Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH2:9][C@@H:10]([F:17])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:21][CH:20]=2)[N:3]=1.C(O)C.[O-2].[Mg+2].[H][H]>[C].[Pd].C1C=CC=CC=1.O>[F:17][C@@H:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8][C:7]1[CH:6]=[N:5][C:4]([C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:23][CH:24]=2)=[N:3][CH:2]=1
Reactant: [H][H]
Reactant: CCCCCCCCCCc1ccc(-c2nc(Cl)c(CC[C@@H](F)CCCCCC)c(Cl)n2)cc1
Agent: [Pd]
Agent: [Mg+2]
Agent: [O-2]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCCCCCCc1ccc(-c2ncc(CC[C@@H](F)CCCCCC)cn2)cc1
Yield: 69 %

Procedure:
72 mg of palladium-carbon (palladium=about 5%), 372 mg (0.73 mM) of (S)-4,6-dichloro-(5-3-fluorononyl)-2-(4-decylphenyl)pyrimidine, 5 ml of 99%-ethanol, 118 mg (2.92 mM) of magnesium oxide and 0.3 ml of distilled water were placed in a two-necked round-bottomed flask and subjected to hydrogen addition for 5 hours at 60° C. After the reaction, benzene was added to the reaction mixture and the catalyst as removed from the reaction mixture, followed by distilling-off of the solvent and purification by thin-layer chromatography (eluent: benzene; Rf=0.5) to obtain 222 mg (0.50 mM) of (S)-5-(3-fluorononyl)-2-(4-decylphenyl)pyrimidine (crude product). The crude product was recrystallized from hexane to obtain an objective product (Yield: 69.2%).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:22]=[CH:21][C:8]([CH2:9][S:10][C@@H:11]2[CH2:15][N:14]([CH3:16])[C@H:13]([C:17]([O:19]C)=[O:18])[CH2:12]2)=[CH:7][CH:6]=1.Cl>CO>[C:17]([C@@H:13]1[CH2:12][C@H:11]([S:10][CH2:9][C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:22][CH:21]=2)[CH2:15][N:14]1[CH3:16])([OH:19])=[O:18]
Reactant: COC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 120.2 %

Procedure:
5.32 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 1.31 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methoxycarbonyl-1-methylpyrrolidine dissolved in 11 ml of methanol, and the mixture was stirred at room temperature for 2 hours. At the end of this time, it was neutralized with 5.32 ml of 1N aqueous hydrochloric acid, and the reaction mixture was freed from the solvent by evaporation under reduced pressure, and the residue was dried and concentrated by evaporation under reduced pressure, to afford 1.5 g of crude (2S, 4S)-2-carboxy-4-(4-methoxybenzylthio)-1-methylpyrrolidine.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[C:5](=[C:10]([NH:14][CH2:15][C:16]2[O:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[CH:20]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8]C)=[O:7].COCCNC1C=CC=C(C(O)=O)C=1C(O)=O>>[O:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=[C:16]1[CH2:15][NH:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:4]([C:3]([OH:25])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: COC(=O)c1cccc(NCc2cc3ccccc3o2)c1C(=O)OC
Agent: COCCNc1cccc(C(=O)O)c1C(=O)O
Product: O=C(O)c1cccc(NCc2cc3ccccc3o2)c1C(=O)O

Procedure:
3-[(Benzofuran-2-ylmethyl)-amino]-phthalic acid dimethyl ester (1.12 g, 3.3 mmol) was treated in the same manner as described above for the synthesis of 3-(2-methoxy-ethylamino)-phthalic acid. The product of the reaction, which contained a mixture of diacid and monomethyl esters, was used without further purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21])C1C=CC=CC=1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[OH:8][C:9]1[CH:10]=[C:11]([CH2:23][C:24]([CH3:29])([CH3:28])[CH2:25][C:26]#[N:27])[CH:12]=[CH:13][C:14]=1[N:15]1[CH2:19][C:18](=[O:20])[NH:17][S:16]1(=[O:22])=[O:21]
Reactant: CC(C)(CC#N)Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CC(C)(CC#N)Cc1ccc(N2CC(=O)NS2(=O)=O)c(O)c1
Reaction time: 6 h

