Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.[CH3:18]C(C)([O-])C.[K+].CI.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:17])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[N:7]([CH3:18])[C:6]=2[CH:13]=1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 4.85 g of methyl 6-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate in 30 ml of dimethylformamide is added 2.7 g of potassium t-butoxide and solution stirred at room temperature for 30 minutes. To the resultant solution is added dropwise a solution of 3.4 g of methyl iodide in 10 ml of dimethylformamide under stirring. After the reaction solution is stirred for 1.5 hours, 200 ml of water is added thereto. The insoluble substance is collected by filtration, washed with water and dried to give 5.1 g of methyl 6-chloro-3,4-dihydro-2,4-dimethyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate, melting at 128°-130° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O.C(OCC)(=O)C>[Cl:22][C:23]1[C:24]([O:8][C:6]2[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[N:11][CH:10]=3)=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=3)=[C:2]([Cl:1])[CH:7]=2)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1cc(Cl)c(-c2cccc(F)c2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4cccc(F)c4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.3 %

Procedure:
2-Chloro-3′-fluoro-5-(pyridazin-4-yl)biphenyl-4-ol (Preparation 67, 98 mg, 0.33 mmol) was dissolved in dimethylsulfoxide (2 mL) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 181 mg, 0.39 mmol) and potassium carbonate (135 mg, 0.98 mmol) were added. The reaction was stirred at room temperature for 18 hours. Water (10 mL) and ethyl acetate (15 mL) were added and the two layers were separated. The aqueous phase was extracted with ethyl acetate (10 mL). The combined organic extracts were washed with brine (10 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% heptane in ethyl acetate) to give the title compound (165 mg, 67%) as an off-white solid.
Reaction SMILES: [C:1](OCC)(=O)[CH2:2][C:3]([CH3:5])=O.[C:10]([CH2:12][C:13]([NH2:15])=O)#[N:11].[OH-]>>[C:10]([CH:12]1[C:3]([CH3:5])=[CH:2][CH2:1][NH:15][CH2:13]1)#[N:11]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#CCC(N)=O
Agent: [OH-]
Product: CC1=CCNCC1C#N

Procedure:
reacting ethyl acetoacetate with cyanoacetamide and a hydroxide of an alkali metal, in the presence of an organic solvent, at a temperature of from 60° C. to 80° C., for 1 to 4 hours, to produce 3-cyano-2,6-dihydro-4-methylpyridine;
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C(N(CC)CC)C.[C:44](Cl)(=[O:47])[O:45][CH3:46]>C(Cl)Cl>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([C:44]([O:45][CH3:46])=[O:47])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Reactant: COC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCc2nc(NC(C)C)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (50 mg, 0.080 mmol) and triethylamine (0.026 mL, 0.185 mmol) in DCM (0.75 mL) was added methyl carbonochloridate (9.3 μL, 0.121 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hr, warmed to 23° C., and concentrated via rotary evaporation. The resulting crude material was reconstituted in DMSO, rinsed with DMSO, and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound as a TFA salt (11.0 mg, 23.8%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.18 (d, J=6.8 Hz, 6H), 1.82-1.94 (m, 2H), 2.02-2.12 (m, 2H), 2.65 (t, J=5.9 Hz, 2H), 2.83-2.93 (m, 2H), 3.21-3.33 (m, 2H), 3.63 (s, 3H), 3.64-3.68 (m, 2H), 4.06-4.17 (m, 1H), 4.34 (br s, 2H), 4.51 (tt, J=8.1, 3.9 Hz, 1H), 5.51-5.65 (m, 1H), 6.99-7.05 (m, 1H), 7.25-7.35 (m, 2H); ESI-MS m/z [M+H]+ 462.4.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]=O)=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1.[OH2:43].O.O.C([O-])(=O)C.[Na+].[NH2:51]O.Cl>C(Cl)Cl.CO>[F:40][C:37]([F:39])([F:38])[C:35]1[CH:34]=[C:5]([CH:4]=[C:3]([C:2]([F:42])([F:1])[F:41])[CH:36]=1)[CH2:6][N:7]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:10]([C:18]([C:20]2[C:21]([CH:32]=[N:51][OH:43])=[N:22][O:23][C:24]=2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])=[O:19])[N:9]=[N:8]1
Reactant: O
Reactant: NO
Reactant: O=Cc1noc(-c2ccccc2Cl)c1C(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1ccccc1)c1c(C=NO)noc1-c1ccccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 4-[1-(3,5-Bis-trifluoromethyl-benzyl)-5-phenyl-1H-[1,2,3]triazole-4-carbonyl]-5-(2-chloro-phenyl)-isoxazole-3-carbaldehyde (0.076 g, 0.13 mmol) in CH2Cl2 (2 mL) and MeOH (2 mL), add sodium acetate trihydrate (0.034 g, 0.25 mmol) and hydroxylamine.HCl (0.018 g, 0.25 mmol) and stir at RT. After 1 h., quench with 75% sat. aq. NH4Cl (4 mL), extract with ethyl acetate, and wash with brine. Dry over MgSO4, filter and concentrate under vacuum. Purify by flash chromatography, (EtOAc/Hexane 10%–50%) to give the title compound. MS(ES) 620.1 (M+1), 1H NMR (300 MHz, CDCl3) δ 8.34 (s, 1H), 7.83 (br s, 2H), 7.74–7.16 (m, 9H), 5.50 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[O:8]C.B(Br)(Br)Br.O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:11]([N:13]2[CH2:18][CH2:17][O:16][C:15]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)=[CH:22][C:14]2=3)=[O:12])[CH:5]=[C:6]([Br:10])[C:7]=1[OH:8]
Reactant: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccccc4)cc32)cc1Br
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=C(c1cc(Br)c(O)c(Br)c1)N1CCOc2ncc(-c3ccccc3)cc21
Reaction time: 15 h
Yield: 59.2 %

