Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9](=[O:18])/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl.[CH2:20]([NH:27][OH:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH2:20]([N:27]1[CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:10][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])([OH:18])[O:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: ONCc1ccccc1
Reactant: O=C(/C=C/c1ccccc1)c1cc(F)ccc1F
Agent: Cl
Solvent: CCO
Product: OC1(c2cc(F)ccc2F)CC(c2ccccc2)N(Cc2ccccc2)O1

Procedure:
A mixture of (2E)-1-(2,5-difluorophenyl)-3-phenylprop-2-en-1-one (1-1) (500 mg, 2.05 mmol, 1 equiv) and N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was heated at reflux in ethanol (10 mL) for 4 h. Additional N-benzylhydroxylamine hydrochloride (327 mg, 2.05 mmol, 1.00 equiv) was added and the mixture was heated at reflux for 16 h. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and ethyl acetate (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenylisoxazolidin-5-ol (1-2); LRMS m/z (M+H) 368.3 found, 368.1 required. Methanesulfonyl chloride (0.093 uL, 1.20 mmol, 1.11 equiv) was added to a solution of (1-2) (400 mg, 1.09 mmol, 1 equiv) and triethylamine (0.455 mL, 3.27 mmol, 3.00 equiv) in dichloromethane (30 mL) at 0° C. and the resultant mixture was warmed to 23° C. and stirred for 30 min. The reaction mixture was partitioned between saturated sodium bicarbonate solution (50 mL) and dichloromethane (2×50 mL). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by flash column chromatography (silica, 100% hexanes initially, grading to 100% EtOAc) to give 2-benzyl-5-(2,5-difluorophenyl)-3-phenyl-2,3-dihydroisoxazole (1-3) as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.46-7.21 (m, 11H), 7.02 (m, 2H), 5.76 (t, 1H, J=3.0 Hz), 5.12 (d, 11H, J=2.8 Hz), 4.41 (d, 1H, J=12.8 Hz), 4.10 (d, 1H, J=12.8 Hz). LRMS m/z (M+H) 350.3 found, 350.1 required.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.COCCN(S(F)(F)[F:32])CCOC.C(=O)(O)[O-].[Na+]>O>[CH:1]([N:14]1[CH2:17][CH:16]([F:32])[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: FC1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C

Procedure:
A 250 mL, round bottom flask was charged with 3.0 g (12.5 mmol) of 1-benzhydryl-3-hydroxyazetidine and 80 mL of dichloromethane. To the stirring solution at −78° C. was added 4.6 mL (25 mmol) of [bis(2-methoxyethyl)amino]sulfur trifluoride via addition funnel over a period of about 3 h. The reaction mixture was allowed to warm slowly to ambient temperature overnight. The reaction mixture was added portionwise (with caution) to a large extractor containing water and saturated aqueous sodium bicarbonate solution. The mixture was extracted three times with 80 mL of dichloromethane. The combined organic layers were washed sequentially with saturated aqueous sodium bicarbonate solution, water and brine, dried over sodium sulfate, and concentrated in vacuo. Purification by flash chromatography using a Biotage® system (gradient, hexane to 80% ethyl acetate/hexane) afforded the desired product. LC/MS 242.1 (M+1).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:9]1[C:10]([CH3:31])=[C:11]([S:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[C:12](=[O:22])[N:13]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[N:14]=1)(=[O:8])[CH3:7].O>N1C=CC=CC=1>[C:6]([C:9]1[C:10]([CH3:31])=[C:11]([S:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:28][CH:29]=2)[C:12](=[O:22])[N:13]([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[N:14]=1)(=[O:8])[CH3:7]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(N)cc2)c1C
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)c1nn(-c2ccc(F)cc2)c(=O)c(Sc2ccc(NS(C)(=O)=O)cc2)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methanesulfonyl chloride (0.1 ml) was added to a solution of 6-acetyl-4-(4-aminophenylthio)-2-(4-fluorophenyl)-5-methyl-3(2H)-pyridazinone (185 mg) in pyridine (2 ml) at 5° C., followed by stirring at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. After washing with a saturated aqueous sodium hydrogen carbonate solution and a brine, the organic layer was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and was crystallized from ether to obtain 6-acetyl-2-(4-fluorophenyl)-5-methyl-4-(4-methylsulfonylaminophenylthio)-3(2H)-pyridazinone (180 mg) (Compound No. 4-01).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:32]([F:35])([F:34])[F:33].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=3[Cl:30])=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:32]([F:34])([F:35])[F:33]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc(C)c1Cl)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(C(=O)c2ncc(Cl)cc2NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1Cl
Temperature: 25 °C
Yield: 6.4 %

