Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:25]1[CH2:30][CH:29]=[C:28]([C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[CH3:24][O:23][C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:25]3[CH2:26][CH:27]=[C:28]([C:31]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[NH:33][CH:32]=4)[CH2:29][CH2:30]3)[O:18][C:17]=2[CH:19]=1
Reactant: COc1ccc2c(c1)O[C@@H](COS(=O)(=O)c1ccc(C)cc1)CO2
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)OC(CN1CC=C(c3c[nH]c4ccccc34)CC1)CO2

Procedure:
[(2R)-7-Methoxy-2,3-dihydro-benzo[1,4]dioxin-2-yl]methyl 4-methylbenzenesulfonate (1.5 g, 4.3 mmole) was dissolved in a mixture of dimethylformamide/tetrahydrofuran (1:1 v/v, 30 mL) and 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.80 g, 4.0 mmole) added, followed by sodium bicarbonate (1.0 g), and the mixture was refluxed under nitrogen for 18 hours. The solvent was removed under vacuum and the residue partitioned between 400 mL each of methylene chloride and water. The layers were separated and the organic phase was washed with water and saturated sodium chloride solution, dried over potassium carbonate and filtered. The filtrate was evaporated to a foam (1.6 g). Chromatography on silica gel using 4% methanol in chloroform as eluant gave 0.20 g of the (S)-enantiomer of the title compound as a yellow solid, m.p. 166-168° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[CH:12])[CH:6]=1)[CH3:2].I[C:15]1[CH:27]=[CH:26][C:18]2[O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][C:17]=2[CH:16]=1.C1COCC1.C(NC(C)C)(C)C>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.CCCCCC>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[C:12][C:15]2[CH:27]=[CH:26][C:18]3[O:19][CH2:20][C:21]([CH3:25])([CH3:24])[CH2:22][O:23][C:17]=3[CH:16]=2)[CH:6]=1)[CH3:2]
Reactant: CC1(C)COc2ccc(I)cc2OC1
Reactant: C#Cc1cccc(C(=O)OCC)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1cccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)c1
Yield: 54.9 %

Procedure:
To a mixture under N2 of 3-ethynyl-benzoic acid ethyl ester (9) (50 mg), 7-iodo-3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepine (5) (87 mg) (example 1b), [PdCl2(PPh3)2] (10 mg) and copper(I) iodide (5.5 mg) is added a degassed mixture of THF (2.5 ml) and diisopropylamine (2.5 ml). After 5.5 h stirring at RT hexane (15 ml) is added and the mixture is washed with 1 N aq. HCl sol. (2×15 ml), H2O (15 ml) and brine (15 ml). After drying over MgSO4 the solvent is evaporated and the product is purified by flash chromatography (silica gel, hexane/1% AcOEt). 55 mg of 3-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-benzoic acid ethyl ester (10) are obtained as a colourless gum, MS (ESI) 350.2 (M•)+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:14]([N:17](S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)[S:18]([C:21]3[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=3)(=[O:20])=[O:19])=[N:15][CH:16]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>CO>[CH2:42]([C:13]1[C:14]([NH:17][S:18]([C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)(=[O:19])=[O:20])=[N:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([OH:4])=[CH:6][CH:7]=2)[N:12]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: CC(=O)Oc1ccc(-c2cnc(N(S(=O)(=O)c3ccc([N+](=O)[O-])cc3)S(=O)(=O)c3ccc([N+](=O)[O-])cc3)c(Cc3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=[N+]([O-])c1ccc(S(=O)(=O)Nc2ncc(-c3ccc(O)cc3)nc2Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 87.7 %

Procedure:
5-(4-Acetoxyphenyl)-3-benzyl-2-bis(4-nitrophenylsulfonyl)aminopyrazine (c-40) (151 mg, 219 μmol) was suspended in methanol (3 mL), and to this was added 10% (w/v) aqueous solution of sodium hydroxide aqueous (600 μL) while stirring at room temperature and then stirred at 65° C. for 30 min. To this were sequentially added methanol (1 mL) and 10% (w/v) aqueous solution of sodium hydroxide (400 μL) and stirred for an hour. After cooling to room temperature, to this was added 2 M hydrochloric to stop the reaction and extracted twice with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated under reduced pressure with a rotary evaporator. The residue was purified by column chromatography (8 g, n-hexane/ethyl acetate=3/2) to give 3-benzyl-5-(4-hydroxyphenyl)-2-[(4-nitrophenyl) sulfonylamino]pyrazine (coelentera-p-nosylamide) (c-36) as an orange solid (88.8 mg, 87.7%). Rf=0.13 (n-hexane/ethyl acetate=3/2). Mp. 176-177.5° C. (dec.). UV (MeOH) λmax (log ε) 338 (4.11), 276.5 (4.42). UV (pH 7.4 PB) λmax (log ε) 347 (4.15), 278.5 (4.49). 1H NMR (400 MHz, DMSO-d6) δ 4.28 (s, 2H), 6.81 (d, J=8.7 Hz, 2H), 7.17-7.25 (m, 1H), 7.29 (s, 4H), 7.81 (d, J=8.6 Hz, 2H), 8.15 (d, J=8.6 Hz, 2H), 8.40 (d, J=8.4 Hz, 2H), 8.52 (s, 1H), 9.81 (s, 1H), 11.25 (s, 1H). IR (KBr, cm−1) 633, 698, 748, 773, 827, 853, 970, 1084, 1121, 1231, 1263, 1277, 1350, 1395, 1501, 1514, 1528, 1611, 3227. HRMS (FAB+) m/z 463.1086 (M+H, C23H19N4O5S requires 463.1076).
