Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][NH:15][CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:32])[F:31])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1.Br[C:35]1[S:36][CH:37]=[CH:38][N:39]=1.[F-].[K+]>C(O)C>[CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][C@@H:10]2[CH2:17][C@H:13]3[CH2:14][N:15]([C:35]4[S:36][CH:37]=[CH:38][N:39]=4)[CH2:16][C@@:12]3([C:18]([N:20]3[CH2:29][CH2:28][C:27]4[N:26]=[CH:25][C:24]([C:30]([F:33])([F:31])[F:32])=[CH:23][C:22]=4[CH2:21]3)=[O:19])[CH2:11]2)[CH2:7][CH2:6][O:5][CH2:4]1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CNC[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1
Reactant: Brc1nccs1
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1C[C@H]2CN(c3nccs3)C[C@@]2(C(=O)N2CCc3ncc(C(F)(F)F)cc3C2)C1

Procedure:
A mixture of Example 1 (HCl salt, 32 mg, 0.0554 mmol), 2-bromothiazole (13.62 mg, 0.0831 mmol), TEA (0.0385 mL, 0.277 mmol) and potassium fluoride (1.61 mg, 0.0277 mmol) in ethanol (1 mL) in a sealed tube was heated at 90° C. for 6 days. After aqueous work up, the residue was purified by CombiFlash (eluent: 5% methanol in DCM) to give the product. 1H-NMR (400 MHz, CDCl3): δ 1.50-1.93 (m, 5H), 2.12-2.47 (m, 2H), 2.65-2.80 (m, 2H), 3.03-4.19 (m, 17H), 4.64-5.01 (m, 2H), 6.55 (d, J=3.5 Hz, 1H), 7.20 (d, J=3.5 Hz, 1H), 7.69 (br. s., 1H), 8.71 (d, J=5.1 Hz, 1H); LC/MS: C26H32F3N5O3S: m/z 552.2 (M+H).
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH:31]=[O:32])=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]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.[BH4-].[Na+]>C(O)C>[Si:1]([O:18][CH2:19][CH2:20][C@H:21]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][OH:32])=[CH:30][C:25]=2[CH2:24][CH2:23][O:22]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(C=O)ccc21)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](OCC[C@@H]1OCCc2cc(CO)ccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of (1S)-1-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-3,4-dihydro-1H-2-benzopyran-6-carbaldehyde (0.97 g, 2.18 mmol) in ethanol (30 mL) was added sodium borohydride (0.116 g, 3.06 mmol) and the mixture stirred for 1.5 h at room temperature. The reaction was extracted from water into ethyl acetate, the combined organic extracts dried (MgSO4), filtered and evaporated in vacuo, to yield the title compound as a colourless oil.
Reaction SMILES: O[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:42]I>C(Cl)Cl>[I:42][CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16]
Reactant: II
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CO)C(=O)CO2
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Yield: 103.5 %

Procedure:
A dry 50 mL r-flask was charged with (S)-4-(3-hydroxy-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (1.0 g, 4.2 mmol), PPh3 (2.2 g, 8.5 mmol), imidazole (0.58 g, 8.5 mmol) and dissolved with CH2Cl2 (25 mL). Iodine (2.2 g, 8.4 mmol) was then added in small portions over 4 h period. After the last addition the reaction was poured onto SiO2 and filtered. Concentration under reduced pressure yielded the crude title compound (1.5 g), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([CH:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:21](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[C:10]([C:14]3[C:15](=[O:20])[CH2:16][CH2:17][C:18]=3[O:19][CH3:21])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1sc(-c2ccc(Cl)cc2)cc1C1C(=O)CCC1=O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COC1=C(c2cc(-c3ccc(Cl)cc3)sc2C)C(=O)CC1
Temperature: 40 °C
Yield: 35.4 %

