Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O-:28])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+].I[C:33]1([C:43]([O-:45])=[O:44])[CH2:38][CH2:37][CH2:36][CH2:35][CH:34]1CC(C)C>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][C@@H:11]2[C:29](=[O:30])[N:13]3[C:14]([C:26]([O:28][CH:14]([O:45][C:43]([CH:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[O:44])[CH:15]([CH3:18])[CH3:16])=[O:27])=[C:15]([CH2:18][O:19][C:20](=[O:25])[CH2:21][C:22]([CH3:24])=[O:23])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Reactant: CC(C)CC1CCCCC1(I)C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)CC(=O)OCC1=C(C(=O)OC(OC(=O)C2CCCCC2)C(C)C)N2C(=O)[C@@H](NC(=O)Cc3csc(N)n3)[C@H]2SC1
Temperature: -5 °C
Yield: 78.6 %

Procedure:
In 30 ml of N,N-dimethylformamide is dissolved 4.76 g of sodium 7β-[2-(2-aminothiazol-4-yl)acetamido]-3-acetoacetoxymethyl-ceph-3-em-4-carboxylate and the solution is cooled to -5° C. With stirring, 5.0 g of 1-iodo-2-methylpropylcyclohexane carboxylate is added dropwise, followed by stirring for further 5 minutes. Thereafter, following the procedure of Example 1, 2.5 g of the title compound is obtained.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:8]([CH2:9][CH3:10])[N:7]=[C:6]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])[C:5]=1[CH2:20][CH3:21].[CH2:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:25][CH2:24][NH:23]1.C(N(CC)CC)C.[OH-].[Na+]>CN(C=O)C.O>[CH2:9]([N:8]1[C:4]([CH2:3][N:23]2[CH2:24][CH2:25][C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22]2)=[C:5]([CH2:20][CH3:21])[C:6]([C:11]2[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH3:19])=[N:7]1)[CH3:10]
Reactant: CCc1c(-c2c(C)cc(C)cc2C)nn(CC)c1CCl
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCc1c(-c2c(C)cc(C)cc2C)nn(CC)c1CN1CCc2ccccc2C1
Temperature: 100 °C

Procedure:
A mixture of the product of step D (from above) and 1,2,3,4-tetrahydroisoquinoline (150 mg, 1.1 mmol) and triethylamine (1 mL in 5 mL of DMF was heated at 100° C. for 1 hour. The mixture was cooled, diluted with water, basified with 1 N NaOH, and finally extracted with ether. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated to give about 500 mg of the crude compound as an oil. The oil was purified through silica gel column chromatography to give 160 mg of the title compound as an oil. 1H NMR (CDCl3): 0.90 (t, 3H), 1.39 (t, 3H), 2.05 (s, 6H), 2.25 (q, 2H), 2.31 (s, 3H), 2.76 (q, 2H), 2.90 (q, 2H), 3.66 (s, 2H), 3.68 (s, 2H), 4.24 (q, 2H), 6.90 (s, 2H), 7.05 (m, 1H), 7.15 (m, 3H)ppm.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.[OH-].[Na+:22]>C(O)C>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:7]=[CH:6][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1.[Na+:22]
Reactant: O=S(=O)(O)c1ccc(O)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1

