Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[O:4][CH2:3]1.C(O)(=O)C.[CH2:26]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47](=O)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:38][CH2:37]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>C(O)C>[CH2:26]([O:33][C:34]([N:36]1[CH2:37][CH2:38][CH:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C@@H:47]([NH:1][C@@H:2]2[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C:6]3[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=3[O:4][CH2:3]2)[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH2:40][CH2:41]1)=[O:35])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)COc2ccccc21
Reactant: CCOC(=O)C(=O)CCCCCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)[C@@H](CCCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@H]1COc2ccccc2N(CC(=O)OC(C)(C)C)C1=O
Reaction time: 0.17 h

Procedure:
A mixture of tert-butyl 3(S)-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine-5-acetate (2.4 l g), ethanol (30 ml), acetic acid (0.5 g), ethyl 7-(1-benzyloxycarbonyl-4-piperidyl)-2-oxoheptanoate (3.2 g) and molecular sieves 3A (10 g) is stirred for 10 minutes. To the stirred mixture is added dropwise a solution of sodium cyanoborohydride (0.51 g) in ethanol (50 ml) for 3 hours at room temperature. After standing overnight at room temperature, the mixture is concentrated in vacuo and diluted with a mixture of water (50 ml) and ethyl acetate (200 ml). The resulting mixture is agitated thoroughly and filtered. The ethyl acetate layer is washed successively with 0.1N hydrochloric acid, 0.1N sodium hydroxide solution and water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is chromatographed on silica gel using hexane-ethyl acetate (2:1) as an eluent. Evaporation of the first fraction affords tert-butyl 3(S)-[6-(1-benzyloxycarbonyl-4-piperidyl)-1(R)-ethoxycarbonylhexyl]amino-4-oxo-2,3,4,5 -tetrahydro-1,5-benzoxazepine-5-acetate (0.35 g) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9][C:8]=2[CH:15]=1)([O-:3])=[O:2].C(Cl)Cl.C(O)(=O)C.[F:23][CH:24]([F:27])[CH2:25][NH2:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[F:23][CH:24]([F:27])[CH2:25][NH:26][CH:11]1[CH2:10][CH2:9][C:8]2[CH:15]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: NCC(F)F
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(NCC(F)F)CC2
Reaction time: 0.08 h

Procedure:
Charge 2-Nitro-5,6,8,9-tetrahydrobenzocyclohepten-7-one (750.00 mg, 3.6548 mmol) to Methylene chloride (20 mL, 300 mmol) and Acetic acid (200 uL, 4 mmol). Allow to stir for 5 min. Charge 2,2-difluorethylamine (0.292 ml, 3.65 mmol) and sodium triacetoxyborohydride (1.55 g, 7.31 mmol). Allow suspension to stir for 2.5 hours. LC at 2.5 hours conforms that starting ketone has been consumed. Pour reaction into 200 ml water and 100 ml saturated sodium bicarbonate solution and extract with 2×100 ml portions of methylene chloride. The combined organic was dried over magnesium sulfate, filtered and evaporated to a yellow oil (approximately 1.0 g). The resulting crude yellow oil was chromatographed on a 12 g Isco cartridge using a gradient of 0-60% EtOAc in hexanes as the eluent. (2,2-Difluoro-ethyl)-(2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-amine was isolated as a beige oil (625 mg, 63% yield). 1H-NMR (CDCl3) δ 7.98 (m, 2H), 7.24 (m, 1H), 5.82 (m, 1H), 3.02 (m, 4H), 2.88 (m, 1H), 2.76 (m, 2H), 2.08 (m, 2H), 1.38 (m, 2H). LC/MS (ESI+): 271 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[N:11]2[CH2:15][C@H:16]([OH:18])[CH2:17][C@H:10]2[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:15][C@H:16]([OH:18])[CH2:17][C@H:10]2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1[C@@H]2C[C@@H](O)CN2C(=O)CN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@@H]1C[C@H]2CN(Cc3ccccc3)CCN2C1
Temperature: 65 °C
Reaction time: 78 h