Procedure:
A mixture of 4-[3-benzyloxy-4-(1,1,4-trioxo-1,2,5-thiadiazolidin-2-yl)-phenyl]-3,3-dimethylbutyronitrile (25 mg) and Pd(OH)2 (25 mg) in EtOAc (5 mL) is hydrogenated at 1 atm for 6 h. The catalyst is filtered and the filtrate evaporated. The residue is purified by preparative HPLC to give the title compound: (M−1)−=322.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[NH:35][C:36](=[NH:38])[CH3:37]>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:38]=[C:36]([CH3:37])[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC(=N)NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (596 mg, 2.00 mmol) in dichloromethane (8ml) was treated with 1,1′-carbonyldiimidazole (364 mg, 2.25 mol) and the solution was stirred at room temperature for 15 minutes. The N-hydroxyacetamidine (Chem.Ber.; 17; 1884; 2746) (148 mg, 2.00 mmol) was then added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was heated neat under a nitrogen atmosphere for 90 minutes. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane to afford the title compound (385 mg).
Reaction SMILES: [F:1][C:2]1[C:3]([C:11]#[N:12])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1F.[OH-].[NH4+:14]>CN(C=O)C.O>[NH2:14][C:7]1[C:6]([F:9])=[C:5]([F:10])[N:4]=[C:3]([C:11]#[N:12])[C:2]=1[F:1]
Reactant: [NH4+]
Reactant: N#Cc1nc(F)c(F)c(F)c1F
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1nc(F)c(F)c(N)c1F
Reaction time: 0.25 h
Yield: 92 %

Procedure:
To a solution of 3,4,5,6-tetrafluoro-2-cyanopyridine in DMF (75 mL) at 0C was slowly added concentrated ammonium hydroxide (15 mL). The reaction was stirred and additional 15 min and the solution was diluted with water (150 mL). The solid was collected and air dried to give 4-amino-3,5,6-trifluoro-2-cyanopyridine (25.5 g, 0.16 mol, 92%); mp 291-30 C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:11])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH2:22]([N:24]=[C:25]=[O:26])[CH3:23]>C1COCC1>[CH2:22]([NH:24][C:25]([N:6]1[CH:7]=[C:2]([F:1])[C:3]([NH:9][C:10]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH3:21])=[O:11])=[N:4][C:5]1=[O:8])=[O:26])[CH3:23]
Reactant: COc1ccccc1CNC(=O)Nc1nc(=O)[nH]cc1F
Reactant: CCN=C=O
Solvent: C1CCOC1
Product: CCNC(=O)n1cc(F)c(NC(=O)NCc2ccccc2OC)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 48.3 %