Procedure:
To a solution of 4-hydroxybenzenesulfonic acid (5.13 grams, 22.1 mmole) in 1N aqueous sodium hydroxide solution (23 mL) was added a solution of 4-fluorobenzylbromide (3.3 mL, 26.5 mmole) in ethanol (20 mL). The resulting mixture was heated at reflux for 2 days. Upon cooling and standing, a white solid precipitated. The precipitated product, sodium 4-(4-fluorobenzyloxy)benzenesulfonate, 4.95 grams (74%) was collected by filtration and washed with ethyl acetate and diethyl ether.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH3:4].[C:6]([SiH2:10][O:11][C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[N:14]=[CH:15][C:16]([NH2:19])=[N:17][CH:18]=1)([CH3:9])([CH3:8])[CH3:7].C([O-])(O)=O.[Na+]>COCCOC.S1(CCCC1)(=O)=O>[C:6]([SiH2:10][O:11][C:12]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]1[N:14]=[CH:15][C:16]2[N:17]([CH:2]=[C:3]([CH3:4])[N:19]=2)[CH:18]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1cnc(N)cn1
Reactant: CC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S1(=O)CCCC1
Solvent: COCCOC
Product: Cc1cn2cc(C(O[SiH2]C(C)(C)C)(c3ccccc3)c3ccccc3)ncc2n1
Temperature: 50 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
Bromoacetone (4.3 g, 31.4 mmol, 2.9 equiv) is added to a solution of 5-(tert-butyl-diphenyl-silanyloxymethyl)-pyrazin-2-ylamine (4.0 g, 10.7 mmol) in 1,2-dimethoxyethane (20 ml) and sulfolane (20 ml). The reaction mixture is stirred overnight at 50° C. Then a 10% aqueous solution of NaHCO3 (30 ml) is added, and the mixture is heated to reflux for 1 hour. After cooling, the mixture is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (hexane/EtOAc 3:1) affords the title compound (1.7 g, 40%). 1H NMR (400 MHz, d6-DMSO): δ=8.78 (d, J=0.9 Hz, 1H), 8.43 (d, J=1.4 Hz, 1H), 7.92 (s, 1H), 7.63-7.61 (m, 4H); 7.41-7.35 (m, 6H), 4.72 (s, 2H), 2.34 (s, 3H), 1.00 (s, 9H). MS (ES+): 402 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[C:14]([NH2:18])(=[O:17])[CH:15]=[CH2:16].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(N(CC)CC)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:11][CH:9]1[C:8](=[O:12])[NH:7][C:6]2[CH:13]=[C:2]([CH:16]=[CH:15][C:14]([NH2:18])=[O:17])[CH:3]=[CH:4][C:5]=2[O:10]1
Reactant: C=CC(N)=O
Reactant: CC1Oc2ccc(Br)cc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CO
Product: CC1Oc2ccc(C=CC(N)=O)cc2NC1=O
Yield: 36 %

Procedure:
726 mg of 6-bromo-2-methyl-1,4-benzoxazin-3-(4H)-one is stirred in 1.5 ml of triethylamine with 0.267 g of acrylamide as well as 8 mg of palladium(II) acetate and 46 mg of tri-ortho-toluyl-phosphine for several hours at 100° C. The product is taken up in methanol and purified by column chromatography with an ethanol/ethyl acetate mixture. Yield 36%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1.[Si:22]([O:29][CH2:30][C:31](=[CH2:35])[C:32](O)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>O1CCCC1>[Si:22]([O:29][CH2:30][C:31](=[CH2:35])[C:32]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]3[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:15][NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:5]=[CH:6][CH:7]=1)=[O:33])([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24]
Reactant: CCOC(=O)c1c[nH]c2ncnc(-c3cccc(N)c3)c12
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Product: C=C(CO[Si](C)(C)C(C)(C)C)C(=O)Nc1cccc(-c2ncnc3[nH]cc(C(=O)OCC)c23)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To ethyl 4-(3-aminophenyl)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylate (80 mg, 0.28 mmol) was added tetrahydrofuran (2.8 mL), TEA (59.2 μL, 0.425 mmol), 2-({[tert-butyl(dimethyl)silyl]oxy}methyl)prop-2-enoic acid (80 mg, 0.37 mmol) and 1-propanephosphonic acid cyclic anhydride (169 μL, 0.283 mmol). The reaction was stirred at 25° C. overnight before being quenched by pouring into a separatory funnel containing aqueous sodium bicarbonate (5%). The solution was extracted with ethyl acetate (×3) and the organic layers were combined and dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was then purified by silica chromatography by MPLC using 1-8% CH2Cl2MeOH. Concentration of the desired fractions afforded the title compound as a colorless solid. LRMS (ESI) calc'd for C25H33N4O4Si [M+H]+, 481; found 481.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[O:7]1[CH:11]=[CH:10][CH2:9][CH2:8]1>ClCCl>[C:1]([O:6][CH:8]1[CH2:9][CH2:10][CH2:11][O:7]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)O
Reactant: C1=COCC1
Solvent: ClCCl
Product: C=C(C)C(=O)OC1CCCO1
Temperature: 25 °C
Reaction time: 14 h
Yield: 34 %