Procedure:
A mixture of 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (58.6 mg, 1.03 mmol) in 4 N HCl in dioxane (4 mL) and water (1 mL) was stirred at 100° C. for overnight. The reaction mixture was cooled to room temperature, evaporated to dryness and treated with saturated aqueous NaHCO3 solution till pH 7-8. The mixture was extracted with EtOAc (2×25 mL), dried (anhydrous Na2SO4) and concentrated. The obtained residue was purified via column chromatography (SiO2, 70% EtOAc in hexanes) to afford 4-chloro-N-[5-chloro-2-(2-chloro-3-methyl-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (34.5 mg) in 64% yield. 1H NMR (400 MHz, CDCl3) δ11.00 (s, 1H), 8.24 (d, 1H), 8.18 (m, 1H), 8.17 (d, 1H), 7.98 (dd, 1H), 7.63 (d, 1H), 7.35 (d, 1H), 7.24 (t, 1H), 7.1 (d, 1H), 2.37 (s, 3H); ESMS m/z (relative intensity): 522.9 (M+H)+ (100), 544.9 (M+Na)+ (100).
Reaction SMILES: [CH2:1]([NH:11][C:12]([O:14][C@H:15]([CH2:41][O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:16][S:17][CH2:18][C@H:19]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:20]([OH:22])=O)=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:89][CH2:90][CH2:91][O:92][CH2:93][CH2:94][O:95][CH2:96][CH2:97][O:98][CH2:99][CH2:100][P:101](=[O:108])([O:105][CH2:106][CH3:107])[O:102][CH2:103][CH3:104]>C(Cl)Cl>[CH2:106]([O:105][P:101]([CH2:100][CH2:99][O:98][CH2:97][CH2:96][O:95][CH2:94][CH2:93][O:92][CH2:91][CH2:90][NH:89][C:20](=[O:22])[C@@H:19]([NH:23][C:24](=[O:40])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:18][S:17][CH2:16][C@H:15]([O:14][C:12](=[O:13])[NH:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:41][O:42][C:43](=[O:55])[NH:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])(=[O:108])[O:102][CH2:103][CH3:104])[CH3:107]
Reactant: CCOP(=O)(CCOCCOCCOCCN)OCC
Reactant: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCCCCCC(=O)N[C@@H](CSC[C@@H](COC(=O)NCCCCCCCCCC)OC(=O)NCCCCCCCCCC)C(=O)NCCOCCOCCOCCP(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-3-((R)-2,3-bis(decylcarbamoyloxy)propylthio)-2-palmitamidopropanoic acid and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (2.4 eq), followed by diethyl 2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethylphosphonate (1.2 eq, from example 18, step 4). The reaction was stirred at room temperature for 4 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-10% MeOH/DCM to afford the title compound as an off-white oil.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][C:11]([OH:13])=[O:12].S(Cl)(Cl)=O.[CH3:18]O>>[CH3:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][C:11]([O:13][CH3:18])=[O:12]
Reactant: CO
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1CC(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)Cc1c(C)[nH]c(=O)[nH]c1=O
Yield: 97 %