Procedure:
To a suspension of 1-(5-fluoro-2-oxo-1,2-dihydropyrimidin-4-yl)-3-(2-methoxybenzyl)urea (as prepared in U.S. Patent Appl. Publ. 2010022538; 0.25 g, 0.855 mmol) in dry THF (5 mL) was added ethyl isocyanate (0.074 mL, 0.941 mmol), and the mixture was stirred at room temperature for 3 h. The solvent was removed in vacuo, and the solid residue was suspended in Et2O (10 mL). The suspension was suction filtered and washed with Et2O (2×10 mL). The resulting solid was dried in vacuo to yield N-ethyl-5-fluoro-4-(3-(2-methoxybenzyl)ureido)-2-oxopyrimidine-1(2H)-carboxamide (0.150 g, 48%) as a white solid: mp 248-250° C.; 1H NMR (300 MHz, DMSO-d6) δ 10.56 (s, 1H), 9.92 (s, 1H), 9.68 (s, 1H), 8.55 (d, J=6.6 Hz, 1H), 7.33-7.20 (m, 2H), 7.02 (d, J=7.9 Hz, 1H), 6.91 (dd, J=7.9, 6.9 Hz, 1H), 4.41 (d, J=6.0 Hz, 2H), 3.88 (s, 3H), 3.38-3.24 (m, 2H), 1.14 (t, J=7.2 Hz, 3H). ESIMS m/z 362 ([M−H]−).
Reaction SMILES: [Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C@@H:12]([OH:14])[CH3:13].C[N+]1([O-])CCOCC1>C(#N)C.C(OCC)(=O)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Br:1]/[CH:2]=[C:3]1\[CH2:4][CH2:5][CH2:6][C@@:7]2([CH3:15])[C@H:11]\1[CH2:10][CH2:9][C@@H:8]2[C:12](=[O:14])[CH3:13]
Reactant: C[C@H](O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)[C@H]1CC[C@H]2/C(=C/Br)CCC[C@]12C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
Under a nitrogen atmosphere, a solution of (S)-1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanol (Compound 18: 58.1 mg, 0.2127 mmol) and N-methylmorpholine-N-oxide (37.4 mg, 0.3190 mmol) in acetonitrile (2 ml) was cooled in an ice bath, and tetra-n-propylammonium perruthenate (3.7 mg, 0.01064 mmol) was added thereto. The reaction mixture was stirred at the same temperature for 5 minutes, and at room temperature (22° C.) for 50 minutes, and the resulting mixture was diluted with ethyl acetate. The mixture was filtered through Celite, and the solids were washed with ethyl acetate, followed by evaporation of the filtrate under reduced pressure. The obtained crude product was purified by flash column chromatography to obtain 1-{(E,3S,3aS,7aR)-7-(bromomethylene)-octahydro-3a-methyl-1H-indene-3-yl}ethanone (58.2 mg, 100%). The spectrum data thereof agreed with the data described in Example 7.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][CH2:8][CH2:9][SH:10].[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]([C:23](F)=[O:24])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12]>O.C(Cl)Cl>[C:11]([O:15][C:16](=[O:26])[NH:17][C@@H:18]([C:23](=[O:24])[NH:7][CH2:8][CH2:9][SH:10])[C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:14])([CH3:12])[CH3:13]
Reactant: NCCS
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)F)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)NCCS)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a 25 mL round-bottom flask charged with a solution of sodium bicarbonate (83.0 mg, 0.99 mmol) in 4.8 mL water was added 2-aminoethanethiol hydrochloride (60.3 mg, 0.53 mmol). To this stirring solution was added dropwise over 60 seconds a solution of 25h (112.6 mg, 0.48 mmol) in 4.8 mL CH2Cl2. The reaction was vigorously stirred for 25 minutes at room temperature, then extracted twice with fresh CH2Cl2. The combined CH2Cl2 extracts were washed once with 5% aqueous HCl, once with 10% aqueous sodium bicarbonate, then once with water. The organic fraction was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to afford 26h as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.C(OCC)C.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]2)=[CH:21][CH:20]=1.C(N(CC)CC)C>[Cl-].[Cl-].[Zn+2].ClCCCl.CC(O)(C)C>[Cl:8][C:6]1[C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=[C:2]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([CH:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:26]3)=[CH:23][CH:24]=2)[N:7]=1
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(N)cc2)C1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCCl
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
2,4-Dichloro-5-(trifluoromethyl)pyrimidine (0.355 g, 1.64 mmol) was stirred in a 1:1 t-BuOH:1,2-dichloroethane mixture (30 mL) at 0° C. and a 1.0 M ZnCl2 solution in diethyl ether (1.87 mL, 1.87 mmol) was added cautiously over 20 minutes and the reaction was left stirring at 0° C. for 30 minutes. A solution of tert-butyl 3-(4-aminophenyl)piperidine-1-carboxylate (I23) (0.431 g, 1.56 mmol) in 1:1 t-BuOH:1,2-dichloroethane (10 mL) was added drop-wise over 15 minutes at 0° C. followed by a solution of triethylamine (0.261 μL, 1.871 mmol) in 1:1 t-BuOH:1,2-dichloroethane (10 mL). The reaction was allowed to warm to room temperature and was stirred for 60 hours. Volatiles were evaporated in vacuo and the resulting oily residue was suspended in water (200 mL), the suspension was sonicated for 30 minutes and the product was collected by filtration, the solid was washed with water (5×10 mL) and dried under a high vacuum to give the title compound (I24) (0.638 g, 90% yield) as a pale pink solid; 1H NMR (400 MHz, d6-DMSO) δ 10.62 (s, 1H), 8.78 (s, 1H), 7.61 (d, J=8.5 Hz, 2H), 7.26 (d, J=8.6 Hz, 2H), 4.05-3.87 (m, 2H), 2.94-2.63 (m, 2H), 2.57 (ddd, J=11.2, 7.7, 3.7 Hz, 1H), 1.87 (d, J=12.8 Hz, 1H), 1.75-1.54 (m, 2H), 1.51-1.35 (m, 10H). LCMS Method C: rt 6.89 min; m/z 455.3 [M+H]−
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8](O/C(/C(OCC)=O)=C\C2C=CC=CC=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[F:39][C:40]1[CH:41]=[C:42]([CH2:46][C:47](=[O:53])[C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:43]=[CH:44][CH:45]=1.[H-].[Na+].[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@H](OC(=O)C)[C@@H](COC(=O)C)O[C@@H]1O)(=O)C>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:53]/[C:47](/[C:48]([O:50][CH2:51][CH3:52])=[O:49])=[CH:46]\[C:42]2[CH:43]=[CH:44][CH:45]=[C:40]([F:39])[CH:41]=2)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1cccc(F)c1
Agent: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Product: CCOC(=O)/C(=C/c1cccc(F)c1)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 19 %

