Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=[CH:4][NH:3]1.CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O1CCCC1>[O:1]=[C:2]1[C:7]([C:8]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:10])=[CH:6][CH:5]=[CH:4][NH:3]1
Reactant: O=C(O)c1ccc[nH]c1=O
Reactant: Nc1ccccc1
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1)c1ccc[nH]c1=O
Temperature: 0 °C
Reaction time: 6 h
Yield: 97.5 %

Procedure:
To a solution of 2-oxo-1,2-dihydropyridine-3-carboxylic acid (1.00 g, 7.18 mmol) in anhydrous tetrahydrofuran (40 mL) was added 4-methyl morpholine (1.01 g, 10.06 mmol). After cooling to 0° C., isobutyl chloroformate (1.27 g, 9.34 mmol) was added to the reaction mixture. The mixture was stirred at ambient temperature for 6 hours followed by the addition of aniline (0.87 g, 9.34 mmol). The resulting mixture was stirred at ambient temperature for 16 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate (100 mL), and washed with saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless solid (1.50 g, 97%): 1H NMR (300 MHz, DMSO-d6) δ 12.71 (br s, 1H), 12.14 (s, 1H), 8.46-8.38 (m, 1H), 7.80-7.52 (m, 1H), 7.65-7.62 (m, 2H), 7.35-7.29 (m, 2H), 7.10-6.95 (m, 1H), 6.58-6.45 (m, 1H); MS (ES+) m/z 215.2 (M+1).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[C:24]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:23]=3[N:22]=2)=[CH:17][CH:16]=1>CN(C=O)C>[Si:10]([O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:25]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)[C:24]3[CH:32]=[CH:33][C:34]([C:36]#[N:37])=[CH:35][C:23]=3[N:22]=2)=[CH:17][CH:16]=1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#Cc1ccc2c(c1)nc(-c1ccc(O)cc1)n2C1CCCCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2nc3cc(C#N)ccc3n2C2CCCCC2)cc1
Reaction time: 15 h

Procedure:
Imidazole (2.72 g, 0.040 mol) and tert-butyldimethylchloro silane (2.89 g, 192 mmol) were added to a stirred solution of compound 6 (5.1 g, 16 mmol) in DMF (10 mL). Stirring was continued for 15 h at 100° C. Upon cooling 20 crystallized. The crystals were collected and washed with ethyl acetate followed by water. The yield of 20 (after drying) was 4.70 g (62%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH:18]=O)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[Cl:27].[C:29]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH:40]1[CH3:45])([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([CH2:18][N:42]2[CH2:43][CH2:44][N:39]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH:40]([CH3:45])[CH2:41]2)[CH:15]=[C:14]2[C:9]=1[CH2:10][NH:11][C:12](=[O:28])[N:13]2[C:20]1[C:21]([Cl:27])=[CH:22][CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: O=Cc1cc(-c2ccccc2Cl)c2c(c1)N(c1c(Cl)cccc1Cl)C(=O)NC2
Reactant: CC1CNCCN1C(=O)OCc1ccccc1
Product: CC1CN(Cc2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CCN1C(=O)OCc1ccccc1

Procedure:
The benzyl 4-{[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]methyl}-2-methylpiperazine-1-carboxylate was prepared from 5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-2-oxo-1,2,3,4-tetrahydroquinazoline-7-carbaldehyde (INTERMEDIATE AAA1) and 1-CBz-2-methylpiperazine as described in EXAMPLE AAA1, STEP A. 1H NMR (CDCl3, 500 MHz): δ 1.08 (d, 3H, J=5.9 Hz), 2.00 (m, 1H), 2.10 (m, 1H), 2.52 (d, 1H, J=11.0 Hz), 2.70 (m, 1H), 3.06 (m, 1H), 3.26 (m, 1H), 3.46 (m, 1H), 3.86 (d, 1H, J=12.5 Hz), 4.24.5 (m, 3H), 5.05 (s, 1H), 5.14 (abq, 2H, J=12.4 Hz), 6.25 (d, 1H, J=13.3 Hz), 6.82 (s, 1H), 7.30-7.60 (m, 12H). MS (API-ES+): 651 (M+H).
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[H-].[Na+].[CH2:19]([N:21]=[C:22]=[S:23])[CH3:20]>>[CH2:19]([NH:21][C:22](=[S:23])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=1)[CH3:20]
Reactant: CCN=C=S
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Agent: [H-]
Agent: [Na+]
Product: CCNC(=S)OCCOc1ccc(OCC=C(C)C)cc1

