Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])=[CH:6][CH:7]=1.[CH3:23][O-:24].[Na+].O>CO>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:5]3[N:4]=[N:3][C:2]([O:24][CH3:23])=[CH:7][CH:6]=3)[CH:12]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)nn1
Temperature: 25 °C

Procedure:
3-Chloro-6-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridazine (100 mg, 0.30 mmol) was dissolved in 2 mL methanol and 1.5 mL sodium methanolate solution were added. The reaction mixture was refluxed for 3 h. After cooling to room temperature the reaction mixture was treated with 30 mL water and extracted three times with ethyl acetate (50 mL each). The combined organic extracts were dried with magnesium sulfate, filtered and evaporated and the desired product was obtained as a white solid (53 mg, 53%), MS: m/e=325.3 (M+H+).
Reaction SMILES: C1(O)C=CC=CC=1.[OH-].[Ca+2].[OH-].C=O.[NH2:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([CH3:20])[CH:19]=1>O>[CH:18]1[CH:17]=[C:16]([OH:21])[CH:15]=[C:14]([NH2:13])[CH:19]=1.[CH3:20][C:18]1[CH:19]=[CH:14][CH:15]=[C:16]([OH:21])[CH:17]=1
Reactant: Cc1cc(N)cc(O)c1
Agent: C=O
Agent: [Ca+2]
Agent: [OH-]
Solvent: Oc1ccccc1
Solvent: O
Product: Cc1cccc(O)c1
Product: Nc1cccc(O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
94 parts (1 mol) of phenol, 100 parts of water and 0.5 part of calcium hydroxide were charged in a kolben reactor equipped with a thermometer, stirrer, reflux condenser and dropping funnel, to which 114 parts (1.4 mols) of 37% formalin was dropwise added for 0.5 hour while stirring at 70° C., and the mixture was further stirred at the same temperature for 5 hours. 172.2 part (1.4 mols) of 3-amino-5-methylphenol was then added to the mixture, stirred at 120° C. for 1 hour, then heated at 150° C. and a reduced pressure of 40 torr for 1 hour to distil off water and further heated at 200° C. and a reduced pressure of 5 torr for 1 hour to reduce the unreacted monomers, thus obtaining a co-condensation resin of phenol.3-amino-5-methylphenol.formaldehyde.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1/[CH:8]=[N:9]/[S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11].[CH3:16][Mg]Br.[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[C@H:8]([NH:9][S@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])[CH3:16]
Reactant: Cn1ncc(/C=N/[S@@](=O)C(C)(C)C)c1Cl
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1cnn(C)c1Cl
Temperature: -78 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
(S,E)-N-((5-chloro-1-methyl-1H-pyrazol-4-yl)methylene)-2-methylpropane-2-sulfinamide(750 mg, 3.03 mmol) was dissolved in THF (25 ml) placed under nitrogen and cooled to −78° C. 1.4M methyl magnesium bromide solution (toluene:THF 3:1, 8.65 ml, 12.1 mmol) was added dropwise and reaction stirred overnight while warming to room temperature. Saturated aqueous ammonium chloride solution (20 ml) was added to the reaction and stirred for 5 minutes. The product was extracted with EtOAc (2×15 ml), combined organics were washed with brine (15 ml), dried over Na2SO4, filtered and concentrated to furnish the title product as a brown gum (690 mg, 86.4% yield). 1H NMR (400 MHz, CDCl3) 1.18-1.19 (9H s) 1.55-1.57 (3H d) 1.62-1.64 (3H s) 3.20-3.22 (1H d) 4.41-4.47 (1H q) 7.42 (1H s) MS (ESI) m/z 264 (M+H)+
Reaction SMILES: CO.[N+:3]([C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21])([O-])=O>[Pd].O1CCCC1>[NH2:3][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][C:7]=1[NH:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[C:20]#[N:21]
Reactant: N#Cc1cccc(Nc2ccc3ccccc3c2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cccc(Nc2ccc3ccccc3c2N)c1
Reaction time: 4 h
Yield: 73.9 %