Procedure:
To a solution of 10 g methacrylic acid in 10 ml dichloromethane was added a solution of 9.28 ml 2,3-dihydrofuran in 30 ml dichloromethane. The reaction was allowed to stir for 14 hr at room temperature. The mixture was washed with a saturated solution of sodium bicarbonate. The organic layer was dried with MgO/MgSO4 and concentrated in vacuo. The residue was distilled at 38° C./0.3 torr, to give 6.2 g (34% yield) of tetrahydrofuran-2-yl methacrylate. A solution of 6.0 g tetrahydrofuran-2-yl methacrylate and 0.066 g AIBN in 6 ml of MEK was heated to 60° C. for two days and 12 ml of MEK was added. This solution was used for further evaluation.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C([Li])CCC.[CH2:15](Cl)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:15]([CH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC=Cc1ccccc1
Reactant: C1=Cc2ccccc2C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C(=Cc1ccccc1)CC1C=Cc2ccccc21
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of 98% indene (364 mmoles) in 300 ml of THF was cooled to -78° C. under argon. An equimolar amount of n-butyllithium was added to the solution. The resulting mixture was allowed to warm to room temperature. It was then charged to an equimolar amount of 95% cinnamyl chloride (58.45 g) in 100 ml of THF at -30° C. The mixture was then allowed to warm to room temperature and react for one hour to form cinnamyl indene. The cinnamyl indene was concentrated down to a residue under strong vacuum, and then washed and concentrated twice with 100 ml of hexane. The residue was washed a third time with 100 ml of warm hexane and filtered while hot. The filtrate was again concentrated down to a residue under vacuum. The cinnamyl indene filtrate melted at 55-69° C. Recovery yield was 62%.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:12][N:11]([CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20](S(C4C=CC(C)=CC=4)(=O)=O)[C:21]([C:23]4[C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=5)[N:25]([CH3:36])[CH:24]=4)=[CH:22][C:15]=23)[CH2:10]1)(C)(C)C.[ClH:48]>>[ClH:48].[ClH:48].[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]([CH3:36])[CH:24]=[C:23]2[C:21]1[NH:20][C:16]2=[N:17][CH:18]=[CH:19][C:14]([CH2:13][N:11]3[CH2:10][CH:9]([CH2:8][NH2:7])[CH2:12]3)=[C:15]2[CH:22]=1
Reactant: COc1cc2c(-c3cc4c(CN5CC(CNC(=O)OC(C)(C)C)C5)ccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1OC
Agent: Cl
Product: COc1cc2c(-c3cc4c(CN5CC(CN)C5)ccnc4[nH]3)cn(C)c2cc1OC

Procedure:
{1-[2-(5,6-Dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-yl}methylamine dihydrochloride is prepared as described in Example 201 starting with 0.027 g of {1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-ylmethyl}carbamic acid tert-butyl ester instead of the {1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-yl}carbamic acid tert-butyl ester used in Example 201 and 1.35 cm3 of hydrochloric acid (4N in dioxane). 0.005 g of {1-[2-(5,6-dimethoxy-1-methyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]pyrid-4-ylmethyl]azetidin-3-yl}methylamine dihydrochloride is obtained, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH:11]=[CH:10]2)=[O:4]>C(O)C>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[S:13][CH2:12][CH2:11][CH2:10]2)=[O:4]
Reactant: COC(=O)c1cccc2c1SCC=C2
Solvent: CCO
Product: COC(=O)c1cccc2c1SCCC2
Yield: 67.6 %

Procedure:
Methyl-2H-thiochromene-8-carboxylate (1.83 g, 8.88 mmol) was dissolved in ethanol (100 ml) and treated with 10% PdC (1.5 g). The mixture was then hydrogenated at atmospheric pressure at room temperature. After 19 h the reaction mixture was filtered through celite and evaporated under reduced pressure to give a colourless oil which was dried in vacuo to give the title compound (1.25 g, 68%)
Reaction SMILES: C([O:8][C:9]1[N:14]=[C:13]2[NH:15][CH:16]=[N:17][C:12]2=[CH:11][CH:10]=1)C1C=CC=CC=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:15]2[C:13]3=[N:14][C:9]([OH:8])=[CH:10][CH:11]=[C:12]3[N:17]=[CH:16]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: c1ccc(COc2ccc3nc[nH]c3n2)cc1
Product: COc1ccc(-n2cnc3ccc(O)nc32)cc1

