Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[NH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1)[OH:22].[C:33](O)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=1.ON1C2C=CC=CC=2N=N1.[ClH:52].C(O)C>CC(C)=O.C(OCC)C.C(OCC)(=O)C.O1CCCC1.C(N(CC)CC)C>[ClH:52].[C:23]1([CH:21]([OH:22])[CH2:20][O:19][CH2:18][CH2:17][NH:16][C:33](=[O:40])[C:34]2[CH:39]=[CH:38][CH:37]=[N:36][CH:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: NCCOCC(O)c1cccc2ccccc12
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: O=C(NCCOCC(O)c1cccc2ccccc12)c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.62 g of N,N'-dicyclohexylcarbodiimide was added to a mixture of 0.7 g of 2-(2-aminoethoxy)-1-(1-naphthyl)ethanol, 0.37 g of nicotinic acid, 0.41 g of 1-hydroxybenzotriazole, 0.42 ml of triethylamine and 4 ml of tetrahydrofuran with ice cooling. The resulting mixture was stirred at the same temperature for 5 minutes and further at room temperature for 1 hour. To the reaction mixture was added 6 ml of ethyl acetate. The insolubles were removed by filtration. To the filtrate were added 15 ml of ethyl acetate and 20 ml of water. The resulting mixture was adjusted to pH 2 with 6N hydrochloric acid. The aqueous layer was separated. The organic layer was extracted twice each with 10 ml of water. The extracts were combined with the previously separated aqueous layer. To the combined aqueous layer was added 30 ml of chloroform and the resulting mixture was adjusted to pH 10.5 with potassium carbonate. The organic layer was separated, washed with water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by column chromatography (eluant: chloroform/ethanol=10/1) to obtain an oily product. The oily product was dissolved in 7 ml of acetone. To the solution was added 0.43 ml of a 5N dry hydrogen chloride-ethanol solution. The resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 3 ml of diethyl ether. The resulting mixture was stirred at the same temperature for 1 hour. The resulting crystals were collected by filtration and dried to obtain 0.67 g of 1-(1-naphthyl)-2-(2-(nicotinoylamino)ethoxy]ethanol hydrochloride (compound no. 269).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](Cl)=[O:15].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:9][O:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8])=[O:15]
Reactant: COC(=O)CCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)CCC(=O)ON1C(=O)CCC1=O
Reaction time: 0.08 h

Procedure:
To a solution of 1-hydroxy-pyrrolidine-2,5-dione (1.23 mL, 10 mmol) in ethyl acetate (50 mL) was added 3-chlorocarbonyl-propionic acid methyl ester (1.15 g, 10 mmol). The mixture was cooled in an ice bath. Triethylamine (1.4 mL, 10 mmol) was added dropwise. The resulting suspension was stirred for 10 min in an ice bath and for 5 min without ice bath. The white solid was removed by filtration and washed with ethyl acetate (3×3 mL). The filtrate was concentrated to a white solid (2.32 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:5]=1[OH:25].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:7]=[CH:6][C:5]=1[O:25][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CCCCCCCCCCCCCCOc1ccc(O)c(C(=O)OC)c1
Reactant: BrCc1ccccc1
Product: CCCCCCCCCCCCCCOc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Yield: 82 %

Procedure:
The reaction of 2-(hydroxy-5-(tetradecyloxy)benzoic acid methyl ester with benzyl bromide under conditions described in Example 59 gave 2-(phenylmethoxy)-5-(tetradecyloxy)benzoic acid methyl ester (82% yield, mp 43°-46°).
Reaction SMILES: NC1[CH:3]=[C:4]([C:8]#[N:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].CI.[CH3:14][N:15]([CH:17]=O)[CH3:16]>>[C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:17]([N:15]([CH3:16])[CH3:14])[CH:3]=1)#[N:9]
Reactant: CN(C)C=O
Reactant: N#Cc1cncc(N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Product: CN(C)c1cncc(C#N)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 23 %

