Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[C:19]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[C:1]([O:5][C:6]([N:8]([CH2:31][C@H:32]([OH:39])[C:33]1[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[C:19]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Cc1cc(-c2ccc(CCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
To a solution of methyl 4′-[2-[[tert-butoxycarbonyl]-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]ethyl]-3-isobutyl-4-biphenylcarboxylate (390 mg) in methanol (3.90 ml) and tetrahydrofuran (1.56 ml) was added 1N aqueous sodium hydroxide solution (2.20 ml) and the mixture was stirred at room temperature for 2 days. Methanol and tetrahydrofuran were removed by evaporation under reduced pressure and to the mixture was added ethyl acetate (20 ml). The pH was adjusted to 4.3 with 1N hydrochloric acid and the organic layer was separated, washed with water (20 ml) and brine (20 ml) and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/2) to give 4′-[2-[[tert-butoxycarbonyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]-ethyl]-3-isobutyl-4-biphenylcarboxylic acid (291 mg) as a white solid (foam).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[CH2:13]([OH:18])[CH:14]([OH:17])[CH2:15]Cl>>[OH:17][CH:14]([CH2:13][OH:18])[CH2:15][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2
Reactant: OCC(O)CCl
Reactant: O=C1CCc2cc(O)ccc2N1
Product: O=C1CCc2cc(OCC(O)CO)ccc2N1

Procedure:
In the same manner as described in Example 7, 6-hydroxy-3,4-dihydrocarbostyril was reacted with gylcerol α-monochlorohydrin to give 6-(2,3-dihydroxy)propoxy-3,4-dihydrocarbostyril as white needle-like crystals having a melting point of 190° - 192° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:11].[H-].[Na+].Br[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH:28]([CH3:33])[C:29]([F:32])([F:31])[F:30])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[F:30][C:29]([F:31])([F:32])[CH:28]([CH3:33])[CH:22]([C:19]1[CH:18]=[CH:17][C:16]([CH2:15][N:5]2[CH2:4][C:3]3[C:7](=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])[C:6]2=[O:11])=[CH:21][CH:20]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C1NCc2c(F)cccc21
Reactant: CCOC(=O)C(c1ccc(CBr)cc1)C(C)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(c1ccc(CN2Cc3c(F)cccc3C2=O)cc1)C(C)C(F)(F)F
Reaction time: 0.5 h

Procedure:
At 0° C., 645 mg (4.27 mmol) of 4-fluoro-2,3-dihydro-1H-isoindol-1-one were added to 170.7 mg (4.27 mmol, 60% pure) of sodium hydride in 4 ml of DMF. The mixture was stirred for 30 min, and 2.11 g (5.98 mmol) of ethyl 2-[4-(bromomethyl)phenyl]-4,4,4-trifluoro-3-methylbutanoate were then added at 0° C. The reaction mixture was stirred for a further 2 h, and water and ethyl acetate were then added. The organic phase was washed with saturated sodium chloride solution and dried over magnesium sulfate. The crude product was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 40:1 to 3:1). This gave 856 mg (33.9% of theory) of the target compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[N:19][C:20]([N+:23]([O-])=O)=[CH:21][CH:22]=3)[CH:13]=[C:12]([CH3:26])[CH:11]=2)=[O:8])=[CH:5][C:4]([CH3:27])=[N:3]1>[C].[Pd].CO>[NH2:23][C:20]1[N:19]=[CH:18][C:17]([O:16][C:14]2[CH:15]=[C:10]([NH:9][C:7]([C:6]3[N:2]([CH3:1])[N:3]=[C:4]([CH3:27])[CH:5]=3)=[O:8])[CH:11]=[C:12]([CH3:26])[CH:13]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc([N+](=O)[O-])nc2)c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(NC(=O)c2cc(C)nn2C)cc(Oc2ccc(N)nc2)c1
Yield: 107.1 %

Procedure:
In the same manner as in Reference Example 13 and using 1,3-dimethyl-N-{3-methyl-5-[(6-nitropyridin-3-yl)oxy]phenyl}-1H-pyrazole-5-carboxamide (7.63 g, 17.3 mmol), palladium carbon (50% water-containing product, 1.88 g) and methanol (50 mL) as starting materials, the title compound (6.25 g, 88%) was obtained as a pale-yellow oil.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.FC(F)(F)C(O)=O.[CH3:35][O:36][CH2:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(N(CC)C(C)C)(C)C>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:41]3[CH2:42][CH2:43][CH:38]([CH2:37][O:36][CH3:35])[CH2:39][CH2:40]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[N:14][CH:15]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: COCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(Cl)Cl
Product: COCC1CCN(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)CC1

