Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[O:18][CH3:19].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>>[CH3:19][O:18][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21]
Reactant: COc1cc(C=Cc2ccccc2)cc(OC)c1Br
Reactant: CCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCc1c(OC)cc(C=Cc2ccccc2)cc1OC

Procedure:
This material was prepared from 2-bromo-1,3-dimethoxy-5-(2-phenylethenyl)benzene and 1-bromo-n-tetradecane by the same procedure as described in example 15. 1HNMR (CDCl3, ppm): δ 0.91 (m, 6H), 1.29 (m, 22H), 2.65 (m, 2H), 3.90 (s, 6H), 6.73 (s, 2H), 7.10 (s, 2H), 7.26 (m, 1H), 7.36 (m, 2H), 7.52 (m, 2H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=1.C(N(CC)CC)C.O>ClCCl>[C:1]1([S:7]([O:11][C:12]2[CH:13]=[CH:14][C:15]([CH3:18])=[N:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1ccc(O)cn1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(OS(=O)(=O)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Benzenesulfonyl chloride (12.9 mL, 101 mmol, 1.10 equiv) was added to a stirred solution of 5-hydroxy-2-methylpyridine (10.0 g, 91.6 mmol, 1 equiv) and triethylamine (15.3 mL, 110 mmol, 1.20 equiv) in dichloromethane (100 mL) at 0° C. After stirring for 2 h at 0° C., water (20 mL) was added and the resulting two-phase mixture was stirred vigorously for 1 h at 23° C. to quench any remaining sulfonyl chloride. Saturated aqueous potassium carbonate solution (100 mL) was added and the layers were separated. The aqueous layer was extracted with a second portion of dichloromethane (150 mL). The combined organic layers were dried over anhydrous potassium carbonate, filtered and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with a gradient of 4:1 to 1:1 of hexane and ethyl acetate to provide 4 (21.8 g, 95%) as an oil. Chromatography may be avoided by using exactly one equivalent of benzenesulfonyl chloride to afford product of sufficient purity for direct submission to benzylic bromination conditions (see below). IR (neat) 3066, 1594, 1480, 1450, 1384, 1286, 1204, 1177, 1093, 1024, 865, 837, 804, 757, 741, 724, 692; 1H NMR (CDCl3) 8.01(d, 1H, J=2.7), 7.84 (d, 2H, J=7.9), 7.70 (t, 1H, J=7.2), 7.55 (t, 2H, J=7.8), 7.33 (dd, 1H, J=8.5, 2.7), 7.13 (d, 1H, J=8.5), 2.53 (s, 3H). Anal. Calcd. for C12H11NO3S: C, 57.82; H, 4.45; N, 5.62. Found C, 57.66; H, 4.33; N, 5.47.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:24][C:23]([NH:30][S:31]([CH3:34])(=[O:33])=[O:32])=[C:22](I)[CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH3:36][CH:37]([CH3:42])[CH:38]([OH:41])[C:39]#[CH:40]>C1COCC1.CCN(CC)CC.CCOC(C)=O.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>[Si:1]([O:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:23](=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27])[N:30]([S:31]([CH3:34])(=[O:33])=[O:32])[C:39]([CH:38]([OH:41])[CH:37]([CH3:42])[CH3:36])=[CH:40]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([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: CC(C)(C)[Si](OCc1cc(I)c(NS(C)(=O)=O)cc1S(C)(=O)=O)(c1ccccc1)c1ccccc1
Reactant: C#CC(O)C(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C(O)c1cc2cc(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c(S(C)(=O)=O)cc2n1S(C)(=O)=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
PdCl2(PPh3)2 (277 mg, 0.38 mmol) and CuI (73 mg, 0.38 mmol) were added to a solution of N-(4-(((tert-butyldiphenylsilyl)oxy)methyl)-2-iodo-5-(methylsulfonyl)phenyl)methanesulfonamide (2.45 g, 3.8 mmol) in THF (20 mL) and Et3N (10 mL). The mixture was purged with nitrogen for 10 min followed by addition of 4-methylpent-1-yn-3-ol (745 mg, 7.6 mmol) and stirred at 65° C. for 8 h. The reaction mixture was diluted with EtOAc (50 mL) and washed with 1N HCl (50 mL). The organic layer was separated, and the aq layer was extracted with EtOAc (3×50 mL). The combined organic solution was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography over silica gel eluting with EtOAc/hexanes (3/7) to provide 1-(5-(((tert-butyldiphenylsilyl)oxy)methyl)-1,6-bis(methylsulfonyl)-1H-indol-2-yl)-2-methylpropan-1-ol (2.1 g, 90% yield). LC-MS m/z 614 [M+H]+. 1H NMR (400 MHz, CDCl3): δ 8.68 (s, 1H), 7.90 (s, 1H), 7.71-7.67 (s, 4H), 7.46-7.35 (m, 6H), 6.77 (s, 1H), 5.21 (d, J=3.2 Hz, 2H), 6.94 (t, J=6.8 Hz, 1H), 3.22 (s, 3H), 2.90 (s, 3H), 2.61 (d, J=6.8 Hz, 1H), 2.37-2.32 (m, 1H), 1.12 (s, 9H), 1.05 (d, J=6.8 Hz, 3H), 1.03 (d, J=6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 147.25, 135.54, 135.28, 135.00, 133.66, 133.00, 132.89, 129.96, 127.85, 121.68, 115.96, 108.69, 72.30, 62.98, 44.33, 41.59, 32.88, 26.89, 20.23, 19.30, 17.61.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16](Cl)(=[O:18])=[O:17])([O-:3])=[O:2].[NH4+:20].C(O)(=O)C>O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([NH:8][C:9](=[O:15])[C:10](=[O:14])[NH:11]2)=[CH:6][C:5]=1[S:16]([NH2:20])(=[O:18])=[O:17])([O-:3])=[O:2]
Reactant: [NH4+]
Reactant: O=c1[nH]c2cc([N+](=O)[O-])c(S(=O)(=O)Cl)cc2[nH]c1=O
Solvent: O
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc2[nH]c(=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Reaction time: 3 h
Yield: 17 %