Procedure:
To a solution of 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-cyclopentane-1,3-dione (2.21 g, 7.25 mmol) in acetone (50 ml) was added potassium carbonate (1514 g, 10.87 mmol) followed by iodomethane (670 μl, 10.87 mmol) and the reaction heated to 40° C. for 6 hours. The solvent was then removed from the crude reaction mixture under reduced pressure and the residue partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated, dry loaded onto silica and purified by flash chromatography to give 2-[5-(4-Chloro-phenyl)-2-methyl-thiophen-3-yl]-3-methoxy-cyclopent-2-enone (818 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[CH:20]=2)[OH:15])=[CH:4][CH:3]=1.[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40](B3OC(C)(C)C(C)(C)O3)=[CH:39][CH:38]=2)[CH2:36][CH2:35]1)=[O:33])[CH3:30]>>[CH2:29]([O:31][C:32]([C:34]1([C:37]2[CH:42]=[CH:41][C:40]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([C:16]4[N:17]=[N:18][N:19]([CH2:21][C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[Cl:28])[CH:20]=4)[OH:15])=[CH:6][CH:7]=3)=[CH:39][CH:38]=2)[CH2:35][CH2:36]1)=[O:33])[CH3:30]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)c1cn(Cc2ccccc2Cl)nn1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)c4cn(Cc5ccccc5Cl)nn4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using [5-(4-Bromo-phenyl)-3-methyl-isoxazol-4-yl]-[1-(2-chloro-benzyl)-1H-[1,2,3]triazol-4-yl]-methanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:14]=4[NH:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[N:20]([CH:23]1[CH2:29][CH2:28][CH:27]2[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:24]1[CH2:25][CH2:26]2)=[C:21]=[O:22].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:15]4[CH2:16][N:17]([C:21]([NH:20][CH:23]5[CH2:29][CH2:28][CH:27]6[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:24]5[CH2:25][CH2:26]6)=[O:22])[CH2:18][CH2:19][C:14]=4[NH:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: Cn1ncc2cc(-c3n[nH]c4c3CNCC4)ccc21
Reactant: CC(C)(C)OC(=O)N1C2CCC(N=C=O)C1CC2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CCC5CCC3N5C(=O)OC(C)(C)C)CC4)ccc21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Dimethylformamide (0.7133 mL) was added to a flask containing 3-(1-methyl-1H-indazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (54.2 mg, 0.214 mmol) and tert-butyl 2-isocyanato-8-azabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.178 mmol). Diisopropylethylamine (0.1474 mL, 0.856 mmoL) was added to the flask, and the reaction was allowed to stir at 70° C. for 16 hrs. The reaction was quenched with water and was extracted using ethyl acetate three times. The ethyl acetate layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude was purified using flash chromatography (methanol in dichloromethane 0-20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]([OH:7])[CH2:4][CH2:5][CH:6]=1.[CH:8](OCC)=[CH2:9]>[Hg](OC(C)=O)OC(C)=O>[Br:1][C:2]1[CH:3]([O:7][CH:8]=[CH2:9])[CH2:4][CH2:5][CH:6]=1
Reactant: OC1CCC=C1Br
Reactant: C=COCC
Agent: CC(=O)O[Hg]OC(C)=O
Product: C=COC1CCC=C1Br