Procedure:
From 5-(benzyloxy)-3H-imidazo[4,5-b]pyridine and 4-methoxyphenylboronic acid, prepared in a similar manner as the one described in Example 1.25, Steps A and B, the title compound was obtained as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 3.9 (s, 3H), 6.92 (d, J=8.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.73 (d, J=8.8 Hz, 2H), 8.10 (d, J=8.8 Hz, 1H), 9.20 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[CH3:18][C@H:19]([NH:28][CH3:29])[C@H:20]([OH:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1.Cl.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:29][N:28]([C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2)[CH:19]([CH3:18])[CH:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[OH:27]
Reactant: CN[C@@H](C)[C@H](O)c1ccccc1
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1nc(N(C)C(C)C(O)c2ccccc2)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 120 °C
Reaction time: 20 h
Yield: 15.1 %

Procedure:
To a 5-mL, Wheaton vial were added 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1 (e)) (100 mg, 0.41 mmol) and ephedrine hydrochloride (Aldrich Chemical Company) (410 mg, 2.1 mmol), followed by addition of a solution of potassium carbonate (0.71 g, 5.1 mmol) in water (2.5 mL). The reaction mixture was stirred at 120° C. for 20 h, allowed to cool to room temperature and extracted with CH2Cl2. The organic layer was dried over Na2SO4, concentrated in vacuo to give a brown residue, which was purified by flash chromatography on silica gel with 1:1 EtOAc/hexanes as eluant to give 23 mg (15%) of the title compound as a tan solid. 1H NMR (DMSO-d6; 400 MHz): d 1.21 (d, 3, J=6.8), 2.42 (s, 3), 3.21 (s, 3), 4.91 (m, 1), 5.02 (m, 1), 5.87 (br s, 1), 6.69 (s, 1), 7.18-7.85 (m, 10), 10.73 (br s, 1). MS m/z: 373 (M+1), 371 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[C:13]([C:14]1[O:10][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:9][C:6]=2[CH:7]=1)(=[O:15])[CH3:12]
Reactant: CC(=O)CBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(=O)c1cc2cc(Br)ccc2o1
Yield: 87.8 %

Procedure:
5-Bromo salicylaldehyde (10.05 g), bromo acetone (8.0 g) and potassium carbonate (13.80 g) were refluxed for 1 hr in 2-butanone (100 ml). 2-Butanone (ca. 50 ml) was evaporated and ice was added. The precipitate was collected by filtration and washed with water and hexane to give the objective compound (10.50 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[N:9][C:8]([NH:11][C:12](=[O:31])[C@@H:13]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[C:22]([Cl:30])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][N:6]=1)=O.[BH4-].[Na+]>CO>[Cl:30][C:22]1[CH:21]=[C:20]([C@@H:13]([CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19]2)[C:12]([NH:11][C:8]2[CH:7]=[N:6][C:5]([CH2:3][OH:2])=[CH:10][N:9]=2)=[O:31])[CH:25]=[CH:24][C:23]=1[S:26]([CH3:29])(=[O:27])=[O:28]
Reactant: COC(=O)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(CO)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 58.6 %

