Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]=[C:8]1[C@@H:14]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:13][C@@H:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]2[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=2[N:9]1[CH3:36]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[O:7]=[C:8]1[C@@H:14]([NH:15][C:16](=[O:25])[CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[CH2:13][C@H:12]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11]2[CH:32]=[CH:33][CH:34]=[CH:35][C:10]=2[N:9]1[CH3:36]
Reactant: CN1C(=O)[C@@H](NC(=O)CCC2CCCCC2)C[C@@H](c2ccccc2)c2ccccc21
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN1C(=O)[C@@H](NC(=O)CCC2CCCCC2)C[C@H](c2ccccc2)c2ccccc21
Temperature: 50 °C

Procedure:
Epimerization of the cis isomer to the trans isomer was accomplished by adding potassium t-butoxide (75 mg, 0.67 mmol) to a solution of cis-N-(2,3,4,5-tetrahydro-2-oxo-1-methyl-5-phenyl-1H-benzazepin-3-yl)-3-cyclohexylpropanamide (90 mg, 0.22 mmol) in tetrahydrofuran (10 ml) and heating to 50° C. for 18 hours. The mixture was diluted with ethyl acetate (50 ml) and saturated aqueous sodium hydrogen carbonate (100 ml). The organic layer was separated and the aqueous layer was extracted again with ethyl acetate (2×40 ml). The organic layers were combined and concentrated at reduced pressure. The resulting mixture of isomers was crystallized from a mixture of ethyl acetate and hexane, from which was obtained the desired trans isomer (35 mg, 39%). m.p. 185°-186° C. 1H NMR 8 7.40-7.09 (m, 8H), 6.74 (d, J=8.4 Hz, 1H), 6.61 (d, J=6.6 Hz, 1H), 4.60-4.50 (m, 1H), 4.32-4.22 (m, 1H), 3.51 (s, 3H), 3.33-3.10 (m, 1H), 2.21 (t, J=7.8 Hz, 2H), 2.15-2.02 (m, 1H), 1.76-1.44 (m, 5H), 1.30-1.15 (m, 4H), 0.96-0.80 (m, 2H). Anal. Calcd. for C26H32N2O2.H2O: C, 76.01; H, 8.02; N, 6.82. Found: C, 76.00; H, 7.75; N, 6.91%.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][C:25]=1[CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:30][C:27]2[CH:28]=[CH:29][C:24]([F:23])=[C:25]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:26]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cc(O)ccc1F
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1F
Yield: 81.7 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (380 mg) in acetonitrile (10 mL) were added ethyl 3-(2-fluoro-5-hydroxyphenyl)propanoate (300 mg) and cesium carbonate (650 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (480 mg) as a colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11](Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][C:17]1([CH3:24])[CH2:22][C:21](=[O:23])[CH2:20][CH2:19][O:18]1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:21]2([OH:23])[CH2:20][CH2:19][O:18][C:17]([CH3:24])([CH3:16])[CH2:22]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)CC(=O)CCO1
Reactant: Brc1cccc(OCc2ccccc2)c1
Product: CC1(C)CC(O)(c2cccc(OCc3ccccc3)c2)CCO1
Yield: 72 %

Procedure:
Using the procedure described in the 2nd paragraph of the portion of Example 3 which is concerned with the preparation of starting materials, 3-benzyloxybromobenzene (1.34 g) was reacted with 2,2-dimethyltetrahydropyran-4-one (0.65 g) to give 4-(3-benzyloxyphenyl)-4-hydroxy-2,2-dimethyltetrahydropyran (1.14 g, 72%), as an oil.
Reaction SMILES: C1(S[C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][C@H:18]4[CH2:22][O:21][C:20](=[O:23])[NH:19]4)[CH:15]=3)[NH:10][CH:9]=2)C=CC=CC=1>[Ni].CC(O)C>[O:23]=[C:20]1[NH:19][C@@H:18]([CH2:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][CH:9]=[CH:8]3)[CH2:22][O:21]1
Reactant: O=C1N[C@@H](Cc2ccc3[nH]cc(Sc4ccccc4)c3c2)CO1
Agent: [Ni]
Solvent: CC(C)O
Product: O=C1N[C@@H](Cc2ccc3[nH]ccc3c2)CO1
Reaction time: 1 h