Reaction SMILES: [C:1]([C:3]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:4]OS(C1C=CC(C)=CC=1)(=O)=O)#[N:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].S([O-])([O-])(=O)=O.[Na+].[Na+].O.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:16]([C:3]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:1][NH:2][CH2:4]1)[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCC(C#N)(COS(=O)(=O)c1ccc(C)cc1)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC1(c2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
To a solution containing 5.26 g (14.1 mmol) of toluene-4-sulfonic acid 2-cyano-2-phenylheptyl ester in 25 mL of THF under nitrogen are added cautiously 600 mg (15.5 mmol) of LiAlH4 powder. The reaction medium is stirred for 1 hour at room temperature and then treated with a sodium sulfate paste (hot water+Na2SO4). After stirring for 30 minutes at room temperature, the salts formed are filtered off and the filtrate is evaporated under reduced pressure. The residue is taken up in dichloromethane and washed with aqueous 1N sodium hydroxide solution. The organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure. 2.90 g of a colourless oil are obtained and used in the following step without further purification.
Reaction SMILES: Cl.[C:2]([O:6][C:7]([N:9]1[CH2:15][CH2:14][C:13]2[C:16]([CH2:21][S:22][C:23](=[NH:25])[NH2:24])=[C:17]([Cl:20])[CH:18]=[CH:19][C:12]=2[CH2:11][CH2:10]1)=[O:8])([CH3:5])([CH3:4])[CH3:3].C[O-].[Na+].[C:29]([S-:31])#[N:30].[K+].BrBr>CO>[NH2:30][C:29]1[S:31][N:24]=[C:23]([S:22][CH2:21][C:16]2[C:13]3[CH2:14][CH2:15][N:9]([C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8])[CH2:10][CH2:11][C:12]=3[CH:19]=[CH:18][C:17]=2[Cl:20])[N:25]=1
Reactant: N#C[S-]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSC(=N)N)c2CC1
Agent: BrBr
Agent: C[O-]
Agent: Cl
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3nsc(N)n3)c2CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 42.7 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-6-carbamimidoylthiomethyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine hydrochloride (0.510 g, 1.256 mmol) in methanol (12.5 mL) at room temperature add solid sodium methoxide (0.14 g, 2.5 mmol) and then KSCN (0.12 g, 1.3 mmol). After cooling the reaction mixture to 0° C., add a solution of bromine (0.20 g, 1.3 mmol) in methanol (4 mL) dropwise. Stir the reaction mixture at room temperature overnight. Concentrate the reaction mixture in vacuo and partition the residue between DCM (100 mL) and water (50 mL). Extract the aqueous phase with DCM (50 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Dissolve the residue in DCM/methanol, add silica gel (5 g) and concentrate to a powder. Load the powder on to a dry column attached to a RediSep® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 95:5 DCM/2M ammonia in methanol over 33 min; 95:5 to 80:20 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 6-(5-amino-[1,2,4]thiadiazol-3-ylthiomethyl)-3-tert-butoxycarbonyl-7-chloro-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.229 g, 43%). MS (ES+) m/z: 427.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:9]=[C:10]([F:11])[C:3]=12.[F:22][C:23]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:24]=1[NH2:25].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:11][C:10]1[C:3]2[C:2]([NH:25][C:24]3[CH:26]=[CH:27][C:28]([N+:30]([O-:32])=[O:31])=[CH:29][C:23]=3[F:22])=[CH:7][CH:6]=[N:5][C:4]=2[N:8]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Cl)ccnc32)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: Cc1ccc(S(=O)(=O)n2cc(F)c3c(Nc4ccc([N+](=O)[O-])cc4F)ccnc32)cc1
Temperature: 25 °C

Procedure:
A solution of 20 mg (0.06 mmol) of 4-chloro-3-fluoro-1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridine, 11.5 mg (0.074 mmol) of 2-fluoro-4-nitroaniline, 5.6 mg (0.006 mmol) of tris(dibenzylideneacetone)dipalladium, 5.8 mg (0.012 mmol) of dicyclohexyl(2′,4′,6′-triisopropyl-biphenyl-2-yl)phosphine and 12.7 mg (0.09 mmol) of potassium carbonate in 1.00 ml of degassed tert-butanol is stirred in a sealed pressure vessel at 100° C. for 3 h. After cooling to RT, the reaction mixture is filtered through kieselguhr, the kieselguhr is washed with ethyl acetate and the solvent is removed from the filtrate. The residue is purified by preparative HPLC.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[CH:16]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: C#CCCCCCl
