Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:27])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:28]([C:35]([NH:37][OH:38])=O)C1C=CC=CC=1>C1COCC1>[OH:38][NH:37][C:35]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:27])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][N:18]=2)[CH2:11][CH2:12]1)=[O:28]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cc(Cl)cnc1CN(Cc1nccc2ccccc12)C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cnc1CN(Cc1nccc2ccccc12)C1CCN(C(=O)NO)CC1
Yield: 50.4 %

Procedure:
A solution of (5-Chloro-3-methyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidine-4-yl-amine (140 mg, 0.37 mmol) and N-(phenoxycarbonyl)hydroxylamine (112 mg, 0.74 mmol) in anhydrous THF (4 mL) was stirred for 16 hours at 70° C. The solution was then cooled and concentrated under reduced pressure and dried in vacuo. The crude material was purified by column chromatography with silica gel (50:1:0.1 CH2Cl2/MeOH/NH4OH) to give COMPOUND 308 as a white solid (82 mg, 51%). 1H NMR (CDCl3): δ 1.73 (q, 2H, J=11.1 Hz), 1.96 (s, 3H), 1.99 (br, 2H), 2.70 (br, 3H), 3.85 (s, 2H), 4.05 (d, 2H, J=13.2 Hz), 4.26 (s, 2H), 6.65 (br, 1H (Oh)), 6.81 (br s, 1H (NH)), 7.33 (s, 1H), 7.42 (t, 1H, J=7.2 Hz), 7.54 (d, 1H, J=4.8 Hz), 7.62 (t, 1H, J=7.8 Hz), 7.77 (d, 1H, J=7.8 Hz), 7.95 (d, 1H, J=7.2 Hz), 8.26 (s, 1H), 8.39 (d, 1H, J=3.6 Hz). 13C NMR (CDCl3) δ 18.75, 28.62 (2C), 45.17 (2C), 56.17, 56.61, 61.23, 122.76, 127.88, 128.44, 128.59, 129.29, 132.10, 132.65, 137.35, 138.33, 139.35, 141.74, 145.51, 156.93, 160.35, 162.80. ES-MS m/z 441 (M+H). Anal. Calcd. for C23H26N5O2Cl.0.2H2O: C, 62.28; H, 6.00; N, 15.79; Cl, 7.99. Found: C, 62.31; H, 5.83; N, 15.50; Cl, 8.06.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9]1.ClC(OCC(C)C)=O.C(N(CC)CC)C.[CH2:38](O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]1[CH2:12][C:11](=[O:13])[C:10]([S:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[O:21])=[CH:9]1
Reactant: OCc1ccccc1
Reactant: O=C(O)CCCCCSC1=CC(OC2CCCCO2)CC1=O
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCCCCSC1=CC(OC2CCCCO2)CC1=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 51 %

Procedure:
2.09 g (6.1 mmoles) of 4(RS)-tetrahydropyranyloxy-2-(5-carboxypentylthio)-2-cyclopentenone was dissolved in 20 ml of dichloromethane, and to this solution were added 5 ml of a dichloromethane solution of 956 mg (7 mmoles) of isobutyl chloroformate and 5 ml of a dichloromethane solution of 808 mg (8 mmoles) of triethylamine. The mixture was stirred at -78° C. for 30 minutes. Then, 5 ml of a dichloromethane solution of 864 mg (8 mmoles) of benzyl alcohol was added, and the reaction was carried out for 18 hours while gradually raising the temperature to room temperature. After the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with an aqueous solution of hydrogen chloride and an aqueous solution of sodium bicarbonate, then dried, and concentrated. The resulting crude product was chromatographed on a silica gel column using hexane/ethyl acetate (3.5/1) as an eluent to give 1.30 g (3.11 mmoles; yield 51%) of 4(RS)-tetrahydropyranyloxy-2-(5-benzyloxycarbonylpentyl-thio)-2-cyclopentenone.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([N+:23]([O-])=O)=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:26][CH3:27])=[CH:10][CH:9]=1)(=[O:4])[CH2:2][CH3:3].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[C:18]3[CH:19]=[CH:20][C:21]([NH2:23])=[CH:22][C:17]=3[N:16]=[C:15]2[CH2:26][CH3:27])=[CH:12][CH:13]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc([N+](=O)[O-])ccc32)cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCC(=O)OCCc1ccc(-n2c(CC)nc3cc(N)ccc32)cc1
Yield: 83 %