Procedure:
To a suspension of Example 54C (60 g, 0.23 mol, 1 equivalent) in tetrahydrofuran (900 mL), lithium aluminum hydride (2 M in tetrahydrofuran, 460 mL, 0.92 mol, 4 equivalents) was added slowly at about 15° C. Then, the mixture was stirred at about 65° C. for 78 hours. The reaction mixture was cooled to 0-5° C., quenched using ethyl acetate (300 mL), water (60 mL), 10% NaOH solution (60 mL), followed by water (60 mL), and the mixture was stirred at 20-25° C. for 30 minutes. The suspension was filtered through diatomaceous earth, and the filtrate was concentrated. This crude material was purified by column chromatography on silica gel using a gradient of methanol-ethyl acetate to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.46-1.49 (m, 2H), 1.68, (t, 1H, J=9.9 Hz), 1.91 (dd, 1H, J=5.4 Hz, J=8.9 Hz), 2.04-2.13 (m, 1H), 2.15-2.49 (m, 2H), 2.67 (d, 1H, J=10.3 Hz), 2.78 (d, 2H, J=5.4 Hz), 3.25 (dd, 1H, J=4.5 Hz, J=8.9 Hz), 3.47 (dd, 2H, J=4.5 Hz, J=17.4 Hz), 4.15-4.22 (m, 1H), 4.73 (bs, 1H), 7.23-7.318 (m, 5H); 13C NMR (75 MHz, DMSO-d6) δ ppm 39.74, 51.34, 52.64, 57.61, 60.72, 62.56, 63.16, 68.46, 127.26, 128.54, 129.2, 138.84; MS (ESI) m/z 233 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:10][CH3:11])=[CH:15][CH:14]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)ccc1OCc1ccc(Cl)cc1
Yield: 92.6 %

Procedure:
To 4-hydroxy-3-methoxybenzaldehyde (21, 600.0 mg, 3.94 mmol) and 4-chlorobenzyl bromide (22, 1.20 g, 5.84 mmol) in acetonitrile (6 mL) was added potassium carbonate (0.390 g, 2.82 mmol). The reaction was microwaved on 300 watts, 120° C. for 10 minutes. The reaction was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the volatiles removed by evaporation. The desired compound was purified by recrystallization from hexanes to provide 23 (1.01 g, 93%). MS (ESI) [M−H+]−=275.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[O:7][C:6]([C:13]([OH:15])=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH2:22]([O:26][NH2:27])[CH2:23][CH2:24][CH3:25]>C(O)C>[CH2:22]([O:26][N:27]1[C:6]([C:13]([OH:15])=[O:14])=[C:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=2)[C:8]1=[O:7])[CH2:23][CH2:24][CH3:25]
Reactant: CCCCON
Reactant: O=C(O)c1oc(=O)c2ccc(Cl)cc2c1-c1ccccc1
Solvent: CCO
Product: CCCCOn1c(C(=O)O)c(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reaction time: 12 h

Procedure:
A mixture of 6-chloro-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid (210 mg), O-n-butylhydroxylamine (620 mg) and ethanol (8.4 ml) was stirred for 12 hrs. at 90° C. in a sealed tube. After cooling, the reaction mixture was concentrated under reduced pressure to give 2-butoxy-6-chloro-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[N:18]1([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:1]1([CH2:4][NH:5][C:6]([NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:21]3[CH2:22][CH2:23][CH2:24][N:18]([CH2:25][C:26]4[CH:27]=[CH:28][C:29]([C:32]([OH:41])([C:37]([F:38])([F:39])[F:40])[C:33]([F:36])([F:34])[F:35])=[CH:30][CH:31]=4)[CH2:19][CH2:20]3)=[O:14])=[CH:15][CH:16]=2)=[O:17])[CH2:2][CH2:3]1
Reactant: OC(c1ccc(CN2CCCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCC1CC1)Nc1ccc(C(=O)N2CCCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 24 h
Yield: 63.8 %