Procedure:
To a 5 ml flask, (3,5-dibromo-4-methoxy-phenyl)-(7-phenyl-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl)-methanone (14 mg, 0.03 mmol) was dissolved in dichloromethane and then cooled to 0□. 1.0M Boron tribromide dissolved in dichloromethane (0.17 ml, 0.17 mmol) was added and then stirred at 0□ for 15 hours. After completion of the reaction, water was added thereto and the mixture was extracted with ethyl acetate and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain the target compound 20 as white solid (8.7 mg, 64%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:21])=O>ClCCl>[ClH:21].[Cl:21][CH2:2][C:3]1[CH:4]=[C:5]([N:9]2[C:13]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=3[N:11]=[CH:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc2c(c1)ncn2-c1cccc(CO)c1
Solvent: ClCCl
Product: Cc1ccc2c(c1)ncn2-c1cccc(CCl)c1
Product: Cl
Reaction time: 0.5 h

Procedure:
1-(3-Hydroxymethylphenyl)-5-methylbenzimidazole (0.3 g, 1.26 mM) was dissolved in dichloromethane (3 ml). Thionyl chloride (92 μl, 1.26 mM) was added and the reaction stirred for 30 minutes. Solvent evaporated to obtain product (0.36 g). MS M+ 957.
Reaction SMILES: S(=O)(=O)(O)O.[N:6]1([C:12]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:13]=2[C:14]#N)[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(=O)(O)[O-:24].[Na+].[CH2:28]([OH:30])[CH3:29]>>[N:6]1([C:12]2[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:13]=2[C:14]([O:30][CH2:28][CH3:29])=[O:24])[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: CCO
Reactant: O=C([O-])O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1N1CCOCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1N1CCOCC1

Procedure:
A 6 ml portion of concentrated sulfuric acid was added at room temperature to a 6 ml ethanol solution of 1.11 g of 2-morpholin-4-yl-4-nitrobenzonitrile, and heated under reflux for 8Hours. After spontaneous cooling, the reaction solution was poured onto ice and neutralized with saturated sodium bicarbonate aqueous solution. The organic layer was extracted with chloroform, and the organic layer was dried with anhydrous sodium sulfate. By evaporating the solvent under a reduced pressure, 1.16 g of ethyl 2-morpholin-4-yl-4-nitrobenzoate was obtained as a dark-red oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]/[C:18]3[CH:30]=[CH:29][C:21]4[O:22][C:23]([CH3:28])([CH3:27])[O:24][C:25](=[O:26])[C:20]=4[CH:19]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]3[CH:30]=[CH:29][C:21]4[O:22][C:23]([CH3:28])([CH3:27])[O:24][C:25](=[O:26])[C:20]=4[CH:19]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Yield: 93.4 %