Procedure:
A suspension of 5-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazine-2-carboxylic acid methyl ester (200 mg, 0.43 mmol) in methanol (2 mL) was cooled to 0° C. and then was treated with sodium borohydride (49.2 mg, 1.29 mmol). The reaction mixture was stirred at 0° C. for 5 min and then at 25° C. for 1.5 h. The reaction was cooled to 0° C. and then quenched with water. The reaction mixture was then diluted with ethyl acetate (75 mL), washed with a 1N aqueous hydrochloric acid solution (3×75 mL) and a saturated aqueous sodium chloride solution (75 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 3/2 ethyl acetate/hexanes) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-pyrazin-2-yl)-propionamide (110.4 mg, 59%) as a white foam: mp 78–81° C. (foam to gel); (ES)+-HRMS m/e calcd for C20H24ClN3O4S (M+H)+ 438.1249, found 438.1252.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:19]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:20]=3[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>C1(C)C=CC=CC=1>[Cl:1][C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[C:14]([O:18][C:19]3[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:20]=3[C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:13]=2)[NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]ccc2c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]cc(Cl)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-Chloro-succinimide (160 mg) was added portionwise to a solution of EXAMPLE 265A (300 mg) in toluene (10 mL) and the mixture was stirred at room temperature for about two hours. The mixture was chromatographed on a silica gel column with 30% ethyl acetate in hexane to give the title compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:29][C:30]([O:32]CC)=[O:31])[C:19]1=[O:35])[CH2:7][S:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:5])C.[OH-].[Na+].CO.C(O)(=O)C>O>[OH2:3].[C:4]([C@@H:6]([NH:17][CH:18]1[CH2:24][CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]([CH2:29][C:30]([OH:32])=[O:31])[C:19]1=[O:35])[CH2:7][S:8][CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CN1C(=O)C(N[C@@H](CSCCC2CCNCC2)C(=O)OCC)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)CN1C(=O)C(N[C@@H](CSCCC2CCNCC2)C(=O)O)CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.5 g of dihydrobromide of the A-isomer of ethyl 3-[1(R)-ethoxycarbonyl-2-{2-(4-piperidyl)ethylthio}ethyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetate obtained in Example 4 is dissolved in 10 ml of water. The resulting aqueous solution is added dropwise to 18 ml of an aqueous solution of 2N sodium hydroxide. After stirring for 1 hour at room temperature, 6 ml of methanol is added, and the system further stirred for 1 hour. After neutralizing the reaction liquid with 7.2 ml of acetic acid, the solvent is distilled off under reduced pressure. After concentration, the residue is purified by HP-20 column chromatography (water:methanol=3:1). The effluent is concentrated under reduced pressure, and the resulting residue is recrystallized from 5 ml of water to give 324 mg of the A isomer of 3-[1(R)-carboxy-2-{2-(4-piperidyl)ethylthio}ethyl]amino-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine-1-acetic acid monohydrate as a colorless powder.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][NH2:7])[CH3:5].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27].ClCCl>O.C(O)C>[CH2:4]([O:6][N:7]=[C:25]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH2:12][C:11]=1[OH:24])[CH2:26][CH3:27])[CH3:5]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)OCO3)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)OCO3)CC1=O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (0.15 g) in water and then ethoxyamine hydrochloride (0.37 g) were added to a solution of 3-hydroxy-5-(3,4-methylenedioxyphenyl)-2-propionylcyclohex-2-en-1-one (1.0 g) in ethanol (40 ml) The mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography (eluant dichloromethane). On completion of the reaction the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane and the organic phase was washed with water and dried over anhydrous sodium sulphate. The solvent was evaporated to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3,4-methylenedioxyphenyl)cyclohex-2-en-1-one as an oil.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.C(O)C.[BH4-].[Na+]>O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of 0.43 g of 11β-fluoro-3-hydroxy-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one in 4 ml of tetrahydrofiran, 2.3 ml of ethanol and 1 ml of water is mixed in portions at 0° C. with 111 mg of sodium borohydride, and it is stirred for 2 hours. Then, it is added to ice water, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/acetone. 0.32 g of 11β-fluoro-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol with [α]D22=+16.2° (c=0.51% in methanol) is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10](N2CCOCC2)=[O:11])[CH:7]=1.[CH3:22][Li]>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10](=[O:11])[CH3:22])[CH:7]=1
Reactant: [Li]C
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.59 g) in THF (1 mL) stirred under argon and cooled on dry ice/acetone was added methyl lithium (1.4 M in pentane, 2 mL) over 2 minutes. The mixture was stirred for 30 minutes and quenched with EtOH (0.3 mL). The mixture was warmed to room temperature and 1 mL of water was added. The organic phase was separated, washed, dried, filtered, and evaporated. The residue was fractionated over a short column of silica gel (eluent: hexanes-methylene chloride (1:1)) to give the title compound as an oil (0.36 g).