Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[N:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].CS(O[CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26][CH2:25]1)(=O)=O.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(OC)C=3)C=CC2=O)CC1)(C)(C)C>C(OCC)(=O)C>[C:34]([O:33][C:31](=[O:32])[NH:30][CH:27]1[CH2:28][CH2:29][N:24]([CH2:23][CH2:22][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[C:6](=[O:14])[N:7]([CH3:13])[C:8]2=[O:12])[CH2:25][CH2:26]1)([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCOS(C)(=O)=O)CC1
Reactant: Cn1c(=O)[nH]c2cc(F)ccc2c1=O
Agent: COc1ccc2ccc(=O)n(CCN3CCC(NC(=O)OC(C)(C)C)CC3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2ccc(F)cc2n(CCN2CCC(NC(=O)OC(C)(C)C)CC2)c1=O
Yield: 23.8 %

Procedure:
7-Fluoro-3-methylquinazoline-2,4(1H,3H)-dione [Intermediate 136] (388 mg, 2.0 mmol) was deprotonated with sodium hydride (100 mg, 60% in oil, 2.4 mmol) and alkylated with 2-{4-[(tert-butoxycarbonyl)amino]piperidin-1-yl}ethyl methanesulfonate (Intermediate 6) 2.75 mmol) as described for Intermediate 2. Chromatography on silica gel using ethyl acetate in hexanes (10-30%) gave the title compound as a yellow oil (200 mg, 24%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH:8]=[CH:7][CH2:6]1)=[O:4]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C@H:5]1[NH:21][C:20](=[O:22])[C@H:19]([CH:23]([CH3:25])[CH3:24])[NH:18][C:17](=[O:26])[C@@H:16]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:15][C:14]2=[CH:35][CH:36]=[C:11]([CH:12]=[CH:13]2)[O:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CC=CCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Agent: [Pd]
Agent: COC(=O)[C@@H]1C/C=C/COc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCCCOc2ccc(cc2)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1

Procedure:
Olefin 45 (1.3.6 g, 2.70 mmol) was dissolved in 40 mL of EtOAc. 10% palladium on carbon catalyst was added (25%) and the reaction mixture was subjected to hydrogenation at rt and atmospheric pressure for 18 h before being filtered through celite and concentrated in vacuo to yield a brown solid, 1.36 g, 100%. m.p. 225-228° C.
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.COC1C=CC(C[O:22][CH:23]([C:29]2[CH:34]=[CH:33][C:32]([N:35]([CH2:39][C:40]#[C:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:36](=[O:38])[CH3:37])=[CH:31][CH:30]=2)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=CC=1>C(Cl)(Cl)Cl.O>[OH:22][CH:23]([C:29]1[CH:30]=[CH:31][C:32]([N:35]([CH2:39][C:40]#[C:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])[C:36](=[O:38])[CH3:37])=[CH:33][CH:34]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCC(OCc1ccc(OC)cc1)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCC(O)c1ccc(N(CC#CCCCC(=O)OC)C(C)=O)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 86.7 %

Procedure:
4,5-Dichloro-3,6-dioxo-1,4-cyclohexadiene-1,2-dicarbonitrile (19 mg, 0.081 mmol) was added to a solution of the MPM-ether 104 (35 mg, 0.071 mmol) in CHCl3 (1.6 mL) and H2O (0.1 mL) at 0° C. After stirring for 2 h at 0° C. the reaction was quenched with sodium bicarbonate and extracted with EtOAc. The organic portion was washed with saturated aqueous sodium hydrogen sulfate and brine, then dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, 3:2 hex/EtOAc) to yield 23 mg (87%) of the hydroxyl-ester 105.
Reaction SMILES: C(O[C:4]([C:6]1[C:7](=[O:35])[N:8]([CH2:25][CH2:26][CH2:27][N:28]2[C:32](=[O:33])[CH2:31][CH2:30][C:29]2=[O:34])[C:9]2[C:14]([C:15]=1[OH:16])=[N:13][CH:12]=[C:11]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1)[CH:10]=2)=[O:5])C.[CH2:36]([CH2:38][NH2:39])[OH:37]>>[O:34]=[C:29]1[CH2:30][CH2:31][C:32](=[O:33])[N:28]1[CH2:27][CH2:26][CH2:25][N:8]1[C:9]2[C:14](=[N:13][CH:12]=[C:11]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:10]=2)[C:15]([OH:16])=[C:6]([C:4]([NH:39][CH2:38][CH2:36][OH:37])=[O:5])[C:7]1=[O:35]
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O
Reactant: NCCO
Product: O=C(NCCO)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCN2C(=O)CCC2=O)c1=O