Procedure:
2-(6-Methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)acetic acid (5.17 g; 28,1 mmol) was suspended in methanol (70.2 mL) and to the stirred mixture was added thionyl chloride (40.7 ml; 562 mmol) dropwise at 0° C. The mixture was stirred under reflux for 12 h. After cooling, the white precipitate was filtered off, washed with methanol and dried under reduced pressure with phosphorus pentoxide to give 5.4 g (97%) of the title compound as a white solid.
Reaction SMILES: Cl[CH:2]([O:4][C:5](=[O:32])[N:6]([C:29](=[O:31])[CH3:30])[CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[CH3:3].[CH:33]1([C:38]([O-:40])=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1.[Cs+].[I-].[Na+].O>C(#N)C>[C:29]([N:6]([CH2:7][C@@H:8]1[O:12][C:11](=[O:13])[N:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:25][CH2:24][S:23](=[O:27])(=[O:26])[CH2:22][CH2:21]3)=[C:16]([F:28])[CH:15]=2)[CH2:9]1)[C:5]([O:4][CH:2]([O:40][C:38]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=[O:39])[CH3:3])=[O:32])(=[O:31])[CH3:30]
Reactant: O=C([O-])C1CCCC1
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)Cl
Agent: [Cs+]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)N(C[C@H]1CN(c2ccc(C3CCS(=O)(=O)CC3)c(F)c2)C(=O)O1)C(=O)OC(C)OC(=O)C1CCCC1
Temperature: 25 °C
Yield: 63 %

Procedure:
Acetyl-{3-[4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-3-fluoro-phenyl]-2-oxo-oxazolidin-5(R)-ylmethyl}-carbamic acid 1-chloro-ethyl ester (11) (0.20 g, 0.41 mmol), cesium cyclopentanecarboxylate (0.20 g, 0.81 mmol) and sodium iodide (0.061 g, 0.41 mmol) in acetonitrile (15 mL) were heated to reflux overnight. Upon cooling to RT, water was added and the reaction mixture was extracted with ethyl acetate and then with dichloromethane. The organic phases were washed with brine, combined, dried over magnesium sulfate, filtered, and conc in vacuo. The isolated residue was subjected to silica gel flash chromatography, eluting with MeOH/CH2Cl2 gradient (0-4% MeOH over 1 hour and 20 minutes) to afford the title compound. Isolated yield: 63%. 1H NMR (400 MHz, DMSO-d6): δ 7.39 (dd, 1H), 7.35-7.31 (m, 1H), 7.24-7.20 (m, 1H), 6.73-6.69 (m, 1H), 4.74-4.70 (m, 1H), 4.12-3.93 (m, 2H), 3.88-3.73 (m, 2H), 3.39-3.28 (m, 2H), 3.26 (s, 3H), 3.18-3.11 (m, 1H), 3.06-3.03 (m, 2H), 2.76-2.68 (m, 1H), 2.37 (d, 3H), 2.15-2.06 (m, 2H), 2.00-1.97-(m, 2H), 1.80-1.70 (m, 2H), 1.68-1.56 (m, 2H), 1.54-1.43 (m+dd, 4H).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:32])[CH:5]([CH:21]([OH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:6]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])([O:8][Si](C)(C)C)[CH:7]=1.N1C=CC=CC=1.N1C=CC=CC=1.F.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:1][S:2][C:3]1[C:4](=[O:32])[CH:5]([CH:21]([OH:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])[C:6]([OH:8])([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=1
Reactant: CCCCCCCCC1(O[Si](C)(C)C)C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCC1(O)C=C(SC)C(=O)C1C(O)CCCCCC(=O)OC
Reaction time: 18 h
Yield: 41 %

Procedure:
To a solution of 63 mg of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-octyl-4-trimethylsilyloxy-2-cyclopentenone obtained in Example 71 dissolved in 6 ml of acetonitrile was added 130 μl of pyridine. A hydrogen fluoride-pyridine solution (260 μl) was added, and the mixture was stirred for 18 hours. The reaction mixture was poured onto saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. After filtration and concentration, the concentrate was subjected to silica gel column chromatography to give 22 mg (yield 41%) of 2-methylthio-5-(1-hydroxy-6-methoxycarbonylhexyl)-4-hydroxy-4-octyl-2-cyclopentenone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@@H:15]([OH:16])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:5][CH:4]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]2[C@@H:15]([O:16][C:34](=[O:36])[CH3:35])[C:14](=[O:17])[N:13]([CH2:18][CH2:19][N:20]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH3:21])[C:12]3[CH:29]=[CH:30][C:31]([Cl:33])=[CH:32][C:11]=3[S:10]2)=[CH:7][CH:8]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2O)cc1
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3cc(Cl)ccc3N(CCN(C)Cc3ccccc3)C(=O)[C@@H]2OC(C)=O)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 1.02 g of (±)-cis-2-(4-methoxyphenyl)-3-hydroxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one, 10 ml of acetic anhydride and one ml of pyridine is stirred at 100° C. for 3 hours. Then, the mixture is evaporated under reduced pressure. Benzene is added to the mixture, and the mixture is evaporated to remove solvent. 0.65 g of (±)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-[2-(N-benzyl-N-methylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepin-4(5H)-one is obtained.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:19](=[O:20])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCCCCBr
Reactant: CC(=O)N1CCc2ccccc21
Product: CC(=O)N1CCc2cc(C(=O)CCCCCBr)ccc21