Procedure:
The title compound was prepared as described for C4 using ethyl 3-(3-fluorophenyl)-2-oxopropanoate B5 (100 mg, 0.476 mmol), sodium hydride (13 mg, 0.523 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-glucose bromide (196 mg, 0.476 mmol). The compound was isolated in the form of white solid in 19% yield.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6](C(O)=O)/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9]O.C(OCC1C=CC([N+]([O-])=O)=CC=1)(=O)C=C>C(OCC)(=O)C>[CH:8]([C:7]1[O:11][C@H:2]2[N:3]([C:4](=[O:5])[CH2:1]2)[CH:6]=1)=[CH2:9]
Reactant: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: C=CC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Product: C=CC1=CN2C(=O)C[C@H]2O1

Procedure:
prepared from 1.01 g clavulanic acid according to Example 1) was dissolved in dry 1,2-dimeth xyethane (10 ml) containing hydroquinolinone (50 mg). p-Nitrobenzyl acrylate (1.8 g) was added to the solution which was then heated at 85° (bath temperature) with exclusion of moisture for 2.5 hours. The mixture was cooled, diluted with ethyl acetate (50 ml), and filtered. The solvent was evaporated from the filtrate under reduced pressure to give a yellow oil which was chromatographed on silica gel (15 g) using gradient elution from 1:7 to 1:3 ethyl acetate/petroleum ether (b.p. 60°-80°). In this way the title compound (Mixture of isomers) was obtained as a yellow gum (150 mg).
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[NH:5]2.C(C(CC)=O)C.N1C=CC=CC=1.[C:28](Cl)([Cl:30])=[O:29]>C1(C)C=CC=CC=1.O>[Cl:30][C:28]([N:5]1[C:6]2[CH:15]=[CH:14][CH:13]=[CH:12][C:7]=2[NH:8][C:9](=[O:11])[C:10]2=[CH:1][S:2][CH:3]=[C:4]12)=[O:29]
Reactant: O=C(Cl)Cl
Reactant: O=C1Nc2ccccc2Nc2cscc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: O=C1Nc2ccccc2N(C(=O)Cl)c2cscc21
Temperature: 40 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
16.2 gm (0.075 mol) of 4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one were admixed with 160 ml of diethylketone and 5.9 gm (0.075 mol) of pyridine at 40° C., and over a period of 20 minutes 75 ml of a 20% solution of phosgene (0.15 mol) in toluene were added thereto. The reaction mixture was stirred for 2 hours at 40° C. and then for 3 hours at 60° C. After cooling to room temperature, the mixture was stirred with 150 ml of water, then filtered, and the organic phase was separated, concentrated by evaporation in vacuo, and the residue was recrystallized from acetonitrile. 4-Chlorocarbonyl-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one, m.p. of 244°-245° C. (decomp.), was obtained with a yield of 50% of theory.
Reaction SMILES: [Na].[NH2:2][CH2:3][CH2:4][SH:5].Cl[C:7]1[S:11][C:10]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9][C:8]=1[C:16](OCC)=[O:17].Cl>C(O)C>[S:12]([C:10]1[S:11][C:7]2[S:5][CH2:4][CH2:3][NH:2][C:16](=[O:17])[C:8]=2[CH:9]=1)(=[O:14])(=[O:13])[NH2:15]
Reactant: NCCS
Reactant: CCOC(=O)c1cc(S(N)(=O)=O)sc1Cl
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NS(=O)(=O)c1cc2c(s1)SCCNC2=O
Reaction time: 0.08 h