Procedure:
In the same manner, 2-[4-(3-methyl-2-butenoxy)phenoxy]-ethanol is reacted with sodium hydride and ethyl isothiocyanate to yield O-2-[4-(3-methyl-2butenoxy)phenoxy]ethyl N-ethylthiocarbamate (compound 37, Table A).
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH:38]([CH2:41][OH:42])[CH2:39][OH:40]>>[OH:40][CH2:39][CH:38]([NH:37][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1)[CH2:41][OH:42]
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Reactant: NC(CO)CO
Product: O=C(NC(CO)CO)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 80.5 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and serinol (46 mg, 0.50 mmol, 1.0M in DMF) were combined (reaction time 3 days at room temperature) to give 46 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 572 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]#[N:15])[N:5]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[CH:6]=1.[F:16][C:17]([F:22])([F:21])C([O-])=O.[Na+]>CN1CCCC1=O>[CH3:13][C:10]1[CH:11]=[CH:12][C:7]([N:5]2[CH:6]=[C:2]([C:17]([F:22])([F:21])[F:16])[CH:3]=[C:4]2[C:14]#[N:15])=[CH:8][CH:9]=1
Reactant: Cc1ccc(-n2cc(Br)cc2C#N)cc1
Reactant: O=C([O-])C(F)(F)F
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: Cc1ccc(-n2cc(C(F)(F)F)cc2C#N)cc1
Temperature: 200 °C
Reaction time: 11 h
Yield: 27.9 %

Procedure:
A mixture of 4-bromo-1-(4-methylphenyl)pyrrole-2-carbonitrile (3.66 g), sodium trifluoroacetate (7.62 g), cuprous iodide (5.34 g) and N-methylpyrrolidone (40 ml) was stirred at 200° C. under a nitrogen atmosphere for 11 hours. The mixture was filtered. The filtrate was poured into water and extracted with ethyl acetate twice. The combined organic layer was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography to afford 1-(4-methylphenyl)-4-trifluoromethylpyrrole-2-carbonitrile (0.98 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:38]([O:40][C:41](=[O:44])[CH2:42]Br)[CH3:39]>CN(C=O)C>[C:1]([O:5][C:6](=[O:31])[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([N:17]([CH2:42][C:41]([O:40][CH2:38][CH3:39])=[O:44])[S:18]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)(=[O:19])=[O:20])=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:28][CH2:29][CH3:30])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCc1nc2cc(N(CC(=O)OCC)S(=O)(=O)c3ccc(F)cc3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product from example 1, step d.) (50 mg, 0.111 mmol) was dissolved in DMF (1 mL), treated with K2CO3 (23 mg, 0.167 mmol), bromo-acetic acid ethyl ester (25 uL, 0.133 mmol), and stirred at ambient temperature overnight. The reaction was heated to 50° C. for 2 hours, then more K2CO3 (23 mg, 0.167 mmol) and bromo-acetic acid ethyl ester (25 uL, 0.133 mmol) were added and the reaction was heated to 80° C. for three hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The organic layer was washed several times with water and concentrated under reduced pressure to give the sub-title compound that was used in crude form without purification.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:18]([S-:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[Na+]>C(O)C>[C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH:16]([S:25][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:15][CH2:14][C:13]1=[O:17])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCCCCCC1=CCCC1=O
Reactant: CCCCCCC[S-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCSC1CCC(=O)C1CCCCCCC(=O)OCC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
3.2 g. of 2-(6-carbethoxyhexyl)-2-cyclopentenone, dissolved in 20 ml. of dry ethanol, is added to a solution of sodium heptanethiolate (producible by dissolving 0.24 g. of sodium in 30 ml. of dry ethanol and adding 1.3 g. of heptylthiol); the reaction mixture is agitated under nitrogen for 24 hours at 40°, then diluted with 150 ml. of ice water and 10 ml. of concentrated HCl, extracted with CH2Cl2, washed with saturated aqueous NaCl solution, dried over Na2SO4, and the solvent is distilled off. After purifying the residue by chromatography, 2-(6-carbethoxyhexyl)-3-heptylthio-cyclopentanone is obtained. Rf = 0.7 (silica gel/chloroform).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH2:11][CH:12]([S:67][S:68][CH:69]([CH3:71])[CH3:70])[CH2:13][C@@H:14]([NH:59]C(OC(C)(C)C)=O)[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16])=[N+:9]=[N-:10]>ClCCl>[NH2:59][C@H:14]([CH2:13][CH:12]([S:67][S:68][CH:69]([CH3:71])[CH3:70])[CH2:11][N:8]=[N+:9]=[N-:10])[C:15]([O:17][C@H:18]1[C@@H:22]([OH:23])[C@H:21]([N:24]2[CH:32]=[N:31][C:30]3[C:25]2=[N:26][CH:27]=[N:28][C:29]=3[NH2:33])[O:20][C@H:19]1[CH2:34][O:35][P:36]([O:39][C@H:40]1[CH2:44][C@H:43]([N:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[N:47][C:46]2=[O:52])[O:42][C@@H:41]1[CH2:53][O:54][P:55]([OH:58])([OH:57])=[O:56])([OH:38])=[O:37])=[O:16]
Reactant: CC(C)SSC(CN=[N+]=[N-])C[C@@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)SSC(CN=[N+]=[N-])C[C@@H](N)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 87 %