Product: COc1ccc(C#CCCCCCl)cc1
Temperature: 25 °C
Reaction time: 25 h
Yield: 65.5 %

Procedure:
Following the general procedure using 4-bromoanisole (60 mg, 0.48 mmol) and 6-chloro-1-hexyne (90 μL, 0.74 mmol), the reaction was stirred for 25 h at rt. Column chromatography on silica gel (eluting with 1% EtOAc/hexanes) afforded the product as a pale yellow oil (70 mg, 66%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[CH:7]=[CH:6][C:5]=1[C:20]1[N:24]([CH:25]2[CH:29]([OH:30])[CH2:28][O:27][CH2:26]2)[N:23]=[CH:22][C:21]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32].[CH3:36]I.[Cl-].[NH4+]>C1COCC1>[F:3][C:4]1[CH:9]=[C:8]([C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[CH:14][C:15]=2[CH3:16])[CH:7]=[CH:6][C:5]=1[C:20]1[N:24]([CH:25]2[CH:29]([O:30][CH3:36])[CH2:28][O:27][CH2:26]2)[N:23]=[CH:22][C:21]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CI
Reactant: CCOC(=O)c1cnn(C2COCC2O)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C2COCC2OC)c1-c1ccc(-c2c(C)cc(C)nc2OC)cc1F
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
Sodium hydride (60% oil dispersion, 86 mg) was added to a solution of ethyl 5-(2-fluoro-4-(2-methoxy-4,6-dimethylpyridin-3-yl)phenyl)-1-[(3RS,4SR)-4-hydroxytetrahydrofuran-3-yl]-1H-pyrazole-4-carboxylate (612 mg) in THF (5 mL) under ice-cooling, followed by stirring for three minutes. Methyl iodide (0.142 mL) was added to the reaction mixture, and the mixture was stirred at the same temperature for five minutes, and then warmed to room temperature and stirred for further two hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was purified by silica gel column chromatography (ethyl acetate/n-heptane, 27% to 48%) to give the title compound (379 mg).
Reaction SMILES: FC(F)(F)C(O[I:6](OC(=O)C(F)(F)F)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[C:22]([N:26]1[C:32](=[O:33])C2C=CC=CC=2[NH:29][C:28](=[O:38])[CH2:27]1)([CH3:25])([CH3:24])[CH3:23].II>C(Cl)Cl.C(OCC)(=O)C>[C:22]([N:26]1[C:32](=[O:33])[C:11]2[CH:12]=[C:7]([I:6])[CH:8]=[CH:9][C:10]=2[NH:29][C:28](=[O:38])[CH2:27]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1CC(=O)Nc2ccccc2C1=O
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)N1CC(=O)Nc2ccc(I)cc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
Bis(trifluoroacetoxy)phenyl iodine (2.05 g, 4.7 mmol) is added to a solution of 4-tert-butyl-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (1.0 g, 4.3 mmol) and iodine (1.1 g, 4.3 mmol) in methylene chloride. The reaction mixture is stirred overnight at room temperature, diluted with ethyl acetate, washed sequentially with saturated sodium hydrogen carbonate solution, 1N sodium thiosulfate solution and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and 20% to 25% ethyl acetate in hexanes solutions gives the title product as a beige solid (0.9 g, mp 230°-232° C.).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][C:6]=1[C:15]([OH:17])=O.Cl.[CH3:19][O:20][C:21](=[O:26])[C:22]([NH2:25])([CH3:24])[CH3:23].C(N(CC)C(C)C)(C)C.C(OCC)C>CN(C)C=O.O>[CH3:19][O:20][C:21](=[O:26])[C:22]([NH:25][C:15]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:14]=2[C:5]=1[O:4][CH2:3][O:2][CH3:1])=[O:17])([CH3:24])[CH3:23]
Reactant: COC(=O)C(C)(C)N
Reactant: COCOc1c(C(=O)O)ccc2c1CCCC2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COCOc1c(C(=O)NC(C)(C)C(=O)OC)ccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