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-methoxymethyl-piperidine trifluoroacetate and N,N-diisopropylethylamine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=O)[NH:5][C@H:4]([CH2:8]O)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].C(N(CC)CC)C.[CH2:26]([O:33]C(Cl)=O)[C:27]1C=CC=C[CH:28]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(Cl)Cl>[CH3:1][C:2]1([CH3:10])[CH2:6][N:5]2[C@H:4]([CH2:8][C:26](=[O:33])[CH2:27][CH2:28]2)[CH2:3]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC1(C)C[C@@H](CO)NC1=O
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C[C@H]2CC(=O)CCN2C1
Temperature: 0 °C
Yield: 116.3 %

Procedure:
A solution of 32.35 g (226 mmol) of (S)4,4-dimethyl-2-hydroxymethyl-5-oxopyrrolidine in 300 ml of tetrahydrofuran was added dropwise over a period of 20 minutes with ice-cooling and stirring to keep the temperature between 8 and 17° C., to a suspension of 25.72 g (678 mmol) of lithium aluminum hydride in 500 ml of tetrahydrofuran. The resulting mixture was then heated under reflux for 7 hours, at the end of which time it was cooled to 0° C. and 103 ml of a 4% aqueous solution of sodium hydroxide were added carefully thereto. Any insoluble material was removed by filtration and the filtrate was concentrated by evaporation under reduced pressure. The residue thus obtained was dissolved in 500 ml of methylene chloride and then 40.94 ml (294 mmol) of triethylamine were added, followed by the further addition of 38.71 ml (271 mmol) of benzyloxycarbonyl chloride with ice-cooling and stirring. The resulting mixture was stirred for 1 hour at the same temperature and then stirred for a further 1 hour at room temperature. At the end of this time, a saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and it was then extracted with methylene chloride. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure. The resulting residue was purified by chromatography on a silica gel column using a 1:1 by volume mixture of hexane and ethyl acetate as the eluant to afford 43.97 g (yield: 74%) of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1B(O)O)(=[O:16])=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.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>[NH2:6][C:5]1[CH:7]=[CH:8][C:2]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[S:14]([NH:13][C:9]([CH3:12])([CH3:11])[CH3:10])(=[O:15])=[O:16])=[CH:3][CH:4]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Reactant: Nc1ccc(Br)cc1
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: c1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Yield: 41.4 %

Procedure:
A mixture of 3.44 g (20 mmol) of 4-bromoaniline and 5.14 g (20 mmol) of 2-(t-butylaminosulfonyl)phenylboronic acid, 1.16 g of tetrakis(triphenylphosphine) palladium(0) (1 mmol), 0.32 g of tetrabutylammonium bromide (1 mmol) and 20 mL of 2M aqueous sodium carbonate were refluxed with 180 mL of benzene under N2 for 5.5 hours. After cooling, the mixture was diluted with methylene chloride and water. The two phases were separated and the organic phase was washed with water, dried with MgSO4 and concentrated in vacuo. The resulting thick oil was chromatographed on silica with 30% EtOAc/hexane to afford 2.52 g (41%) of the aniline. 1H NMR (CDCl3): δ8.14 (d, 1H); 7.53 (t, 1H); 7.43 (t, 1H); 7.33 (d, 2H); 7.27 (d, 1H); 6.76 (d, 2H); 3.7 (br s, 1H); 0.99 (s, 9H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][OH:11])[CH:9]=1.[CH3:20]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]2[CH2:18][CH3:19])=[C:8]([CH2:10][O:11][CH3:20])[CH:9]=1
Reactant: CI
Reactant: CCC1CCCCN1c1ccc(Br)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC1CCCCN1c1ccc(Br)cc1COC
Reaction time: 0.5 h
Yield: 97 %