Procedure:
Trifluoroacetic acid (0.1 mL) was added to a solution of (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidine-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-azido-2-((tert-butoxycarbonyl)amino)-4-(isopropyldisulfanyl)pentanoate (Compound 46) (27.7 mg, 28 μmol) in dichloromethane (0.4 mL), and the mixture was stirred for 35 minutes at room temperature. Following concentration under reduced pressure, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 2-amino-5-azido-4-(isopropyldisulfanyl)pentanoate (Orn(N3) (4-SSiPr)-pdCpA) (Compound 47) (21.5 mg, 86%).
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[SH:8][CH2:9][CH2:10][C:11](O)=[O:12].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[CH:1]1([O:7][C:11](=[O:12])[CH2:10][CH2:9][SH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)CCS
Reactant: OC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: O=C(CCS)OC1CCCCC1
Temperature: 25 °C

Procedure:
Into a 250 ml reaction flask equipped with stirrer, thermometer, reflux condenser and heating mantle are placed 100 grams of cyclohexanol; 26 grams of 3-mercaptopropionic acid and 0.5 grams of paratoluene sulfonic acid. The reaction mass is heated to reflux and refluxed for a period of 11 hours. At the end of the 11 hour period of refluxing, the reaction mass is cooled to room temperature. 200 ml Diethylether are added to the reaction mass. The reaction mass is then washed with two 100 ml volumes of 10% aqueous sodium bicarbonate solution followed by one 100 ml volume of water. The reaction mass is dried over anhydrous sodium sulfate and the solvent is recovered on a Buchi evaportor. The reaction mass is then micro distilled on a micro distillation apparatus yielding the following fractions:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:31])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([CH:17]=[O:31])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(-c2nc3c(CBr)cccc3o2)cc1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1cccc2oc(-c3ccc(Cl)cc3)nc12

Procedure:
A mixture of 2-(4-chlorophenyl)-4-(bromomethy)benzoxazole (P0002; 2.0 g) and hexamethylenetetramine (1.27 g) in acetic acid (15 ml) and water (7.5 ml) was refluxed for 3 hours and evaporated. EtOAc and an aqueous NaHCO3 solution were added, and the organic layer was separated, dried, and evaporated. The residue (1.47 g) was purified by silica gel (25 g) column chromatography eluting with hexane-CH2Cl2-EtOAc (5:1:1) to give pale yellow crystals of 2-(4-chlorophenyl)benzoxazole-4-carbaldehyde (P0003; 0.89 g).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][CH2:5][NH:6][C:7]1([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]4)[CH:17]=3)[CH:12]=2)[CH2:10][O:9][CH2:8]1.[OH-].[Li+].O1CCCC1.O>>[C:28]([C@H:25]1[CH2:24][CH2:23][C@H:22]([O:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[C:11]([C:7]2([NH:6][CH2:5][CH2:4][C:3]([OH:32])=[O:2])[CH2:8][O:9][CH2:10]2)[CH:20]=[CH:19]3)[CH2:27][CH2:26]1)([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)CCNC1(c2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)COC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(C4(NCCC(=O)O)COC4)ccc3c2)CC1