In a round bottom flask was placed 0.96 g 1-methoxymethoxy-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid, 1.25 g 2-amino-2-methyl-propionic acid methyl ester hydrochloride, 3.09 g of O-(7-azabenzotriazole-1-yl)-N,N,N,N-tetramethyluronium hexafluoro phosphate and 2.83 ml of N,N-diisopropylethylamine in 60 ml of N,N-di-methylformamide. It was left stirring at room temperature overnight. 60 ml of diethylether and 60 ml of water were added to the reaction. The organic layer was separated and washed again with 50 ml of water. It was dried over magnesium sulphate, filtered and concentrated in vacuo to afford a crude yellow oil. Purification was performed by flash chromatography (silica, heptanes/ethyl acetate) to give 1.04 g 2-[(1-methoxymethoxy-5,6,7,8-tetrahydro-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH:18](O)[CH3:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:21]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[C:1]([O:5][C:6]([N:8]([CH2:16][CH2:17][CH2:18][CH:19]=[CH2:21])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)CCN(CCC(C)O)C(=O)OC(C)(C)C
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: C=CCCCN(CCC(=O)OCC)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
To a solution of ethyl N-(tert-butoxycarbonyl)-3-(3-hydroxybutylamino)propionate (1.06 g, 3.66 mmol) in dichloromethane (DCM)(15 mL) was added Dess-Martin periodinate (1.17 g, 4.03 mmol). The mixture was stirred for 2 hours, then, a mixture of a saturated aqueous NaHCO3 solution and Na2S2O3 was added. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was dissolved in THF (10 mL), then a Wittig reagent, which was prepared from methyltriphenylphosphonium bromide (1.57 g, 4.4 nmmol) and 1N-tert-BuOK solution in THF (4.4 mL), in THF (10 mL) was added to the solution at 0° C. The mixture was stirred for an hour at room temperature, then quenched by a saturated aqueous NH4Cl solution, and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with a mixture of ethyl acetate and n-hexane (1:10) to give ethyl N-(tert-butoxycarbonyl)-3-(4-pentenylamino)propionate (487 gm, 1.71 mmol, 46.6%) as a colourless oil.
Reaction SMILES: [OH-].[K+].[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([C:12]3([C:20]([F:23])([F:22])[F:21])[O:19][CH:13]3C(OCC)=O)=[CH:6][C:5]=2[O:4]1>C(O)C.O>[CH2:3]1[O:11][C:10]2[CH:9]=[CH:8][C:7]([CH:12]([C:20]([F:21])([F:22])[F:23])[CH:13]=[O:19])=[CH:6][C:5]=2[O:4]1
Reactant: CCOC(=O)C1OC1(c1ccc2c(c1)OCO2)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=CC(c1ccc2c(c1)OCO2)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
Into a solution of 9.5 g of potassium hydroxide in 80 ml of ethanol and 20 ml of water, 24.0 g of ethyl 3-(3,4-methylenedioxyphenyl)-2,3-epoxy-4,4,4-trifluorobutyrate was added with ice-cooling. The reaction solution was stirred at room temperature for 17 hours. Thereafter, the reaction solution was poured into ice water. The resulting solution was washed with diethyl ether and adjusted to pH 2 with 10% HCl and extracted twice with ethyl acetate. The ethyl acetate layers were combined and washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure and the residue was subjected to distillation under a reduced pressure by heating in an oil bath (140°-160° C.) to obtain 7.7 g of the desired aldehyde (b.p. 121°-122° C./18 mmHg).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][NH:16][CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:33])C.[SH-].[Na+]>O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([OH:33])[CH:17]2[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OCc3ccccc3)NCSC12
Agent: [Na+]
Agent: [SH-]
Solvent: O
Product: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(O)C2C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of benzyl 7-phenoxyacetamido-8-oxo-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (635 mg.) and cupric sulfate pentahydrate (75 mg.) in a mixed solution of acetic acid (4 ml.) and water (0.4 ml.) was stirred at room temperature. After stirring for 10 minutes, an additional cupric sulfate pentahydrate (300 mg.) was added thereto and the mixture was stirred for additional 1.5 hours. The reaction mixture was cooled to 10° C. and sodium bisulfide (86 mg.) was added thereto. The resultant mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was taken up into ethyl acetate, washed with a dilute aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride. Drying over magnesium sulfate and removal of the solvent gave a residue (648 mg.), which was chromatographed on silica gel (20 g.) with a mixed solvent of benzene and ethyl acetate (5:1 to 2:1 by volume) to give an oil (307 mg.), which was crystallized from diethyl ether to afford benzyl 7-phenoxyacetamido-8-oxo-3-hydroxy-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate (300 mg.), mp 184°-186° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)=[C:4]([O:21][CH3:22])[CH:3]=1.