Procedure:
A solution of 6-[((E)-{4-[(4-chlorophenyl)ethynyl]phenyl}methylidene)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (3.73 g, 8.97 mmol), sodium triacetoxyborohydride (5.70 g, 26.9 mmol) and acetic acid (0.77 mL, 13.5 mmol) in anhydrous DCE (120 mL) was stirred for 48 hrs at rt. Then the reaction mixture was diluted with water (150 mL) and an aqueous saturated solution of NaHCO3 (100 mL) and extracted with DCM (250 mL and 100 mL). The combined organic layers were dried over MgSO4 and evaporated under reduced pressure. The residue was crystallized from a DCM/pentane solution. The solid was filtered, washed with pentane (2×) and dried under reduced pressure to give 3.50 g (93%) of the title compound as a yellow powder. HPLC, Rt: 5.0 min (purity: 98.1%). 1H NMR (CDCl3) δ: 7.51 (d, J=8.2 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.34 (m, 4H), 7.18 (d, J=2.6 Hz, 1H), 6.86 (dd, J=8.8, 2.6 Hz, 1H), 6.81 (d, J=8.8 Hz, 1H), 4.35 (s, 2H), 4.21 (brs, 1H), 1.71 (s, 6H).
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([N:16]2[CH2:23][CH2:22][C@:21]3([CH3:27])[C:24]([CH3:26])([CH3:25])[C@H:17]2[CH2:18][C:19]2[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:20]=23)=[O:15])[CH2:10]1.C(N(C(C)C)C(C)C)C>CN(C)C=O>[C:1]([NH:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@@H:11]([C:14]([N:16]2[CH2:23][CH2:22][C@:21]3([CH3:27])[C:24]([CH3:25])([CH3:26])[C@H:17]2[CH2:18][C:19]2[C:31]([OH:32])=[CH:30][CH:29]=[CH:28][C:20]=23)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N=C=O
Reactant: CC1(C)[C@H]2Cc3c(O)cccc3[C@]1(C)CCN2C(=O)[C@@H]1CC[C@@H](N)C1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)N[C@@H]1CC[C@@H](C(=O)N2CC[C@@]3(C)c4cccc(O)c4C[C@@H]2C3(C)C)C1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
tert-Butylisocyanate (30 mg) is added to a solution of [(1R,3R)-3-amino-cyclopentyl]-[(2R,6S)-10-hydroxy-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-methanone (100 mg) and ethyldiisopropylamine (120 μL) in N,N-dimethylformamide (2 mL). The resulting solution is stirred at 40° C. overnight. Then, the solution is concentrated under reduced pressure and the residue is purified by HPLC on reversed phase (MeCN/H2O/F3CCO2H) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[CH:32]1(CCCC(O)=O)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:5]1([CH2:4][CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:6][CH2:7][CH2:2][CH2:3][CH2:32]1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CCCC1CCCCC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCCCC2CCCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-cyclohexyl-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [CH3:1][CH:2]1[O:6][CH2:5][S:4][C:3]1=[N:7][OH:8].[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11](F)=[O:12].C(N(CC)CC)C>O1CCOCC1>[CH3:9][N:10]([S:14][S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:8][N:7]=[C:3]1[CH:2]([CH3:1])[O:6][CH2:5][S:4]1)=[O:12]
Reactant: CN(SSc1ccccc1)C(=O)F
Reactant: CC1OCSC1=NO
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC1OCSC1=NOC(=O)N(C)SSc1ccccc1

Procedure:
4-[[O-[N-Methyl-N-(phenylthiosulfenyl)carbamoyl]oximino]]-5-methyl-1,3-oxathiolane was prepared by the procedure described in Example I by reacting 5.0 g (0.0375 m) of 5-methyl-4-oximino-1,3-oxathiolane, 8.15 g (0.0375 m) of N-methyl-N-(phenylthiosulfenyl) carbamoyl fluoride and 3.79 g (0.0375 m) of triethylamine in 100 ml of dioxane. The crude residual oil was purified using silica gel column to yield 3.5 g of an oil.
Reaction SMILES: ClCCl.[C:4]([O:8][C:9](C(C)(C)C)=[O:10])([CH3:7])([CH3:6])[CH3:5].[NH2:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C>[S:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][CH2:16][NH:15][C:9](=[O:10])[O:8][C:4]([CH3:5])([CH3:6])[CH3:7])=[CH:23][CH:22]=1)(=[O:25])(=[O:26])[NH2:27]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)C(C)(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCc1ccc(S(N)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 53.3 %