Procedure:
To a stirred solution of 2-[4-(2-ethyl-5-nitro-1H-benzimidazol-1-yl)phenyl]ethyl propionate (step 3, 1.12 g, 3.0 mmol) in ethanol/water (v/v, 2:1, 15 mL) was added ammonium chloride (80 mg, 1.5 mmol) and iron powder (840 mg, 15 mmol) at room temperature. The mixture was heated at reflux temperature for 4 h and filtered through a pad of Celite. The filtrate was concentrated, and the residue was dissolved in dichloromethane (200 mL), then dried (MgSO4). Removal of solvent gave 0.84 g (83%) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.3 Hz), 7.29 (2H, d, J=8.6 Hz), 7.10 (1H, d, J=1.8 Hz), 6.89 (1H, d, J=8.4 Hz), 6.63 (1H, dd, J=2.2, 8.4 Hz), 4.37 (2H, t, J=7.0 Hz), 3.05 82H, t, J=7.1 Hz), 2.79 (2H, q, J=7.5 Hz), 2.35 (2H, q, J=7.5 Hz), 1.33 (3H, t, J=7.50 Hz), 1.14 (3H, t, J=7.7 Hz).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][N:18]=2)[C:15]([N:19]2[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]2=[O:29])=[N:14][CH:13]=[CH:12]3)=CC=1.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][N:18]=1)[C:15]([N:19]1[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]1=[O:29])=[N:14][CH:13]=[CH:12]2
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2cc3ccnc(N4C(=O)c5ccccc5C4=O)c3cn2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cc2ccnc(N3C(=O)c4ccccc4C3=O)c2cn1
Temperature: 40 °C
Reaction time: 19 h
Yield: 96.4 %

Procedure:
A mixture of 4-6 (3.94 g, 7.43 mmol), trifluoroacetic acid (30.0 mL, 392 mmol), and dichloromethane (30.0 mL) was stirred at 40° C. for 19 hours under an atmosphere of nitrogen gas and concentrated under reduced pressure. To the resulting residue was added saturated aqueous NaHCO3 (300 mL) and hexane/dichloromethane (5:1) (150 mL) at ambient temperature. The resulting mixture was stirred vigorously at ambient temperature for 30 minutes. The precipitated solid was filtered, washed with water (60 mL) and hexane/dichloromethane (5:1) (60 mL), and dried under high vacuum to give 2.08 g (96%) of 4-7 as a pale yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 9.04 (1H, br s), 8.28 (1H, d, J=6.0 Hz), 8.05 (2H, m), 7.97 (2H, m), 7.55 (1H, br d, J=6.0 Hz), 6.78 (2H, br s), 6.63 (1H, br s); ESI-MS m/z 291 [C16H10N4O2+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>C(O)C>[CH2:13]1[CH:14]2[N:10]([CH2:2][CH:3]=[C:4]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][N:5]=4)[NH:1][CH:2]=3)[CH2:9]2)[CH2:11][CH2:12]1
Reactant: c1cnc2cc[nH]c2c1
Reactant: C1CCNC1
Solvent: CCO
Product: C1=C(c2c[nH]c3cccnc23)CC2CCCN2C1