Procedure:
Raney nickel (3.0 g) was added to a solution of the product from step (a) (3.1 g) in IPA (150 ml) and the suspension refluxod for 1 hour. More Raney nickel (2.0 g) was added and refluxing continued for a further 2 hours. The suspension was filtered hot through Hyflo and the filtrate evaporated in vacuo to give an oil. The latter was eluted through a silica column using ethyl acetate as eluant to give the desired product as a froth (1.3 g). 1H NMR and MS were consistent with the proposed structure.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]1COC[CH2:12]1.C([Mg]Cl)=C.[Cl-].[NH4+]>O>[OH:5][CH:4]([C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([CH3:10])[C:2]=1[OH:1])[CH:11]=[CH2:12]
Reactant: Cc1cccc(C=O)c1O
Reactant: C1CCOC1
Agent: C=C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: C=CC(O)c1cccc(C)c1O
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A 1 L four-necked round-bottomed flask was equipped with a magnetic stirrer bar, a thermometer and a pressure-equalizing dropping funnel. A 2-hydroxy-3-methylbenzaldehyde (30.0 g, 0.22 mol) and THF (300 ml) were added to it under a nitrogen atmosphere. After the mixture was cooled to 0° C., a solution of vinyl magnesium chloride in THF (1.9 M, 237 ml, 0.45 mol) was added thereto over 45 minutes while maintaining the mixture temperature of 15° C. or less. The mixture was gradually warmed to room temperature and stirred at room temperature for 18 hours. The mixture was cooled to 0° C. and a 20% aqueous ammonium chloride solution (600 ml) was added thereto at 0° C. After the mixture was stirred at room temperature for 30 minutes, the mixture was poured into water (500 ml). The mixture was extracted with ethyl acetate (3×500 ml). The organic layer was combined and successively washed with a 20% aqueous ammonium chloride solution (300 ml), water (2×300 ml) and a saturated aqueous NaCl solution (300 ml), followed by drying with anhydrous sodium sulfate (150 g). The solid was removed by filtration and the filtrate was concentrated to obtain 34.3 g of 2-(1-hydroxy-2-propenyl)-6-methylphenol as a brown gum.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4].[CH2:26]([O:28][C:29]1[C:30]([C:35](OC)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=1)[CH3:27].[Cl-].[NH4+]>C(COC)OC.CO>[CH2:3]([O:5][C:6]1[CH:7]=[C:8]([C:15]2[S:16][CH:17]=[C:18]([CH2:20][CH:21]([C:35]([C:30]3[C:29]([O:28][CH2:26][CH3:27])=[CH:34][CH:33]=[CH:32][N:31]=3)=[O:36])[C:22]([O:24][CH3:25])=[O:23])[N:19]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:4]
Reactant: CCOc1cccnc1C(=O)OC
Reactant: CCOc1ccc(-c2nc(CCC(=O)OC)cs2)cc1OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CO
Product: CCOc1ccc(-c2nc(CC(C(=O)OC)C(=O)c3ncccc3OCC)cs2)cc1OCC
Temperature: 25 °C
Yield: 50.9 %

Procedure:
Sodium hydride (239 mg, 6.0 mmol) and a drop of methanol were added to a solution (10 ml) of methyl 3-[2-(3,4-diethoxyphenyl)thiazole-4-yl]propionate (1.0 g, 3.0 mmol) and methyl 3-ethoxypyridine-2-carboxylate (702 mg, 3.9 mmol) in dimethoxyethane, followed by heating under reflux for 2 hours. After cooling to room temperature, a saturated aqueous ammonium chloride solution was added to the reaction mixture, and the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated salt solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=2/3). The solvent was distilled off under reduced pressure, to thereby obtain 740 mg (yield: 51%) of methyl 2-[2-(3,4-diethoxyphenyl)thiazole-4-ylmethyl]-3-(3-ethoxypyridine-2-yl)-3-oxopropionate as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2].O1CCCC1.[OH-].[Na+]>C(O)C>[C:1]([C:3]1[C:7]2[CH:8]=[C:9]([O:12][CH3:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]=1[CH:14]([NH:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=1)[CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)#[N:2]
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(OC)cc3c2C#N)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2oc(C(Nc3ccc(C(=O)NCCC(=O)O)cc3)C3CCCCC3)c(C#N)c2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.4 %