Procedure:
To a methanol (10 mL) and an anhydrous tetrahydrofuran (50 mL) solution of 3-(1-nitro-2-naphthylamino)benzonitrile (1.60 g, 5.53 mmol) was added 10% palladium-active carbon (160 mg), and the mixture was hydrogenated for 4 hours at room temperature under atmospheric pressure. After removal of the catalyst by filtration, the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=7/3) to obtain the titled compound as a pale brown powder (1.06 g, yield 74%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:29][CH2:30][CH3:31])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:10]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO.O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:29][CH2:30][CH3:31])[C:17]2[CH:18]=[CH:19][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:10]=1
Reactant: CCCN(Cc1cccc(-c2c(C)cccc2C)c1)c1ccc(CCC(=O)OC)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCN(Cc1cccc(-c2c(C)cccc2C)c1)c1ccc(CCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.9 %

Procedure:
To a solution of methyl 3-{4-[[(2′,6′-dimethylbiphenyl-3-yl)methyl](propyl)amino]phenyl}propanoate (0.735 g, 1.77 mmol) in a mixture of methanol (8 mL) and tetrahydrofuran (8 mL) was added 2 M aqueous sodium hydroxide solution (2.5 mL), and the mixture was stirred at room temperature for 19 hr. Water was added to the reaction mixture, and the mixture was weakly acidified with 10% aqueous citric acid solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20%-70% ethyl acetate/hexane) to give the title compound (0.710 g, yield 99%) as a yellow oil.
Reaction SMILES: CCOC(C)=O.[F:7][C:8]([F:34])([C:23]1([OH:33])[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]1)[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]1[CH:20]=[C:19]([CH2:21][OH:22])[O:18][N:17]=1)=[O:10].CCN(CC)CC.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>O>[CH3:42][S:43]([O:22][CH2:21][C:19]1[O:18][N:17]=[C:16]([C@@H:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9](=[O:10])[C:8]([F:7])([F:34])[C:23]2([OH:33])[CH2:24][C:25]([CH3:32])([CH3:31])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[CH:20]=1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(CO)on2)C1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Reaction time: 0.5 h

Procedure:
To an AcOEt (3 mL) solution of the compound (45 mg) obtained in Example 3-(4) and Et3N (31 μL), MsCl (13 μL) was added at 0° C. and after stirring the mixture for 30 minutes, MsCl (13 μL) was added and the mixture was stirred at 0° C. for 30 minutes, followed by addition of Et3N (31 μL) and stirring at 0° C. for 2.5 hours. The reaction mixture was added to water (50 mL) and the organic layer extracted with AcOEt (50 mL) was dried (MgSO4), filtered and concentrated to give the titled compound (58 mg, colorless oil.)
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([C:18]1[N:23]=[CH:22][C:21]([OH:24])=[CH:20][N:19]=1)[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Br[CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:10]([O:9][C:8]([N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:32])[F:33])[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=1)[C:18]1[N:19]=[CH:20][C:21]([O:24][CH2:35][CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:22][N:23]=1)=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C(OCc1ccccc1)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)OCc2ccccc2)nc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
Benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-carbamate (9.70 g) and ethyl 4-bromobutyrate (3.53 g) are dissolved in N,N-dimethylformamide (50 mL) and thereto is added potassium carbonate (3.41 g) and the mixture is stirred at 50° C. for 1 hour. Thereto are added ethyl acetate and a saturated brine, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give ethyl 4-{2-[benzyloxycarbonyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (8.29 g). MS (m/z): 586 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([CH:14]2[CH2:16][CH2:15]2)=[C:7]([F:13])[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:14]2[CH2:16][CH2:15]2)=[C:7]([F:13])[CH2:8][OH:9])=[CH:17][CH:18]=1
Reactant: CCOC(=O)C(F)=C(c1ccc(Cl)cc1)C1CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCC(F)=C(c1ccc(Cl)cc1)C1CC1
Temperature: -55 °C
Reaction time: 1.5 h
Yield: 97 %