Procedure:
A mixture of 4.58 g (0.015 mole) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxalinesulfonyl chloride and 30 ml of 25% ammonium hydroxyde is stirred at a temperature between 5° C. and 10° C. for 3 hours and then allowed to stand for 16 hours. To the mixture 6 ml of acetic acid and 40 ml of water are added, the separated crystals are filtered off, washed with water and acetone, dried and dissolved in a slight amount of hot dimethyl sulfoxide. The product is precipitated from this solution with 2-propanol. Thus 1.40 g (17%) of 1,2,3,4-tetrahydro-7-nitro-2,3-dioxo-6-quinoxaline sulfonamide are obtained, m.p.: >330° C.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([NH:9][C:10]([CH:12]3[CH2:14][CH2:13]3)=[O:11])[S:8][C:4]=2[CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1.C(N(CC)CC)C>CC(C)=O>[CH:12]1([C:10]([NH:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([O:1][S:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)(=[O:26])=[O:25])[CH:16]=[CH:15][C:5]=3[N:6]=2)=[O:11])[CH2:13][CH2:14]1
Reactant: O=C(Nc1nc2ccc(O)cc2s1)C1CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
A solution of cyclopropanecarboxylic acid (6-hydroxybenzothiazol-2-yl)amide (intermediate 6) (1.81 g, 7.72 mmol), 4-fluorobenzenesulfonyl chloride (1.5 g, 7.72 mmol) and triethylamine (2.14 ml, 15.45 mmol) in 43 ml of acetone, in a 100 ml round-bottomed flask equipped with a magnetic bar, is stirred for 1 hour at room temperature. The precipitate obtained is filtered off and the filtrate is evaporated. The residue is washed with acetone and ethyl ether, to give 1.92 g of 4-fluorobenzenesulfonic acid 2-(cyclopropanecarbonylamino)-benzothiazol-6-yl ester (off-white powder) in a yield of 66%.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH2:41][C:42]([Cl:45])([Cl:44])[Cl:43])=[O:39])[C:5]([NH:7][CH:8]1[C:33](=[O:34])[N:10]2[C:11]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:47][C:48]([NH2:50])=[S:49].C([O-])(=O)C.[Na+]>O1CCCC1.O>[NH2:50][C:48]1[S:49][CH:2]=[C:3]([C:4](=[N:35][O:36][CH2:37][C:38]([O:40][CH2:41][C:42]([Cl:44])([Cl:45])[Cl:43])=[O:39])[C:5]([NH:7][CH:8]2[C:33](=[O:34])[N:10]3[C:11]([C:17]([O:19][CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:18])=[C:12]([CH:15]=[CH2:16])[CH2:13][S:14][C@H:9]23)=[O:6])[N:47]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)C(=O)CBr)[C@H]2SC1
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OCC(Cl)(Cl)Cl)c3csc(N)n3)[C@H]2SC1
Temperature: 35 °C
Reaction time: 3 h
Yield: 49.5 %

