Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=[C:14]2Cl)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:25][CH2:26][O-:27].[Na+]>C(O)C>[CH2:26]([O:27][C:14]1[N:13]([C:9]2[C:10]([F:12])=[CH:11][C:2]([Cl:1])=[C:3]([CH:8]=2)[C:4]([O:6][CH3:7])=[O:5])[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1)[CH3:25]
Reactant: CC[O-]
Reactant: COC(=O)c1cc(-n2c(Cl)nc(C(F)(F)F)cc2=O)c(F)cc1Cl
Agent: [Na+]
Solvent: CCO
Product: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(C(=O)OC)c(Cl)cc1F

Procedure:
using methyl 2-chloro-5-[2-chloro-6-oxo-4-trifluoromethyl-1(6H)-pyrimidinyl]-4-fluorobenzoate and sodium ethylate in ethanol there is obtained methyl 5-[2-ethoxy-6-oxo-4-trifluoromethyl -1(6H)-pyrimidinyl]-2-chloro-4-fluorobenzoate, m.p. 96°-98° C.;
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][NH:8][C:7]=1[NH2:11])=[O:5])[CH3:2].[H-].[Na+].[CH3:14][C:15]([CH3:25])=[CH:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=O.[BH4-].[Na+]>CN(C=O)C.CCOC(C)=O.CCO>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[CH:9][N:8]2[C:15]([CH3:25])([CH3:14])[CH2:16][CH:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:11][C:7]=12)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc[nH]c1N
Reactant: CC(C)=CC(=O)c1ccccc1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCO
Product: CCOC(=O)c1ccn2c1NC(c1ccccc1)CC2(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
Compound 1 (0.68 g, 4.41 mmol) was dissolved in DMF (5 mL). NaH (60% in mineral oil, 0.19 g, 4.7 mmol) was added at room temperature affording rapid gas evolution. The reaction stirred for 0.5 h upon which 3-methyl-1-phenyl-but-2-en-1-one (0.50 g, 3.15 mmol) was added. The reaction stirred for 0.5 h upon which EtOH (5 mL) and NaBH4 (1.19 g) were added. The solution was brought to 60° C. for 0.5 h. and then cooled to room temperature. The solution was quenched with water, extracted with Et2O (3 times), dried (Na2SO4) and concentrated. Flash chromatography (10% AcOEt) to give the desired product as a tan solid (0.60 g, 63% yield). MS Calcd.: 298. Found 299 (M+H).
Reaction SMILES: [NH2:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[CH2:29]([S:31][C:32]1[N:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35])[CH3:30]>>[CH2:29]([S:31][C:32]1[N:40]=[CH:39][CH:38]=[CH:37][C:33]=1[C:34]([NH:1][C@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=2)[CH2:7][CH2:6]1)=[O:35])[CH3:30]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](N)c3ccccc3)CC2)c1
Reactant: CCSc1ncccc1C(=O)Cl
Product: CCSc1ncccc1C(=O)N[C@@H](CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccccc1

Procedure:
Prepared by Procedure Q1 and Scheme AC using N-(3-{1-[(3S)-3-amino-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-(ethylsulfanyl)nicotinoyl chloride: ESMS m/e: 545.3 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30]Cl)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1>>[F:16][C:17]([F:34])([F:35])[C:18]1[CH:33]=[CH:32][C:21]([CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][O:14][C:12]3[CH:11]=[CH:10][C:9]4[C:5]([CH2:4][C:3]([OH:2])=[O:15])=[CH:6][O:7][C:8]=4[CH:13]=3)=[CH:26][CH:25]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Reactant: FC(F)(F)c1ccc(COc2ccc(CCl)cc2)cc1
Product: O=C(O)Cc1coc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12