Procedure:
To a mixture of 4-(3-(cyclopropylmethyl)ureido)benzoic acid (2.134 mmol, 0.5 g), 2-(4-((1,4-diazepan-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (2.134 mmol, 0.761 g) and triethylamine (5.34 mmol, 0.744 mL, 0.540 g) in dichloromethane (30 mL) was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.56 mmol, 0.491 g). The reaction was stirred for 24 hours then was chromatographed on silica eluting with dichloromethane to dichloromethane/methanol (6%) then re-chromatographed on silica eluting with ethyl acetate to ethyl acetate/methanol (2%) to give the title compound (780 mg). MS (ESI) m/z 573.0 [M+H]+
Reaction SMILES: [Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=1>CN1C(=O)CCC1.O>[Br:1][C:2]1[C:3]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][N:18]=3)=[CH:11][CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(F)nc1
Reactant: Nc1ccc(Oc2ncccc2Br)cc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc(Nc2ccc(Oc3ncccc3Br)cc2)nc1
Temperature: 170 °C

Procedure:
To a pressure vessel was added 4-(3-bromopyridin-2-yloxy)aniline (7.23 g, 27.3 mmol) and 2-fluoro-5-methylpyridine (3.03 mL, 27.2 mmol) in NMP (13.61 mL) to stir at 170° C. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with water, sat NaCl, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide N-(4-(3-bromopyridin-2-yloxy)phenyl)-5-methylpyridin-2-amine.
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[O-].[Na+].[CH3:24][C:25](C)=O>>[C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:24][CH3:25]
Reactant: CC(C)=O
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Agent: C[O-]
Agent: [Na+]
Product: CCCCCCCCCCCCCCCCCCCC(=O)O
Yield: 29 %

Procedure:
High-oleic sunflower oil having 86% of oleic acid content relative to the constituent fatty acid and fully hydrogenated rapeseed oil were mixed and the mixture was subjected to random interesterification using sodium methylate to obtain a reaction oil. The reaction oil was subjected to solvent fractionation with acetone to remove high melting point fraction and low melting point fraction, and to obtain mid fraction at a yield of 29%. The obtained mid fraction was purified by conventional methods to obtain StStO fat (StOSt=22.4%, StLSt=2.5%, StOO=1.6%, arachidic acid content=0.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[S:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=2)[CH:3]=1.[CH3:16][NH:17][C:18]([N:20]1[CH2:24][CH2:23][CH:22]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:21]1)=[O:19].CCN(C(C)C)C(C)C>C(O)CCC>[C:14]([C:11]1[S:10][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([N:28]3[CH2:29][CH2:30][N:25]([CH:22]4[CH2:23][CH2:24][N:20]([C:18]([NH:17][CH3:16])=[O:19])[CH2:21]4)[CH2:26][CH2:27]3)[CH:3]=2)=[N:13][CH:12]=1)#[N:15]
Reactant: N#Cc1cnc(Nc2cc(Cl)ncn2)s1
Reactant: CNC(=O)N1CCC(N2CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CNC(=O)N1CCC(N2CCN(c3cc(Nc4ncc(C#N)s4)ncn3)CC2)C1

Procedure:
35-1 (0.106 g, 0.45 mmol), 45-5 (0.095 g, 0.45 mmol) and DIEA (0.18 g, 1.79 mmol) were heated at 150° C. for 3 hours in n-butanol. Upon cooling the precipitate was filtered off, washed with n-butanol and ethyl ether and then dried to afford 45-6. Hi-Res MS: calc: 414.1819 found: 414.1827. 1H-NMR (DMSO-d6): 12.08(s, 1H); 8.42(s, 1H); 8.26(s, 1H); 6.22(s, 1H); 6.02(d, 1H); 3.55(m, 4H); 3.38 (m, 1H); 3.13(m, 1H); 2.97(m, 1H); 2.78(m, 1H); 2.50(complex, 6H); 2.45(m, 2H); 2.06(m, 1H); 1.69(m, 1H).
Reaction SMILES: [CH2:1]([CH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][C:11]1=O)[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=O.[NH2:20][C:21]1[CH:29]=[C:25]([C:26]([OH:28])=[O:27])[C:24]([OH:30])=[CH:23][CH:22]=1>C(O)(=O)C>[C:26]([C:25]1[CH:29]=[C:21]([N:20]2[C:2]([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:1][C:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH2:12][C:11]2=3)[CH:22]=[CH:23][C:24]=1[OH:30])([OH:28])=[O:27]
Reactant: O=C(CC1C(=O)Cc2ccccc21)c1ccccc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Solvent: CC(=O)O
Product: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2Cc2ccccc2-3)ccc1O