Procedure:
To a solution of 5-amino-3-cyanopyridine (0.50 g, 4.20 mmol) in DMF (5 ml) was added NaH (60% in oil) (0.37 g, 9.26 mmol) under ice-cooling, and the mixture was stirred for 20 minutes. Methyl iodide (0.58 ml, 9.31 mmol) in DMF (2 ml) was added dropwise under ice-cooling. The mixture was stirred for 2 hours while the temperature was raised up to room temperature. Ice was added to the reaction mixture, and the mixture was extracted with diethyl ether (30 ml×3). The diethyl ether layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (Wako Gel C-200, 20 g; eluted with chloroform:methanol=200:1) to give 3-cyano-5-dimethylaminopyridine (145 mg, yield 23%).
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:11]([F:27])=[C:12]([NH:17][C@H:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH3:19])[CH:13]=[CH:14][C:15]=3[NH2:16])[CH:5]=2)[CH2:3][CH2:2]1.[C:28](O)(=O)C.C(N)=N.C(=O)(O)[O-].[Na+].CCOC(C)=O>CCO>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([N:9]3[C:10]4[C:11]([F:27])=[C:12]([NH:17][C@H:18]([C:20]5[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=5)[CH3:19])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:28]3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1ccc(N)c(Nc2cc(C3CC3)[nH]n2)c1F)c1ccc(F)cc1
Reactant: CC(=O)O
Agent: N=CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H](Nc1ccc2ncn(-c3cc(C4CC4)[nH]n3)c2c1F)c1ccc(F)cc1
Yield: 32.9 %

Procedure:
A mixture of (S)-N3-(5-cyclopropyl-1H-pyrazol-3-yl)-2-fluoro-N1-[1-(4-fluorophenyl)ethyl]benzene-1,3,4-triamine (Method 71; 0.370 g, 1.00 mmol) and formamidine acetate (0.209 g, 2.00 mmol) in EtOH (10 ml) was heated at reflux for 1 hour. After cooling, the reaction mixture was treated with saturated sodium bicarbonate solution (5 ml) and EtOAc (15 ml). The organic layer was separated, washed with brine (3 ml), and dried over Na2SO4. The solvent was removed under reduced pressure and the residue was purified by column chromatography (hexane:EtOAc=1:1) to give the title compound as an off-white solid (0.125 g, 33%). NMR (400 MHz) 12.79 (s, 1H), 8.08 (s, 1H), 7.45 (m, 2H), 7.20 (d, J=8.4 Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 6.60 (t, J=8.2 Hz, 1H), 6.19 (s, 1H), 5.68 (d, J=7.2 Hz, 1H), 4.65 (m, 1H), 1.98 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.01 (m, 2H), 0.77 (m, 2H). MS: Calcd.: 379; Found: [M+H]+ 380.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([C:23](=[O:25])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1.C(O)C.[BH4-].[Na+]>>[F:26][C:2]([F:1])([F:27])[CH2:3][N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]([OH:25])[CH3:24])[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1
Reactant: CC(=O)c1ccc2c(c1)OCCc1sc(-c3ncnn3CC(F)(F)F)nc1-2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1ccc2c(c1)OCCc1sc(-c3ncnn3CC(F)(F)F)nc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 31.6 %

Procedure:
To a solution of 1-{2-[2-(2,2,2-Trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl}-ethanone (0.2357 g, 0.0005976 mol) in ethanol (2.5 mL, 0.043 mol) was added sodium tetrahydroborate (0.02713 g, 0.0007172 mol). The reaction was stirred at room temperature for 5 hours. The reaction was quenched with 2N HCl and diluted with water. Ethyl acetate was added and the aqueous layer was extracted 3× with ethyl acetate. The organic phases were combined, dried with MgSO4, and concentrated. The crude was purified by reverse-phase HPLC to give 292 (74.8 mg) as a white solid. MS(ESI+) 397.0. 1H NMR (400 MHz, DMSO) δ 8.28 (s, 1H), 8.25 (d, J=8.2, 1H), 7.16 (dd, J=8.2, 1.1, 1H), 7.05 (m, 1H), 5.85 (q, J=8.7, 2H), 5.19 (d, J=4.4, 1H), 4.79-4.63 (m, 1H), 4.36 (t, J=5.0, 2H), 3.45 (t, J=5.0, 2H), 1.34 (d, J=6.4, 3H)
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.Cl.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.Cl>C(O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:15]3[CH2:16][CH2:17][NH:12][CH2:13][C:14]=3[C:5]=2[CH:4]=1
Reactant: O=C1CCNCC1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: CCO
Product: Brc1ccc2[nH]c3c(c2c1)CNCC3
Temperature: 25 °C
Yield: 101.9 %