Procedure:
Dichloromethane (4 mL) and di-tert-butylcarboxylic acid (218 mg, 1.0 mmol) were added to 4-(2-aminoethyl)benzenesulfonamide (200 mg, 1.0 mmol) and the mixture was stirred at room temperature for 1.5 hours. Ethyl acetate (100 mL) was added to the reaction mixture and the solid was collected by filtration. Thus, tert-butyl 4-sulfamoylphenethylcarbamate (Compound GI) (160 mg, yield: 53%) was obtained.
Reaction SMILES: C(OC(=O)C[O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][C:14](=[O:19])[C:13]=2[CH:12]=[C:11](C2C=CC=CC=2)[CH:10]=1)(C)(C)C.C(N(C(C)C)CC)(C)C.[F:36][C:37]([F:50])([F:49])[S:38]([O:41]S(C(F)(F)F)(=O)=O)(=[O:40])=[O:39]>ClCCl.O>[O:19]=[C:14]1[C:13]2[CH:12]=[C:11]([O:41][S:38]([C:37]([F:50])([F:49])[F:36])(=[O:39])=[O:40])[CH:10]=[C:9]([O:8][S:38]([C:37]([F:50])([F:49])[F:36])(=[O:40])=[O:39])[C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)COc1cc(-c2ccccc2)cc2c1CCCC2=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C1CCCc2c(OS(=O)(=O)C(F)(F)F)cc(OS(=O)(=O)C(F)(F)F)cc21
Temperature: 2.5 °C
Reaction time: 0.75 h
Yield: 69.2 %

Procedure:
To a suspension of 5,7-dihydroxy-3,4-dihydro-2H-naphthalen-1-one (XXV, prepared as described in Scheme 3 above, 320 mg, 1.79 mmol) in dichloromethane (25 mL) was added diisopropylethylamine (925 mg, 7.16 mmol) at −5 to 0° C. To the resulting solution was then added trifluoromethanesulfonic anhydride (1.06 g, 3.76 mmol) dropwise over 5 minutes at this temperature. The resulting brown solution was stirred for 45 minutes at ˜0-5° C. and then warmed to room temperature and stirred for another 15 minutes. The reaction mixture was then diluted with dichloromethane (50 mL) and water (70 mL). The aqueous layer was separated and extracted with dichloromethane (25 mL). The combined organic extracts were washed with brine (100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude product was dissolved in dichloromethane (10 mL) and diluted with hexanes (50 mL). The brown solution was stored in the refrigerator for 15 h. The resulting solids were collected by filtration and washed with hexanes. After drying in the air, trifluoro-methanesulfonic acid 8-oxo-4-trifluoromethanesulfonyloxy-5,6,7,8-tetrahydro-naphthalen-2-yl ester (0.548 g, 69%) was obtained as a light brown solid: EI(+)-HRMS m/e calcd. for C12H8F6O7S2 (M+) 442.9616, obsd. 442.9618.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]2[CH:8]3[CH2:18][CH2:17][C:12]4(OCC[O:13]4)[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:21])[CH3:2].C(O)=O.O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:20]=[CH:19][C:7]2[CH:8]3[CH2:18][CH2:17][C:12](=[O:13])[CH2:11][CH:9]3[O:10][C:6]=2[C:5]=1[F:21])[CH3:2]
Reactant: CCOc1ccc2c(c1F)OC1CC3(CCC21)OCCO3
Solvent: O=CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOc1ccc2c(c1F)OC1CC(=O)CCC21
Reaction time: 18 h

Procedure:
135.0 g (459 mmol) of (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-spiro[dibenzo[b,d]furan-3,2′-1,3-dioxolane] are dissolved in 1800 ml of toluene and stirred vigorously together with 550 ml (14.6 mol) of formic acid with addition of 10.0 ml (0.56 mol) of water. After 18 h, the organic phase is separated off, and the formic acid is extracted with toluene. The combined organic phases are washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=4:1), giving (±)-(4aR*, 9bS*)-7-ethoxy-6-fluoro-1,4,4a,9b-tetrahydro-2H-dibenzofuran-3-one as colourless solid.
Reaction SMILES: [Br:1][CH:2]([CH2:15]Br)[CH2:3][CH:4]([OH:14])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Ca+2].[OH-].[Br-].[Ca+2].[Br-]>CO.O>[Br:1][C@H:2]1[CH2:15][O:14][C@@H:4]([CH2:5][O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3]1
Reactant: OC(COCc1ccccc1)CC(Br)CBr
Agent: [Br-]
Agent: [Ca+2]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Br[C@H]1CO[C@@H](COCc2ccccc2)C1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
A solution of 10.0 g of product from Example 3 in 25 ml of methyl alcohol is diluted with 50 ml of distilled water. To this heterogeneous mixture isadded 1.6 g of calcium hydroxide followed by 16.95 g of calcium bromide. The reaction is stirred vigorously while heating in an oil bath, at 100° C., for 24 hours. The internal temperature is maintained at 85° C. The reaction is cooled, extracted with methylene chloride, filtered thru diatomaceous earth and the layers partitioned. The organic layer is washed with water and saturated sodium chloride, dried and concentrated in vacuo to give 7.18 g of an oil. The oil is purified by chromatography (Silica Gel: 5% ethyl acetate/hexane) to give 2.82 g of thetrans-isomer and 2.89 g of the cis-isomer.
Reaction SMILES: [CH2:1]([N:3]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:4][CH3:5])[CH3:2].C(N(CC)CC)C.[C:21]1([C:27](=[O:31])[C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C>[CH2:1]([N:3]([CH2:4][CH3:5])[CH:6]=[C:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:28](=[O:29])[C:27]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:31])[CH3:2]
Reactant: O=C(Cl)C(=O)c1ccccc1
Reactant: CCN(C=Cc1ccccc1)CC
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCN(C=C(C(=O)C(=O)c1ccccc1)c1ccccc1)CC
Reaction time: 1.25 h