Procedure:
To a solution of benzhydryl 7-[4-bromo-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)-3-oxobutyramido]-3-vinyl-3-cephem-4-carboxylate (26.0 g) in tetrahydrofuran (100 ml) was added a solution of thiourea (3.1 g) and sodium acetate (3.3 g) in water (100 ml), and the mixture was stirred at 35° C. for 3 hours. The reaction mixture was extracted with ethyl acetate, and the extract was washed with water, followed by drying over magnesium sulfate. Removal of the solvent gave benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-(2,2,2-trichloroethoxycarbonylmethoxyimino)acetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (12.5 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3].[N+:13]([O-])([OH:15])=[O:14].CCOC(C)=O>C(O)(=O)C.CCCCCC>[CH3:1][C:2]([C:4]1[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]2[O:10][CH2:11][O:12][C:6]=2[CH:5]=1)=[O:3]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1ccc2c(c1)OCO2
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(=O)c1cc2c(cc1[N+](=O)[O-])OCO2
Temperature: 0 °C

Procedure:
A solution of 50 g (0.305 mole) 3,4-methylenedioxy-acetophenone (Aldrich) in 200 mL glacial acetic acid was added dropwise over 30 minutes to 700 mL of cold (2-4° C.) 70% HNO3 with stirring (NOTE: the reaction will overheat without external cooling from an ice bath, which can be dangerous and lead to side products). At temperatures below 0° C., however, the reaction can be sluggish. A temperature of 3-5° C. seems to be optimal). The mixture was left stirring for another 60 minutes at 3-5° C., and then allowed to approach ambient temperature. Analysis by TLC (25% EtOAc in hexane) indicated complete conversion of the starting material within 1-2 hr. When the reaction was complete, the mixture was poured into ˜3 liters of crushed ice, and the resulting yellow solid was filtered off, washed with water and then suction-dried. Yield ˜53 g (84%), used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]([Cl:21])[CH:14]=1.CN(C)C1C=CC=CC=1.S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:19][C:17]1[CH:18]=[C:13]([CH:14]=[C:15]([Cl:21])[C:16]=1[OH:20])[NH:12][C:7](=[O:9])[C:6]1[CH:10]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:11]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(O)c1cc(F)ccc1O
Solvent: CN(C)c1ccccc1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1cc(F)ccc1O
Yield: 54.7 %

Procedure:
5Fluorosalicylic acid (5.15 g.) and 4-amino-2,6-dichlorophenol (5.88 g.) were well mixed to which was added benzene (10 ml.) and N,N-dimethylaniline (4.35 ml.). Then with stirring thionyl chloride (3.3 ml.) was added and refluxed 30 minutes. The resulting solution was evaporated and the residue was dissolved in ethyl acetate and subjected to decolorization with activated charcoal followed by washing with 2 N hydrochloric acid and 2.5% sodium bicarbonate solution. The ethyl acetate was then extracted several times with 2 N sodium carbonate solution and the aqueous extracts were combined and brought to pH 1-2 with hydrochloric acid to give a precipitate which was recrystallized from aqueous acetone to give white needle-like crystals (5.7 g.) of 3',5'-dichloro-2,4'-dihydroxy-5-fluorobenzanilide. Yield: 55%. Melting point: 227°-229° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH2:11][C@H:12]([C:20](O)=[O:21])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)(O)[O-].[Na+]>C(O)C.O>[CH2:13]([C@@H:12]1[NH:11][C:2]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[NH:8][C:20]1=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C1Nc2ccccc2N[C@H]1Cc1ccccc1
Reaction time: 8 h
Yield: 63.1 %