Procedure:
To a round bottomed flask were added ethanol (200 mL) followed by solid sodium (1.0 g, 43.5 mmole). After the sodium dissolved, 2-aminoethanethiol was added (1.57 g, 20.4 mmole). The reaction was stirred for approximately 5.0 minutes and 5-chloro-4-carboethoxythiophene-2-sulfonamide (5.0 g, 18.5 mmole) was added. The reaction was heated at reflux for 24 hrs. The cooled reaction mixture was acidified (6.0N HCl) and the solvent was removed under vacuum. The residue was triturated with water and the resulting solid collected: 4.77 g (98%) mp>270° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(N(CC)CC)C>CCOCC>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([Cl:25])=[CH:27][CH:28]=3)[CH3:21])[CH2:18][CH2:19]2)=[C:10]([CH2:22][NH:23][CH3:24])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](NC)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CNCc1cc(C(=O)OC(C)(C)C)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
8 g (0.024 Mol) of trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-methylcyclohexylamine are reacted in 300 ml of ether with 4.6 g (0.026 Mol) of 4-chlorobenzoylchloride in the presence of 2.7 g (0.026 Mol) of triethylamine. 10.3 g of the title compound are obtained, melting point 152°-154° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([Si:7]([CH3:37])([CH3:36])[O:8][CH2:9][C@@H:10]([NH:20][C:21]1[C:26]([NH:27][CH2:28][C:29](OCC)=[O:30])=[CH:25][CH:24]=[C:23]([O:34][CH3:35])[N:22]=1)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:6])[CH3:5]>C1COCC1>[CH3:3][C:4]([Si:7]([CH3:36])([CH3:37])[O:8][CH2:9][C@@H:10]([N:20]1[C:29](=[O:30])[CH2:28][NH:27][C:26]2[CH:25]=[CH:24][C:23]([O:34][CH3:35])=[N:22][C:21]1=2)[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:6])[CH3:5]
Reactant: CCOC(=O)CNc1ccc(OC)nc1N[C@@H](COCc1ccccc1)CO[Si](C)(C)C(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(n1)N([C@@H](COCc1ccccc1)CO[Si](C)(C)C(C)(C)C)C(=O)CN2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.9 %

