Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[N:19]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][C:20]=1[CH2:21][C:22](Cl)=[O:23]>>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH:2]([NH:1][C:22]([CH2:21][C:20]2[CH:25]=[CH:26][C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)=[O:23])[CH2:3][CH2:4][N:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccc2ccccc2n1
Reactant: COc1ccc(C(N)CCN2CCCCC2)cc1
Product: COc1ccc(C(CCN2CCCCC2)NC(=O)Cc2ccc3ccccc3n2)cc1
Yield: 82.2 %

Procedure:
The procedure of Example 1 was repeated using 745 mg (3.0 mmol.) of 1-[3-amino-3-(4-methoxyphenyl)propyl]piperidine and 575 mg (3.0 mmol.) of quinaldinoyl chloride, to obtain 1.03 g (yield: 85%) of the subject compound as a pale yellow oily product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13](=O)[CH:12]3[CH:10]([CH2:11]3)[C:9]2=O)[CH:5]=[CH:6][CH:7]=1.CO.O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH:10]3[CH:12]([CH2:11]3)[CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C2CC2C(=O)N1c1cccc(Br)c1
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Brc1cccc(N2CC3CC3C2)c1
Temperature: 50 °C
Yield: 95.3 %

Procedure:
3-(3-Bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione (4.25 g, 16.0 mmol) was suspended in 80 mL of THF. Borane dimethyl sulfide complex (14.2 mL of a 10.1 M solution) was added and the reaction was heated at 50° C. for 1 h. The reaction was cooled in an ice bath. Methanol (65 mL) was slowly added, followed by 150 mL of water. This mixture was extracted with EtOAc (2×) and the combined organics were dried over MgSO4 and concentrated. The residue was taken up in dichloromethane and the resulting suspension was filtered. The filtrate was concentrated and the residue was purified by SiO2 chromatography using a gradient of 0% to 20% ethyl acetate/heptane to afford 3.63 g (95%) of 3-(3-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl[CH2:10][CH2:11][O:12][CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][CH2:11][O:12][CH3:13])[CH:3]=1
Reactant: COCCCl
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cccc(Br)c1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 79.1 %

Procedure:
A mixture of 3-bromophenol (5 g, 28.9 mmol), 1-chloro-2-methoxyethane (3.77 g, 40 mmol) and K2CO3 (12.63 g, 0.178 mol) in DMF (90 mL) was stirred at 100° C. for 4.5 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue is taken up in 100 ml of tert-butyl methyl ether, and the organic phase was washed once each with 50 ml of 1 N NaOH, 50 ml of water and 50 ml of brine. The organic layer was dried with sodium sulphate, filtered and concentrated to give 1-bromo-3-(2-methoxyethoxy)benzene (5.28 g, 79%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].O[C@@H]1C[C@H](CN(C)C(=O)OC(C)(C)C)C1.[CH2:22]([NH:29][C:30]([CH:32]1[CH2:35][C:34](=[O:36])[CH2:33]1)=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[OH-].[Na+]>C1COCC1.O>[CH2:22]([NH:29][CH2:30][C@@H:32]1[CH2:35][C@H:34]([OH:36])[CH2:33]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C1CC(C(=O)NCc2ccccc2)C1
Agent: CN(C[C@H]1C[C@@H](O)C1)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: O[C@H]1C[C@@H](CNCc2ccccc2)C1
Yield: 58.3 %

Procedure:
LiAlH4 (2.7 g, 0.07 mol) was added to a solution of intermediate 7, N-Benzyl-3-oxocyclobutanecarboxamide (7.12 g, 0.035 mol) in absolute THF (100 mL) under stirring in argon. The mixture was refluxed under stirring for 2 h and cooled. Then 10 N NaOH (2 mL) and water (1 mL) were added. The organic layer was decanted, and the aqueous one was extracted with THF (2×50 mL). The organic layers were evaporated to afford the title compound (3.9 g, 58%) as a colorless oil. 1H NMR-data (DMSO-d6): 7.00-7.49 (m, 6H, NH, Ph); 4.80 (br.s, 1H, OH); 3.81-3.95 (m, 1H); 3.67 (s, 2H, CH2); 2.48 (d, 2H, CH2, J=6.8 Hz); 2.19-2.30 (m, 2H); 1.70-1.84 (m, 1H); 1.35-1.50 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[N:10]\O)/[CH3:9])=[CH:4][C:3]=1[NH:12][S:13]([CH3:16])(=[O:15])=[O:14].[H][H].CO>C1COCC1.[Ni].O>[NH2:10][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:4]=1)[CH3:9]
Reactant: [H][H]
Reactant: C/C(=N/O)c1ccc(F)c(NS(C)(=O)=O)c1
Agent: [Ni]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(N)c1ccc(F)c(NS(C)(=O)=O)c1
Reaction time: 1 h