Procedure:
A solution of 2-bromo-cyclopent-2-enol (Intermediate D3) (21.7 g, 133.1 mmol) in ethyl vinyl ether (300 mL) was treated with Hg(OAc)2 (31.8 g, 99 mmol) at rt for 60 h. The mixture was quenched with 5% NaOH (150 mL) and filtered through celite. The residue was concentrated to yield 1-bromo-5-vinyloxy-cyclopentene as a pale yellow oil, 14.2 g (46%). 1-Bromo-5-vinyloxy-cyclopentene (14.1 g, 74.4 mmol) in toluene was heated in a re-sealable tube at 130° C. for 24 h. (2-Bromo-cyclopent-2-enyl)-acetaldehyde (Intermediate ONE1) was isolated after flash chromatography on silica gel with hexanes to 5% ethyl acetate:hexanes, 10.4 g (74%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:24][CH3:25].[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.ClCCl>[CH3:32][C:31]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][C:3]=2[O:24][CH3:25])[C:27]([CH3:29])=[CH:26][CH:30]=1
Reactant: CC(=O)CCC(C)=O
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: ClCCl
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
A solution of (4-amino-3-methoxy-phenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone prepared in the manner of Albright et al., E.P.636625-A2 (0.675g, 2 mmol) and acetonyl acetone (0.3 mL, 2.5 mmol) in benzene (100 mL) was treated with a crystal of para-toluenesulfonic acid. The stirred solution was warmed to reflux for 46 hrs using a Dean Stark trap. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate then water. The residue (oil, 0.900 g) was flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield 0.610 g of the title compound as a white foam. Recrystallization of a sample of this material yielded yellow crystals, m.p. 141–144° C.
Reaction SMILES: [C:1]1([CH:11]=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH2:18]([O:17][C:15]([CH:14]1[CH:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[O:12]1)=[O:16])[CH3:19]
Reactant: O=Cc1cccc2ccccc12
Reactant: CCOC(=O)CCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1OC1c1cccc2ccccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a −78° C. solution of 1-naphthaldehyde (13.0 mL, 96.1 mmol) and ethyl chloroacetate (10.3 mL, 96.1 mmol) in tetrahydrofuran (900 mL) was added (1.0 M in tetrahydrofuran) sodium bis(trimethylsilyl)amide (96.1 ml, 96.1 mmol) dropwise. The reaction mixture was stirred at −78° C. for 30 minutes and then warmed to 0° C. The reaction was then quenched with water (200 mL). The reaction mixture was then diluted with ethyl acetate (800 mL). The organic reaction layer was then washed in succession with water and saturated sodium chloride, the organic layer was then dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield a pale oil. The crude residue was chromatographed (silica gel with 5% ethyl acetate-95% hexane) to give 3-naphthalen-1-yl-oxirane-2-carboxylic acid ethyl ester as a clear oil. 1H NMR(300 MHz, DMSO) 8.12 (d, 1H), 7.95 (m, 2H), 7.51 (m, 4H), 4.77 (d, 1H), 4.24 (q, 2H), 3.72 (d, 1H), 1.27 (t, 3H). MS(APCI) m/z 241.1 (M−H). Anal. Calcd. for C15H14O3: C, 74.36; H, 5.82. Found: C, 74.47; H, 5.87.
Reaction SMILES: [OH-].[Na+].Cl[CH2:4][CH:5]([OH:12])[CH2:6][N:7]([CH2:10][CH3:11])[CH2:8][CH3:9]>O>[CH2:6]([N:7]([CH2:10][CH3:11])[CH2:8][CH3:9])[CH:5]1[O:12][CH2:4]1
Reactant: CCN(CC)CC(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CC1CO1
Reaction time: 1 h
Yield: 76 %

Procedure:
A solution of sodium hydroxide (47.9 g, 1.2 mole) in 78 mL water was added 1-chloro-3-diethylamino-propan-2-ol. The resultant was stirred at 20–25° C. for 1 hour, diluted with 178 mL of water and extracted with ether twice. The combined ether solution was dried with solid potassium hydroxide and evaporated to give 135 g of crude product which was purified by fraction distillation to give pure glycidyldiethylamine (98 g, 76%) as an oil.
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[C:13]=1[OH:20])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]=[C:30]=[O:31]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:8][S:9]([C:12]1[C:13]([OH:20])=[C:14]([NH:19][C:30]([NH:29][C:23]2[CH:24]=[CH:25][CH:26]=[C:27]([Cl:28])[C:22]=2[Cl:21])=[O:31])[CH:15]=[CH:16][C:17]=1[Cl:18])(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O
Reactant: O=C=Nc1cccc(Cl)c1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c(S(=O)(=O)NCc2ccccc2)c1O)Nc1cccc(Cl)c1Cl
Yield: 11.7 %