Procedure:
from 4-azaindole (1.0 g, 8.46 mmol), 1,2,3,5,6,8,8a-heptahydrohydro-7-oxo-indolizine (1.77 g, 12.7 mmol) and pyrrolidine (3.5 g, 42.3 mmol) in ethanol (8 mL), heating at reflux for 3 hrs.
Reaction SMILES: [CH3:1][C@H:2]1[O:4][C@@:3]1([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5].[CH3:12][SH:13].[Na]>CO>[CH3:12][S:13][C@H:2]([CH3:1])[C@@:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([OH:4])[CH3:5]
Reactant: CS
Reactant: C[C@H]1O[C@]1(C)c1ccccc1
Agent: [Na]
Solvent: CO
Product: CS[C@H](C)[C@](C)(O)c1ccccc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a solution of trans-2,3-dimethyl-2-phenyloxirane (14 g, 76 mmol) in methanol (100 mL) was added 15% aqueous sodium methyl mercaptan solution (61 mL, 190 mmol) under nitrogen atmosphere at room temperature, and the mixture was warmed to 60° C. and stirred for 2 hours. The mixture was concentrated under reduced pressure, and the residue was extracted twice with diethyl ether (50 mL), sequentially washed with water (50 ml) and saturated aqueous sodium chloride solution (50 mL), and dried over sodium sulfate. The resultant mixture was filtrated and the solvent was evaporated to give the title compound (16 g, yield 99%) as a colorless oil.
Reaction SMILES: [CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([OH:17])=O)[C:5]1=[O:18])([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:25][CH2:26][CH:27]1[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C)C=O>[CH:1]([N:4]1[C:13]2[C:8](=[C:9]([CH3:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:15]([NH:25][CH2:26][CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:17])[C:5]1=[O:18])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Cc1cccc2c1cc(C(=O)O)c(=O)n2C(C)C
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccc2c1cc(C(=O)NCC1CCN(C(=O)OC(C)(C)C)CC1)c(=O)n2C(C)C
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 1-isopropyl-5-methyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (8.00 g, 32.6 mmol, step 4 in preparation 2) in dichloromethane (200 mL) was added dropwise oxalyl chloride (8.5 mL, 98 mmol) at 0° C. Then, N,N-dimethylformamide (3 drops) was carefully added to the mixture. The resulting mixture was stirred at 0° C. for 30 min and at room temperature for 3 h. Then, the mixture was evaporated in vacuo to give crude acid chloride as a yellow solid. Then, to a mixture of tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (9.08 g, 42.4 mmol) and diisopropylethylamine (11.4 mL, 65.2 mmol) in dichloromethane (200 mL) was added dropwise a solution of crude acid chloride in dichloromethane (50 mL) at 0° C., and the mixture was stirred at room temperature for 3 h. The resulting mixture was poured onto water (300 mL), and the aqueous layer was extracted with dichloromethane (200 mL×3). The combined organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was chromatographed on a column of silica gel with ethyl acetate/hexane (1/1.5) and then methanol/dichloromethane (1/40˜1/10) to give 15.0 g (quant.) of the title compound as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:32][CH2:33][CH3:34])[C:5]#[C:6][C:7](=[N:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](F)(F)[F:9])[CH3:2].[F:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH2:33]([O:32][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[N:44]=[C:43]([CH2:42][C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)[C:8]([F:9])=[C:7]([NH:12][C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:6]=1)[CH3:34]
Reactant: NCCc1ccc(F)cc1
Reactant: CCOC(C#CC(=NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(F)(F)F)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(OCC)c1cc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)c(Cc2ccc(F)cc2)n1
Yield: 57.6 %

Procedure:
Using the procedure of Example 9, N-(5,5-diethoxy-1,1,1-trifluoropent-3-yn-2-ylidene)-1,1,1-triphenylmethanamine (4.66 g, 10 mmol), 2-(4-fluorophenyl)ethanamine (1.670 g, 12.00 mmol), cesium carbonate (8.15 g, 25.00 mmol) and DMSO (30 mL) gave 6-(diethoxymethyl)-3-fluoro-2-(4-fluorobenzyl)-N-tritylpyridin-4-amine (3.25 g, 56.4%) as a yellow glass, which crystallized from CH3CN (25 mL): mp 129-130° C.; 1H NMR (400 MHz, CDCl3) δ 7.27 (m, 19H), 6.94 (m, 2H), 6.19 (d, J=6.6 Hz, 1H), 5.71 (d, J=4.3 Hz, 1H), 5.06 (s, 1H), 4.05 (d, J=2.9 Hz, 2H), 3.23 (dq, J=9.4, 7.1 Hz, 2H), 3.13 (dq, J=9.4, 7.0 Hz, 2H), 1.00 (t, J=7.0 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 161.48 (d, J=243.8 Hz), 152.10 (d, J=5.9 Hz), 147.04 (d, J=246.0 Hz), 144.65 (d, J=13.9 Hz), 144.13, 140.88 (d, J=9.4 Hz), 134.69 (d, J=3.1 Hz), 130.28 (d, J=7.8 Hz), 128.86, 128.20, 127.24, 114.99 (d, J=21.2 Hz), 108.23, 101.87, 71.24, 61.05, 37.45, 15.05; 19F NMR (376 MHz, CDCl3) δ−117.27, −151.26 (dd, J=6.6, 3.6 Hz); HRMS-ESI (m/z) [M+H]+ calcd for C36H34F2N2O2, 564.2588. found, 564.2595.
Reaction SMILES: C(OC(N[C@H](C(OC[CH:20]([CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:21][C:22](O)=[O:23])=O)C(C)C)=O)C1C=CC=CC=1.S(Cl)([Cl:48])=O>>[C:27]([O:26][CH2:25][CH2:20][CH2:21][C:22]([Cl:48])=[O:23])(=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCCCCCCCCCCC(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)CC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)OCCCC(=O)Cl