Procedure:
To a stirred solution of 4-bromophenylhydrazine hydrochloride (5.0 g, 22.36 mmol) in ethanol (100 mL), piperidin-4-one hydrochloride (1.316 g, 8.5984 mmol) was added and the mixture was heated to reflux. The reflux was maintained for 4 hours, then cooled to room temperature and dry hydrogen chloride gas was passed for 1 hour through the reaction mixture. The mixture was then again heated to reflux and maintained for 2 h. After completion of reaction, ethanol was distilled off under vacuum and the residue was dissolved in water. The aqueous layer was neutralized with 2N sodium hydroxide solution and was extracted in dichloromethane (2×100 mL). The pH of the aqueous layer was then adjusted to 12.0 with 2N sodium hydroxide solution and the product was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude solid was washed with diethyl ether (50 mL) to obtain 8-bromo-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2.2 g, 39.3%) with purity 98.82% by HPLC. 1HNMR (200 MHz, DMSO-d6) δ: 2.7 (t, 2H, CH2), 3.0 (t, 2H, CH2), 3.8 (d, 2H, CH2), 7.05 (d, 1H, Ar—H), 7.2 (d, 1H, Ar—H), 7.45 (s, 1H, Ar—H), 10.97 (bs, 1H, NH). m/e=251 (M++1).
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[CH:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]>CO>[C:1]([NH:4][C@@H:5]([C:13]([OH:15])=[O:14])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:28])[C@H:19]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:20]
Reactant: COC(=O)C(N)Cc1ccccc1
Agent: CC(=O)N[C@H](Cc1ccccc1)C(=O)O
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1

Procedure:
10.35 Parts of N-acetyl-D-phenylalanine is dissolved in 40 parts of methanol, then treated with 17.9 parts of DL-phenylalanine methyl ester. A precipitate forms immediately and an additional 60 parts of methanol is added. The mixture then is filtered and the solid remaining is washed with additional methanol and dried to yield the crude salt of N-acetyl-D-phenylalanine and L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([C:11]([OH:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O>CO>[O:6]=[C:4]1[C:3]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=[O:12])=[CH:10][C:2]=2[CH:1]=[CH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]1=2
Reactant: Cc1cc(C(=O)O)ccc1C(=O)O
Solvent: CO
Product: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
5-Oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared by esterifying 2-methylterephthalic acid with methanol, in the presence of acid catalyst, to afford the corresponding dimethyl ester which, in turn, is reacted with N-bromosuccinimide to afford 2-bromomethylterephthalic acid dimethyl ester. This diester is reacted with triphenylphosphine to afford 2,5-bis(carbomethoxy)benzyltriphenyl phosphonium bromide which is treated with benzaldehyde and a non-nucleophilic base, such as diazabicylononene, to afford, after alkaline hydrolysis, cis and trans stilbene 2,5-dicarboxylic acid. Hydrogenation of this latter compound with hydrogen over a 5% palladium on carbon catalyst affords 2-(2-phenethyl)terephthalic acid. Treatment with polyphosphoric acid yields 5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid which can be recrystallized from aqueous dimethylformamide. 5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared by successively treating 5-oxo-5 H-dibenzo[a,d]cycloheptane-2-carboxylic acid with diazomethane, N-bromosuccinimide, and dimethylformamide/diazabicyclononene, followed by base hydrolysis and acidification.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH2:4][CH3:5].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([F:24])[CH:18]=2)[CH2:11][CH2:10]1>O1CCCC1>[F:24][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C@H:12]2[CH2:13][CH2:14][Si@H:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:10][CH2:11]2)[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: Fc1ccc(CCC2CC[SiH](Cl)CC2)cc1F
Reactant: CCCCC[Mg]Cl
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](CCc2ccc(F)c(F)c2)CC1

Procedure:
60 ml of a THF solution of 2.0M n-pentylmagnesium chloride was dripped into a mixture of 27.5 g (100 mmol) of 1-chloro-4-(2-(3,4-difluorophenyl)ethyl)-1-silacyclohexane and 200 ml of tetrahydrofuran (hereafter referred to as "THF"). The silacyclohexane rings of the target product thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 21.1 g of the trans isomers (yield 68%), which was the target product. This compound was in a liquid form at temperatures down to -60° C.
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4]1.[CH:10](=[O:12])[CH3:11]>O.CCOCC>[O:3]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:11][CH:10]=[O:12])=[CH:4]1
Reactant: O=Cc1ccoc1
Reactant: CC=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=CC=Cc1ccoc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 40.9 %