Procedure:
N-{2-Fluoro-5-[(1Z)-N-hydroxyethanimidoyl]phenyl}methanesulfonamide (Method 62, 200 mg, 812 μmol) was dissolved in 15 ml THF, to which was added Raney nickel 2800 slurry in water (200 μl). The mixture was charged with nitrogen and stirred over 1 atm of hydrogen. After 1 hour, MeOH (4 ml) was added and the reaction mixture was stirred overnight. The following morning the solution was filtered through celite, and the cake washed with MeOH, and the organic layer was concentrated to a yellow solid which was dried under high vacuum (181 mg, 96%). 1H NMR: 1.26 (d, 3H, CH3), 2.92 (s, 3H, SO2Me), 3.33 (HOD), 4.04 (q, 1H, CH), 5.70 (br, 2H, NH2), 7.06-7.16 (m, 2H, Ar), 7.35 (m, 1H, Ar). LC/MS: 0.79 min, 231.08 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[N:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:15][CH3:16])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH2:8]([O:7][C:5](=[O:6])[C:4]1[CH:10]=[CH:11][C:12]([N:13]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:15][CH3:16])=[C:2]([NH:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH:3]=1)[CH3:9]
Reactant: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1N
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC(C)C)c1ccc(C(=O)OCC)cc1NS(C)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 94 %

Procedure:
To a solution of ethyl 3-amino-4-[isobutyl(propyl)amino]benzoate (5 g, 0.0179 mol) in dry DCM (50 mL) was added triethyl amine (7.24 g, 0.0716 mol) at RT. Methane sulphonyl chloride (2.67 g, 0.0233 mol) was added in drops at 0° C. The reaction mixture was stirred at RT for 4 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in water, extracted with ethylacetate (2×75 mL), washed with 0.5M HCl, brine, dried over sodium sulphate and evaporated to afford the title compound as a yellow oil (6 g, 93%). 1H NMR (DMSO-d6, 400 MHz) δ 8.45 (s, 1H), 7.86 (s, 1H), 7.65 (m, 1H), 7.28 (m, 1H), 4.28 (m, 2H), 3.09 (s, 3H) 3.01 (m, 2H), 2.86 (m, 2H), 1.68 (m, 1H), 1.42 (m, 2H), 1.28 (m, 3H), 0.80 (m, 9H). LC/MS (Method A): 357.0 (M+H)+. HPLC (Method B) Rt 5.09 min (purity: 94.40%).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[NH:13][CH:14]=[C:15]([NH:16][C:17](=[O:19])[CH3:18])[C:8]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:20]([O:24][C:25]([NH:27][C@H:28]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1C=CC2N(O)N=NC=2C=1.O.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:17]([NH:16][C:15]1[C:8]2[C:9](=[N:10][CH:11]=[CH:12][C:7]=2[N:1]2[CH2:6][CH2:5][N:4]([C:29](=[O:30])[C@H:28]([NH:27][C:25](=[O:26])[O:24][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:32][C:33]3[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=3)[CH2:3][CH2:2]2)[NH:13][CH:14]=1)(=[O:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Cl)cc1)C(=O)O
Reactant: CC(=O)Nc1c[nH]c2nccc(N3CCNCC3)c12
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(=O)Nc1c[nH]c2nccc(N3CCN(C(=O)[C@@H](Cc4ccc(Cl)cc4)NC(=O)OC(C)(C)C)CC3)c12
Reaction time: 5 h
Yield: 57.9 %

Procedure:
Crude N-(4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)acetamide (0.050 g, 0.15 mmol, see Example 52), (R)-2-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (0.0496 g, 0.166 mmol), HOBT-H2O (0.0323 g, 0.211 mmol), and EDCI (0.0375 g, 0.196 mmol) were placed in DCM (5 mL). DIEA (d 0.742; 0.131 mL, 0.752 mmol) was then added, and the reaction was stirred for 5 hours. The reaction was then poured into saturated Na2CO3 and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give a crude residue that was purified by column chromatography (500:13-500:18 DCM:MeOH) to give (R)-tert-butyl 1-(4-(3-acetamido-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)-3-(4-chlorophenyl)-1-oxopropan-2-ylcarbamate (0.047 g, 57.7% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=1[O:11][CH2:12][CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28].[Cl-].[NH4+]>C(Cl)(Cl)Cl>[CH3:26][S:27]([O:14][CH2:13][CH2:12][O:11][C:10]1[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: OCCOc1ccccc1OCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OCCOc1ccccc1OCc1ccccc1
Reaction time: 2 h
Yield: 92.8 %