Procedure:
A mixture of 4.0 g. (0.016 mole) of 1-phenacyl-2-indanone, 2.45 g. (0.016 mole) of 5-aminosalicylic acid and 10 ml. of glacial acetic acid was heated under reflux under nitrogen for 2 hours, cooled and filtered. The collected solid was washed with petroleum ether and recrystallized from acetic acid to provide 4.6 g. (78%) of yellow crystals, m.p. 201°-205°.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[C:4]([CH3:11])[CH:3]=1.[Br:12]Br>C(O)(=O)C.O>[Br:12][C:3]1[C:4]([CH3:11])=[N:5][CH:6]=[C:7]([C:2]=1[OH:1])[C:8]([OH:10])=[O:9]
Reactant: BrBr
Reactant: Cc1cc(O)c(C(=O)O)cn1
Solvent: CC(=O)O
Solvent: O
Product: Cc1ncc(C(=O)O)c(O)c1Br
Temperature: 60 °C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
4-Hydroxy-6-methylnicotinic acid 19 (95.6 g, 0.625 mol) was dissolved in acetic acid (950 ml) and water (190 ml), and bromine (39 ml, 0.750 mol) was added over 15 minutes. After the solution was stirred at 60° C. for 5 hours, the solvent was distilled off under reduced pressure, methanol (200 ml) was added and, crystals were collected by filtration. The solution was distilled off under reduced pressure, methanol was added again to the residue, and crystalls were collected by filtration. A total of 142.2 g (98%) of 5-bromo-4-hydroxy-6-methylnicotinic acid 20 was obtained as a colorless crystal.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5](Cl)(=[O:7])=[O:6].ClCCl.[CH2:12]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(N(CC)CC)C>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([N:19]([CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:30](=[O:35])[CH:29]=[CH:28]2)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:7])=[O:6]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: O=c1ccc2cc(OCCCCNCc3ccccc3)ccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ccc2cc(OCCCCN(Cc3ccccc3)S(=O)(=O)CCCCl)ccc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
6.6 ml of 3-chloropropanesulfonyl chloride was dropwise added, at 0° C., to a dichloromethane solution containing 8 g of 6-(4-benzylaminobutoxy)carbostyril and 7.6 ml of triethylamine. The mixture was stirred at room temperature for 1 day. The reaction mixture was washed with 10% hydrochloric acid and water in this order and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was dissolved in 30 ml of dioxane. To the solution was added 10.ml of a 10% potassium hydroxide solution, followed by stirring at room temperature for 30 minutes. The reaction mixture was neutralized with 10% hydrochloric acid, followed by extraction with chloroform. The extract was dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from diethyl ether to obtain 7.3 g of 6-{4-[N-(3-chloro-propylsulfonyl)-N-benzylamino]butoxy}carbostyril.
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:16][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=2)[CH:3]([OH:2])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 4-fluorobenzoyl chloride (70 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (152 mg, 83%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5](Br)=[CH:6][N:7]=1.[CH3:13][N:14]([CH3:26])[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O.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>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:20]2[CH:21]=[CH:22][C:17]([C:15](=[O:16])[N:14]([CH3:13])[CH3:26])=[CH:18][CH:19]=2)=[CH:6][N:7]=1
Reactant: COC(=O)c1nc(Br)cnc1N
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1nc(-c2ccc(C(=O)N(C)C)cc2)cnc1N
Temperature: 110 °C