Procedure:
3-(N-benzyloxycarbonyl-L-valyloxymethyl)-4-stearoyloxy-butyric acid (1.26 g, 2 mmol), was treated with thionyl chloride (50 ml) at 35° C. for 3 hr, evaporated and coevaporated to give the product 3-N-benzyloxycarbonyl-L-valyloxy)-4-stearoyloxy-butyroyl chloride (1.3 g).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[NH:12]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][O:35][CH2:34]1)(=O)=O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:15][CH3:16])[N:12]2[CH2:29][CH2:30][CH2:31][CH2:32][CH:33]2[CH2:38][CH2:37][CH2:36][O:35][CH2:34]2)=[C:8]([NH2:17])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CS(=O)(=O)OCCCCC1CCCOC1
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCC3CCCOC3)c2n1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 123.5 %

Procedure:
To a solution of N2-butyl-8-(methoxy)-9H-purine-2,6-diamine (250 mg) in dry N,N-dimethylformamide (4.46 ml) at room temperature was added potassium carbonate (395 mg). The reaction mixture was stirred at 60° C. for 90 min. The reaction was cooled to room temperature and 4-(tetrahydro-2H-pyran-3-yl)butyl methanesulfonate (186 mg) was added and the reaction stirred at 90° C. for 2 hours. The reaction mixture was taken up in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil (366 mg). The product was purified by C18 reverse phase chromatography using water (containing 0.1% formic acid)-acetonitrile (containing 0.05% formic acid) as eluant (30-70%) to afford the title compound as an orange gum (172 mg).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=3)[C:14](O)=[O:15])=[C:8]([CH3:20])[C:6]=2[N:7]=1.[OH:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:14]([N:31]4[CH2:32][CH2:33][CH:28]([OH:27])[CH2:29][CH2:30]4)=[O:15])[CH:17]=[CH:18][CH:19]=3)=[C:8]([CH3:20])[C:6]=2[N:7]=1
Reactant: OC1CCNCC1
Reactant: Cc1c(-c2cccc(C(=O)O)c2)sc2c(N3CCOCC3)nc(Cl)nc12
Product: Cc1c(-c2cccc(C(=O)N3CCC(O)CC3)c2)sc2c(N3CCOCC3)nc(Cl)nc12

Procedure:
3-(2-Chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (60 mg) was reacted with 4-hydroxypiperidine via General Procedure B to yield 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone. Crude 3-(2-chloro-7-methyl-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(4-hydroxypiperidin-1-yl)methanone (72 mg) was coupled to 7-azaindole-5-boronic acid pinacol ester via General Procedure A. The product was purified by reverse phase HPLC to yield 29.5 mg of 425. MS (Q1) 555.2 (M)+
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1B(O)O.N>>[Cl:24][C:25]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:26]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: OB(O)c1ccc(Cl)cc1Cl
Agent: N
Product: CC(C)(C)OC(=O)N1CC[C@@H]2[C@H](C1)c1cc(-c3ccc(Cl)cc3Cl)cc3c1N2CC3
Yield: 50.2 %

Procedure:
The title compound (55.9 mg, 50%) was prepared by the method of Example 89 Step C from tert-butyl (±)-cis-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)-carboxylate (94 mg, 0.25 mmol) and 2,4-dichlorophenylboronic acid (95 mg, 0.5 mmol) as a white amorphous solid. MS (CI, NH3): 445 (base, M+H).
Reaction SMILES: [BH4-].[Na+].[N+:3]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:13][CH:12]=[CH:11][CH:10]=2)([O-])=O>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:3][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CC(C)(C)OC(=O)NCCCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCCCCNc1c(N)cnc2ccccc12
Temperature: 5 °C
Reaction time: 1 h
Yield: 85.7 %

Procedure:
Nickel(II) chloride hexahydrate (18.4 g) was dissolved in MeOH (360 mL) and cooled to 5° C. Sodium borohydride (2.9 g) was added followed by the product from step (i) (28 g). More sodium borohydride (11.7 g) was added slowly keeping the temperature below 23° C. then stirred for 1 h. The reaction mixture was filtered through celite and the filtrate was poured into sodium bicarbonate solution (300 mL). The solvent was reduced by half and then extracted with chloroform, combined organics were dried, and solvent removed to give the subtitle compound as a solid (22 g); MS multimode (+) 331
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1>ClCCl.[O-2].[O-2].[Mn+4]>[S:6]1[CH:7]=[C:3]([CH:2]=[O:1])[N:4]2[CH:10]=[N:9][CH:8]=[C:5]12
Reactant: OCc1csc2cncn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=Cc1csc2cncn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.1 %

