Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.CS(C)=O.[Si:18]([O:25][C:26]1[C:34]([CH2:35][CH:36]([C:38]2[CH2:42][CH2:41][CH2:40][CH:39]=2)[OH:37])=[C:33]([O:43][CH3:44])[C:32]([CH3:45])=[C:31]2[C:27]=1[C:28](=[O:46])[O:29][CH2:30]2)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(N(CC)CC)C>C(Cl)Cl>[C:38]1([C:36]([CH2:35][C:34]2[C:26]([O:25][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[C:27]3[C:31](=[C:32]([CH3:45])[C:33]=2[O:43][CH3:44])[CH2:30][O:29][C:28]3=[O:46])=[O:37])[CH2:42][CH2:41][CH2:40][CH:39]=1
Reactant: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(O)C1=CCCC1)C(=O)OC2
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c2c(c(O[Si](C)(C)C(C)(C)C)c1CC(=O)C1=CCCC1)C(=O)OC2
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
Trifluoroacetic anhydride (1.6 ml) in methylene chloride (3.6 ml) was added dropwise to dimethyl sulfoxide (1.05 ml) and CH2Cl2 (7.5 ml) under nitrogen over 5 minutes at -60° C. and stirred for 30 minutes. After addition of (±)-2-(4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-1-cyclopentenyl-1-hydroxyethane (2 g) in methylene chloride (6 ml) over 15 minutes, the mixture was warmed to -40° C. over 1 hour. Triethylamine (10 ml) was added at -70° C., the cooling bath was removed, and after reaching ambient temperature the solution was diluted with ethyl acetate, washed twice with saturated aqueous potassium dihydrogen phosphate, brine, dried and evaporated. The solid residue was chromatographed on silica gel with 7:1 hexane, eluting with ethyl acetate to afford cyclopentenyl (4-tert-butyldimethylsilyloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-ylmethyl) methanone (1.65 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([N:25]3[CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[NH:27][C:26]3=[O:35])[CH2:21][CH2:20]2)=[O:18])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CCOC(=O)C(Cc1ccc(C)c(C)c1)NC(=O)N1CCC(N2Cc3ccccc3NC2=O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(CC(NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.5 g (36.6 mmol) ethyl 3-(3,4-dimethyl-phenyl)-2-{[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidine-1-carbonyl]-amino}-propionate dissolved in 100 mL MeOH was combined with 200 mL 1 M NaOH and stirred overnight at RT. The reaction mixture was filtered, the filtrate washed three times with tert-butylmethylether and combined with 200 mL 1 M HCl. The aqueous phase was extracted three times with EtOAc, the combined organic phases were dried, filtered and evaporated down under reduced pressure. The residue was triturated with diisopropylether, suction filtered, stirred with diethyl ether and dried at 50° C. in the circulating air dryer.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[C:5]([CH3:12])[CH:4]=1.[CH3:13][O:14][C:15]([C:17]1[S:18][C:19](Br)=[C:20]([CH3:22])[CH:21]=1)=[O:16].C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][O:14][C:15]([C:17]1[S:18][C:19]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[CH3:12])=[C:20]([CH3:22])[CH:21]=1)=[O:16]
Reactant: COC(=O)c1cc(C)c(Br)s1
Reactant: COc1ccc(B(O)O)c(C)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(C)c(-c2ccc(OC)cc2C)s1
Temperature: 80 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
To a mixture of 4-methoxy-2-methylphenylboronic acid (912 mg, 6 mmol), 5-bromo-4-methyl-thiophene-2-carboxylic acid methyl ester (1.1 g, 5 mmol) and K2CO3 (1.38 g, 10 mmol) in toluene (30 mL) and water (5 mL) is bubbled N2 for 15 minutes followed by addition of tetrakis(triphenylphosphine) palladium (289 mg, 0.25 mmol). The mixture is stirred at 80° C. under N2 overnight. The reaction mixture is filtered through a Celite® pad eluting with EtOAc. The combined filtrate is concentrated under reduced pressure and the residue is purified by column chromatography (0-15% EtOAc in hexanes) to give 5-(4-methoxy-2-methyl-phenyl)-4-methyl-thiophene-2-carboxylic acid methyl ester (540 mg, 39%). 1H NMR (CDCl3): δ 7.63 (s, 1H), 7.15 (d, 1H, J=8.4 Hz), 6.82 (d, 1H, J=2.8 Hz), 6.78 (dd, 1H, J=2.8, J=8.4 Hz), 4.79 (bs, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 2.17 (s, 3H), 2.02 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)O)[CH2:15]2)[N:7]([CH3:24])[C:6]1=[O:25].[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[F:1][C:2]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[N:14]2[CH2:19][CH2:18][CH2:17][C@@H:16]([NH2:20])[CH2:15]2)[N:7]([CH3:24])[C:6]1=[O:25]
Reactant: Cn1c(=O)n(Cc2cc(F)ccc2F)c2c(N3CCC[C@@H](NC(=O)O)C3)ccnc21
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)n(Cc2cc(F)ccc2F)c2c(N3CCC[C@@H](N)C3)ccnc21
Yield: 77.4 %