Procedure:
To ortho-fluoronitrobenzene (18) (6.5 g, 46 mmol) in ethanol (200 mL) and water (200 mL) under nitrogen was added L-phenylalanine (5.10 g, 31 mmol) and sodium bicarbonate (5.19 g, 62 mmol) and the suspension heated at reflux for 48 h. The red solution was coled, extracted with ether (2×50 mL—to remove any unreacted ortho-fluoronitrobenzene and concentrated to ½ volume. Pd/C (20%, 0.5 g) was added and a hydrogen balloon was attached. After stirring overnight the mixture was filtered, acidifed with 1N HCl to pH 4 and the solid that formed was collected. This was dried under high vacuum to afford the title compound (4.66 g, 53%) of sufficient purity (19) to use directly.
Reaction SMILES: Cl.[NH2:2][C@:3](OC(C)(C)C)([CH2:7][C:8]([N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:11][C:12](=[O:32])[C@@H:13]([C@@H:18]([C:28](=[O:31])[NH:29][OH:30])[CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:14][CH:15]([CH3:17])[CH3:16])=[O:9])[C:4]([OH:6])=[O:5].[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>ClCCl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[NH2:2][C@@H:3]([CH2:7][C:8]([N:10]([CH2:33][CH:34]([CH3:36])[CH3:35])[NH:11][C:12](=[O:32])[C@@H:13]([C@@H:18]([C:28](=[O:31])[NH:29][OH:30])[CH2:19]/[CH:20]=[CH:21]/[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:14][CH:15]([CH3:16])[CH3:17])=[O:9])[C:4]([OH:6])=[O:5]
Reactant: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C[C@](N)(OC(C)(C)C)C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)C(=O)C[C@H](N)C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 0.050 g of (E)-2(S)-amino-3-[[2-[2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleryl]-1-isobutylhydrazino]carbonyl]tert.butoxypropionate hydrogen chloride in 1 ml of dichloromethane was treated with 0.400 mL of trifluoroacetic acid. The mixture was stirred for 4 hours at room temperature and evaporated. The residue was triturated with diethyl ether, filtered off and dried to give 0.022 g of (E)-2(S)-amino-3-[[2-[2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-4-methylvaleryl]-1-isobutylhydrazino]carbonyl]propionic acid trifluoroacetate in the form of a white solid.
Reaction SMILES: [OH:1][C:2]([CH3:24])([CH3:23])[CH2:3][C@@:4]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]2[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:6][CH2:5]1.[Cl:25][C:26]1[CH:31]=[C:30](Cl)[N:29]=[N:28][C:27]=1[CH3:33]>>[Cl:25][C:26]1[CH:31]=[C:30]([N:13]2[CH2:14][CH2:15][CH2:16][C@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:24])[CH3:23])([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[O:9][C:8]3=[O:10])[CH2:12]2)[N:29]=[N:28][C:27]=1[CH3:33]
Reactant: CC(C)(O)C[C@]1(c2ccccc2)CCN([C@H]2CCCNC2)C(=O)O1
Reactant: Cc1nnc(Cl)cc1Cl
Product: Cc1nnc(N2CCC[C@H](N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)C2)cc1Cl

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-piperidin-3-yl)-1,3-oxazinan-2-one and 4,6-dichloro-3-methylpyridazine following a procedure analogous to that described in Example 1. LC-MS Method 1 tR=1.37 min, m/z=459, 461(M+1).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=1.C([Sn](CCCC)(CCCC)[C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)CCC.C1(C)C=CC=CC=1>CCOCC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]([C:11]1[C:5]2[O:6][CH2:7][C:8]([CH3:10])([CH3:9])[C:4]=2[CH:3]=[C:2]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)[CH:12]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(Br)cc2c1OCC2(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CC(C)(C)c1cc(-c2cccs2)cc2c1OCC2(C)C
Temperature: 25 °C
Yield: 281 %