Procedure:
A solution of N-benzyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (54 mg, 0.17 mmol) and 2,3-dichlorophenylisocyanate (34 μL, 0.26 mmol) in 2 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (60/40, v/v), gave the desired product (10 mg, 12%). EI-MS (m/z) 498.2, 500.1, 502.1 (M−).
Reaction SMILES: [Na].[C:2]([SH:6])([CH3:5])([CH3:4])[CH3:3].[CH2:7]([C:14](=[CH2:19])[C:15]([O:17][CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>CO>[CH2:7]([CH:14]([CH2:19][S:6][C:2]([CH3:5])([CH3:4])[CH3:3])[C:15]([O:17][CH3:18])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)S
Reactant: C=C(Cc1ccccc1)C(=O)OC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: COC(=O)C(CSC(C)(C)C)Cc1ccccc1

Procedure:
To sodium (3.05 g, 133 mmol) in methanol (135 ml) was added tert-butylmercaptan (17.0 ml, 151 mmol). After 20 min methyl a-benzylacrylate (17.05 g, 96.8 mmol) in methanol (100 ml) was added and after 1 h at room temperature the mixture was heated at reflux for 17 h. After cooling, the mixture was acidified with 2M HCl (70 ml), concentrated, taken up in ether, washed with water and brine, then dried over MgSO4 and evaporated to 23.59 g (92%) of an oil. 1H NMR (CDCl3) δ 7.15-7.35 (m,5H), 3.63 (s,3H), 2.60-3.05 (m,5H), 1.28 (s,9H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH:10]=[CH:11][O:12]C)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C=O)=CC=1)C>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(CC=COC)cc1
Agent: CCc1ccc(C=O)cc1
Product: CCc1ccc(CCC=O)cc1

Procedure:
4-Ethyl 1-(3-methoxy-2-propen-1-yl)benzene was similarly prepared as described in Examples I and II. First, 4-ethyl benzaldehyde (925 g, commercially available from Mitsubishi Gas Chemical Company, Inc.) was used to obtain 3-(4-ethyl-phenyl)-propionaldehyde (878 g) with a boiling point of 129° C. at a pressure of 12 mmHg. 3-(4-Ethyl-phenyl)-propionaldehyde (235 g) was consequently used to provide 4-ethyl 1-(3-methoxy-2-propen-1-yl)benzene (128 g) with a boiling point of 120° C. at a pressure of 10 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][C:3]=1[CH2:4][C:5]1[CH:10]=[C:9]([F:11])[C:8]([N:12]2[S:16](=[O:18])(=[O:17])[N:15]([CH2:19][O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:14](=[O:28])[CH2:13]2)=[C:7]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:6]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>N1C=CC=CC=1.CCOC(C)=O>[CH2:30]([O:29][C:7]1[CH:6]=[C:5]([CH:10]=[C:9]([F:11])[C:8]=1[N:12]1[CH2:13][C:14](=[O:28])[N:15]([CH2:19][O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[S:16]1(=[O:17])=[O:18])[CH2:4][C:3]1[CH:37]=[CH:38][C:39]([CH3:41])=[CH:40][C:2]=1[NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cc2cc(F)c(N3CC(=O)N(COCc4ccccc4)S3(=O)=O)c(OCc3ccccc3)c2)c(NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 5-[4-(2-amino-4-methylbenzyl)-2-benzyloxy-6-fluorophenyl]-2-benzyloxymethyl-1,1-dioxo-1,2,5-thiadiazolidin-3-one (240 mg, 0.42 mmol) in pyridine (5 mL) is added methanesulfonyl chloride (0.064 mL, 0.84 mmol) and the solution is stirred at RT for 2 h. The mixture is then diluted in EtOAc, and it is washed with 1N HCl, brine and water. The organic layer is dried with MgSO4, and concentrated. The residue is purified to give the title compound.
Reaction SMILES: C([O:8][C:9]1[C:17]([O:18][CH2:19]C)=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([CH3:21])[NH:13]2)C1C=CC=CC=1.C(OC1C(OC)=CC=C2C=1C=C(C)N2)C1C=CC=CC=1>>[OH:8][C:9]1[C:17]([O:18][CH3:19])=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([CH3:21])[NH:13]2
Reactant: CCOc1ccc2[nH]c(C)cc2c1OCc1ccccc1
Agent: COc1ccc2[nH]c(C)cc2c1OCc1ccccc1
Product: COc1ccc2[nH]c(C)cc2c1O