Procedure:
To a solution of 2-(2-benzyloxyphenoxy)ethanol (3.07 g, 12.6 mmol) and triethylamine (2.63 ml, 18.8 mmol) in chloroform (30 ml) was added methanesulfonyl chloride (1.12 ml, 14.4 mmol) under ice-cooling, and the mixture was stirred for 2 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. Hexane was added to the obtained residue and the precipitated solid was collected by filtration and washed with hexane. The obtained solid was dried in vacuo to give 2-(2-benzyloxyphenoxy)ethyl methanesulfonate (3.77 g, yield 93%).
Reaction SMILES: [Br:1]Br.C(O)(=O)C.[OH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]([O:20][CH3:21])=[O:19])[CH:16]=2)[CH:11]=[CH:10][N:9]=1>O>[Br:1][C:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=2)[C:8]([OH:7])=[N:9][CH:10]=1
Reactant: COC(=O)c1ccc2ccnc(O)c2c1
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(Br)cnc(O)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.4 %

Procedure:
A mixture of bromine (940 mg) and acetic acid (10 mL) was added dropwise to a mixture of methyl 1-hydroxyisoquinoline-7-carboxylate (1.2 g) and acetic acid (50 mL) and stirred at room temperature for 30 minutes. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain methyl 4-bromo-1-hydroxyisoquinoline-7-carboxylate (1.4 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=2)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=1.[OH:28][C:29]1[CH:30]=[CH:31][C:32]([CH3:35])=[N:33][CH:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC(N(C)C)=O>[CH3:35][C:32]1[CH:31]=[CH:30][C:29]([O:28][C:2]2[CH:3]=[C:4]([N:8]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][C:24]([F:27])([F:26])[F:25])[CH:18]=3)[CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][CH:7]=2)=[CH:34][N:33]=1
Reactant: Cc1ccc(O)cn1
Reactant: OC(CN(Cc1cccc(OC(F)(F)F)c1)c1cccc(Br)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc(Oc2cccc(N(Cc3cccc(OC(F)(F)F)c3)CC(O)C(F)(F)F)c2)cn1
Temperature: 105 °C
Yield: 60.9 %

Procedure:
The 3-[(3-bromophenyl)[[3-(trifluoromethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (500 mg, 1.1 mmol) product from EX-633B and 5-hydroxy-2-methylpyridine (262 mg, 2.4 mmol) were dissolved in dimethylacetamide (6 mL). Cs2CO3 (1.0 g, 3.1 mmol) and (CuCF3SO3)2C6H6 (150 mg) were added, and the mixture was heated to 105° C. for 96 h under an atmosphere of nitrogen, at which time HPLC analysis indicated that most of the starting materials had been consumed. After adding water, the reaction mixture was extracted with ether, and the ether extracts were washed with brine and dried over anhydrous MgSO4. The crude product was purified by flash column chromatography on silica gel eluting with ethyl acetate:hexane (1:12) to give 326 mg (61%) of the desired 3-[[3-(2-methyl-5-pyridyloxy)phenyl][[3-(trifluoro-methoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as a light amber oil, 99% pure by HPLC analysis. 1H NMR (CDCl3) δ 8.00 (s, 1H), 7.29 (t 1H), 6.99 (s, 1H), 7.02-7.15 (m, 5H), 6.46 (dd, 1H), 6.29 (t, 1H), 6.25 (dd, 1H), 4.88 (br s, 1H), 4.67 (ABq, 2H), 4.36 (m, 1H), 3.88 (dd, 1H), 3.56(dd, 1H), 2.49 (s, 3H). 19F NMR (CDCl3) δ −58.2, (s, 3F), −79.1 (d, 3F). HRMS calcd. for C23H20N2O3F6: 487.1456 [M+H]+, found: 487.1425.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH:18]C(=O)OC(C)(C)C)=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[ClH:28]>C(OCC)C>[ClH:28].[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]3[CH2:17][C@H:16]3[NH2:18])=[CH:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Agent: Cl
Solvent: CCOCC
Product: N[C@@H]1C[C@H]1c1ccc(-c2cccc(C(F)(F)F)c2)cc1
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a solution of tert-butyl (trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropylcarbamate (200 mg, 0.53 mmol), in diethyl ether (5 mL) at 10° C. was added HCl in diethyl ether (3 mL), slowly dropwise over a period of 10 min, stirred the reaction mixture for 4 h. After completion, the solvent was evaporated, residue was triturated with hexane (5 mL) and diethyl ether (5 mL), and dried under reduced pressure to get (trans)-2-(3′-(trifluoromethyl)biphenyl-4-yl)cyclopropanamine hydrochloride (140 mg, 77.8%) as a white solid. 1H-NMR (DMSO-d6) δ (ppm): 1.27 (q, 1H), 1.46 (quin, 1H), 2.41 (m, 1H), 2.86 (m, 1H), 7.29 (d, 2H), 7.69 (m, 4H), 7.96 (m, 2H), 8.53 (s, 1H), 8.61 (br, 2H). MS (M+H): 278.3
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>CCCCCC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[C:21]([C:20]([F:19])([F:28])[F:29])[CH:22]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCCCCC
Product: O=C(Nc1cccc(C(F)(F)F)c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxoacetic acid (Example 5b) and 3-(trifluoromethyl)-aniline (Aldrich) according to the method described in Example 1c. Melting Point: 87-89° C. (hexane)
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH:18](Cl)(Cl)Cl>>[CH3:1][C:2]1([CH3:17])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[O:8])[CH:3]1[C:14]([OH:16])=[O:15].[CH3:17][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH:10]([CH2:11][CH3:13])[CH3:18])=[O:8])[CH:3]1[C:14]([O-:16])=[O:15]
Reactant: ClC(Cl)Cl
Agent: CC1(C)C(C=CC(=O)OCC2CC2)C1C(=O)O
Product: CCC(C)OC(=O)C=CC1C(C(=O)[O-])C1(C)C