Procedure:
A mixture of 5-bromo-7-tert-butyl-2,3-dihydro-3,3-dimethylbenzo[b]furan (2.26 g, 8.0 mmol), 2-(tributylstannyl)thiophene (3.05 mL, 9.6 mmol), tetrakis(triphenylphosphine)palladium (0.92 g, 0.8 mmol), and 40 mL of toluene is heated under argon at reflux for 2 h. The reaction mixture is cooled to room temperature, diluted with ether, washed with 10% aqueous ammonium hydroxide solution and with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 6.44 g of a dark oil. Purification by flash column chromatography on silica gel (0.5% ethyl acetate-hexane) yields about 0.98 g (43%) of the title compound initially as a colorless oil, which solidifies upon standing: mp 61-63° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:10]=[C:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(O)C>CO>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C=C(CCCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: Sc1ccc(Cl)c(Cl)c1
Solvent: CO
Solvent: CCO
Product: CC(C)(C)OC(=O)CCCC(CSc1ccc(Cl)c(Cl)c1)C(=O)OC(C)(C)C
Temperature: 170 °C
Reaction time: 17 h

Procedure:
A mixture of 3,4-dichlorobenzenethiol (0.20 ml), di-tert-butyl 2-methyleneadipate (350 mg), ethanol (2 ml), and triton B (40% methanol solution, 2 drops) was stirred at 170° C. in a sealed tube for 17 hours. After the reaction mixture was concentrated in vacuo, the resulting residue was dissolved in chloroform, washed with a 0.5% sodium hydroxide solution, water and a saturated sodium chloride solution respectively, and dried over MgSO4. The solvent was evaporated at reduced pressure, and the residue was purified by flash column chromatography on silica by eluting with diethyl ether/hexane (1:10) to give 430 mg of di-tert-butyl 2-(3,4-dichlorophenylthiomethyl)adipate as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:26][C@@H:25]4[C@H:21]3[CH2:22][N:23]([C:27](=O)[CH2:28][CH3:29])[CH2:24]4)=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Cl>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([C@@H:20]3[CH2:26][C@@H:25]4[C@H:21]3[CH2:22][N:23]([CH2:27][CH2:28][CH3:29])[CH2:24]4)=[CH:16][CH:15]=2)(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCC(=O)N1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(C(C)C)cc4)cc3)[C@@H]2C1
Agent: Cl
Solvent: C1CCOC1
Product: CCCN1C[C@@H]2C[C@@H](c3ccc(NS(=O)(=O)c4ccc(C(C)C)cc4)cc3)[C@@H]2C1
Temperature: 25 °C
Yield: 9 %

Procedure:
0.9 g of 4-isopropyl-N-[4-((1R,5S,6R)-3-propionyl-3-aza-bicyclo[3.2.0]hept-6-yl)-phenyl]-benzenesulfonamide (2.11 mmol) were dissolved in tetrahydrofuran and 11 ml of a 1 M borane/THF complex in tetrahydrofuran (10.8 mmol) was added at room temperature. The reaction mixture was heated under reflux for 30 minutes, 10 ml of aqueous 2 N hydrochloric acid were added, and the mixture was again refluxed for 3 h. After cooling to room temperature, the solvent was evaporated, the residue was treated with 50% aqueous sodium hydroxide solution, and the aqueous layer was extracted twice with diethyl ether. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated to yield 0.824 g of crude product which was then purified via preparative HPLC (column Delta Pak, 40 mm diameter, methanol/water/0.1% acetic acid) to yield 0.078 g of the purified product.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C@H:9]([NH:29][C:30](=[O:39])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:10]([NH:12][C@H:13]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)[CH2:14][C:15](O)=[O:16])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[BH4-].[Na+]>C1COCC1.O>[CH:1]1([CH2:7][CH2:8][C@H:9]([NH:29][C:30](=[O:39])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=2)[C:10](=[O:11])[NH:12][C@H:13]([CH2:18][N:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[CH2:21][CH2:20]2)[CH2:14][CH2:15][OH:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CC(=O)O)CN2CCc3cc(F)ccc32)c1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(C(=O)N[C@@H](CCC2CCCCC2)C(=O)N[C@@H](CCO)CN2CCc3cc(F)ccc32)c1
Temperature: 0 °C
Reaction time: 0.42 h
Yield: 51.6 %