Procedure:
To a mixture of ethyl 3-{[(4-{[(3-cyano-5-methoxy-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}phenyl)carbonyl]amino}propanoate (285 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (246 mg, 92%) as a pale-yellow solid.
Reaction SMILES: O[C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5].P(Cl)(Cl)(Cl)(Cl)[Cl:15].C(O)C>P(Cl)(Cl)(Cl)=O>[Cl:15][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1nc(O)c(C#N)cc1[N+](=O)[O-]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: Cc1nc(Cl)c(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
A suspension of the compound prepared in Example 442 (5.00 g) and phosphorus pentachloride (6.97 g) in phosphorus oxychloride (25 mL) was stirred and heated in an oil bath set to 110° C. for 30 minutes. The resulting solution was cooled to ambient temperature and concentrated. The residual liquid was cooled in an ice bath, whereupon a solid formed. This solid was carefully treated with 50% aqueous ethanol (10 mL), and then the mixture was stirred and heated in the 110° C. oil bath for 5 minutes. This redissolved the solid, and then the flask was again placed in the ice bath. The solid reappeared on cooling, and it was collected by filtration, washed with water, and air-dried. The solid was then recrystallized by stirring it with methanol (20 mL), and heating to boiling until all solid dissolved. On cooling to ambient temperature crystallization began, and the mixture was stored in the refrigerator overnight. The crystals were collected by filtration, washed with cold methanol, and dried under vacuum to provide the title compound (2.09 g) with the following physical data.
Reaction SMILES: [Si:1]([O:8][CH:9]([CH:27]([CH3:29])[CH3:28])[C:10](=O)/[C:11](=[CH:22]/[N:23](C)C)/[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[NH2:30]N>C(O)C>[Si:1]([O:8][CH:9]([C:10]1[C:11]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])=[CH:22][NH:23][N:30]=1)[CH:27]([CH3:29])[CH3:28])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)/C(=C/N(C)C)C(=O)OCc1ccccc1
Solvent: CCO
Product: CC(C)C(O[Si](C)(C)C(C)(C)C)c1n[nH]cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of benzyl (2Z)-4-{[tert-butyl(dimethyl)silyl]oxy}-2-[(dimethylamino)methylene]-5-methyl-3-oxohexanoate (0.13 g, 0.31 mmol) in ethanol (3.1 mL) was added hydrazine (0.28 mL, 3.1 mmol). The mixture was stirred at ambient temperature. After 30 min, the mixture was concentrated to dryness and taken into the next reaction. MS 389.1 (M+1).
Reaction SMILES: CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.Br[C:44]1[CH:57]=[CH:56][C:47]([O:48][CH2:49][CH2:50][N:51]2[CH2:55][CH2:54][CH2:53][CH2:52]2)=[CH:46][CH:45]=1.[CH3:58][S:59]([C:62]1[CH:67]=[CH:66][C:65]([C:68]2[N:73]3[N:74]=[C:75]([NH2:77])[N:76]=[C:72]3[CH:71]=[CH:70][CH:69]=2)=[CH:64][CH:63]=1)(=[O:61])=[O:60].C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[CH3:58][S:59]([C:62]1[CH:67]=[CH:66][C:65]([C:68]2[N:73]3[N:74]=[C:75]([NH:77][C:44]4[CH:57]=[CH:56][C:47]([O:48][CH2:49][CH2:50][N:51]5[CH2:55][CH2:54][CH2:53][CH2:52]5)=[CH:46][CH:45]=4)[N:76]=[C:72]3[CH:71]=[CH:70][CH:69]=2)=[CH:64][CH:63]=1)(=[O:60])=[O:61]
Reactant: CS(=O)(=O)c1ccc(-c2cccc3nc(N)nn23)cc1
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(-c2cccc3nc(Nc4ccc(OCCN5CCCC5)cc4)nn23)cc1
Temperature: 80 °C