Procedure:
A solution of 3-{3-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-yl]-oxetan-3-ylamino}-propionic acid methyl ester (18.0 mg, 0.0409 mmol) and Lithium hydroxide (6.41 mg, 0.268 mmol) in Tetrahydrofuran (0.6 mL, 8 mmol) and Water (0.2 mL, 9 mmol) was stirred at r.t. overnight. LCMS showed a single desired product peak M+Na at m/z 448.20, RT 1.56 min. The solvent was concentrated and neutralized with citric acid and concentrated and purified on HPLC to give product (5.8 mg, 33%). 1H NMR (400 MHz, MeOD) d=7.91 (d, J=8.4 Hz, 1H), 7.87 (s, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.31 (s, 1H), 7.20 (d, J=6.8 Hz, 1H), 5.26 (d, J=7.9 Hz, 2H), 5.13 (d, J=7.7 Hz, 2H), 4.43-4.32 (m, 1H), 3.05 (t, J=5.1 Hz, 2H), 2.70-2.62 (m, 2H), 2.27 (d, J=11.2 Hz, 2H), 1.96-1.85 (m, 2H), 1.50-1.35 (m, 2H), 1.34-1.18 (m, 2H), 1.17-1.04 (m, 1H), 0.91 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20].B1C2CCCC1CCC2.[OH:35]O.[OH-].[Na+]>>[F:1][C:2]([F:25])([C:21]([F:22])([F:23])[F:24])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:35]
Reactant: C=CCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Product: OCCCCCCCCCCCOCCCCCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
Into a clean flame dried 1 L RBF under current of N2, was put 12.86 g (34.48 mmol) of 54. To this was added 172 mL (86.2 mmol) of 9-BBN (0.5 M in THF). The reaction was stirred for 3 h. 23 mL of 30% H2O2 was then added dropwise to the reaction mixture followed by 49 mL of 15% aq. NaOH and the reaction mixture was stirred at 85° C. for 3 h. The mixture was then cooled to room temperature and THF was evaporated and the residue was diluted with H2O and extracted with EtOAc (3×). The combined organic layer was then washed with brine (1×), dried over MgSO4, filtered and the solvent was evaporated under vacuum. The residue was then purified using combiflash (120 g silica column) with hexane/ethyl acetate as eluent to furnish 10.15 g (76%) of compound 55 as a white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.[CH3:17][O:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>C(OCC)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([C:13](=[O:15])[C:12]([NH:11][C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[NH:3][C:2](=[O:1])[CH2:10]4)=[O:16])[CH2:28][CH2:29]2)=[CH:30][CH:31]=1
Reactant: COc1ccc(CC2CCNCC2)cc1
Reactant: O=C1Cc2cc(NC(=O)C(=O)O)ccc2N1
Solvent: CCOCC
Product: COc1ccc(CC2CCN(C(=O)C(=O)Nc3ccc4c(c3)CC(=O)N4)CC2)cc1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-1H-indol-5-yl)-oxalamic acid (Example 101b) and 4-(4-methoxy-benzyl)-piperidine [U.S. Pat. No. 3,632,767 (1972)] according to the method described in Example 1c. Melting Point: 215-217° C. (diethylether)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[O:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1>N1C=CC=CC=1.C(Cl)Cl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:18][C:15]2[CH:16]=[CH:17][C:12]([CH3:11])=[C:13]([O:19][CH:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(N)cc1OC1CCN(C)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(F)cc2)cc1OC1CCN(C)CC1
Reaction time: 20 h
Yield: 86.2 %