Procedure:
To a solution of 2N NaOH (115 mL) was added 3-furaldehyde (4.5 mL, 52.0 mmol) dropwise. The solution was stirred until homogeneous (approximately five minutes) and then cooled to 0° C. and acetaldehyde (1.65 mL, 57.2 mmol) in 5 mL water was added. The reaction was stirred at 0° C. for 30 min and was then diluted with ether. The mixture was separated and the aqueous layer was extracted with ether (3×50 mL). The combined organic extract was washed with brine, dried over MgSO4, filtered and evaporated to yield 4.56 g of crude product. Chromatography (silica gel ,30% ether/hexanes) yielded 2.6 g (41%) of 3-(furan-3-yl)propenal.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:13]1[CH:14]=[CH:15][C:16]([CH3:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=1.[CH3:27]B(O)O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([CH3:27])=[C:3]([C:13]3[CH:14]=[CH:15][C:16]([CH3:26])=[C:17]([NH:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:18]=3)[N:4]=2)[N:7]=1
Reactant: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(Br)n2n1
Reactant: CB(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2nc(-c3ccc(C)c(NC(=O)C(C)(C)C)c3)c(C)n2n1
Temperature: 100 °C
Yield: 5.7 %

Procedure:
To a mixture of N-(5-(3-bromo-6-methoxyimidazo[1,2-b]pyridazin-2-yl)-2-methylphenyl)pivalamide (0.050 g, 0.119 mmol), methylboronic acid (0.357 mmol), tripotassium phosphate (0.714 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.0238 mmol) in toluene (4 mL) and water (0.4 mL) that has been degassed with N2 (5 minutes) is added Pd(OAc)2 (0.0119 mmol). The reaction mixture is heated at 100° C. for 14 hours, then cooled and concentrated to dryness. The crude product is purified via chromatography (hexanes to EtOAc) to afford 2.4 mg (6%) of the title compound as a white solid: Rf 0.64 (EtOAc); LCMS (m/z)=353.4 [M+H]+, tR=2.15 min. (compound same as Example 121)
Reaction SMILES: C([O:3][C:4](=[O:21])[CH:5]([C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:6][CH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1)C.[OH-].[Li+]>O1CCCC1.O>[CH:7]1([CH2:6][CH:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[C:4]([OH:21])=[O:3])[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CCOC(=O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C(CC1CCCC1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 94.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid ethyl ester (14.1 g, 48.06 mmol) in tetrahydrofuran/water (300 mL, 3:1) was treated with lithium hydroxide (4.35 g, 103.67 mmol). The reaction was stirred at 25° C. for 21 h. The tetrahydrofuran was then removed in vacuo. The residue was diluted with water (75 mL) and extracted with ether (3×75 mL). The aqueous layer was acidified to pH=1 with a 3 N aqueous hydrochloric acid solution. The product was extracted into methylene chloride (3×75 mL), washed with a saturated aqueous sodium chloride solution (2×100 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo to give 3-cyclopentyl-2-(4-nitro-phenyl)-propionic acid (11.97 g, 93.6%) as a yellow solid: mp 119-125° C.; EI-HRMS m/e calcd for C14H17NO4 (M+) 263.1157, found 263.1162.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[CH:17]=[CH:16]4)[C@H:13]([CH3:28])[CH2:12][C:11]=2[CH:10]=1>CS(C)=O>[CH3:7][O:8][C:9]1[CH:26]=[CH:25][C:24]2[C@@H:23]3[C@H:14]([C@@H:15]4[C@@:19]([CH2:21][CH2:22]3)([CH3:20])[C:18](=[O:27])[C@H:17]3[CH2:2][C@@H:16]43)[C@H:13]([CH3:28])[CH2:12][C:11]=2[CH:10]=1
Reactant: C[S+](C)(C)=O
Reactant: COc1ccc2c(c1)C[C@@H](C)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@H]12
Agent: [I-]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)C[C@@H](C)[C@H]1[C@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@H]21
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 131.8 %