Procedure:
The specific operation referred to the step (6) described in Example 1. 264 mg (R)-1-[1-(2,5-difluorobenzyl)-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidin-3-yl carbamic acid ter.-butyl ester (0.558 mmol) and 3.83 mL trifluoroacetic acid were charged to afford 161 mg titled product with a yield of 77.4%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[CH:19]=[CH:18][N:17]=[N:16]1.FC1C=C(F)C=CC=1[C@]1([C@H](N2N=CC=N2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[CH:19]=[CH:18][N:17]=[N:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: c1c[nH]nn1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1nccn1)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ccnn1)[C@@]1(c2ccc(F)cc2F)CO1

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (497 mg) and 1H-1,2,3-triazole, (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(2H-1,2,3-triazol-2-yl)ethyl]oxirane (150 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1,2,3-triazol-1-yl)ethyl]oxirane (204 mg) were obtained by the same way as in Reference Example 2.
Reaction SMILES: C([O:8][C:9](=[O:40])[C@@H:10]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C1C=CC=CC=1>C(OCC)(=O)C>[C:36]([O:35][C:33]([NH:32][C@@H:10]([CH2:11][CH2:12][CH2:13][O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:9]([OH:40])=[O:8])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OCc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)O
Reaction time: 16 h

Procedure:
To a solution of 1.92 g (S)-2-tert-Butoxycarbonylamino-5-(tert-butyl-diphenyl-silanyloxy)-pentanoic acid benzyl ester in 40 ml ethyl acetate were added under argon 0.2 g Pd/C (10%) and the suspension was stirred under an atmosphere of hydrogen (3 bar) for 16 h. The suspension was filtered over a plug of Celite® and washed with ethyl acetate. The crude product was obtained after evaporation of the solvent. Yield: 1.61 g colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4](P(O)(O)=O)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].N12CCCN=C1CCCCC2.[CH:32]12[CH:38]([CH:39]=O)[CH:35]([CH2:36][CH2:37]1)[CH2:34][CH2:33]2>ClCCl>[CH3:1][O:2][C:3](=[O:20])[C:4]([NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])=[CH:39][CH:38]1[CH:35]2[CH2:36][CH2:37][CH:32]1[CH2:33][CH2:34]2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(O)O
Reactant: O=CC1C2CCC1CC2
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(=CC1C2CCC1CC2)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 33.5 %