Procedure:
To an oven dried tube was added palladium acetate (16.0 mg, 0.0000713 mol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (41.0 mg, 0.0713 mmol), 1,4-dioxane (5 mL), 1-[2-(4-bromo-phenoxy)-ethyl]-pyrrolidine (87 μL, 0.412 mmol), 5-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100.0 mg, 0.346 mmol), and cesium carbonate (240 mg, 0.73 mmol) were added all-at-once. The reaction mixture was evacuated with high vacuum and repressurized with nitrogen three times. The tube was sealed and heated at 80° C. for 24 hours. The mixture was cooled to room temperature, filtered through a plug of diatomaceous earth, rinsed with dichloromethane and evaporated. The material was purified via chromatography utilizing an ISCO automated purification apparatus using a silica gel column (40 g) with 0%→20% methanol in dichloromethane solvent gradient. [5-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-[4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-amine was isolated as an orange gummy solid (0.011 g, 7%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.47 (s, 1H), 8.32 (d, J=8.5 Hz, 2H), 8.13 (d, J=8.5 Hz, 2H), 7.67 (m, 2H), 7.59 (d, J=9.6 Hz, 2H), 7.28 (d, J=6.4 Hz, 1H). 6.91 (d, J=8.5 Hz, 2H), 4.10 (br s, 2H), 3.34 (s, 3H), 2.54 (s, 2H), 1.78 (br s, 2H), 1.24 (br s, 2H). MS=478 (MH)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.F[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:32]=[C:31]([N:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[S:30][N:29]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:23]1([C:28]2[N:32]=[C:31]([N:33]3[CH2:38][CH2:37][N:36]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][CH:3]=[N:2]5)=[CH:11][CH:10]=4)=[O:20])[CH2:35][CH2:34]3)[S:30][N:29]=2)[CH:22]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Fc1ccccc1-c1nsc(N2CCNCC2)n1
Reactant: O=C(Nc1ccc(-n2cccn2)cc1)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-n2cccn2)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(1H-pyrazol-1-yl)phenyl]carbamate (200 mg, 0.598 mmol), 1-[3-(2-fluorophenyl)-1,2,4-thiadiazol-5-yl]piperazine (147 mg, 0.598 mmol), diisopropylethylamine (0.208 ml, 1.20 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from ethyl acetate to give 63.7 mg (24.7%) of the desired product as a solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.P(O)(O)O.C(N(CC)CC)C.[OH-].[Na+]>O>[CH2:1]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: NCc1ccccc1
Agent: OP(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Product: c1ccc(CNCc2ccccc2)cc1
Yield: 98 %

Procedure:
The imine from benzaldehyde and benzylamine (19.5 g; 0.1 mole) was heated with phosphorous acid (8.2 g; 0.1 mole) and triethylamine (10.1 g; 0.1 mole) for 2 hours at reflux (125°-130°). After cooling to 90° the reaction mixture was diluted with water (50 ml), basified (NaOH) and extracted with chloroform. The extract was concentrated by evaporation of the chloroform and triethylamine to yield dibenzylamine 19.3 g (98% yield).
Reaction SMILES: C(C1C(=O)[NH:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH:13]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH:14]([CH3:16])[CH3:15])=[CH:8][CH:7]=2)C.O=[C:24]([CH2:28][CH3:29])[C:25](O)=[O:26]>>[CH2:28]([C:24]1[C:25](=[O:26])[NH:12][C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[C:9]([CH:13]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH:14]([CH3:15])[CH3:16])[CH:10]=2)[CH3:29]
Reactant: CCC(=O)C(=O)O
Reactant: CCc1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Product: CCc1nc2ccc(C(C(C)C)n3ccnc3)cc2[nH]c1=O

Procedure:
3-ethyl-6-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2(1H)-quinoxalinone; mp. 203.7° C. (comp. 104) and 3-ethyl-7-[1-(1H-imidazol-1-yl)-2-methylpropyl]-2(1H)-quinoxalinone (comp. 314) were prepared following substantially the same procedures as in example 23a were used except that 2-oxobutanoic acid was used in place of 2-oxopentanoic acid.
Reaction SMILES: C([O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:11]([CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:10]=1)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH2:30]([C:11]1[CH:10]=[C:9]([OH:8])[CH:29]=[CH:28][C:12]=1[O:13][CH2:14][CH2:15][C:16]1[N:17]=[C:18]([C:22]2[CH:27]=[CH:26][C:25]([C:9]3[CH:29]=[CH:28][CH:12]=[CH:11][CH:10]=3)=[CH:24][CH:23]=2)[O:19][C:20]=1[CH3:21])[CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(OCc2ccccc2)cc1CCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1oc(-c2ccc(-c3ccccc3)cc2)nc1CCOc1ccc(O)cc1CCc1ccccc1

Procedure:
A solution of 4-[2-(4-benzyloxy-2-phenethylphenoxy)ethyl]-5-methyl-2-phenyloxazole (3.16 mmol) in ethanol (100 mL) was treated with 5% Pd/C (160 mg) and hydrogen (60 psi) at ambient temperature for 18 h. The mixture was filtered and concentrated in vacuo to give a tan solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][NH2:25])=[CH:19][CH:18]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2].[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH2:1]([N:3]([CH2:6][C:7]1[S:11][C:10]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][NH:25][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:21][CH:22]=3)[N:13]=2)=[CH:9][C:8]=1[CH3:26])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCN)cc3)no2)cc1C
Reactant: CS(=O)(=O)Cl
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(CCNS(C)(=O)=O)cc3)no2)cc1C
Yield: 24.8 %