Procedure:
—Sodium hydride (60% suspension in mineral oil, 1.15 g) was added to a suspension of trimethylsulfoxonium iodide (5.57 g) in dry dimethyl sulfoxide (115 ml) and the mixture was stirred at room temperature for 20 min. (7α,14β)-3-Methoxy-7-methylestra-1,3,5(10),15-tetraen-17-one (Example 7, step iv; 1.92 g) was added and stirring was continued for 1.5 h. The reaction mixture was poured into ice-water and the product was extracted into ethyl acetate. The combined organic phases were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure, to give (7α,14β,15β,16β)-3-methoxy-7-methyl-15,16-methyleneestra-1,3,5(10)-trien-17-one (2.65 g). The product was used in the following step without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[S:6]1)=O.[NH3:15]>CO>[C:3]([CH:5]1[CH2:10][NH:9][C:8]2[CH:11]=[CH:12][CH:13]=[CH:14][C:7]=2[S:6]1)(=[O:2])[NH2:15]
Reactant: COC(=O)C1CNc2ccccc2S1
Reactant: N
Solvent: CO
Product: NC(=O)C1CNc2ccccc2S1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
580 mg of 2(R,S)-methoxycarbonyl-3,4-dihydro-2H-1,4-benzothiazine are dissolved in 3 ml of a 6N ammonia solution in methanol and the solution is stirred at 50° C. for 16 h. Purification by chromatography over 50 g of silica gel gives 2(R,S)-carbamoyl-3,4-dihydro-2H-1,4-benzothiazine: Rf (Y)=0.19.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.OB(O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14]([C:15]2[CH:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:18]=[CH:17][C:16]=2[OH:22])=[O:23])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OB(O)c1ccccc1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-c2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61 %

Procedure:
N-[3,5-Bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide (200 mg, 0.42 mmol) was dissolved in 1,2-dimethoxyethane (3 mL). Tetrakis(triphenylphosphine)palladium(16 mg, 0.0014 mmol) was added under argon atmosphere, and the mixture was stirred at room temperature for 5 minutes. Then dihydroxyphenylborane (57 mg, 0.47 mmol) and 1M sodium carbonate (1.3 mL) were added and refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the ethyl acetate layer was washed with water and brine one after another, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=6:1→3:1) to give the title compound (109 mg, 61.1%) as a white crystal.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH3:21])=[N:10][C:11]=2[NH2:17].F[C:24](F)(F)[C:25](O)=O.COC1N=C2C(N=1)=C(N)NC(O[C@@H](C)CCCC)=N2.BrCCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:14]([O:15][CH3:16])=[N:13][C:12]2[C:7]1=[N:8][C:9]([O:18][C@@H:19]([CH3:22])[CH2:20][CH2:21][CH2:24][CH3:25])=[N:10][C:11]=2[NH2:17]
Reactant: O=C(O)C(F)(F)F
Reactant: CC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1
Agent: CCCC[C@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Agent: ClCCCCBr
Product: CCCC[C@H](C)Oc1nc(N)c2nc(OC)n(CCCCCl)c2n1

Procedure:
Prepared similarly to Intermediate 44 from 8-(methyloxy)-2-{[(1S)-1-methylpentyl]oxy}-1H-purin-6-amine trifluoroacetate and 1-bromo-4-chlorobutane.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:11]=1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)=[O:22]>>[CH2:1]([O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[N:12][C:11]=1[C:26]1[CH:27]=[CH:28][C:23]([C:21]([O:20][CH3:19])=[O:22])=[CH:24][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)OCc2ccccc2)c(Cl)n1
Reactant: COC(=O)c1ccc(B(O)O)cc1
Product: COC(=O)c1ccc(-c2nc(C)ccc2C(=O)OCc2ccccc2)cc1
Yield: 81.8 %

Procedure:
2-Chloro-6-methylnicotinic acid benzyl ester (1.0 g) and 4-methoxycarbonylphenylboronic acid (722 mg) were treated in a similar manner to Step b) of Reference Example 1 to give the title compound (1.13 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[H][H]>CO.O=[Pt]=O>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: [H][H]
Reactant: NC(=O)c1cccc2nc(-c3ccc(-c4ccccn4)cc3F)oc12
Agent: O=[Pt]=O
Solvent: CO
Product: NC(=O)c1cccc2nc(-c3ccc(C4CCCCN4)cc3F)oc12
Yield: 61.1 %

Procedure:
2-(2-Fluoro-4-(pyridin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (380 mg, 1.1 mmol) and PtO2 (190 mg) in methanol (20 ml) was hydrogenated under 25 atm of hydrogen at 45° C. for two days. The mixture was filtered. The solvent was removed in vacuum. The crude product was purified by prep-HPLC to give 2-(2-fluoro-4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (228 mg, yield 44%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.76-1.90 (m, 2H), 1.96-2.06 (m, 3H), 2.13-2.16 (m, 1H), 3.19-3.25 (m, 1H), 3.52-3.55 (d, J=12.4 Hz, 1H); 4.37-4.40 (d, J=11.2 Hz, 1H); 7.27-7.40 (m, 1H); 7.49-7.53 (m, 3H); 7.92-7.93 (m, 2H); 8.35-8.39 (t, J=7.2 Hz, 3H); LC-MS (ESI) m/z: 340 (M+1)+.