Procedure:
In a round bottom flask was placed N-(benzyloxycarbonyl)-α-phosphonoglycine methyl ester (680 mg, 2.05 mmol) in dichloromethane (5 mL) and cooled to 0° C. in an ice bath. To this mixture was added slowly 1,8-diazabicyclo[5.4.0]undec-7-ene (266 μL, 1.78 mmol) and stirred at 0° C. for 20 min. The mixture was treated with a solution of bicyclo[2.2.1]heptane-7-carbaldehyde (170 mg, 1.36 mmol) in dichloromethane (5 mL). After the addition was complete, the mixture was allowed to warm to 25° C. and stirred overnight. The mixture was concentrated in vacuo and the residue taken up in ethyl acetate (50 mL) and washed with a saturated aqueous ammonium chloride solution (2×25 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. Purification by AnaLogix IntelliFlash flash chromatography (4 g column, 5% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) afforded 2-benzyloxycarbonylamino-3-bicyclo[2.2.1]hept-7-yl-acrylic acid methyl ester (150 mg, 33%) as a clear colorless oil.
Reaction SMILES: N1C=CC=CC=1.[C:7]([Cl:10])(Cl)=[O:8].ClCCCl.[CH:15]([NH:18][S:19]([Cl:22])(=[O:21])=[O:20])([CH3:17])[CH3:16]>O>[Cl:10][C:7]([N:18]([CH:15]([CH3:17])[CH3:16])[S:19]([Cl:22])(=[O:21])=[O:20])=[O:8]
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: O=C(Cl)Cl
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)N(C(=O)Cl)S(=O)(=O)Cl
Temperature: 22 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
316.4 parts of pyridine are introduced at -10° C., whilst stirring, into a solution of 400 parts of phosgene in 2,500 parts of 1,2-dichloroethane. 630.4 parts of isopropylsulfamic acid chloride are then added at the same temperature and the reaction mixture is stirred for one hour at 22° C. Thereafter, the mixture is stirred for 8 minutes with 700 parts of water at 6° C. and pH 1. The organic phase is then separated off from the 2-phase mixture formed, and is filtered and subjected to fractional distillation. 763 parts (87% of theory) of N-chlorocarbonyl-N-isopropylsulfamic acid chloride, of boiling point 57°-62° C./0.11 mbar and nD25 =1.4749, are obtained.
Reaction SMILES: [N:1]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([C:28](=O)[CH2:29]Br)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]>C(#N)C>[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([CH2:28][CH2:29][N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:22]([CH3:27])([CH3:23])[CH3:21])=[O:8])[CH2:2][CH2:3]3)=[CH:25][CH:26]=2)[CH2:21][CH2:20]1)(=[O:18])[CH3:17]
Reactant: CC(=O)N1CCc2cc(C(=O)CBr)ccc21
Reactant: O=C(O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)N1CCc2cc(CCN3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Temperature: 70 °C
Yield: 55 %

Procedure:
To a solution of piperazine-1-carboxylic acid tent-butyl ester (0.750 g, 4.03 mmol) in dry acetonitrile (20 mL) grounded potassium carbonate (0.486 mL, 8.05 mmol) was added followed by the product mixture from Example 38a (1.134 g) and the reaction was heated at 70° C. under argon over night. The acetonitrile was evaporated and DCM and water was added. The layers were separated and the aq phase was extracted with DCM (3×). The combined organic phases were dried (Na2SO4), filtered and evaporated. The crude mixture was purified by flash chromatography (heptane/EtOAc 75/25 to 0/100) to give 0.823 g (55%) of the title compound.
Reaction SMILES: [C:1]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH2:4][CH3:5])([CH3:3])[CH3:2].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:24](O)=[O:25]>>[C:1]([C:6]1[CH:7]=[CH:8][C:9]([CH:24]=[O:25])=[CH:10][CH:11]=1)([CH2:4][CH3:5])([CH3:2])[CH3:3]
Reactant: CCC(C)(C)c1ccccc1
Reactant: O=C(O)C(F)(F)F
Agent: C1N2CN3CN1CN(C2)C3
Product: CCC(C)(C)c1ccc(C=O)cc1

Procedure:
A solution of tert-pentylbenzene (10.04 g, 67.72 mmol) and hexamethylenetetramine (9.49 g, 67.7 mmol) in trifluoroacetic acid (100 ml) was stirred at 90° C. overnight. The reaction solution was evaporated under reduced pressure, diluted with water, alkalified with potassium carbonate, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give a crude product of 4-(tert-pentyl)benzaldehyde as a dark brown liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6]>CO>[CH3:1][O:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[C@@H:5]([OH:7])[CH3:6]
Reactant: COC(=O)C(C)(C)C(C)=O
Solvent: CO
Product: COC(=O)C(C)(C)[C@H](C)O
Temperature: 30 °C
Reaction time: 40 h
Yield: 93.5 %

Procedure:
The reaction is carried out in a 100-mL autoclave. 2,2-Dimethyl-3-oxo-butyric acid methyl ester (4.0 g, 27.8 mmol) is dissolved in 35 mL of degassed methanol under Argon atomosphere. Dichloro[(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]ruthenium (II) (230.0 mg, 0.28 mmol) is added and the reaction mixture is purged with nitrogen twice and once with hydrogen. The autoclave is pressurized with hydrogen to 500 psi and stirred at 30° C. for 40 h. After this time, the reaction mixture is filtered through celite and concentrated under reduced pressure to provide 3.8 g of the title compound as a green oil with ee of 98%. Yield: 95%. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 (3H, d, J=6.4 Hz), 1.2 (6H, d, J=5.2 Hz), 2.6 (1H, br. S), 3.7 (3H, s), 3.9 (1H, q, J=6.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[C:4]([Cl:11])N=1.[CH3:12]C(=O)OCC>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:12]=[C:4]([Cl:11])[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CCOC(C)=O
Agent: [Fe]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 95 %