Procedure:
The title compound (3 mg) is prepared in analogy to Example 155 starting from 2-{4-[5-(5-diethylaminomethyl-4-methyl-thiophen-2-yl)-[1,2,4]oxadiazol-3-yl]-phenyl}-ethylamine (10 mg, 27 μmol) and methanesulfonyl chloride (4 mg, 35 μmol); LC-MS: tR=0.78 min; [M+1]+=448.99; 1H NMR (CDCl3): δ 1.11 (t, J=7.0 Hz, 6H), 2.26 (s, 3H), 2.64 (q, J=7.3 Hz, 4H), 2.89 (s, 3H), 2.96-3.01 (m, 2H), 3.49 (q, J=6.8 Hz, 2H), 3.73 (s, 2H), 4.23 (t br, J=6.3 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.67 (s, 1H), 8.13 (d, J=8.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:9]=[C:8]([OH:16])[C:3]=1[C:4](OC)=[O:5].[Li+].[BH4-].CCOC(C)=O>C1COCC1>[F:1][C:2]1[C:3]([CH2:4][OH:5])=[C:8]([OH:16])[CH:9]=[C:10]([S:12]([CH3:15])(=[O:14])=[O:13])[CH:11]=1
Reactant: COC(=O)c1c(O)cc(S(C)(=O)=O)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1cc(O)c(CO)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 95.6 %

Procedure:
Methyl 2-fluoro-6-hydroxy-4-(methylsulfonyl)benzoate (0.14 g, 0.57 mmol) was dissolved in THF (dry) (5 ml). LiBH4 (2M in THF) (0.57 ml, 1.14 mmol) was added dropwise under nitrogen at 0° C. The mixture was allowed to warm to RT and stirred under nitrogen for 45 min. EtOAc was added and the mixture was further quenched with MeOH, then water. The mixture was acidified with 1N HCl and extracted with EtOAc. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to give the crude title compound (0.12 g) 1H-NMR (400 MHz, CD3OD): δ 7.20 (1H, s), 7.16 (1H, dd, J 8.4, 2), δ 4.73 (2H, d, J 1.6), δ 3.10 (3H, s) ppm (J-values are in Hz and shifts relative to solvent-peak at 3.31 ppm).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7](O)=[O:8])[C@@H:3]([CH3:6])[O:4][CH3:5].CN1CCOCC1.ClC(OCC(C)C)=O.[BH4-].[Na+]>ClC(Cl)C.O>[C:13]([O:12][C:10](=[O:11])[NH:1][C@H:2]([CH2:7][OH:8])[C@H:3]([O:4][CH3:5])[CH3:6])([CH3:15])([CH3:14])[CH3:16]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: O
Product: CO[C@H](C)[C@@H](CO)NC(=O)OC(C)(C)C
Reaction time: 0.02 h
Yield: 103.6 %

Procedure:
To a cold solution (−15° C.) of BocThr(Me)OH (5.14 g, 22 mmol) in dichloroethane (22 mL) were successively added N-methyl morpholine (2.44 mL, 22 mmol) and isobutyl chloroformate (2.99 mL, 22 mmol). After one min, the precipitate was filtered and washed with dichloroethane (5×4 mL). The filtrate and washings were combined in a large three neck flask in an ice-salt bath. A solution of NaBH4 (1.26 g, 33 mmol) in H2O (11 mL) was added at once, proceeding a strong evolution of gas, followed by H2O (500 mL). The mixture was then extracted with EtOAc (5×150 mL). The combined EtOAc was dried (Na2SO4) and concentrated to give the titled compound (5 g). MS (MH+ 220).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH2:8].[N:9]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:10]=[S:11]>C(OCC)(=O)C>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][NH:8][C:10]([NH:9][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[S:11]
Reactant: Cn1cccc1CN
Reactant: S=C=NCCc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1cccc1CNC(=S)NCCc1ccccc1
Reaction time: 12 h
Yield: 60.1 %

Procedure:
(1-methyl-1H-pyrrol-2-yl)methylamine (65 mg) and (2-isothiocyanatoethyl)benzene (100 mg) were dissolved in ethyl acetate (20 ml) and the solution was stirred for 12 hours. After the completion of the reaction, the resulting mixture was purified by column-chromatography (ethyl acetate/hexane=1/3) to yield the compound 17-3 (97 mg, 60%) as a brown liquid.