Procedure:
Using 1-acetylindoline and 6-bromohexanoyl chloride according to the same method as that of Reference Example 1, the title compound (1.27 g) was obtained as colorless crystals having a melting point of 110 to 111° C.
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][N:9]=1)(C)(C)C.Cl[C:36]1[N:37]=[C:38]([N:56]2[CH2:61][CH2:60][O:59][CH2:58][CH2:57]2)[C:39]2[CH:44]=[C:43]([CH2:45][N:46]3[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][CH2:47]3)[S:42][C:40]=2[N:41]=1>>[CH3:55][S:52]([N:49]1[CH2:50][CH2:51][N:46]([CH2:45][C:43]2[S:42][C:40]3[N:41]=[C:36]([C:11]4[CH:12]=[CH:13][C:8]([CH2:7][OH:6])=[N:9][CH:10]=4)[N:37]=[C:38]([N:56]4[CH2:57][CH2:58][O:59][CH2:60][CH2:61]4)[C:39]=3[CH:44]=2)[CH2:47][CH2:48]1)(=[O:54])=[O:53]
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4ccc(CO)nc4)nc3s2)CC1

Procedure:
2-(tert-Butyl-diphenyl-silanyloxymethyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine was reacted with 2-chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[2,3-d]pyrimidine in General Procedure A. Purification on silica yielded 362. NMR: (CDCl3): 2.58-2.60 (4H, m), 2.73 (3H, s, Me), 3.20-3.22 (4H, m), 3.75 (2H, s), 3.81-3.84 (4H, m), 3.90-3.92 (4H, m), 4.76 (2H, s, NH2), 6.92 (1H, s, Ar), 7.25 (1H, d, J 8.3, Ar), 8.61 (1H, d, J 8.3, Ar) and 9.51 (1H, s, Ar). MS: (ESI+): MH+=505.14
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]([C:12](=O)[CH2:13][CH2:14][C:15]([OH:17])=O)[S:10][CH:11]=1.O.[NH2:20][NH2:21]>O>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:8]=[C:9]([C:12]2[CH2:13][CH2:14][C:15](=[O:17])[NH:20][N:21]=2)[S:10][CH:11]=1
Reactant: NN
Reactant: O=C(O)CCC(=O)c1cc(Cc2ncc[nH]2)cs1
Solvent: O
Product: O=C1CCC(c2cc(Cc3ncc[nH]3)cs2)=NN1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 5.6 g of 4-[4-(1-imidazolylmethyl)-thien-2-yl]-4-oxobutyric acid, 1.1 g hydrazine hydrate and 50 ml water was stirred for 2 hours at 90° C. After cooling, the precipitated solid was filtered off, washed with water and dried.
Reaction SMILES: Cl[S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])(=[O:4])=[O:3].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(Cl)Cl>[N:18]1([S:2]([CH2:5][C@H:6]([CH3:17])[C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])(=[O:4])=[O:3])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNCC1
Reactant: C[C@@H](CS(=O)(=O)Cl)C(=O)OCc1ccccc1
Solvent: ClCCl
Product: C[C@@H](CS(=O)(=O)N1CCCCC1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A 100 mL round bottom flask equipped with magnetic stir bar was charged with 1 g benzyl 3-chlorosulfonyl-2(R)-methylpropionate from Example 3 in 25 mL CH2Cl2. The solution was cooled to 0° C. and 4 mL of piperdine was slowly added. The reaction was stirred 1 hour then concentrated in vacuo. The residue was partioned between ethyl acetate and water. The organic phase was washedwith brine, dried, and concentrated in vacuo to give 1 g of benzyl 3-(1-piperidinyl)sulfonyl-2(R)-methylpropionate suitable for use without further purification.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]([N:14]2[CH2:20][CH2:19][CH2:18][C@H:17]([N:21]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[C:31]([C:39]([F:42])([F:41])[F:40])[CH:30]=3)[C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:16]3[CH:43]=[C:44]([CH3:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:15]2=3)=[O:13])[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+].Cl>CO.O>[C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]([N:14]2[CH2:20][CH2:19][CH2:18][C@H:17]([N:21]([CH2:28][C:29]3[CH:34]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:32]=[C:31]([C:39]([F:41])([F:40])[F:42])[CH:30]=3)[C:22]3[N:23]=[N:24][N:25]([CH3:27])[N:26]=3)[C:16]3[CH:43]=[C:44]([CH3:51])[C:45]([C:47]([F:50])([F:49])[F:48])=[CH:46][C:15]2=3)=[O:13])[CH2:7][CH2:6]1)([OH:4])=[O:2]
Reactant: COC(=O)C1CCC(OC(=O)N2CCC[C@H](N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3nnn(C)n3)c3cc(C)c(C(F)(F)F)cc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc2c(cc1C(F)(F)F)N(C(=O)OC1CCC(C(=O)O)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Temperature: 60 °C