Procedure:
A solution of ethyl p-chloro-β-cyclopropyl-α-fluorocinnamate, (E)- and (Z)- (32.25 g, 0.12 mol) in ether is added dropwise to a mixture of lithium aluminum hydride (5.46 g, 0.144 mol) in ether while maintaining the temperature at −55° C. After the addition is complete, the reaction mixture is warmed to and stirred at −20° C. for 90 minutes, quenched sequentially with ethyl acetate, methanol and 2 N hydrochloric acid, and extracted with ether. The organic extracts are combined, washed sequentially with water, saturated sodium hydrogen carbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to give the title product as a colorless oil (26.4 g, 97%).
Reaction SMILES: [P:1]([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C@@H:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:28][N:27]2[C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH:21]=1)([O:11]CC1C=CC=CC=1)([O:3]CC1C=CC=CC=1)=[O:2].C1CCC=CC=1>CO.[Pd]>[P:1]([OH:11])([OH:3])([O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C@@H:26]2[CH:30]=[C:29]([C:31]3[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=3[F:38])[CH2:28][N:27]2[C:39]([N:41]([CH3:42])[CH3:43])=[O:40])[CH:21]=1)=[O:2]
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Solvent: C1=CCCC=C1
Product: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1cccc(OP(=O)(O)O)c1
Reaction time: 0.25 h

Procedure:
Dibenzyl 3-{(2S)-4-(2,5-difluorophenyl)-1-[(dimethylamino)carbonyl]-2,5-dihydro-1H-pyrrol-2-yl)phenyl phosphate (8-1, 108 mg, 0.18 mmol) was dissolved in 4:1 MeOH:cyclohexadiene (2 mL) and treated with 10% Palladium on carbon (100 mg). The reaction was stirred vigorously for 15 min, and then filtered over celite using MeOH to wash the compound throughly from the celite. The washings were concentrated and purified by reverse phase column chromatography (C-8, 10-90% CH3CN/H2O with 0.1% TFA gradient) to provide 3-{(2S)-4-(2,5-difluorophenyl)-1-[(dimethylamino)carbonyl]-2,5-dihydro-1H-pyrrol-2-yl}phenyl dihydrogen phosphate (8-2) as a white solid: 1H NMR (300 MHz, CD3OD) δ 7.20 (m. 7H), 6.42 (br s, 1H), 6.08 (m, 1H), 5.00 (dd, J=14.0, 3.6 Hz, 1H), 4.55 (d, J=14.0 Hz, 1H), 2.92 (s, 6H). LRMS m/z (M+H) 425.4 found, 425.3 required.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[OH-].[K+]>O1CCOCC1.O>[F:1][C:2]([F:16])([F:17])[C:3]([C:6]1[CH:15]=[CH:14][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)([OH:5])[CH3:4]
Reactant: COC(=O)c1ccc(C(C)(O)C(F)(F)F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)(c1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C
Yield: 87 %

Procedure:
A mixture of methyl 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoate (6.0 g, 24.2 mmol) and KOH (2.72 g, 48.4 mmol) in 1,4-dioxane (100 mL) and H2O (50 mL) was refluxed for 2 h. The reaction mixture was cooled to room temperature, and 1,4-dioxane evaporated in vacuo. The aqueous residue was acidified with 2N HCl and extracted with CH2Cl2. The extracts were washed with brine and dried. Flash chromatography of the residue, using 3:7 EtOAc-Hexane, gave 4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)benzoic acid (4.93 g). 1H NMR (CDCl3) δ 11.0(br, 1H), 7.95(d, J=6.8 Hz, 2 H), 7.71(d, J=6.8 Hz, 2 H), 6.73 (s, 1 H), 1.71(s, 3H). MS 235.0 (M+H+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C[O:7][C:8](=O)[C@H:9]([CH3:11])[OH:10]>>[OH:10][C@@H:9]([CH3:11])[C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:7]
Reactant: C1CCNC1
Reactant: COC(=O)[C@H](C)O
Product: C[C@H](O)C(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84.4 %