Procedure:
The title compound was prepared in the manner analogous to example 1E using (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (example 24A) and 1-(4-trifluoromethyl-benzyloxy)-4-chloromethyl-benzene (example 5E). MS m/z 471 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][CH:17]=1)[CH2:6]P(=O)(OCC)OCC.C[O-].[Na+].C1OCCOCCOCCOCCOCCOC1.[Br:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44]([CH:47]=1)[CH:45]=O>CN(C)C=O>[Br:39][C:40]1[CH:41]=[N:42][CH:43]=[C:44](/[CH:45]=[CH:6]/[C:5]2[CH:15]=[CH:16][CH:17]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:47]=1
Reactant: CCOP(=O)(Cc1cccc(OC)c1)OCC
Reactant: O=Cc1cncc(Br)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(/C=C/c2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of diethyl 3-methoxybenzylphosphonate (5 g, 19.36 mmol) in dimethylformamide (50 mL) at room temperature was added sodium methoxide (2.092 g, 38.7 mmol) and 18-Crown-6 (2.047 g, 7.74 mmol). After stirring at room temperature for 5 min, the reaction was cooled to 0° C. and treated with 5-bromonicotinaldehyde (4.32 g, 23.23 mmol) as a solid in one portion. The ice bath was removed and the reaction stirred at room temperature for 2 h. The reaction was poured into water (500 mL) with vigorous stirring. The resulting suspension was extracted with diethyl ether, washed with water (3×), then brine, dried over magnesium sulfate, and concentrated to an oil which crystallized upon standing. The solid was triturated with a minimum of ethanol (ca. 12 mL) and placed in the freezer for 72 h. The resulting solid was broken up with a spatula, collected by filtration, and rinsed with a minimum of cold ethanol to give 3.79 g (68%) as a white crystalline solid. 1H-NMR (CDCl3, 500 MHz) δ 8.64 (d, J=1.8, 1H), 8.57 (d, J=2.1, 1H), 8.00 (dd, J=2.1, 1.8, 1H), 7.33 (dd, J=7.9, 7.9, 1H), 7.10-7.20 (m, 2H), 7.07 (m, 1H), 7.01 (d, J=16.5, 1H), 6.91 (dd, J=7.6, 2.1, 1H), 3.88 (s, 3H). 13C-NMR (CDCl3, 126 MHz) δ 160.1, 149.5, 146.7, 137.7, 135.1, 134.8, 132.4, 130.0, 123.7, 121.1, 119.6, 114.4, 112.2, 55.4. Mass spec.: 290.14 (MH)+.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)N.[CH3:12][CH2:13][C:14](=O)[CH2:15][CH3:16].S(=O)(=O)(O)O.[CH2:23](O)[CH3:24]>>[CH2:13]([C:14]1[NH:1][C:3]2[C:11]([C:15]=1[CH3:16])=[CH:10][C:6]([C:7]([O:9][CH2:23][CH3:24])=[O:8])=[CH:5][CH:4]=2)[CH3:12]
Reactant: CCC(=O)CC
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc2[nH]c(CC)c(C)c2c1
Temperature: 85 °C
Reaction time: 24 h

Procedure:
A 5.00 g portion of 4-hydrazinobenzoic acid was suspended in 50 ml of ethanol, and 5.6 ml of 3-pentanone and 2.7 ml of sulfuric acid were added, followed by stirring at 85° C. for 24 hours. After evaporation of ethanol under a reduced pressure, water was added to the residue under ice-cooling, followed by stirring at the same temperature for 30 minutes. The resulting solid was collected by filtration and then washed with water to obtain 6.34 g of ethyl 2-ethyl-3-methyl-1H-indole-5-carboxylate as a light brown solid.
Reaction SMILES: C([O:3][CH:4](OCC)[C:5]1[N:9]([CH3:10])[N:8]=[C:7]([CH2:11][CH3:12])[N:6]=1)C.[ClH:16]>>[OH2:3].[ClH:16].[CH2:11]([C:7]1[N:6]=[C:5]([CH:4]=[O:3])[N:9]([CH3:10])[N:8]=1)[CH3:12]
Reactant: CCOC(OCC)c1nc(CC)nn1C
Agent: Cl
Product: CCc1nc(C=O)n(C)n1
Product: O
Yield: 59 %