[CH3:23][S:24]([C:27]1[CH:28]=[C:29]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[C:30](O)=[O:31])(=[O:26])=[O:25]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH2:15][CH:16]2[CH2:20][CH2:19][O:18][CH2:17]2)[C:30](=[O:31])[C:29]2[CH:33]=[C:34]([C:36]([F:39])([F:37])[F:38])[CH:35]=[C:27]([S:24]([CH3:23])(=[O:26])=[O:25])[CH:28]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: COc1cc(F)ccc1-c1ccncc1NCC1CCOC1
Product: COc1cc(F)ccc1-c1ccncc1N(CC1CCOC1)C(=O)c1cc(C(F)(F)F)cc(S(C)(=O)=O)c1

Procedure:
The title compound was prepared in analogy to example 90, from [4-(4-fluoro-2-methoxy-phenyl)-pyridin-3-yl]-(tetrahydro-furan-3-ylmethyl)-amine and 3-(methylsulfonyl)-5-(trifluoromethyl)benzoic acid (example 114, intermediate a) after a reaction time of 72 hours at room temperature. The compound was purified by silica gel chromatography on a 20 g column using an MPLC (Flashmaster) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The resulting brown oil was further purification by preparative HPLC (Gemini NX) with a gradient of MeOH:water (containing 0.05% formic acid) (80:20 to 98:2). Colorless foam (11%). MS (ESI): m/z=553.141 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[C:11]([O:13]C)=[O:12].[OH-].[Na+].O.CO>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:10][CH:9]1[C:11]([OH:13])=[O:12]
Reactant: COC(=O)C1CC1c1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CC1c1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 2-(2-fluorophenyl)cyclopropanecarboxylate (4.8 g, 24.72 mmol) in tetrahydrofuran (25 mL), was added 10M sodium hydroxide solution (approximately 2 mL), a small amount of water, and sufficient methanol to achieve a homogeneous reaction mixture. The reaction mixture was then allowed to stir at rt for approximately 2 h. After concentrating the reaction mixture, 1N HCl was added until the mixture was acidic. The organic layer was extracted twice with ethyl acetate, then washed with brine, dried over anhydrous Na2SO4, and concentrated to afford the title compound. M.S. (M+1): 181.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13]3[CH:14]=[C:15]([NH:25][C:26](=[O:38])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33](F)(F)F)[C:28]=4F)[CH:16]=[C:17]4[C:23](=[O:24])[NH:22][N:21]=[CH:20][C:19]=2[C:18]=34)[CH:8]=[CH:9][CH:10]=1)[CH3:3].[C:39]1([C@@H]2C[C@H]2C(O)=O)C=CC=C[CH:40]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>C(O)(C)C.C(Cl)Cl.CN(C)C=O>[CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[NH:12][C:13]3[CH:14]=[C:15]([NH:25][C:26]([C@@H:27]4[CH2:32][C@H:28]4[C:29]4[CH:30]=[CH:31][CH:40]=[CH:39][CH:33]=4)=[O:38])[CH:16]=[C:17]4[C:23](=[O:24])[NH:22][N:21]=[CH:20][C:19]=2[C:18]=34)[CH:8]=[CH:9][CH:10]=1)[CH3:3]
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CN(C)Cc1cccc(-c2[nH]c3cc(NC(=O)c4cccc(C(F)(F)F)c4F)cc4c3c2C=NNC4=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN(C)Cc1cccc(-c2[nH]c3cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)cc4c3c2C=NNC4=O)c1
Yield: 76.1 %

Procedure:
Preparation of example 83a from Intermediate 73(d) of Example 73 (0.11 g, 0.33 mmol), (1R,2R)-2-phenyl-cyclopropanecarboxylic acid (0.08 g, 0.5 mmol), triethylamine (0.183 mL, 1.32 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.188 g, 0.5 mmol) and N,N-dimethylformamide (0.2 M, 1.7 mL) was carried out analogously to Example 11. Silica gel chromatography (90:10 to 80:20 CH2Cl2/2M ammonia in isopropyl alcohol) afforded the title compound (0.12 g) as a yellow powder in 76% yield.