Procedure:
Methyl 3-amino-6-bromo-pyrazine-2-carboxylate (6.012 g, 25.91 mmol), [4-(dimethylcarbamoyl)phenyl]boronic acid (5 g, 25.91 mmol), sodium carbonate (5.492 g, 51.82 mmol) and Pd(PPh3)4 (2.994 g, 2.591 mmol) in a mixture of acetonitrile (28.85 mL) and water (28.85 mL) was heated at 110° C. The reaction mixture was allowed to cool and the residual solid filtered off. The filtrate was diluted with EtOAc and water and the layers separated. The aqueous layer was acidified to pH4 (by addition of 1M HCl) and then extracted with dichloromethane (3×), dried (MgSO4), filtered and concentrated in vacuo to leave the product as a yellow solid. The ethyl acetate extracts were concentrated in vacuo and combined with the filtered solid. Preabsorbed onto silica and purified by column chromatography on silica using the companion eluting with ethyl acetate/petroleum ether (0-100% EtOAc). Product eluted with 100% EtOAc. Product fractions combined and conc in vacuo to leave a yellow solid (1.95 g, 50% Yield). 1H NMR (400.0 MHz, DMSO) d 3.02 (3H, s), 3.15 (3H, s), 4.04 (3H, s), 7.54 (2H, m), 7.97 (2H, m), 8.71 (1H, s) ppm; MS (ES+) 301.13
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][N:8](CC2C=CC=CC=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[H][H]>C(O)C.O.[Pd]>[C:1]([O:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OC1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: CC(=O)OC1CCNCC1
Yield: 92 %

Procedure:
10% Pd/C (500 mg) was added to a solution of 1-benzylpiperidin-4-yl acetate [(11 g, 47 mmol), J. Org. Chem. 68(2), 613-616; 2003] in a mixture of ethanol and water (90:10, 110 mL), and the mixture was stirred at 60° C., under 60 psi of hydrogen gas for 18 hours. The reaction mixture was then filtered through Arbocel®, washing through with ethanol, and the filtrate was concentrated in vacuo to afford the title product in 92% yield, 7.2 g.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]([OH:15])=[O:14])[N:10]=[N:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH2:22][OH:23]>>[OH:23][CH2:22][CH2:21][O:14][C:13](=[O:15])[CH2:12][N:11]1[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]=[N:10]1
Reactant: O=C(O)Cn1nnnc1-c1ccccc1
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: O=C(Cn1nnnc1-c1ccccc1)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 51.8 %

Procedure:
To a solution of 1 g (4.85 mM) of (5-phenyltetrazol-1-yl) acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=9/1) for separation and purification, to give 630 mg (yield 51.8%) of (5-phenyltetrazol-1-yl) acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [CH3:1][C:2]1[C:6]([I:7])=[C:5]([CH3:8])[NH:4][N:3]=1.[H-].[Na+].CC1C=CC(S(O[CH:22]2[CH2:31][CH2:30][C:25]3([O:29][CH2:28][CH2:27][O:26]3)[CH2:24][CH2:23]2)(=O)=O)=CC=1>CN(C=O)C>[O:26]1[C:25]2([CH2:30][CH2:31][CH:22]([N:3]3[C:2]([CH3:1])=[C:6]([I:7])[C:5]([CH3:8])=[N:4]3)[CH2:23][CH2:24]2)[O:29][CH2:28][CH2:27]1
Reactant: Cc1ccc(S(=O)(=O)OC2CCC3(CC2)OCCO3)cc1
Reactant: Cc1n[nH]c(C)c1I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(C2CCC3(CC2)OCCO3)c(C)c1I
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 3,5-dimethyl-4-iodopyrazole (400.0 mg, 1.802 mmol) in DMF (7 mL, 100 mmol) was added sodium hydride (56.20 mg, 2.342 mmol), and the mixture was stirred at rt for 10 min. A solution of 1,4-dioxaspiro[4.5]dec-8-yl 4-methylbenzenesulfonate (619.1 mg, 1.982 mmol), prepared according to U.S. Pat. No. 4,360,531 example 1.B, in DMF was added, and the mixture was heated to 50° C. overnight. The material was extracted with EtOAc, and washed with water (3×). The organic layer was dry-loaded onto silica gel for column chromatography, eluting with 20-30% EtOAc/hexanes. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a clear oil. 1H NMR (400 MHz, DMSO-d6): δ=1.61-1.80 (m, 6H), 1.94-2.06 (m, 2H), 2.08 (s, 3H), 2.25 (s, 3H), 3.82-3.93 (m, 4H), 4.23 (tt, J=11.5, 3.7 Hz, 1H). MS (ES+): m/z=364.07 (100) [MH+]. HPLC: tR=1.51 min (polar—3 min, UPLC-ACQUITY).