Procedure:
Using the procedure of Example 9, (1R, cis, ΔZ) 2,2-dimethyl-3-(3-sec-butoxy-3-oxo-1-propenyl)-cyclopropane-carboxylic acid and (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methanol were reacted to obtain (3-propyn-2-yl-2,5-dioxo-imidazolidinyl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-sec-butoxy-3-oxo-1-propenyl)-cyclopropane-carboxylate with a specific rotation of [α]D20 =+16.5°±1° (c=0.8% in chloroform).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@@H:23]([OH:40])[CH2:24][CH2:25][C:26]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)=[O:27])[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:4])=[O:3].[BH4-].[Na+]>C1COCC1.CO.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C@@H:23]([OH:40])[CH2:24][CH2:25][CH:26]([C:28]2[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=2)[OH:27])[CH:8]=[C:9]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:10]=1[O:11][CH2:12][CH2:13][CH3:14])(=[O:3])=[O:4]
Reactant: CCCOc1c(OCc2ccccc2)cc([C@@H](O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCOc1c(OCc2ccccc2)cc([C@@H](O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
35 g of (-)-(1S)-1-(3-methylsulfonyl-4-n-propoxy-5-benzyloxyphenyl)-4-(3,4,5-trimethoxyphenyl)butan-1-ol-4-one dissolved in a mixture of 300 mL dry THF and 100 mL of methanol was treated with 3.5 g of NaBH4 at 0° C. and stirred for 3 h. The reaction mixture was then allowed to gradually warm to room temperature and stirring was continued for additional 2 h. After the completion of the reaction, the solvent was evaporated at reduced pressure and the residue obtained as such was redissolved in 300 ml of ethyl acetate. The organic layer was washed with 1.5N HCl, distilled water and brine respectively, and then dried over MgSO4 and evaporated to yield a colorless syrup which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C(=O)C)=[CH:11][CH:10]=1)=[O:5])[CH3:2].[O-]CC.[Na+]>C(O)C>[CH2:1]([O:3][C:4]([NH:6][CH:7]=[CH:8][C:9]1[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)NC=Cc1ccc(OC(C)=O)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)NC=Cc1ccc(O)cc1
Temperature: 50 °C