Procedure:
Pyrrolidine (39.25 g, 0.48 mole) was added dropwise to methyl-(S)-(−)-lactate (25.0 g, 0.24 mol) at 0° C. and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was concentrated under reduced pressure and purified with distillation to afford (2S)-2-hydroxy-1-(pyrrolidin-1-yl)propan-1-one 2 (29.0 g, 84%) at 150° C.-160° C. as light yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2Br)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:31]1(B(O)O)[CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH:31]2[CH2:33][CH2:32]2)[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)C1CC1
Reactant: CC1C(=O)NN=C2COc3cc(Br)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC1C(=O)NN=C2COc3cc(C4CC4)c(C4CCN(C(=O)OC(C)(C)C)CC4)cc3N21
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A degassed mixture of 4-(7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (Example #75, Step A, 0.06 g, 0.127 mmol), cyclopropylboronic acid (0.021 g, 0.250 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)dichloride dichloromethane complex (0.020 g, 0.025 mmol) and K2CO3 (0.035 g, 0.250 mmol) in dioxane (1 mL) and water (0.2 mL) was heated to reflux for 8 h. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative TLC (eluting with 50% EtOAc in petroleum ether) to give 4-(7-cyclopropyl-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-piperidine-1-carboxylic acid tert-butyl ester (0.024 g, 44%) as a pale-white solid. LC/MS (Table 1, Method 2) Rt=1.223 min.; MS m/z: 441 [M+H]+.
Reaction SMILES: [CH3:1]N(C)C=O.[OH:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O>[CH3:1][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[CH:17]=[O:18]
Reactant: O=Cc1c(O)ccc2ccccc12
Reactant: CN(C)C=O
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1ccc2ccccc2c1C=O
Temperature: 50 °C

Procedure:
500 ml of a dimethylformamide solution containing 103.2 g (0.6 mole) of 2-hydroxy-1-naphthaldehyde and 107.6 g (0.78 mole) of anhydrous potassium carbonate was stirred with heating at 50° C. To the solution was added dropwise 145 g (0.78 mole) of methyl p-toluenesulfonate. After the completion of the dropwise addition, the mixture was stirred at 60° C. for 2 hours. The reaction mixture was added to 1.5 liters of water, and the precipitated crystals were collected by filtration. The crude crystals were recrystallized from a solvent mixture of n-hexane and ethyl acetate (5/1 by volume) to obtain 93.8 g (0.504 mole) of 2-methoxy-1-naphthaldehyde.
Reaction SMILES: CO.[OH-].[K+].C([O:8][C@@H:9]1[CH2:33][CH2:32][C@@:31]2([CH3:34])[C@H:11]([CH2:12][C@@H:13]([O:36]C(=O)C)[C@@H:14]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:35])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[C@H:19]([CH3:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH2:10]1)(=O)C>C(O)(C)C>[CH3:26][C@@H:19]([C@@H:18]1[C@@:27]2([CH3:35])[CH2:28][CH2:29][C@@H:30]3[C@@:31]4([CH3:34])[CH2:32][CH2:33][C@@H:9]([OH:8])[CH2:10][C@H:11]4[CH2:12][C@@H:13]([OH:36])[C@H:14]3[C@@H:15]2[CH2:16][CH2:17]1)[CH2:20][CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@H](OC(C)=O)C[C@@H]4C[C@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CO
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
To a solution of 3 ml of methanol, 5 ml of isopropanol and 0.8 g of potassium hydroxide was added 0.294 g (0.000599 mol) of methyl 3α,7α-diacetyloxy-5β-cholan-24-oate. The mixture was heated to reflux under an argon atmosphere for 4 hr. then stirred overnight at room temperature. The solvents were removed in vacuo. The mixture was acidified with 1 N HCl and extracted with 3×25 ml of ethyl acetate. The combined ethyl acetate extracts were washed with water then dried over anhydrous sodium sulfate. The mixture was filtered and solvents removed in vacuo. The residue were recrystallized from ethyl acetate to give 0.163 g (69.3%) of chenodeoxycholic acid, mp 117°-118° C., which did not depress when mixed with authentic material (mp 117°-118° C. from ethyl acetate).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][N:13]2[C:17]3[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[CH:21][C:16]=3[N:15]([CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:14]2=[O:31])=[C:10]([O:34][CH3:35])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:36][N:37](C)[CH2:38]C(N)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH:25]1([N:15]2[C:16]3[CH:21]=[C:20]([O:22][CH2:23][CH3:24])[CH:19]=[CH:18][C:17]=3[N:13]([CH2:12][C:11]3[CH:32]=[CH:33][C:8]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:2])[CH2:3][N:37]([CH3:38])[CH3:36])=[CH:9][C:10]=3[O:34][CH3:35])[C:14]2=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)C)cc1OC
Reactant: CN(C)CC(C)(C)N
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc2c(c1)n(C1CCCCC1)c(=O)n2Cc1ccc(C(=O)NC(C)(C)CN(C)C)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.2 %