Procedure:
To a solution of sodium hydride (2.3 g, 93 mmol) in anhydrous DMF (130 mL) was added a solution of [5-bromo-2-(2-ethylpiperidin-1-yl)phenyl]methanol (15 g, 48.3 mmol) in DMF (20 mL) drop wise at 0° C. After 30 minutes, methyl iodide was added drop wise at 0° C. The reaction mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL), then diluted with water (100 mL) and extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (15.2 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[C:6]([S:7]([CH2:10][CH2:11][CH3:12])(=[O:9])=[O:8])=[CH:5][S:4][C:3]=1[C:13]([OH:15])=[O:14].[OH2:16].[OH-].[Na+:18]>C(O)C>[NH2:1][C:2]1[C:6]([S:7]([CH2:10][CH2:11][CH3:12])(=[O:9])=[O:8])=[CH:5][S:4][C:3]=1[C:13]([OH:15])=[O:14].[C:13]([O-:15])([OH:16])=[O:14].[Na+:18]
Reactant: O
Agent: CCCS(=O)(=O)c1csc(C(=O)O)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])O

Procedure:
Coupling of ligand to NHS-activated thiopropionic acid Sepharose: 3-amino-4(propylsulfonyl)thiophene-2-carboxylic acid was prepared as described in WO 02/05959 (ligand 12). A soluble mixture of a solution of 565 mg of 3-amino-4(propylsulfonyl)thiophene-2-carboxylic acid (2.27 mmol) in 2 ml of dist. water, 2 ml of 1M NaHCO3 and 2 ml of ethanol was prepared and adjusted to pH 8.5 with careful addition of 50% aqueous NaOH.
Reaction SMILES: Cl.[NH2:2][CH2:3][NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)([C:17]([F:20])([F:19])[F:18])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29].Cl[C:32]([O:34][CH3:35])=[O:33].C(N(CC)CC)C>ClCCl>[CH3:35][O:34][C:32](=[O:33])[NH:2][CH2:3][NH:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH2:16][C:15]([C:21]3[CH:22]=[C:23]([Cl:28])[CH:24]=[C:25]([Cl:27])[CH:26]=3)([C:17]([F:18])([F:19])[F:20])[O:14][N:13]=2)=[CH:8][C:7]=1[CH3:29]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)NCN
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Temperature: 25 °C
Yield: 44.2 %

Procedure:
In a suspended solution of 0.13 g of N-aminomethyl-4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methyl benzoic acid amide hydrochloride synthesized in Synthetic Example 32 in 4 ml of dichloromethane, 0.03 g of methyl chloroformate and 0.08 g of triethyl amine were added with stirring at room temperature, and stirred at room temperature for 3 hours. After the completion of the reaction, the solvent was distilled under reduced pressure, the residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (1:1) to obtain 0.06 g of the aimed product as colorless resinous substance.
Reaction SMILES: [CH2:1]([O:3][CH:4](O)[CH3:5])[CH3:2].N1C(C)=CC=CC=1C.[F:15][C:16]([F:29])([F:28])[S:17]([O:20]S(C(F)(F)F)(=O)=O)(=[O:19])=[O:18].[Cl-].[NH4+]>C(Cl)Cl>[O:20]([CH2:2][CH2:1][O:3][CH2:4][CH3:5])[S:17]([C:16]([F:29])([F:28])[F:15])(=[O:19])=[O:18]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(C)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCOCCOS(=O)(=O)C(F)(F)F
Reaction time: 1 h
Yield: 67.6 %

Procedure:
In a round bottom flask containing a stirring bar was placed 9.0 g (100 mmol) of ethoxyethanol. The atmosphere in the flask was replaced with nitrogen by using a nitrogen bubbler. The flask was given 160 mL of methylene chloride and 23.3 mL (120 mmol) of 2,6-lutidine. The flask cooled with ice was given dropwise 20.2 mL (120 mmol) of trifluoromethanesulfonic acid anhydride over 20 minutes. After stirring for 1 hour, the reaction liquid was mixed with 20 mL of saturated solution of ammonium chloride. The resulting mixture was washed sequentially with 1N hydrochloric acid (100 mL), deionized water (100 mL), saturated solution of sodium hydrogen carbonate (100 mL), and saturated aqueous solution of sodium chloride (100 mL). The organic layer was separated and dried with anhydrous sodium sulfate. With the sodium sulfate filtered off, the solution was concentrated under reduced pressure. The residue underwent silica gel chromatography. Thus there was obtained 15.03 g (67.6% yields) of 2-ethoxyethyl triflate from the fraction in eluate of 20% ethyl acetate-hexane.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([C:16]#[C:17][CH2:18][OH:19])=[CH:4][N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:16]=[C:17]([CH2:18][OH:19])[N:8]([CH:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]3)[C:6]=2[N:7]=1
Reactant: OCC#Cc1cnc(Cl)nc1NC1CCCCCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCc1cc2cnc(Cl)nc2n1C1CCCCCC1
Temperature: 63 °C
Yield: 72.2 %