Procedure:
In 20 ml of dichloromethane was suspended 0.211 g of 3-hydroxymethylimidazo[5,1-b]thiazole. Manganese dioxide (1.1 g) was added to the suspension, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was filtered, and the filtrate was evaporated to dryness under reduced pressure to give 0.146 g (yield 71%) of the title compound.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]2[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]=12)C1C=CC=CC=1.OC1C(=O)N=C(CC2(C3C=CC(C(F)(F)F)=CC=3)CCCC2)N2CCN(C(C)C)C(=O)C=12>>[Cl:29][C:24]1[CH:23]=[C:22]([C:17]2([CH2:16][C:12]3[N:11]4[CH2:30][CH2:31][N:32]([CH:35]([CH3:37])[CH3:36])[C:33](=[O:34])[C:10]4=[C:9]([OH:8])[C:14](=[O:15])[N:13]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: CC(C)N1CCn2c(CC3(c4ccc(Cl)c(Cl)c4)CCCC3)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: CC(C)N1CCn2c(CC3(c4ccc(C(F)(F)F)cc4)CCCC3)nc(=O)c(O)c2C1=O
Product: CC(C)N1CCn2c(CC3(c4ccc(Cl)c(Cl)c4)CCCC3)nc(=O)c(O)c2C1=O

Procedure:
6-((1-(3,4-Dichlorophenyl)cyclopentyl)methyl)-9-hydroxy-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (492) was synthesized as a white solid from 9-(benzyloxy)-6-((1-(3,4-dichlorophenyl)cyclopentyl)methyl)-2-isopropyl-3,4-dihydro-1H-pyrazino[1,2-c]pyrimidine-1,8(2H)-dione (491) following the procedure described for 6-[1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl]-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (248).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][OH:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[H-].[Na+].CN(C)C=O.Br[CH2:34][F:35]>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14](=[O:25])[C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:16][O:17][CH2:34][F:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: FCBr
Reactant: COc1ccc(CCNC(=O)C(=CO)c2ccc(Cl)cc2)cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CCNC(=O)C(=COCF)c2ccc(Cl)cc2)cc1OC
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
One gram (1.00 g) of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-hydroxy-2-(4-chlorophenyl) acrylamide (2.66 mmol), 130 mg (3.25 mmol) of 60% sodium hydride and 10 ml of anhydrous N,N-dimethylformamide were mixed and 0.46 g of bromofluoromethane was added thereto at −15° C. The mixture was stirred at −15° C. for 30 minutes and then stirred at 0° C. for 1 hour. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with 5% hydrochloric acid and saturated brine subsequently, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel preparative thin layer chromatography (eluent, hexane:ethyl acetate=1:1) to give 100 mg of N-[2-(3,4-dimethoxyphenyl)ethyl]-3-fluoromethoxy-2-(4-chlorophenyl)acrylamide (the present compound 1016).
Reaction SMILES: N1C=CC=C(C)C=1.Cl.C(O)CCCCC.[CH:16](=[C:21]1[CH2:25][CH2:24][CH2:23][C:22]1=[O:26])[CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+]>>[CH2:16]([C:21]1[C:22](=[O:26])[CH2:23][CH2:24][CH:25]=1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCC=C1CCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1cccnc1
Solvent: CCCCCCO
Product: CCCCCC1=CCCC1=O
Temperature: 160 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
15.09 g (0.16 mol) of 3-picoline and 5.63 g (0.055 mol) of a 35% hydrochloric acid were mixed with 82.2 g of n-hexanol and heated to 160° C. Then, 164.4 g (1.08 mol) of 2-pentylidene cyclopentanone were added dropwise thereto at the same temperature for 2 hours and a 35% hydrochloric acid was simultaneously added dropwise thereto at the rate of 1.41 g (0.014 mol)/h for 2 hours. After the dropping addition was finished, the resultant mixture was stirred for 5 hours under heating at the same temperature while the 35% hydrochloric acid was continuously added dropwise. After the reaction was finished, the mixture was cooled to the room temperature and neutralized with an aqueous solution of sodium hydroxide. Then, the resultant organic layer was analyzed in the same manner as in Example 1. As the result, 148.3 g of 2-pentyl-2-cyclopentenone were obtained (yield: 90.2%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[OH-].[Li+:30].[Li]>>[OH:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][C:14]2[CH:23]=[CH:22][C:21]3[C:20]([CH3:25])([CH3:24])[CH2:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=3[CH:15]=2)[CH:8]=[CH:7][C:3]=1[C:4]([O-:6])=[O:5].[Li+:30]
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)O)c(O)c3)ccc21
Agent: [Li+]
Agent: [Li]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)[O-])c(O)c3)ccc21

Procedure:
In a similar manner to Example 10, by reaction of 200 mg (5.5 mmol) of 2-hydroxy-4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoic acid with 23 mg (5.5 mmol) of lithium hydroxide hydrate, 150 mg (74%) of the expected lithium salt are obtained, with a melting point of 225-9° C.