Procedure:
To a solution of (S)-5-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid 4-methoxycarbonyl-cyclohexyl ester (0.14 mmol) in methanol (5 mL), add 5N sodium hydroxide (14 mmol). After heating the mixture at 60° C. for 2 h, cool to room temperature and dilute with water (20 mL). Neutralize the mixture using 5M HCl and extract the organics using ethyl actate (3×5 mL). Dry the combined organics over sodium sulfate, filter, and remove the solvent under vacuum. Chromatograph the crude product over silica gel, eluting with methanol/dichloromethane (0-5%) to obtain the separated cis and trans isomers. MS (ES+): 723 (M+H).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[O:4].C([O-])(=O)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=O)=[CH:15][CH:14]=1.O>C(O)(=O)C>[OH:4][C:3]1[N:2]=[N:1][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[N:5]=1
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Reactant: NNC(N)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(-c2nnc(O)nc2-c2ccc(OC)cc2)cc1
Yield: 95 %

Procedure:
Semicarbazide chlorohydrate (2.22 g, 20 mmol) and sodium acetate (1.80 g, 22 mmol) are added to a solution of 1,2-bis(4-methoxyphenyl)-ethane-1,2-dione (5.4 g, 20 mmol) prepared according to example 1 in acetic acid (25 ml). The mixture is heated at reflux for 12 hours. After returning to ambient temperature, the reaction mixture is poured into water. The raw reaction product is collected by filtration and washed with water. The residue is recrystallized in acetic acid. After filtration and washing in water, 5.9 g (95%) of a yellow solid is obtained after drying. δH (200 MHz, CDCl3), 3.86 (s; 6H), 6.94 (m; 4H), 7.67 (s; 4H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[C:19](=[N:32][C:33]1[S:34][C:35](Br)=[C:36]([CH3:38])[N:37]=1)([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>O.O1CCOCC1>[C:19](=[N:32][C:33]1[S:34][C:35]([C:7]2[CH:8]=[CH:9][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[C:36]([CH3:38])[N:37]=1)([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
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: Cc1nc(N=C(c2ccccc2)c2ccccc2)sc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(-c2sc(N=C(c3ccccc3)c3ccccc3)nc2C)cc1

Procedure:
4-Acetylphenyl boronic acid (1.8 g, 0.011 mol, 1.1 eq), tetrakistriphenylphosphine palladium(0) (0.7 g, 0.6 mmol), caesium carbonate (9.8 g, 0.03 mol) in water (10 ml), are added to a solution of benzhydrylidene-(5-bromo-4-methyl-thiazol-2-yl)-amine (3.5 g, 0.01 mol) in dioxane (80 ml) and heated at reflux for 6 h. The solvent is removed in vacuo, to yield an oily suspension which is partitioned between DCM (75 ml) and sat. sodium bicarbonate (75 ml). The layers are separated and the organics washed with water (75 ml) and brine (75 ml), dried (MgSO4 and charcoal), filtered and evaporated to a brown solid.