Procedure:
5.0 g (0.02 mol) of p-(2-ethoxycarbonylaminovinyl)-acetoxybenzene, after dissolving in 75 ml of absolute ethanol, addition of a solution of 1.36 g (0.02 mol) of sodium ethoxide in 10 ml of absolute ethanol, 15 minutes' heating to 50°C and subsequent evaporation to dryness in vacuo, yield the crude sodium salt of p-(2-ethoxycarbonylaminovinyl)-phenol. This is heated with 20 ml of epichlorohydrin to the boil for 24 hours under a reflux condenser and whilst stirring. Thereafter, the excess epichlorohydrin is removed by vacuum distillation. The residue is partitioned between water and methylene chloride and the organic phase is separated off, dried over sodium sulphate and evaporated. 1-[p-(2-Ethoxycarbonylaminovinyl)-phenoxy]-2,3-epoxy-propane of melting point 112-113°C (from ether) is obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH:8]=O)[CH2:3]1.O.[NH2:11][NH2:12]>CCCCO>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]2[NH:11][N:12]=[CH:8][CH:4]2[CH2:3]1
Reactant: NN
Reactant: CN1CCC=C(C=O)C1
Solvent: O
Solvent: CCCCO
Product: CN1CCC2NN=CC2C1

Procedure:
3.2 g 1-Methyl-1,2,5,6-tetrahydro-pyridine-3-carbaldehyde was dissolved in 10 mL n-BuOH. Added were 2 equiv. of hydrazine hydrate, the mixture was refluxed for 24 hours and subsequently concentrated in vacuo. The residue was taken up in DCM and extracted with 2M NaOH, and the organic phase was dried over Na2SO4, filtrated and concentrated in vacuo to yield 1.78 g of a brown oil which was used without further purification in the subsequent step.
Reaction SMILES: [OH:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([F:12])[CH:6]=1>O1CCCC1>[OH:1][C:2]([CH3:14])([CH3:13])[C:3]#[C:4][C:5]1[CH:10]=[CH:9][C:8](/[CH:13]=[CH:2]/[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[C:7]([F:12])[CH:6]=1
Reactant: CC(C)(O)C#Cc1ccc(Br)c(F)c1
Solvent: C1CCOC1
Product: CCCCC/C=C/c1ccc(C#CC(C)(C)O)cc1F
Yield: 160.4 %

Procedure:
In the same manner as in the first step of Example 2 except that a solution of E-1-heptenylcatecholborane (20 mmol) in tetrahydrofuran (50 ml) was used in place of the solution of E-1-pentenylcatecholborane and 4-(3-hydroxy-3,3-dimethyl-1-propynyl)-2-fluoro-1-bromobenzene (3.9 g, 15 mmol) was used in place of 4-(3-hydroxy-3,3-dimethyl-1-propynyl)-3-fluoro-1-bromobenzene, the reaction was carried out to obtain 4-(3-hydroxy-3,3-dimethyl-1-propynyl)-1-(1-trans-heptenyl)-2-fluorobenzene (3.3 g). Yield: 81%.
Reaction SMILES: [O:1]=[S:2]1(=[O:16])[CH2:7][CH2:6][N:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:4][CH2:3]1.Cl[C:18]1[C:19]2[CH:27]=[C:26]([CH:28]3[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29]3)[S:25][C:20]=2[N:21]=[C:22]([CH3:24])[N:23]=1.[NH4+].[Cl-]>COCCOC>[CH3:34][C:31]1([CH3:35])[CH2:32][CH2:33][CH:28]([C:26]2[S:25][C:20]3[N:21]=[C:22]([CH3:24])[N:23]=[C:18]([CH:9]([C:8]([N:5]4[CH2:6][CH2:7][S:2](=[O:1])(=[O:16])[CH2:3][CH2:4]4)=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:19]=3[CH:27]=2)[CH2:29][CH2:30]1
Reactant: CCOC(=O)CC(=O)N1CCS(=O)(=O)CC1
Reactant: Cc1nc(Cl)c2cc(C3CCC(C)(C)CC3)sc2n1
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Product: CCOC(=O)C(C(=O)N1CCS(=O)(=O)CC1)c1nc(C)nc2sc(C3CCC(C)(C)CC3)cc12
Reaction time: 0.17 h
Yield: 43.3 %

Procedure:
Under an argon atmosphere, to DME (12.5 mL) that had been ice-cooled was added Nall (60% oil, 203 mg), followed by stirring for 10 minutes. To this mixture was added dropwise a solution of ethyl 3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropanoate (1.40 g) in DME (10 mL), followed by stirring at the same temperature for 30 minutes. Then, 4-chloro-6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidine (750 mg) was added thereto, followed by stirring at 60° C. overnight. The reaction mixture was left to be cooled, and then a saturated aqueous NH4Cl solution was added thereto, followed by extraction with EtOAc. The organic layer was washed sequentially with water and brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column to obtain ethyl 2-[6-(4,4-dimethylcyclohexyl)-2-methylthieno[2,3-d]pyrimidin-4-yl]-3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropanoate (559 mg).