Procedure:
To a solution of 2,6-dichloro-3-nitropyridine (100 g, 0.518 mol) in acetic acid (1 L) was added iron powder (86.49 g, 1.555 mol) portion wise. The resulting reaction mixture was stirred at room temperature for 6 h. The completion of the reaction was confirmed by checking TLC system (PE/EA=8:2). The reaction mass was concentrated under high vacuum. The crude was dissolved in water (1 L) and EtOAc (2 L). While stirring, the pH of the aqueous solution was adjusted to 6.5 using powder Na2CO3. The mixture was filtered through CELITE® and the organic layer was separated, dried and concentrated to give 2,4-dichloroaniline (80 g, 95%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.14-7.2 (2H, m); 5.78 (2H, s).
Reaction SMILES: Cl[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[OH:16][C:17]1[CH:30]=[CH:29][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][CH:18]=1.N1C2C(=CC=CC=2)C=CC=1>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:29][CH:30]=1)[C:11]([N+:12]([O-:14])=[O:13])=[CH:10]2
Reactant: CCOC(=O)C(C)Oc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc2cc(Cl)ccc2nc1Cl
Solvent: c1ccc2ncccc2c1
Product: CCOC(=O)C(C)Oc1ccc(Oc2nc3ccc(Cl)cc3cc2[N+](=O)[O-])cc1

Procedure:
Ethyl 2-[4-(6-chloro-3-nitroquinolin-2-yloxy)phenoxy]propionate was prepared from 2,6-dichloro-3-nitroquinoline and ethyl 2-(4-hydroxyphenoxy)-propionate following essentially the same procedure as that described in Example 1. Proton magnetic resonance spectrum (CDCl3, δ in ppm): 8.6 (1H, s, C4 quinoline proton); 7.8-7.6 (3H, m, quinoline protons); 7.0 (4H, d of d, phenyl protons); 4.6 (1H, q, CHCH3); 4.2 (2H, q, OCH2CH3); 1.6 (3H, d, CHCH3); 1.2 (3H, t, OCH2CH3).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O1CCCCC1[O:19][CH2:20][CH2:21][O:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]>CO>[OH:19][CH2:20][CH2:21][O:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33]
Reactant: O=C1c2ccccc2C(=O)N1OCCOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: O=C1c2ccccc2C(=O)N1OCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.56 g of p-toluenesulfonic acid monohydrate was added to a solution of 8.62 g of N-[2-(tetrahydropyran-2-yloxy)ethoxy]phthalimide [prepared as described in step (a) above] in 86 ml of methanol, and the resulting mixture was stirred at room temperature for 2 hours. At the end of this time, the reaction mixture was concentrated by evaporation under reduced pressure, and then the resulting residue was dissolved in a mixture of ethyl acetate and water and neutralyzed with sodium hydrogen carbonate. The ethyl acetate layer was separated and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, giving the title compound as a crystalline powder. This was washed with diisopropyl ether to give 4.10 g of the pure compound, melting at 82°-85° C.
Reaction SMILES: [C:1]([NH:7][C:8]1[N:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][N:9]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]>C(O)C.[Pt]=O>[C:1]([NH:7][C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][N:9]=1)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Nc1ncc([N+](=O)[O-])cn1
Agent: O=[Pt]
Solvent: CCO
Product: CCCCC(=O)Nc1ncc(N)cn1
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Platinum oxide (50 mg, 0.22 mmol) was added to a solution of 2-(N-pentanoyl)amino-5-nitropyrimidine (650 mg, 2.9 mmol) in ethanol (100 ml) at ambient temperature and the reaction stirred for 1 hour under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and the solvents were evaporated in vacuo. Trituration with diethylether and drying yielded 2-(N-pentanoyl)amino-5-aminopyrimidine (307 mg, 55% yield) as brown solid:
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:6][N:5]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[C@H:4]([C:17]([O:19]C)=[O:18])[CH2:3]1.[OH-].[Na+]>CO>[CH2:10]([O:9][C:7]([N:5]1[CH2:6][C:2]([F:21])([F:1])[CH2:3][C@H:4]1[C:17]([OH:19])=[O:18])=[O:8])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COC(=O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1