Procedure:
A sample of the title compound of example 47 (114 mg, 0.21 mmol) in THF (5 mL) was cooled in an ice/water bath and treated with triethylamine (21 mg, 0.21 mmol) followed by isobutyl chloroformate. After stirring for 25 minutes, the solution was transferred to a precooled (ice/water bath) stirring solution of excess NaBH4 in water (5 mL). After stirring for 1 hour, the solution was quenched by addition of excess 1 M HCl at 0° C. The reaction was diluted with ethyl acetate and extracted with 1 M NaOH solution. The organics were dried over MgSO4 and the solvent was removed. The residue was purified on silica gel using a gradient of 0 to 100% ethyl acetate in hexane to afford 57 mg (51%) of the title material as a solid; 1H NMR (CDCl3, 400 MHz) δ 0.65-0.82 (m, 2H), 1.00-1.25 (m, 6H), 1.47-1.66 (m, 6H), 1.66-1.78 (m, 2H), 1.82-1.97 (m, 2H), 2.88-2.95 (m, 2H), 3.01 (dd, 1H, J1=5.6, J2=13.7), 3.21 (dd, 1H, J1=7.7, J2=13.7), 3.29 (dd, 1H, J1=8.7, J2=17.3), 3.44-3.52 (m, 1H), 3.55-3.68 (m, 2H), 3.83 (s, 3H), 4.31-4.41 (m, 1H), 4.64 (dd, 1H, J1=6.9, J2=14.1), 6.34 (dd, 1H, J1=4.1, J2=8.6), 6.568 (ddd, 1H, J1=2.5, J2=J3=8.9), 6.79 (dd, 1H, J1=2.4, J2=8.3), 7.03-7.08 (m, 1H), 7.15 (d, 1H, J=7.7), 7.22 (d, 1H, J=8.8), 7.29-7.35 (m, 3H); HPLC-MS calcd. for C30H40FN3O4 (M+H+) 526.3, found 526.5.
Reaction SMILES: C([N:3]1[CH2:12][CH2:11][C@@:10]2([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[C@@H:5]([CH2:6][CH2:7][C:8](=[O:21])[CH2:9]2)[CH2:4]1)C.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.C(OC([Cl:43])=O)=C>ClCCCl>[ClH:43].[CH3:20][O:19][C:15]1[CH:14]=[C:13]([C@@:10]23[CH2:9][C:8](=[O:21])[CH2:7][CH2:6][C@H:5]2[CH2:4][NH:3][CH2:12][CH2:11]3)[CH:18]=[CH:17][CH:16]=1
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Reactant: C=COC(=O)Cl
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Solvent: ClCCCl
Product: COc1cccc([C@]23CCNC[C@@H]2CCC(=O)C3)c1
Product: Cl
Reaction time: 0.25 h
Yield: 70.8 %

Procedure:
A solution of 1.2 g (4.2 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline and 1.8 g (12.6 mmol) of proton sponge in 34 ml of 1,2-dichloroethane was treated with 1.4 ml (16.8 mmol) of vinylchloroformate at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at this temperature for 15 min and then refluxed for 3 h, the solvent was removed in vacuo, the residue was taken up in water and extracted with Et2O. The organic layer was washed with 3% HCl, then was dried over Na2SO4 and the solvent was removed in vacuo. The dark residue was dissolved in EtOH, 3 ml of concentrated HCl were added and the solution refluxed for 3 hours. The solvent was removed in vacuo, obtaining 0.88 g of the title compound which was used as such in the subsequent step. M.p.=90° C. dec.