Procedure:
To a suspension of 3-(2-chloro-4-(cycloheptylamino)pyrimidin-5-yl)prop-2-yn-1-ol (8.64 g, 30.9 mmol) in THF (200 mL) was added a solution of TBAF in THF (1 M, 66 mL, 2.1 equiv) and the resulting mixture was heated at 63° C. for 5 h. The reaction mixture was concentrated to remove THF, diluted with EtOAc (350 mL), washed with water (140 mL) and brine (140 mL), dried over Na2SO4, filtered and concentrated. Trituration of the residue using iPrOH, CH2Cl2, and MeCN followed by column chromatography of the mother liquor (EtOAc/heptane 20 to 100%) provided (2-chloro-7-cycloheptyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)methanol (6.24 g) in 72% yield. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 6.45 (s, 1H), 4.83 (s, 2H), 4.61 (m, 1H), 2.54 (m, 2H), 1.98-1.86 (m, 4H), 1.73-1.55 (m, 6H); MS m/z 280.4 (M+H)+
Reaction SMILES: [C:1]([N:4]1[C:16]2[CH:15]=[CH:14][C:13](Br)=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=O)[CH3:2].[CH:18]1[C:30]2[NH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]=2C=C[CH:19]=1>[Cu]=O>[CH:15]1[C:16]2[N:4]([C:1]3[CH:19]=[CH:18][C:30]4[NH:29][C:28]5[C:23]([C:22]=4[CH:2]=3)=[CH:24][CH:25]=[CH:26][CH:27]=5)[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:11]=2[CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)n1c2ccccc2c2cc(Br)ccc21
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: O=[Cu]
Product: c1ccc2c(c1)[nH]c1ccc(-n3c4ccccc4c4ccccc43)cc12
Temperature: 170 °C
Yield: 82.4 %

Procedure:
A mixture of 4.0 g of 9-Acetyl-3-bromocarbazole prepared as described above and 2.8 g of carbazole were stirred together in 30 ml N,N′-dimethylacetamide. To this was added 0.8 g of copper oxide and heated to 170° C. for 24 h. The reaction was quenched with water and the solid was filtered, washed with methanol, and dried under vacuum. The solid (5.0 g) was then taken up for further deprotection using 1.2 g KOH with THF (6 ml), methanol (12 ml) and water (12 ml) at reflux temperature. The reaction mixture was then extracted using ethylacetate; and the organic layer was dried over anhydrous sodium sulfate and evaporated to dryness under vacuum. Subsequent silica gel column chromatography using toluene:hexane (1:2) as eluent, yielded 3.8 g of 3-(9-carbazolyl)carbazole as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C@@H:17]1[CH2:29][C:30]([OH:32])=[O:31].S(=O)(=O)(O)O.[CH3:38]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH2:13][CH2:14][CH2:15][C@@H:16]1[CH2:21][CH2:20][NH:19][CH2:18][C@@H:17]1[CH2:29][C:30]([O:32][CH3:38])=[O:31]
Reactant: CO
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3CC(=O)O)c2c1
Agent: O=S(=O)(O)O
Product: COC(=O)C[C@H]1CNCC[C@H]1CCCc1ccnc2ccc(OC)cc12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
A mixture of 2.8 g of (3R,4R)-4-(3-(6-methoxyquinolin-4-yl)propyl]-1-(tert-butyloxycarbonyl)piperidine-3-acetic acid in 100 cm3 of anhydrous methanol to which had been added 1 cm3 of 95% sulfuric acid was heated with stirring at a temperature in the region of the boiling point for 2 hours. After cooling to a temperature in the region of 20° C., the reaction mass was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then 20 cm3 of a saturated aqueous sodium hydrogencarbonate solution were added to the residue obtained. The mixture was extracted with 4 times 20 cm3 of dichloromethane. The combined extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 2.25 g of methyl (3R,4R)-4-[3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate were obtained in the form of an oil with a brown color.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].Cl>C(O)C>[CH2:20]([O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCBr
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCOc1ccc(-c2ccc(C(=O)O)cc2)cc1
Yield: 69 %