Procedure:
Add 4-fluorobenzoyl chloride (222 mg, 1.4 mmol) to a solution of 4-Methyl-3-(1-methyl-piperidin-4-yloxy)-phenylamine (preparation 34, 280 mg, 1.27 mmol) in pyridine (10 mL), beat at 55° C. for 20 hr. Remove volatiles in vacuo, dissolve the residue in CH2Cl2, wash with 0.1N NaOH and saturated NaCl solution sequentially, dry over Na2SO4, filter and concentrate to give a residue. Chromatography on a silica gel column eluting with 6% 2M NH3-methanol in CH2Cl2) provides the title compound as a colorless oil (375 mg, 86%). Mass spectrum (ion spray): m/z=343.3 (M+1); 1H NMR (CDCl3, ppm): 7.94 (s, br, 1H), 7.88 (m, 2H), 7.85 (s, br, 1H), 7.12 (m, 3H), 6.87 (dd, 1H), 4.39 (m, 1H), 2.62 (m, 2H), 2.33 (m, 2H), 2.31 (s, 3H), 2.22 (s, 3H), 2.06-1.83 (m, 4H); Anal calcd for C20H23FN2O2.HCl H2O: C, 60.53; H, 6.60; N, 7.06. Found: C, 60.77; H, 6.20; N, 7.10.
Reaction SMILES: [CH3:1][C:2]1([CH3:40])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C:11]([CH3:23])([CH3:22])[O:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=3[C@@:5]2([CH3:24])[N:4]=[C:3]1[N:25]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>CCOC(C)=O.CO.[Pd]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]2[O:12][C:11]([CH3:23])([CH3:22])[CH2:10][C@H:6]3[S:7](=[O:8])(=[O:9])[C:2]([CH3:40])([CH3:1])[C:3]([N:25]([C:26]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:32])[C:33](=[O:34])[O:35][C:36]([CH3:37])([CH3:38])[CH3:39])=[N:4][C@:5]3([CH3:24])[C:14]=2[CH:15]=1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc([N+](=O)[O-])ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=N[C@]2(C)c3cc(N)ccc3OC(C)(C)C[C@H]2S(=O)(=O)C1(C)C
Reaction time: 16 h
Yield: 100 %

Procedure:
A mixture of tert-butyl N-[(4aR,11bR)-3,3,6,6,11b-pentamethyl-10-nitro-4,4-dioxo-4a,5-dihydro-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (105 mg, 0.180 mmol) and 10% Pd/C (58 mg, 0.054 mmol) in EtOAc (1.1 mL) and MeOH (1.1 mL) was stirred under hydrogen atmosphere for 16 hours. The mixture was passed through a celite cake and rinsed with ethyl acetate and ethanol. The filtrate was concentrated in vacuo to afford the title compound (99 mg, 0.180 mmol, 100% yield) as a white foam. MS m/z=574.3 (M+Na).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[CH2:14]([O:17][C:18]1[CH:34]=[CH:33][CH:32]=[CH:31][C:19]=1[CH2:20][N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29]Cl)[CH2:23][CH2:22]1)[CH2:15][CH3:16]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:29][CH2:28][CH2:27][N:24]3[CH2:25][CH2:26][N:21]([CH2:20][C:19]4[CH:31]=[CH:32][CH:33]=[CH:34][C:18]=4[O:17][CH2:14][CH2:15][CH3:16])[CH2:22][CH2:23]3)[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: CCCOc1ccccc1CN1CCN(CCCCl)CC1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Product: CCCOc1ccccc1CN1CCN(CCCOc2ccc3[nH]c(=O)cc(C)c3c2)CC1
Yield: 53 %

Procedure:
In a manner analogous to that described in Example 9, 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline is reacted with 3-[4-(2-propoxybenzyl)-piperazin-1-yl]-propyl chloride. There is obtained 4-methyl-6-{3-[4-(2-propoxybenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline in a yield of 53% of theory in the form of an oily base. The corresponding hydrochloride is obtained from an acetone solution of the base, by the addition of ethereal hydrochloric acid, in amorphous fomrm with a melting point of about 140°-145° C.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][C@H:14]1[CH2:19][NH:18][CH2:17][C@@H:16]([CH3:20])[NH:15]1.C(#N)C>O>[CH3:13][C@H:14]1[NH:15][C@@H:16]([CH3:20])[CH2:17][N:18]([C:2]2[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])[CH2:19]1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: C[C@@H]1CNC[C@H](C)N1
Solvent: CC#N
Solvent: O
Product: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
2-Chloro-5-nitrobenzonitrile (13.3 g) and cis-2,6-dimethylpiperazine (25 g) were added to acetonitrile (25 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added to water and extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was recrystallized from diisopropyl ether to give cis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g), melting point: 109–110° C.