25][C:26](=O)[C:27](OC)=[O:28].C(Cl)(=O)C(Cl)=O>ClCCl.CN(C=O)C.C(OCC)(=O)C.CCCCCC>[Cl:25][C:26]1[C:27](=[O:28])[N:9]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH3:15])[C:4]2[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=2[N:8]=1
Reactant: CCCOCCNc1cc(Cl)ncc1N
Reactant: COC(=O)C(=O)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCOCCn1c(=O)c(Cl)nc2cnc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 66 %

Procedure:
A 0° C. solution of 6-chloro-N4-(2-propoxyethyl)pyridine-3,4-diamine (2.80 g, 12.2 mmol) and diisopropylethylamine (4.6 mL, 25.7 mmol) in dichloromethane (100 mL) was treated with methyl chlorooxoacetate (1.1 mL, 11.7 mmol, Aldrich), allowed to warm to room temperature and stirred for four hours. The reaction was diluted with dichloromethane and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, and solvent was removed at reduced pressure. The residue was dissolved in toluene (30 mL) and heated at 105° C. for four hours. The solvent was removed at reduced pressure and the resulting solid taken up in dichloromethane (100 mL) and treated with oxalyl chloride (2.1 mL, 24.1 mmol) and DMF (3 drops). The reaction was stirred at room temperature for 6 hours. The solvent was removed at reduced pressure to give a brown solid. This was passed through a column of silica gel with 70% ethyl acetate/hexane to give 3,7-dichloro-1-(2-propoxyethyl)pyrido[3,4-b]pyrazin-2(1H)-one as a white solid. (2.44 g, 66% yield). 1H NMR (CDCl3) δ 8.78 (1H), 7.59 (1H), 4.40 (2H), 3.80 (2H), 3.35 (2H), 1.52-1.46 (2H), 0.82 (3H).
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([O:16]C)=[O:15])=[CH:10][CH:9]=1>Cl>[ClH:1].[OH:2][CH:3]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:4][NH:5][CH2:6][CH2:7][C:8]1[CH:19]=[CH:18][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: COC(=O)COc1ccc(CCNCC(O)COc2ccccc2)cc1
Agent: Cl
Product: O=C(O)COc1ccc(CCNCC(O)COc2ccccc2)cc1
Yield: 70.5 %

Procedure:
Methyl 4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]-phenoxyacetate hydrochloride (3.0 g) was suspended in 2N hydrochloric acid (150 ml) and heated on the steam bath for 2 hours. A clear solution was produced, from which the product crystallised on cooling. The crystals were filtered off, washed with a small volume of 2N hydrochloric acid followed by ether, and dried over phosphorus pentoxide. Thus was obtained 4-[2-(2-hydroxy-3-phenoxypropylamino)-ethyl]phenoxyacetic acid hydrochloride (2.04 g) mp 192°-94° C.; NMR 2.86-3.33[m,6H, CH2NHCH2CH2 ]: 4.02[m,2H, PhOCH2 ]; 4.22[m,1H,CHOH]; 4.63[s,2H, OCH2CO]; 6.84-7.38[m,9H, aromatic H]: microanalysis: found C, 59.8; H, 6.3; N, 3.5; Cl, 9.3%; C19H23NO5.HCl requires: C, 59.8; H, 6.3; N,3.7; Cl, 9.3 %.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]>[Pd]>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(C=CCCCC(=O)O)cc1
Agent: [Pd]
Product: CCCCCc1ccc(CCCCCC(=O)O)cc1
Yield: 86.1 %

Procedure:
This compound was synthesized from 6-(p-pentylphenyl)-5-hexenoic acid (1.30 g, 5 mmol) by hydrogenation reaction using Pd/C (130 mg). Crystallization (petroleum ether) afforded the product (1.13 g, 87%) as white crystals (mp 29-30° C.), IR: 3400-2500, 1730 cm-1 ; 1H-NMR: 0.89 (t, 3 H), 1.32 (m, 6 H), 1.60 (m, 6 H), 2.35 (t, 2 H), 2.58 (m, 4 H), 7.07 (s, 1 H), 10.30 (bs, 1 H). Anal. Calcd. for C17H26O2 : C, 77.82, H, 9.99%; Found: C, 77.56, H, 9.90%.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][S:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>C(O)C>[NH2:8][C@@H:12]([CH2:13][CH2:14][S:15][C:16]1[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=1)[CH2:11][OH:10]
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCSc2ccc(F)cc2)COC1(C)C
Agent: Cl
Solvent: CCO
Product: N[C@H](CO)CCSc1ccc(F)cc1
Reaction time: 16 h
Yield: 82.6 %