Procedure:
Seven grams of N,N-diethylstyrylamine was dissolved in 100 ml. of diethyl ether and the solution was cooled to 0°C. Four grams of anhydrous triethylamine was added. A 7 g. portion of phenylglyoxyloyl chloride was dissolved in 50 ml. of diethyl ether and the solution was added dropwise, with stirring, to the first solution over about 75 minutes. As soon as the addition was complete, the reaction mixture was filtered, and the precipitated amine hydrochloride was washed with an additional 50 ml. of diethyl ether. The filtrate contained the intermediate enamine, 1-diethylamino-2,4-diphenyl-1-buten-3,4-dione, in dissolved form, and was used in the next step of the synthesis without purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:23])[CH:4]=[C:5](Cl)[C:6](=[O:21])[C:7]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1([CH3:20])[CH2:19][CH2:18]1.[OH-:24].[Na+].[OH2:26].OS(O)(=O)=O>CO>[OH:24][C:2]1[C:3](=[O:23])[CH:4]=[C:5]([OH:26])[C:6](=[O:21])[C:7]=1[C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:17]1([CH3:20])[CH2:19][CH2:18]1
Reactant: [OH-]
Reactant: O
Reactant: CC1(c2[nH]c3ccccc3c2C2=C(Cl)C(=O)C=C(Cl)C2=O)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: CC1(c2[nH]c3ccccc3c2C2=C(O)C(=O)C=C(O)C2=O)CC1
Yield: 87 %

Procedure:
To a refluxing solution of 2,5-dichloro-3-[2-(1-methyl-cyclopropyl)-1H-indole-3-yl]-[1,4]benzoquinone (0.056 g, 0.16 mmol) in MeOH (6 mL) was added 10% aqueous NaOH (3 mL) dropwise. After refluxing for a half hour, the mixture was poured into cold water (20 mL). H2SO4 (10%) was added to acidify the mixture, which was extracted with EtOAc (3×10 mL). The organic layer was washed with brine (10 mL) and dried over Na2SO4. The solution was concentrated and purified by flash column chromatography (oxalic acid-coated silica gel) using 30% EtOAc in hexane as the eluent to afford 2,5-dihydroxy-3-[2-(1-methyl-cyclopropyl)-1H-indol-3-yl]-[1,4]benzoquinone (0.044 g, 87%) as dark blue needles from acetone/hexane. Melting Point 103° C. (dec). 1H NMR (d6-acetone): 0.55–0.62 (2H, m), 0.81–0.87 (2H, m), 1.45 (3H, s), 6.08 (1H, s), 6.93 (1H, dt, J=0.9, 8.1 Hz), 7.04 (1H, dt, J=1.2, 8.1 Hz), 7.22 (1H, d, J=7.8 Hz), 7.31 (1H, dd, J=0.9, 8.1 Hz), 9.0–10.1 (2H, br s), 10.34 (1H, br s). 13C NMR (d6-acetone): 13.3, 14.8, 24.4, 101.4, 103.6, 110.8, 112.3, 119.0, 119.5, 121.1, 128.4, 135.8, 142.2. IR (KBr): 3300, 3077, 2958, 2924, 1640, 1360, 1190, 746 cm−1. HRMS (EI): calculated for C18H15NO4 309.1001; found 309.0999.