Procedure:
A mixture of 1.5 g of the compound obtained in Example 15 Step B, 1 g of 2-dimethylamino-1,1-dimethylethylamine (synthesized according to J. Am. Chem. Soc., 1946, 68, 12-14), 1.6 g of BOP and 2 g of DIPEA in 20 ml of DCM is left stirring for 1 hour at RT. The reaction mixture is concentrated under vacuum, the residue is extracted with EtOAc, the organic phase is washed with 1N NaOH solution, with water and dried over Na2SO4, and the solvent is evaporated off under vacuum. The residue is chromatographed on silica, eluting with a DCM/MeOH mixture (98/2; v/v). 0.15 g of the expected product is obtained after crystallization from iso ether, mp=161° C.
Reaction SMILES: Cl.[CH:2]12[NH:11][CH:6]([CH2:7][C:8](=[O:10])[CH2:9]1)[CH2:5][O:4][CH2:3]2.[C:12](Cl)([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>ClCCl>[O:10]=[C:8]1[CH2:9][CH:2]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:6]([CH2:5][O:4][CH2:3]2)[CH2:7]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC2COCC(C1)N2
Agent: Cl
Solvent: ClCCl
Product: O=C1CC2COCC(C1)N2C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.2 %

Procedure:
3-oxa-9-azabicyclo[3.3.1]nonan-7-one hydrochloride (CAS 1126795-00-3) (10 g) was dissolved in 200 ml of dichloromethane which was cooled to 0° C. Then, CbzCl (14.3 g, 84.7 mmol) was added to the mixture followed by the dropwise addition of a solution of TEA (14.6 ml, 112.8 mmol) in 20 ml of dichloromethane. The mixture was allowed to warm up to room temperature. After stirring 2 h, it was quenched with 20 ml of a saturated aqueous solution of NaHCO3. The two layers were separated and the aqueous layer was extracted with dichloromethane (3×150 ml). The combined organic layers were washed with water, dried over Na2SO4 and the solvent was evaporated under reduced pressure. The crude product was purified by chromatography on silica gel, yielding 10.1 g of benzyl 7-oxo-3-oxa-9-azabicyclo[3.3.1]nonane-9-carboxylate 100b (64%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])=[O:14])[CH:7]=[CH:6]2.[N:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.C(N(CC)CC)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:17][CH2:18][N:19]([C:32](=[O:33])[C:31]3[CH:30]=[CH:29][C:28]([C:25]4[CH:24]=[CH:23][N:22]=[CH:27][CH:26]=4)=[CH:36][CH:35]=3)[CH2:20][CH2:21]1)(=[O:14])=[O:15])[CH:7]=[CH:6]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(-c2ccncc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a solution of 1-(6-chloronaphthalene-2-sulfonyl)piperazine hydrochloride (90 mg), 4-(4-pyridyl)benzoic acid (52 mg), triethylamine (35 mg) and HOBt (39 mg) in DMF (10 ml) was added WSC hydrochloride (55 mg) under ice-cooling and the solution was stirred at room temperature 4 hours and concentrated. To the residue was added ethyl acetate and sodium bicarbonate solution. The organic layer was separated, washed with water, and extracted with 1 N hydrochloric acid. The extract was made alkaline with sodium hydroxide solution and extracted with dichloromethane. The extract was dried and concentrated, and the residue was crystallized with ether to give colorless crystals of the title compound (122 mg).
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[Br:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][CH:12]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]([NH:15][CH2:16][C:17](=O)[CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])=O)=[CH:9][CH:8]=1>C1(C)C(C)=CC=CC=1>[Br:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][CH:12]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:13]2[NH:15][CH:16]=[C:17]([CH2:18][C:19]([CH3:23])([CH3:22])[CH2:20][CH3:21])[N:5]=2)=[CH:9][CH:8]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC(=O)OCc2ccccc2)n1
Temperature: 150 °C
Reaction time: 2 h

Procedure:
Ammonium acetate (48 g, 620 mmol) was added to an ambient temperature solution of benzyl {1-(4-bromobenzyl)-2-[(4,4-dimethyl-2-oxohexyl)amino]-2-oxoethyl}carbamate (6.23 g, 12.4 mmol) in xylene (124 mL). After stirring at 150° C. for 2 h, the reaction mixture was quenched with saturated aqueous sodium bicarbonate and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford benzyl {2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}carbamate which was used in the subsequent step without further purification.