Procedure:
A solution of 5-(diethoxymethyl)-3-ethyl-1-methyl-1H-1,2,4-triazole from Step 3 (35.6 g, 0.167 mol) in 3.6 M HCl (150 mL) was heated (60° C.) for 10 h, then evaporated to dryness. The residual oil was washed with THF (3×100 mL), then treated with dry acetone (200 mL) causing crystallization. The product was filtered and dried, affording 18.8 g (59%) of the title product. Satisfactory C,H,N-analysis was obtained. The compound was observed by 1H NMR to be a 60:40 mixture of non-covalent (free aldehyde) and covalent hydrates, respectively. 1H NMR (400 MHz, DMSO-d6): δ 1.22 (m, overlap, 3H), 2.67 (q, J=7.8 Hz, 0.6×2H), 2.79 (q, J=7.8 Hz, 0.4×2H), 3.96 (s, 0.4×3H), 4.04 (s, 0.6×3H), 6.21 (s, 0.4×1H), 8.35 (br s, 3H), 9.87 (s, 0.6×1H). LC-MS (APCI) calcd for C6H9N3O: 139.07, found (M+H+): 140.1; (M+18+H+) 158.1 m/z.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=1.[CH:24](=O)[CH2:25][CH2:26][CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:24]([N:11]1[CH2:10][CH2:9][CH:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[C:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[CH2:17][C:16]([CH3:23])([CH3:22])[CH:15]=2)[CH2:13][CH2:12]1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1(C)C=C(c2ccc(F)cc2C2CCNCC2)CC(C)(C)C1
Reactant: CCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCN1CCC(c2cc(F)ccc2C2=CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 67.3 %

Procedure:
To a solution of 4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine (70 mg, 0.22 mmol) produced in Example (106g) in tetrahydrofuran (2 mL) were added butyraldehyde (19.2 mg, 0.27 mmol), sodium triacetoxyborohydride (71 mg, 0.33 mmol) and acetic acid (27 mg, 0.44 mmol), followed by stirring for 15 hours at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and the filtrate was concentrated under reduced pressure to give a residue, which was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 55 mg of 1-butyl-4-[5-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenyl]piperidine as a light yellow oil.
Reaction SMILES: [I-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)C=CC=CC=1.CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.O=[C:48]1[CH2:53][CH2:52][N:51]([C:54]([O:56][C:57]([CH3:60])([CH3:59])[CH3:58])=[O:55])[CH2:50][CH2:49]1>C1COCC1>[C:57]([O:56][C:54]([N:51]1[CH2:52][CH2:53][C:48](=[CH:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:49][CH2:50]1)=[O:55])([CH3:60])([CH3:58])[CH3:59]
Reactant: c1ccc(CCCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [I-]
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=CCCCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of triphenyl(4-phenylbutyl)phosphonium iodide (975 mg, 1.87 mmol) in THF (8 mL) under Ar at −78° C. was added HMPA (1 mL) followed by n-BuLi (1.6 M in hexane; 1.28 mL, 2.05 mmol, 1.1 equiv.). After stirring at room temperature for 2 h, the mixture was cooled to −78° C. again, and tert-butyl 4-oxopiperidine-1-carboxylate (409 mg, 2.05 mmol, 1.1 equiv.) in THF (2 mL) was added. The mixture was allowed to warm to room temperature and to stand for 2 days. The reaction was quenched with H2O, and the mixture was extracted three times with EtOAc. The combined organic layers were washed with brine and dried over Na2SO4. After concentration, the residue was purified by CC (SiO2, hexane/EtOAc 10:1) to obtain 1-(tert-butoxycarbonyl)-4-(4-phenylbutylidene)piperidine (216 mg, 37%) as a pale yellow oil. 1H NMR (CDCl3, 400 MHz) δ 7.25 (m, 2H), 7.15 (m, 3H), 5.22 (t, 1H, J=7.2 Hz), 3.55 (m, 4H), 2.60 (t, 2H, J=8.0 Hz), 2.15 (m, 4H), 2.03 (m, 2H), 1.66 (m, 2H), 1.46 (s, 9H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]([NH2:26])([C:23](=[O:25])[NH2:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:27](Cl)(Cl)=[S:28].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][C:20]2([NH:26][C:27](=[S:28])[NH:24][C:23]2=[O:25])[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: S=C(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C(N)=O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=S)NC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
N,N-Diisopropylethylamine (1.67 ml, 9.84 mmol) was added to a solution of 4-amino-4-carbamoyl-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 4.1 mmol) in THF (10 ml) at 0° C., and thiophosgene (0.376 ml, 4.9 mmol) was further added dropwise slowly. The reaction solution was warmed to room temperature and stirred overnight. A 10% aqueous citric acid solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layers were combined and dried over magnesium sulfate, and the solvent was then distilled off. The residue was purified by silica gel column chromatography to give 4-oxo-2-thioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (944 mg, 81%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6](/[CH:7]=[N:8]/[C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[C:21]1([CH2:27][CH:28]=O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>O1CCCC1.CS(C)=O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]2[C:27]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:28][C:18]3[C:9](=[CH:10][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=3)[N:8]=2)=[CH:5][CH:4]=1
Reactant: O=CCc1ccccc1
Reactant: COC(=O)c1cccc(/N=C/c2ccc(OC)cc2)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc(-c3ccccc3)c(-c3ccc(OC)cc3)nc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 4.7 %