Procedure:
This compound was prepared from ethyl1-[3-(2,5-dioxo-1-pyrrolidinyl)propyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and ethanolamine employing methods similar to those described in Example 202 and was obtained as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.36 (t, J=5.3 Hz, 1 H), 8.55 (d, J=1.2 Hz, 1 H), 7.34 (s, 1 H), 7.19 (dd, J=8.5, 5.4 Hz, 2 H), 7.04 (t, J=8.5 Hz, 2 H), 4.17-4.13 (m, 4 H), 3.85 (t, J=5.0 Hz, 2 H), 3.63 (m, 2 H), 3.56 (t, J=7.1 Hz, 2 H), 2.72 (s, 4 H), 1.92 (m, 2 H); HRMS C25H25FN4O6 (M+H)+ calcd 497.1758, found 497.1832.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]2[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:25][NH2:26]>CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH:11]=[C:10]([NH:26][CH2:25][C:24]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:22]([C:21]([F:20])([F:34])[F:35])[CH:23]=2)[C:9]2[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CC(C)OC(=O)N1CCCC(=O)c2c(F)cccc21
Agent: [Ti+4]
Agent: CC(C)[O-]
Product: CC(C)OC(=O)N1CCC=C(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2c(F)cccc21
Reaction time: 14 h
Yield: 77.4 %

Procedure:
Inject titanium isopropoxide (1.3 mL, 4.32 mmol) to a mixture of 6-fluor-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (572 mg, 2.16 mmol) and 3,5-bis(trifluoromethyl)benzylamine (972 mg, 3.2 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 14 h. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3-dihydro-benzo[b]azepine-1-carboxylic isopropyl ester (820 mg, 77%). Add methanol (9.3 mL) and platinum oxide (37 mg, 0.16 mmol) to 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3-dihydro-benzo[b]azepine-1-carboxylic isopropyl ester (742 mg, 1.5 mmol) and hydrogenate the mixture at 1 atmosphere and room temperature for 2 h. Filter through celite and remove the solvent under reduced pressure to afford 5-(3,5-Bis-trifluoromethyl-benzylamino)-6-fluoro-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (730 mg, quantitative). Add acetic anhydride (0.5 mL, 5.78 mmol) dropwise to a suspension of the amine (190 mg, 0.385 mmol) and pyridine (0.5 mL, 5.78 mmol) in dichloromethane (1.5 mL), stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (141 mg, 68%); MS (ES+): 535 (M+H).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:25])[CH2:23][N:24]=2)=[CH:15][CH:14]=1)(=[O:12])[CH3:11]>O1CCCC1>[C:10]([C:13]1[CH:14]=[CH:15][C:16]([C:19]2[O:20][CH:21]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([O:25][C:8](=[O:9])[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:23][N:24]=2)=[CH:17][CH:18]=1)(=[O:12])[CH3:11]
Reactant: O=C=Nc1ccccc1
Reactant: CC(=O)c1ccc(C2=NCC(O)C(c3ccccc3)O2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(C2=NCC(OC(=O)Nc3ccccc3)C(c3ccccc3)O2)cc1
Temperature: 50 °C
Yield: 67.7 %