Procedure:
To (S)-4-[2-(4-fluoro-phenylsulfanyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.5 g) was added under an argon atmosphere 5.5 M HCl solution in ethanol (2 ml). The mixture was stirred for 16 h. The mixture was concentrated. The residue was dissolved in dichloromethane and an excess of ammonia in methanol and some silica gel was added. The solvents were evaporated and the crude product was purified by column chromatography (column: Isolute® Flash-NH2 from Separtis; eluent: dichloromethane/methanol=90:10) to give (S)-2-amino-4-(4-fluoro-phenylsulfanyl)-butan-1-ol (0.25 g) as a colourless liquid. MS (ISP): 216.3 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH2:23][C:24]#[N:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].CC[O-].[Na+]>C(O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([C:23](=[CH:6][C:5]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:24]#[N:25])[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COc1ccc(C=O)cc1OC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(C=C(C#N)c2ccc(OC)c(OC)c2)cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 92.2 %

Procedure:
To a stirred solution of 3,4-dimethoxybenzaldehyde (1.66 g, 100 mmol) and 3,4-dimethoxyphenyl-acetonitrile (1.77 g, 10 mmol) in 50 ml of absolute ethanol, cooled at 0° C. and maintained under nitrogen atmosphere, sodium ethylate (30 mmol) was portionwise added (10 portions, 1 portion/2 min). After complete addition and stirring for further 6 h at room temperature the reaction mixture was cooled to 0° C. and a yellow precipitate occurs. This precipitate was filtered off, washed with ethanol (100 ml) and dried under reduced pressure. This afford the desired stilbene as yellow powder (yield 3 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11]O)[CH:10]=1)[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]2.[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[CH3:30])=[O:20]>>[CH3:17][O:18][C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH2:11][C:9]1[CH:10]=[C:2]([Br:1])[CH:3]=[C:4]3[C:8]=1[N:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[N:6]=[CH:5]3)[N:25]=[C:24]2[CH3:30])=[O:20]
Reactant: CC(C)Cn1ncc2cc(Br)cc(CO)c21
Reactant: COC(=O)c1ccc2[nH]nc(C)c2c1
Product: COC(=O)c1ccc2c(c1)c(C)nn2Cc1cc(Br)cc2cnn(CC(C)C)c12
Yield: 76 %

Procedure:
Compound 37 was prepared following general method 3A, using compound 18 as a starting material and 3-methyl-1H-indazole-5-carboxylic acid methyl ester as the heterocycle. Yield: 76%.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[NH2:42][C:43]1[CH:47]=[N:46][N:45]([CH2:48][C:49]2[O:50][CH:51]=[C:52]([C:54](=[O:56])[CH3:55])[N:53]=2)[N:44]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:54]([C:52]1[N:53]=[C:49]([CH2:48][N:45]2[N:44]=[C:43]([NH:42][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:47]=[N:46]2)[O:50][CH:51]=1)(=[O:56])[CH3:55]
Reactant: CC(=O)c1coc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(=O)c1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (590 mg, 2.72 mmol) in CH2Cl2 (20 mL) was treated at rt with DMAP (82 mg, 0.68 mmol), HOBt (441 mg, 3.62 mmol), EDC (1.3 g, 6.79 mmol) and DIPEA (1.8 mL, 10.86 mmol) and the resulting mixture was stirred for 30 min at rt. A solution of 1-(2-((4-amino-2H-1,2,3-triazol-2-yl)methyl)oxazol-4-yl)ethanone (WO 2009/077990, p. 105) (562 mg, 2.72 mmol) in CH2Cl2 (7.0 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (50 mL), the org. phase was washed with water (50 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (4:6 hept-EA) gave the title compound as a white solid: TLC: rf (4:6 hept-EA)=0.35. LC-MS-conditions 07: tR=0.88 min, [M+H]+=407.05.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[C:16]([C:17]4[C:22]([C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:15][CH:14]=[C:13]1[C:8]=3[CH:9]=[CH:10][CH:11]=[CH:12]1.CN(C)C=O.[Br:28]N1C(=O)CCC1=O>O>[Br:28][C:14]1[CH:15]=[C:16]2[C:7](=[C:8]3[C:13]=1[CH:12]=[CH:11][CH:10]=[CH:9]3)[C:6]1[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=1[C:22]1[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc2c(c1)ccc1c3ccccc3c3ccccc3c21
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc2c3ccccc3c3ccccc3c2c2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
5.21 g of benzo[g]chrysene and 50 mL of N,N-dimethylformamide were placed in a flask. 10 mL of N,N-dimethylformamide solution of 4.00 g of N-bromosuccinimide were added. The resulting solution was heated with stirring at 80° C. for 8 hours. After cooling to room temperature, the reaction solution was poured to 200 mL of water. Deposited solids were filtered off, and washed with water and methanol. The resulting solids were purified by silica gel column chromatography, whereby 5.87 g (yield 88%) of 10-bromobenzo[g]chrysene was obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([C:13](Cl)=[O:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[CH2:16]([CH:23]1[CH2:28][NH:27][CH2:26][CH2:25][N:24]1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)(=[O:31])=[O:30])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH2:16]([CH:23]1[CH2:28][N:27]([C:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:26][CH2:25][N:24]1[S:29]([C:32]1[CH:41]=[CH:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=1)(=[O:31])=[O:30])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=S(=O)(c1ccc2ccccc2c1)N1CCNCC1Cc1ccccc1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Product: O=C(C1CCN(c2ccncc2)CC1)N1CCN(S(=O)(=O)c2ccc3ccccc3c2)C(Cc2ccccc2)C1
Yield: 70 %