Procedure:
A mixture of (E)-methyl 3-(4-methoxybenzylideneamino)benzoate (1.1 g, 4.08 mmol, 1.00 equiv), 2-phenylacetaldehyde (480 mg, 4.00 mmol, 1.00 equiv), hydrochloric acid in tetrahydrofuran (0.5 mL, 10M) and DMSO (2 mL) was placed in a 10-mL sealed tube and stirred overnight at 70° C. in an oil bath. The resulting mixture was concentrated under vacuum and purified via Flash-Prep-HPLC (H2O/CH3CN=10% increasing to H2O/CH3CN=60% within 5 min; Detector, UV 254 nm) affording 70 mg (5%) of methyl 2-(4-methoxyphenyl)-3-phenylquinoline-7-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1CC=[CH:6][CH2:5][CH:4]=1.[O:9]=[O+][O-].CSC.[BH4-].[Na+].[CH2:17]([OH:19])[CH3:18]>CO>[OH:19][CH2:17][CH2:18]/[CH:6]=[CH:5]\[CH2:4][C:3]([O:2][CH3:1])=[O:9]
Reactant: COC1=CCC=CC1
Reactant: CCO
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CSC
Product: COC(=O)C/C=C\CCO
Temperature: -78 °C
Reaction time: 1.33 h

Procedure:
A mixture of 2.85 g. (26 mmoles)of 1-methoxy-1, 4-cyclohexadiene and 30 ml. of absolute methanol was treated with ozone (1.25 g., 26 mmoles) at -78°C. The resulting mixture was flushed with nitrogen. The mixture was allowed to come to 0°C and 2.42 g. (39 mmoles) of dimethylsulfide were added and the mixture stirred at this temperature for 80 minutes. After cooling to -78°C, a suspension of 1.47 g/ (39 mmoles) of sodium borohydride in 20 ml. of absolute ethanol was added dropwise. The resulting mixture was allowed to come up to room temperature and then stirred for 80 minutes. The methanol was removed under vacuum to produce 3.3 g. of product (88% of theory). B.p. 60° (0.2 mm., short path distillation).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][CH:9]=[N:10]2)=[C:5]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[CH:4]=1.C(N(C(C)C)CC)(C)C.P(Cl)(Cl)([Cl:33])=O>ClCCl>[Cl:33][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]2)[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc(OC2CCN(C)CC2)c2c(=O)[nH]cnc2c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Temperature: 25 °C
Yield: 75 %

Procedure:
A solution of 7-methoxy-5-((1-methylpiperidin-4-yl)oxy)quinazolin-4(3H)-one (3.00 g, 10.4 mmol) and diisopropyl ethylamine (5 ml) in dichloromethane (300 ml) was stirred at ambient temperature under an atmosphere of nitrogen. Phosphoryl chloride (10 ml) was added, and the resultant orange solution was heated at reflux for 20 hours. The reaction mixture was then cooled to ambient temperature and concentrated in vacuo. Residual phosphoryl chloride was then removed by azeotrope with toluene to give the crude product as an orange oil. Purification by chromatography on silica gel, eluting with 5% triethylamine in dichloromethane, gave an orange solid, which was further purified by trituration under acetonitrile, and then dried in vacuo to yield 4-chloro-5-(N-methylpiperidin-4-yloxy)-7-methoxyquinazoline (2.4 g, 75% yield) as a pale yellow amorphous solid:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([O:11]C)=[O:10])[CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]3[N:24]=[C:25]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[O:26][C:27]=3[CH3:28])=[CH:17][CH:16]=2)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COC(=O)Cc1cc(C)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CC(=O)O)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 75 %