Procedure:
Phenyl isocyanate (0.95 g) is added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of (5RS, 6SR)-2-(4-acetylphenyl)-6-phenyl-5,6-dihydro-4H-1,3-oxazin-5-ol (2 g) in tetrahydrofuran (25 cc). The solution obtained is heated to 50° C. for 5 hours and then concentrated to dryness under reduced pressure (2.7 kPa). After recrystallization in ethanol, (5RS, 6SR)-2-(4-acetylphenyl)-6-phenyl-5-phenylcarbamoyloxy-5,6-dihydro-4H-1,3-oxazine (1.9 g), m.p. 168° C., is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][NH:26]2.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:21][C:22]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][CH2:25][N:26]2[C:16](=[O:18])[CH2:15][C:3]1[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=1
Reactant: Fc1ccc2c(c1F)CCN2
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CCc3c2ccc(F)c3F)nc(N2CCOCC2)cc1=O
Yield: 39.7 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 287 mg of 4,5-difluoroindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 241 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 155 mg of 2-[2-(4,5-difluoro-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a brick-red coloured powder, the characteristics of which are the following:
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:41][C:42]1[C:43]([CH:49]=O)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1>CO>[CH3:41][C:42]1[C:43]([CH2:49][N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=3)=[O:32])=[CH:18][CH:19]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[N:44][CH:45]=[C:46]([CH3:48])[CH:47]=1
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc(C)cc3C)Cc3nccn3C)cc2)cc1
Yield: 88.1 %

Procedure:
The compound (155 mg) obtained in Example 15-5 was dissolved in anhydrous methanol (3.0 ml) and added with sodium cyanoborohydride (33.7 mg), acetic acid (0.50 ml), and the compound (58.0 mg) obtained in Example 15-6, and the whole was stirred at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, followed by stirring for a while. Then, the solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (174 mg) of the subject compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][NH:5][CH:6]=1.[CH2:11]=[O:12]>C(N(CC)CC)C.CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][N:5]([CH2:11][OH:12])[CH:6]=1
Reactant: C=O
Reactant: CC(C)(C)c1n[nH]cc1Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(C)(C)c1nn(CO)cc1Br
Temperature: 130 °C
Reaction time: 7 h
Yield: 105.2 %

Procedure:
The mixture of 3.14 g of 4-bromo-3-t-butyl-1H-pyrazole, 0.93 g of paraformaldehyde and 0.11 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 3.79 g of 4-bromo-3-t-butyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [C:1]1(=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:11][N:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: O=C1CCc2ccccc21
Reactant: CNc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CN(C1=CCc2ccccc21)c1ccccc1

Procedure:
Into a dry flask equipped with a Dean-Stark trap and a reflux condenser were placed 1-indanone (10.0 g, 75.7 mmol). N-methylaniline (15.1 g, 141 mmol) and toluene (200 mL). A catalytic amount of p-toluenesulfonic acid (0.1 g) was added and the mixture was refluxed under N2 for 96 hours. The reaction was cooled and the toluene was removed under reduced pressure before the remaining material was distilled under vacuum. The highest boiling fraction (6.8 g; bp 150-2° C./0.7 mm Hg) was collected as a yellow oil which solidified to a yellow-orange solid on standing. This material was stored in a glove box. Analysis by NMR indicated ca. 10 percent N-methylaniline in the product. However, further distillation on another sample of distilled enamine was not successful in lowering the amount of unwanted amine in the product.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:21])[N:5]([C:12]1([CH3:20])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19])[C:6]2=[O:11].[C:22](Cl)(=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].CO>C1COCC1>[CH3:20][C:12]1([N:5]2[C:4](=[O:21])[C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[NH:1][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:6]2=[O:11])[CH2:17][CH2:16][C:15](=[O:18])[NH:14][C:13]1=[O:19]
Reactant: CCCCCCC(=O)Cl
Reactant: CC1(N2C(=O)c3cccc(N)c3C2=O)CCC(=O)NC1=O
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCC(=O)Nc1cccc2c1C(=O)N(C1(C)CCC(=O)NC1=O)C2=O
Reaction time: 0.25 h
Yield: 71.5 %