Procedure:
A solution of 1-benzyl 2-methyl (2S)-4,4-difluoropyrrolidine-1,2-dicarboxylate in methanol was refluxed with 2N NaOH (2 eq) for 2 hours. Methanol was removed and pH adjusted to 1 with 3 N HCl obtaining a suspension which was extracted several times with ethyl acetate. Combined organics were dried over Na2SO4 and evaporated to give title product as a dark brown oil.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:40]1[C:45]([F:46])=[C:44]([F:47])[CH:43]=[CH:42][C:41]=1[F:48].OC1C=C2C(=CC=1)C(C(C1C=CC(OCCN3CCCCC3)=CC=1)=O)=C(C1C=C(F)C=C(F)C=1F)C=C2>>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:40]3[C:41]([F:48])=[CH:42][CH:43]=[C:44]([F:47])[C:45]=3[F:46])=[O:16])=[CH:37][CH:38]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: Fc1ccc(F)c(Br)c1F
Agent: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2cc(F)cc(F)c2F)ccc2cc(O)ccc12
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3c(F)ccc(F)c3F)ccc2c1
Yield: 46.3 %

Procedure:
Couple trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.48 g, 2.67 mmol) with 2-bromo-1,3,4-trifluoro-benzene (1.13 g, 5.35 mmol) in a procedure similar to the preparation of [6-hydroxy-2-(2,3,5-trifluoro-phenyl)-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone to give 0.66 g (46%) of the title compound: mass spectrum (ion spray) m/z=534.4 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[CH2:13].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CC(=O)OCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([CH:7]=1)[CH:13]=[CH:12][C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COc1ccc(Cl)cc1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cc(Cl)ccc1OC
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of 10.6 g (48.2 mmol) of 2-bromo-4-chloroanisole in 30 ml of triethylamine was treated with 1 0.1 ml (81.2 mmol) of ethyl acrylate, 1.23 g of tri-o-tolylphosphine, and 0.45 g of palladium(II) acetate in an argon atmosphere. The reaction mixture was stirred at 100° C. for 2 days, then diluted with EA and filtered through Celite. The filtrate was washed with 1 N HCl and saturated NaCl solution, dried over Na2SO4, and concentrated. After chromatographic purification over SiO2 using EA/heptane (1:8) as an eluent, 0.85 g of the title compound resulted as a pale yellow oil.
Reaction SMILES: [C:1]1([CH:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:8]2[CH2:13][CH2:12][CH:11]([N:14]=[CH:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][O:24][C:18]=4[CH:17]=3)[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+]>C(O)C>[C:25]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]4[O:22][CH2:23][O:24][C:18]=4[CH:17]=3)[CH2:10][CH2:9]2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C(=NC1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc2c(c1)OCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: c1ccc(C(c2ccccc2)N2CCC(NCc3ccc4c(c3)OCO4)CC2)cc1
Temperature: 25 °C

Procedure:
A suspension of 4 parts of 1-(diphenylmethyl)-N-[3,4-(methylenedioxy)benzylidene]-4-piperidinamine in 100 parts by volume of ethanol, stirred at room temperature, is treated with 1 part of sodium borohydride. The resultant reaction mixture is stirred at room temperature overnight and evaporated to dryness in vacuo. The residue is partioned between 100 parts by volume of water and 100 parts by volume of chloroform and the layers separated. The acequeous layer is extracted with additional 100 parts by volume of chloroform and the chloroform layers combined. The combined chloroform fraction is washed with 150 parts by volume of water, dried over anhydrous sodium sulfate, filtered and evaporated to dryness in vacuo to yield, as a colorless oil, 1-(diphenylmethyl)-N-[3,4-(methylenedioxy)benzyl]-4-piperidinamine. This compound has the following formula ##STR38##
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[N:3]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:4]3[C:9]([C:10]=2[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: CC(C)(C)OC(=O)N1CCN(c2c(C=O)c3ccccc3n2-c2ccccc2)CC1
Yield: 43 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with t-butyl-1-piperazinecarboxylate as described in Step 2 of Example 29 to afford 4-(3-formyl-1-phenyl-1H-indol-2-yl)piperazine-1-carboxylic acid tert-butyl ester (43% yield) as a yellow solid. ESI/MS 300 (M), 306 [M-CO2C(CH3)3], 350 [M-C(CH3)3], 406 (M+H); RT=3.89 min; NMR 10.15 (1H, s); 8.14 (1H, d, J=9 Hz); 7.69 (5H, m); 7.22 (2H, m); 6.94 (1H, d, J=9 Hz); 3.22 (8H, 2 br m); 1.37 (9H, s).