Procedure:
Using an analogous procedure to that described in Example 1, 1-(4-pyridyl)piperidine-4-carbonyl chloride was reacted with 2-benzyl-1-(2-naphthylsulphonyl)piperazine to give 2-benzyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-ylcarbonyl]piperazine in 70% yield; m.p. 186-188° C.;
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:19])[CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[N:15]1.Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)=[CH:26][CH:27]=1.O>CN(C)C=O>[CH3:39][C:23]1[C:22]([CH2:21][O:19][C:6]2[CH:7]=[CH:8][C:9]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]3[CH:18]=[CH:17][N:16]=[N:15]3)=[C:4]([CH3:3])[CH:5]=2)=[CH:27][CH:26]=[C:25]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:32][CH:33]=2)[N:24]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)ccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(OC(F)(F)F)cc3)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91.5 %

Procedure:
26 mg (0.66 mmol) of 60% sodium hydride were added to at 0° C. to a solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)-phenol in 8.0 ml N,N-dimethylformamide and stirred for 30 min. at 0° C. 200 mg (0.66 mmol) 3-chloromethyl-2-methyl-6-(4-trifluoromethoxy-phenyl)-pyridine were given to the reaction mixture and stirring continued at room temperature (r.t.) overnight. After addition of 16 ml water the mixture was stirred for 1 h, the formed precipitate isolated by filtration, washed with water, n-heptane, and ether. The residue was dried at 40° C. in vacuum to give 300 mg (91%) of the title compound as white powder.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:35])[F:34])=[CH:27]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([C:33]([F:36])([F:34])[F:35])=[CH:27]2
Reactant: Oc1ccc2[nH]c(C(F)(F)F)cc2c1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C(F)(F)F)cc4c3)ncnc2cc1OCC1CCN(C)CC1
Temperature: 90 °C
Yield: 46.4 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (50 mg, 0.155 mmol), (prepared as described for the starting material in Example 10), and 5-hydroxy-2-trifluoromethylindole (34 mg, 0.17 mmol) in DMF (1.5 ml) containing potassium carbonate (43 mg, 0.31 mmol) was heated at 90° C. for 2 hours. After cooling, the mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried (MgSO4) and the volatiles were removed by evaporation. The residue was purified by column chromatography eluting with methanol/ethyl acetate/methylene chloride (10/50/40) followed by 2.5M ammonia in methanol/ethyl acetate/methylene chloride (10/50/40) to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-trifluoromethylindol-5-yloxy)quinazoline (35 mg, 48%).
Reaction SMILES: [CH3:1][C:2]([OH:11])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4]O.[OH-].[Na+].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C:25]1([N:31]2[C:35]([SH:36])=[N:34][N:33]=[N:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:1][C:2]([OH:11])([CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:3][CH2:4][S:36][C:35]1[N:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:32]=[N:33][N:34]=1
Reactant: CCCCCC(C)(O)CCO
Reactant: Sc1nnnn1-c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCCCC(C)(O)CCSc1nnnn1-c1ccccc1
Yield: 87.9 %