Procedure:
To a suspension of 4-amino-2-(3-methyl-2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione (0.10 g, 0.35 mmol) in THF (15 ml) was added heptanoyl chloride (0.10 g, 0.70 mmol). The mixture was heated to reflux for 18 h. The reaction mixture was allowed to cool and to the solution was added methanol (2 ml). The reaction mixture was stirred for an additional 15 minutes followed by solvent evaporation in vacuo. The resulting solid was slurried in diethyl ether (20 ml) and filtered to give 0.10 g (74%) of product as an off-white solid: mp 172-174° C.; 1H NMR (DMSO-d6) 11.05 (s, 1H), 9.65 (s, 1H), 8.50 (d, J=8.3 Hz, 1H), 7.79 (t, J=7.6 Hz, 1H), 7.52 (d, J=7.2 Hz, 1H), 2.77-2.43 (m, 5H), 2.08-2.03 (m, 1H), 1.90 (s, 3H), 1.61 (t, J=6.4 Hz, 2H), 1.29 (bs, 6H), 0.87 (t, J=6.3 Hz, 3H); 13C NMR (DMSO-d6) 172.12, 172.02, 168.74, 167.36, 136.41, 135.90, 131.20, 125.70, 117.71, 116.31, 58.81, 36.51, 30.93, 29.07, 28.54, 28.12, 24.69, 21.94, 20.98, 13.86; Anal. Calcd. For C21H21N3O5: C, 62.83; H, 6.33; N, 10.47 Found: C, 62.45; H, 6.18; N, 10.24+0.50H2O.
Reaction SMILES: [NH2:1][CH:2]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)[OH:4].[CH:23]1([C:29](Cl)=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:2]([NH:1][C:29]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:30])[CH:3]([OH:4])[C:5]2[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][CH:6]=2)=[CH:21][CH:20]=1
Reactant: NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(F)cc1)C(O)c1ccc(C(F)(F)F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-3-(4-fluorophenyl)-1-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (15 ml) were added cyclohexanecarbonyl chloride (288 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (15 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. Recrystallization of the residue from ethyl acetate-hexane gave the title compound (550 mg, 90%).
Reaction SMILES: [OH:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:17]1[O:19][CH2:18]1)Cl.[OH-].[Na+].O>CS(C)=O>[O:19]1[CH2:18][CH:17]1[CH2:15][O:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cccc2[nH]c3ccccc3c12
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Temperature: 40 °C
Reaction time: 8 h

Procedure:
10.4 g of 4-hydroxy-carbazole (57 mmol) were dissolved in 31.1 ml of DMSO. 6.9 ml of epichlorohydrin (88 mol) were added and next 57 ml of a 1 N sodium hydroxide solution. The mixture was stirred for 8 h at 40° C. It was cooled to 20° C. and 130 ml of water were added. The product was filtered under suction, and washed with 3×30 ml water. The crude material was recrystallized from isopropanol. The substance was dried at 60° C. for 12 h.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[CH3:9][NH2:10]>CO.[Pd]>[CH3:9][NH:10][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: CN
Reactant: O=Cc1ccccn1
Agent: [Pd]
Solvent: CO
Product: CNCc1ccccn1
Reaction time: 2 h