Procedure:
To a solution of NaH (50.5 g, 57-63% dispersion in mineral oil, 1.26 mol) in THF (8.5 L) was added ethyl N-[2-[((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)amino]-6-(methyloxy)-3-pyridinyl]glycinate (577.8 g, 1.147 mol) at −5° C. When the addition was complete the mixture was warmed to room temperature and stirred for 30 min. The reaction was quenched by the addition of saturated aqueous NH4Cl (610 ml) and the mixture was stirred for 10 min. Na2SO4 (1 kg) was added and the mixture was stirred for 10 min before being filtered through celite. The filter cake was washed with EtOAc (5 L). The filtrate was evaporated and the dark purple oil was purification by column chromatography and mixtures of heptane and EtOAc as eluent to give 477 g (91%) of 4-((1S)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-1-{[(phenylmethyl)oxy]methyl}ethyl)-6-(methyloxy)-1,4-dihydropyrido[2,3-b]pyrazin-3(2H)-one as a viscous purple oil.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[CH3:12])[C:5]([O:13][CH3:14])=[N:4][CH:3]=1.[Li]CCCC.CN([CH:23]=[O:24])C>C1COCC1>[CH3:14][O:13][C:5]1[C:6]2[C:11](=[C:10]([CH3:12])[CH:9]=[CH:8][CH:7]=2)[C:2]([CH:23]=[O:24])=[CH:3][N:4]=1
Reactant: CN(C)C=O
Reactant: COc1ncc(Br)c2c(C)cccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ncc(C=O)c2c(C)cccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
To a stirred solution of 4-bromo-1-methoxy-5-methylisoquinoline (Intermediate-6) (2 g, 7.9 mmol) in dry THF (20 mL) was added, n-BuLi (15 mL, 23.7 mmol) drop wise at −78° C. under N2 atmosphere and stirred for 1 h. To this, dry DMF (3 mL) was added and the reaction mixture was stirred at −78° C. for another 1 h. Then it was quenched with saturated NH4Cl solution, extracted with EtOAc (3×100 mL), washed with water (1×200 mL), dried over Na2SO4, filtered and concentrated to afford the title compound (1.2 g, 78%).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[C:3]#[CH:4].C([Mg]Cl)#C.O(C1C=CC(C=O)=CC=1)C1C=CC=CC=1.I[C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1/[C:40](=[CH:48]/[C:49]1[NH:50][CH:51]=[CH:52][C:53]=1[O:54][CH3:55])/[C:41](=[O:47])[NH:42]2>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)[C:3]#[C:4][C:38]1[CH:46]=[CH:45][CH:44]=[C:43]2[C:39]=1/[C:40](=[CH:48]/[C:49]1[NH:50][CH:51]=[CH:52][C:53]=1[O:54][CH3:55])/[C:41](=[O:47])[NH:42]2
Reactant: C#CC(O)c1ccc(Oc2ccccc2)cc1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#C[Mg]Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(O)c3ccc(Oc4ccccc4)cc3)c21

Procedure:
Using Method C above, 3-hydroxy-3-(4-phenoxyphenyl)-1-propyne (200 mg, 0.89 mmol) (prepared by the addition of ethynylmagnesium chloride (Aldrich) to 4-phenoxybenzaldehyde (Aldrich) according to Method A above) was coupled to (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2) (146 mg, 0.40 mmol) using (Ph3P)2PdCl2 (30 mg) (Aldrich) and CuI (16 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 16 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(4-phenoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 100 mg, 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[C:8](=[O:17])[C:9]([CH3:16])([S:11][C:12]([F:15])([F:14])[F:13])[CH3:10])=[CH:4][CH:3]=1.[BH4-].[Na+].O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH:8]([OH:17])[C:9]([CH3:16])([S:11][C:12]([F:13])([F:15])[F:14])[CH3:10])=[CH:23][CH:24]=1
Reactant: CC(C)(SC(F)(F)F)C(=O)C(Oc1ccc(Cl)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(SC(F)(F)F)C(O)C(Oc1ccc(Cl)cc1)n1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
10 g (0.026 mol) of 1-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylthio-butan-2-one (Example 1) were dissolved in 100 ml of methanol and 1 g (0.025 mol) of sodium borohydride was added in portions to the solution. The reaction mixture was further stirred at room temperature for 30 minutes and was thereafter introduced into water. The mixture was extracted with methylene chloride, and the organic phase was dried over sodium sulphate and concentrated in vacuo. The residue crystallized after a short time. 9.5 g (95% of theory) of 1-(4-chlorophenoxy)-3-methyl-1-(1,2,4-triazol-1-yl)-3-trifluoromethylthio-butan-2-ol of melting point 85°-87° C. were obtained.