Procedure:
This compound is obtained according to the operating method described in Example 2c, in which the 4-benzyloxy-5-ethoxy-2-methylindole is replaced by 4-benzyloxy-5-methoxy-2-methylindole. Following the operating method of Example 2 a pale yellow powder is obtained (yield =89%, m.p. =118°-119° C.).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:26]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:30][CH2:31][C:32]([OH:34])=[O:33].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[O:5])[C:7]=2[OH:26])[N:14]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2Cc2ccccc2F)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(Cc3ccccc3F)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(2-fluoro-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 403 (M+H)+.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@@H:25]([C:26]([OH:28])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8].[C:35](=O)(O)[O-].[Na+]>CO>[CH3:5][O:6][C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C@H:16]1[C@H:25]([C:26]([O:28][CH3:35])=[O:27])[C:24]2[C:19](=[CH:20][C:21]([O:31][CH3:32])=[C:22]([O:29][CH3:30])[CH:23]=2)[C:18](=[O:33])[N:17]1[CH3:34])=[O:8]
Reactant: COC(=O)Nc1ccccc1[C@H]1[C@@H](C(=O)O)c2cc(OC)c(OC)cc2C(=O)N1C
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CO
Product: COC(=O)Nc1ccccc1[C@H]1[C@H](C(=O)OC)c2cc(OC)c(OC)cc2C(=O)N1C
Temperature: 0 °C
Reaction time: 6 h
Yield: 96 %

Procedure:
Thionyl chloride (10 mL) was added slowly to a suspension of cis 10 (0.75 g, 1.8 mmol) and trans 10 (1.35 g, 3.3 mmol) in methanol (100 mL) at 0° C. The resulting mixture was stirred for 6 h at 0° C. After completion of the reaction (TLC), the reaction mixture was poured slowly into a mixture of ice (200 g) and a saturated solution of sodium bicarbonate (100 mL). The resulting mixture was extracted with chloroform (3×150 mL), and the combined extracts were dried with sodium sulfate, filtered though a thin pad of silica gel, and evaporated to dryness to obtain 11 as amorphous glassy solid (2.1 g, 96%). IR (film) 1733, 1637 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.67 (s, 1 H), 7.52 (d, J=7.7 Hz, 1 H), 7.25 (t, J=7.0 Hz, 1 H), 7.03 (t, J=7.5 Hz, 1 H), 6.83 (d, J=7.8 Hz, 1 H), 6.73 (s, 1 H), 6.54 (s, 1 H), 5.45 (s, 1 H), 3.95 (s, 3 H), 3.89 (s, 1 H), 3.82 (s, 3 H), 3.72 (s, 3 H), 3.63 (s, 1 H), 3.03 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 172.06, 164.17, 155.49, 152.15, 149.18, 134.39, 132.53, 129.10, 126.67, 126.53, 125.93, 125.14, 121.60, 111.86, 110.17, 59.32, 56.29, 56.20, 53.27, 53.06, 48.66, 34.57; ESIMS m/z (rel intensity) 429 (MH+, 100), 451 (56); ESIHRMS m/z MH+ calcd. for C22H24N2O7, 429,1662; found, 429.1665.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH:23]4[CH2:25][CH2:24]4)[N:20]([CH3:26])[C:19]=3[CH:27]=2)[C:11](=[O:28])[CH:10]=1)C1C=CC=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[CH:23]1([C:21]2[N:20]([CH3:26])[C:19]3[CH:27]=[C:15]([N:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]4=[O:28])[CH:16]=[CH:17][C:18]=3[N:22]=2)[CH2:24][CH2:25]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Temperature: 130 °C
Yield: 122.3 %