Procedure:
A solution of 2-picolinaldehyde (107.11 g, 1 mol, a severe irritant) in 100 mL of methanol was added to 50 mL of methylamine, and the solution was shaken under N2 for 2 hours. Pre-wetted 10% Pd/C (2.5 g) in 20 mL MeOH was added to the first solution, and the mixture was shaken under 4 arm of H2 for 5 hours. The solution was filtered, the filter cake washed with methanol (2×100 mL), and the solution was filtered through a nylon membrane filter and concentrated in vacuo. Toluene was added, and the solution was concentrated in vacuo to afford 122 g of the title product as an orange oil; bp 80°-82° C.@8 mm Hg. NMR (CDCl3) δ:2.00 (bs,1H), 2.49 (s,3H), 3.88 (s,2H), 7.18 (m, 1H), 7.32 (d,1H), 7.65 (dt,1H), 8.56 (m, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].[N+:8]([C:11]1[C:12]([Cl:20])=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14][NH2:15])([O-:10])=[O:9]>C1COCC1>[N+:8]([C:11]1[C:12]([Cl:20])=[C:13]([CH:16]=[CH:17][C:18]=1[Cl:19])[CH2:14][NH:15][C:3](=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1])([O-:10])=[O:9]
Reactant: NCc1ccc(Cl)c([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c([N+](=O)[O-])c1Cl
Reaction time: 8 h

Procedure:
2,2-Dimethyl-propionic acid chloride (0.124 mL, 1.01 mmol) is added to a mixture of 3-nitro-2,4-dichloro-benzylamine (0.28 g, 1.01 mmol) and TEA (0.35 mL, 2.52 mmol) in THF (10 mL) and it is stirred overnight. The reaction mixture is concentrated, diluted with EtOAc, washed successively with 5% aq NaHCO3 solution and brine, dried with Na2SO4 filtered and concentrated.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([O:32]C)=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1.C1COCC1.Cl>CO>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][CH:11]([C:13]2[CH:14]=[C:15]([C:30]([OH:32])=[O:31])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)=[CH:19][C:18]3=[O:29])[CH3:12])[CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(C(C)Nc2cccc(Cl)c2F)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(Nc1cccc(Cl)c1F)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
Sodium hydroxide (0.217 mL, 0.43 mmol) was added to a stirred solution of methyl 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylate (200 mg, 0.43 mmol) dissolved in MeOH (2 mL). The resulting solution was stirred at room temperature for 16 hrs. THF was added and the resulting solution was stirred at 50° C. for 8 hrs. The pH was adjusted to 3 with HCl 2N, the solvent was removed under vacuum and the residue diluted with H2O. The solid was collected by filtration, washed with water and dried to give 8-(1-(3-chloro-2-fluorophenylamino)ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (171 mg, 88%) as a white solid. Mass Spectrum: M+H+ 447.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2.O[CH2:20]C1C=C2C(=CC=1)C=C(C(C)C(O)=O)C=C2.[H-].[Na+].CI.Cl>C1C=CC=CC=1>[CH3:20][O:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([CH3:18])[C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: CC(C(=O)O)c1ccc2cc(CO)ccc2c1
Reactant: COC(=O)C(C)c1ccc2cc(CO)ccc2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: c1ccccc1
Product: COCc1ccc2cc(C(C)C(=O)OC)ccc2c1
Reaction time: 2 h

Procedure:
To a mixture of 24.4 g. of methyl 6-hydroxymethyl-2-naphthyl-α -methylacetate (prepared from 6-hydroxymethyl-2-naphthyl-α -methylacetic acid by esterifying the latter by means of the procedure described in Part A of this example) and 500 ml. of benzene are added 2.4 g. of sodium hydride. The resulting mixture is stirred for two hours; then 12.2 g. of methyliodide are added. The resulting mixture is next neutralized by the addition of aqueous 1N hydrochloric acid after it has been allowed to stand for one hour; the mixture is then washed with water, dried over sodium sulfate, and evaporated to give methyl 6-methoxymethyl-2-naphthyl-α-methylacetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[O:17]=[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)[CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[CH:25]=1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC(Cc1cccc(C(F)(F)F)c1)C(=O)N1CCSC1
Product: O=C(NC(Cc1cccc(C(F)(F)F)c1)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3(3-trifluoromethyl-phenyl)-1-thiazolidin3yl-propan-1-one.