Procedure:
To a mixture of methyl 2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate (0.22 g), tetrahydrofuran (1 mL) and methanol (1 mL) was added a 1N aqueous sodium hydroxide solution (1 mL) and the mixture was stirred at 50° C. for 1.5 hrs. 1N Hydrochloric acid (1 mL) and water were added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (0.16 g, 76%) of 2-[5-methyl-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23]CC)=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:26])[N:8]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:7]=1[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:2][CH2:3][CH3:4].C(O)C.[OH-].[Na+].Cl>O1CCCC1.O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[CH:14]=2)[C:9](=[O:26])[N:8]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:7]=1[CH2:31][NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)OCC)cs3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCCCOc1c(CNC(=O)OC(C)(C)C)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)O)cs3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of ethyl 2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (1.12 g, 2 mmol) in tetrahydrofuran (10 ml)-ethanol (5 ml) was added 1N sodium hydroxide (4 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylic acid (0.97 g, 92.4%) as crystals.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[CH2:26][CH2:27]Br>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[CH3:23])[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1ccccc1CCBr
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(N(CCc2ccccc2C)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 2-methylphenethylbromide (278 mg, 1.4 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 404 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)=[N:4][CH:5]=[CH:6][N:7]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[C:21]1([CH2:20][CH2:19][S:16]([N:13]2[CH2:12][CH2:11][CH:10]([CH2:9][NH:8][C:3]3[CH:2]=[N:7][CH:6]=[CH:5][N:4]=3)[CH2:15][CH2:14]2)(=[O:18])=[O:17])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(CCc1ccccc1)N1CCC(CNc2nccnc2Cl)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2cnccn2)CC1

Procedure:
EXAMPLE 90 was prepared from (3-chloro-pyrazin-2-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=361.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].N([O-])=O.[Na+].[N-:23]=[N+:24]=[N-].[Na+]>C(O)(=O)C.O>[N:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17])=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccccc1N1C(=O)c2ccccc2C1=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: [N-]=[N+]=Nc1ccccc1N1C(=O)c2ccccc2C1=O
Reaction time: 0.17 h
Yield: 94.1 %

Procedure:
To a suspension of the 2-(2-aminophenyl)isoindole-1,3-dione (360 mg, 1.5 mmol) in acetic acid (20 mL) and water (4 mL) was added dropwise a solution of sodium nitrite (98 mg, 1.42 mmol) in water (2 mL). The mixture was allowed to stir for 10 minutes and then sodium azide (98 mg, 1.51 mmol) was added. The reaction mixture was stirred for 15 minutes before it was poured into water and was extracted with dichloromethane (3×50 mL). The extracts were washed with water and brine and dried over magnesium sulfate. Filtration and concentration in vacuo gave 373 mg (94%) of 2-(2-azidophenyl)isoindole-1,3-dione as a solid: 1H NMR (300 MHz, DMSO-d6) δ 7.94 (m, 4H), 7.58 (m, 1H), 7.48 (m, 2H), 7.32 (m, 1H).
Reaction SMILES: [NH:1]1[C@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C(OC(Cl)=[S:18])C=C.[CH:20]1[CH:25]=CC=[CH:22][CH:21]=1>O>[CH2:20]([C:25]([N:1]1[C@H:10]2[C@@H:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1)=[S:18])[CH:21]=[CH2:22]
Reactant: C=CCOC(=S)Cl
Reactant: c1ccccc1
Reactant: C1CC[C@H]2NCCC[C@@H]2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCC(=S)N1CCC[C@@H]2CCCC[C@H]21
Reaction time: 3 h
Yield: 70 %

Procedure:
Beneath a solution of 20 g of trans-decahydroquinoline in 100 ml of benzene is introduced a layer consisting of a solution of 5.8 g of sodium hydroxide in 100 ml of water. While stiring vigorously and cooling to 5°-10°C, 20 g of chlorothioformic acid allyl ester are then added dropwise to the mixture. Upon completion of the reaction, stirring is continued for 3 hours, the phases are separated, the benzene phase is washed until neutral, dried, and the benzene evaporated in vacuo. The residual oil is distilled in vacuo to yield 24 g (70% of theory) of 1-(allylthiocarbonyl)-trans-decahydroquinoline (b.p. 110°-116°C/0.2 Torr).