Procedure:
1.12 g of sodium hydroxide was dissolved in 100 ml of ethyl alcohol. Then, 2.0 g of 4-(4'-hydroxyphenyl) benzoic acid and 2.3 ml of 1-bromononane were added to the solution and refluxed for 19 hours. 50 ml of 10% aqueous sodium hydroxide solution was added and refluxed for another two hours. After cooling, concentrated HCl was dropped into the solution until it was acidic. After filtration and recrystallization from ethyl alcohol gave 2.18 g of pure product (yield 69%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[C:11]([F:26])=[C:12]([N:16]2[CH2:19][CH:18]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH2:17]2)[CH:13]=[CH:14][CH:15]=1)(C(C)(C)C)(C)C.[CH3:27][O:28][CH2:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[OH-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[F:26][C:11]1[C:10]([CH2:9][OH:8])=[CH:15][CH:14]=[CH:13][C:12]=1[N:16]1[CH2:19][CH:18]([CH:20]2[CH2:25][CH2:24][N:23]([C:30](=[O:31])[CH2:29][O:28][CH3:27])[CH2:22][CH2:21]2)[CH2:17]1
Reactant: CC(C)(C)[Si](C)(C)OCc1cccc(N2CC(C3CCNCC3)C2)c1F
Reactant: COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COCC(=O)N1CCC(C2CN(c3cccc(CO)c3F)C2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
4-{1-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]azetidin-3-yl}piperidine (120 mg) and methoxy acetic acid (47 mg) was mixed with dichloromethane (3 ml), and WSC hydrochloride (100 mg) and HOBt (70 mg) was added thereto, followed by stirring at room temperature for 3 hours. A 1M aqueous NaOH solution and CHCl3 were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with THF (3 ml), and a 1M TBAF/THF solution (0.66 ml) was added thereto, followed by stirring at room temperature for 1 hour. EtOAc and a saturated aqueous ammonium chloride solution were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 1-(4-{1-[2-fluoro-3-(hydroxymethyl)phenyl]azetidin-3-yl}piperidin-1-yl)-2-methoxyethanone (106 mg).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6](/[CH:14]=[CH:15]/[N+:16]([O-:18])=[O:17])[CH:5]=1>C(Cl)(Cl)Cl.C(O)(C)C>[F:3][C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH3:13])[CH:7]=[C:6]([CH2:14][CH2:15][N+:16]([O-:18])=[O:17])[CH:5]=1
Reactant: CCCOc1cc(F)cc(/C=C/[N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Product: CCCOc1cc(F)cc(CC[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
Add sodium borohydride (1.30 g, 34.46 mmol) to 1-fluoro-3-((E)-2-nitro-vinyl)-5-propoxy-benzene (1.94 g, 8.61 mmol) and silica gel (17 g) in chloroform (86 mL) and isopropanol (25 mL) at room temperature in portions over 5 minutes. Stir at room temperature 2 hours and filter. Concentrate the filtrate and dissolve in ethyl acetate. Wash with water and saturated aqueous sodium chloride, dry over magnesium sulfate, filter and concentrate. Purify on 40 g silica gel eluting with 100:0 to 70:30 hexanes:ethyl acetate to give 1.1 g (56.2%) of the desired compound as an oil.
Reaction SMILES: I[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][N:5]1[CH:9]=[N:8][CH:7]=[N:6]1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([S:31]([O-:33])=[O:32])[CH:25]=[CH:24]3)=[CH:17][CH:16]=1.[Na+]>>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]=[C:26]([S:31]([C:2]2[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=2[CH2:4][N:5]2[CH:9]=[N:8][CH:7]=[N:6]2)(=[O:33])=[O:32])[CH:25]=[CH:24]3)=[CH:17][CH:16]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: Ic1ccccc1Cn1cncn1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1ccccc1Cn1cncn1

Procedure:
Prepared according to the method of Example 6 Step 4 using 1-(2-iodobenzyl)-1H-1,2,4-triazole and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate, to give the title compound as a white solid (11 mg). 1H NMR (500 MHz, d6-DMSO): δ 8.78 (1H, s), 8.59 (1H, s), 8.37 (1H, s), 8.32 (1H, d, J=8.6 Hz), 8.25-8.19 (2H, m), 8.05 (1H, dd, J=1.7, 8.5 Hz), 7.94-7.90 (3H, m), 7.86 (1H, dd, J=1.8, 8.6 Hz), 7.71-7.65 (2H, m), 7.38 (2H, t, J=8.8 Hz), 6.88 (1H, d, J=6.8 Hz), 5.81 (2H, s); m/z (ES+) 444 [MH+].