Procedure:
To a solution of the compound 38 (8.05 g) in toluene (98 mL) were added tetrabutylammonium bromide (1.62 g) and 2N sodium hydroxide (98 mL) at 0° C. and was added dropwise a suspension of tosyl chloride (10.5 g) in toluene (40 mL). The solution temperature was risen to room temperature and the solution was stirred for 1 Hour. A solution of 1-phenyl-1H-tetrazole-5-thiol (10.74 g) in toluene was added thereto and the solution was stirred at 60° C. for 3.5 Hours. The reaction solution was extracted with tert-butoxymethyl. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by Yamazen Parallel Prep (Brand name; column: 3 L, inject column: 2 L, n-hexane:ethyl acetate=81:19) to give the title compound (14.15 g) having the following physical data.
Reaction SMILES: Cl.Cl.[O:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:19][NH:18][CH2:17][CH2:16][NH:15]3)=[CH:10][CH:9]=2)=[N:4]1.C(N(CC)CC)C.Cl[C:28]1[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[C:30]([C:36]2[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=2)[N:29]=1>O1CCCC1>[O:3]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]3[NH:15][CH2:16][CH2:17][N:18]([C:28]4[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[C:30]([C:36]5[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=5)[N:29]=4)[CH2:19]3)=[CH:10][CH:9]=2)=[N:4]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: c1nc(-c2ccc(C3CNCCN3)cc2)no1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCN[C@@H](c3ccc(-c4ncon4)cc3)C2)nc(-c2ccncc2)cc1=O
Reaction time: 24 h
Yield: 74.4 %

Procedure:
To a suspension of 2-(4-(1,2,4-oxadiazol-3-yl)phenyl)piperazine dihydrochloride (102 mg, 0.34 mmol) in tetrahydrofuran (6 mL) was added triethylamine (0.23 mL, 1.65 mmol) and then 2-chloro-3-methyl-6-(4-pyridyl)-3H-pyrimidin-4-one (73 mg, 0.33 mmol) at room temperature. After stirring for 24 h, the resulting mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and saturated sodium bicarbonate aqueous solution, and the solution was passed through CHEM ELUT CE1010 (manufactured by VARIAN). The filtrate was concentrated in vacuo to yield crystals, which were washed with diisopropyl ether and ethanol to afford (S)-2-(3-(4-(1,2,4-oxadiazol-3-yl)phenyl) piperazin-1-yl)-3-methyl-6-(4-pyridyl)pyrimidin-4-one (102 mg 74%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([OH:17])=O)[CH:9]=2)=[O:4].[C:24]([CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23]2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15](=[O:17])[NH:34][CH:31]1[CH2:32][CH2:33][CH:28]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:29][CH2:30]1)[CH:9]=2)=[O:4]
Reactant: COC(=O)c1cc2ccc(C(=O)O)cc2c(CC2CCCC2)n1
Reactant: CC(C)(C)C1CCC(N)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[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: COC(=O)c1cc2ccc(C(=O)NC3CCC(C(C)(C)C)CC3)cc2c(CC2CCCC2)n1
Yield: 104.5 %

Procedure:
A solution of 1-cyclopentylmethyl-isoquinoline-3,7-dicarboxylic acid 3-methyl ester (38 mg, 0.121 mmol) in DMF(1.5 mL) was treated with 4-tert-butylcyclohexylamine (0.028 g, 0.181 mmol), HBTU (69 mg, 0.181 mmol), and DIEA (0.075 mL, 0.424 mmol) by the General Procedure A to give 57 mg of the desired 7-(4-tert-butyl-cyclohexylcarbamoyl)-1-cyclopentylmethyl-isoquinoline-3-carboxylic acid methyl ester as a colorless oil. This was used directly for the next step without purification.
Reaction SMILES: [S:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:4])(=[O:3])[NH2:2].CCN(CC)CC.ClC(OCC)=O.[CH2:27]([O:29][C:30]([C:32]1[C:37](=[O:38])[N:36]2[CH:39]=[CH:40][CH:41]=[C:42]([SH:43])[C:35]2=[N:34][CH:33]=1)=[O:31])[CH3:28]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:27]([O:29][C:30]([C:32]1[C:37](=[O:38])[N:36]2[CH:39]=[CH:40][CH:41]=[C:42]([S:43][C:9](=[O:11])[C:8]3[CH:7]=[CH:6][C:5]([S:1](=[O:3])(=[O:4])[NH2:2])=[CH:13][CH:12]=3)[C:35]2=[N:34][CH:33]=1)=[O:31])[CH3:28]
Reactant: NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1cnc2c(S)cccn2c1=O
Agent: CCOC(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc2c(SC(=O)c3ccc(S(N)(=O)=O)cc3)cccn2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a solution of 0.48 g (2.4 mmol) of 4-sulfamoylbenzoic acid in 10 ml of DMF are added 0.29 g of Et3N and then 0.28 g ethyl chloroformate, and the mixture is stirred at room temperature for 1 hour and mixed with 0.5 g of solid 3-ethoxycarbonyl-9-mercapto-4H-pyrido[1,2-a]pyrimidin-4-one II-1. The mixture is stirred at room temperature for 2 hours, diluted with 100 ml of water and shaken with ethyl acetate. The organic layer is washed with water, dried and concentrated in vacuo. The residue is washed with ethyl acetate to give 0.68 g of the titled compound.