Procedure:
To a stirred solution of 4-(benzyloxy)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (840 mg) in TFA (21 ml) was added anisole (7 ml), and the reaction mixture was heated at 130° C. for 4 h. The mixture was cooled and concentrated in vacuo. The residue was triturated with Et2O to give the title compound (778 mg) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[C:20]([OH:23])(=[O:22])[CH3:21].C([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=O)C>>[Cl:2][C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]2[C:27]3[CH:28]([CH2:21][C:20]([OH:23])=[O:22])[CH2:29][CH2:30][CH2:31][C:26]=3[C:15]3[C:10]2=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=3)=[CH:5][CH:4]=1
Reactant: CC(=O)O
Reactant: CCC1CCCCC1=O
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Agent: Cl
Product: COc1ccc2c(c1)c1c(n2Cc2ccc(Cl)cc2)C(CC(=O)O)CCC1

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochloride and ethyl-2-cyclohexanone acetate as starting materials, the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:9]2=[CH:10][N:11](S(C2C=CC(C)=CC=2)(=O)=O)[N:12]=3)=[CH:4][CH:3]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[C:9]2=[CH:10][NH:11][N:12]=3)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c(n2)CCCC3c2ccc(Cl)cc2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc(C2CCCc3n[nH]cc32)cc1
Temperature: 65 °C
Yield: 38.4 %

Procedure:
4-(4-Chlorophenyl)-2-(p-tolylsulfonyl)-4,5,6,7-tetrahydroindazole (0.4 g, 1.04 mmol) is added to a solution of KOH (0.29 g, 5.21 mmol) in MeOH (25 mL) and the solution is heated to 65° C. for 2 hours. The solution is cooled to ambient temperature, the solvent removed under reduced pressure and the resulting solid diluted with water. HCl is added to pH 4, the mixture is extracted with ethyl acetate, the layers are separated and the aqueous layer is re-extracted with ethyl acetate. The organic layers are combined, dried over Na2SO4, filtered, and concentrated to dryness. The residue is purified by chiral chromatography (Chiralpak AD-H, 4.6×150 mm, 100% EtOH 0.2% DMEA, 225 mm, Tr=3.318 min) to give the title compound (93 mg, 38%) as the second eluting isomer. ES/MS m/z 234 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[S:14]([NH2:17])(=[O:16])=[O:15])([CH3:4])([CH3:3])[CH3:2].O.O.Cl[Sn]Cl.C([O-])(O)=O.[Na+]>CCO.CCOC(C)=O.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[S:14]([NH2:17])(=[O:15])=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc([N+](=O)[O-])cc1S(N)(=O)=O
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc(N)cc1S(N)(=O)=O
Yield: 102.2 %

Procedure:
A solution of 2-tert-butyl-5-nitrobenzene-1-sulfonamide (32 mg, 0.12 mmol) and SnCl2.2H2O (138 mg, 0.61 mmol) in EtOH (1.5 mL) was heated in microwave oven at 100° C. for 30 min. The mixture was diluted with EtOAc and water, basified with sat. NaHCO3 and filtered through Celite. The organic layer was separated from water and dried over Na2SO4. Solvent was removed by evaporation to provide 2-tert-butyl-5-aminobenzene-1-sulfonamide (E-7) (28 mg, 100%), which was used without further purification. HPLC ret. time 1.99 min, 10-99% CH3CN, 5 min run; ESI-MS 229.3 m/z (MH+).