Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:12][O:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>C1COCC1.[Cu](Br)Br>[CH2:1]([O:8][CH2:9][C@@H:10]([OH:11])[CH2:12][CH2:15][CH:14]=[CH2:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(COC[C@@H]2CO2)cc1
Reactant: C=CC[Mg]Br
Agent: Br[Cu]Br
Solvent: C1CCOC1
Product: C=CCC[C@H](O)COCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of (2S)-2-[(benzyloxy)methyl]oxirane (50 g, 305 mmol) in THF (1500 mL) at 0° C. was added copper bromide (4.37 g, 30.5 mmol). The resulting solution was stirred at 0° C. for 10 minutes and allylmagnesium bromide (1M in THF, 335 mL, 335 mmol) was added. The reaction was stirred for 2 hours at 0° C. and then quenched at 0° C. with saturated aqueous NH4Cl and diluted with DCM. The mixture was stirred at ambient temperature for 20 minutes and filtered to remove insoluble material. The filtrate was extracted with DCM (3×) and the combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography eluted with 10 to 40% EtOAc/hexanes provided (2S)-1-(benzyloxy)hex-5-en-2-ol. 1H NMR (400 MHz, CDCl2): δ 7.37-7.26 (m, 5 H); 5.88-5.74 (m, 1 H); 5.08-4.93 (m, 2 H); 4.54 (s, 2 H); 3.83 (s, 2 H); 3.53-3.44 (m, 1 H); 3.33 (dd, J=9.1, 8.2 Hz, 1 H); 2.49 (s, 1 H); 2.30-2.00 (m, 2 H); 1.64-1.39 (m, 2 H).
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([NH2:14])[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[O:16])=[O:8])=[CH:4][N:3]=[CH:2]1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>[OH-].[Na+].C(Cl)Cl>[NH:1]1[C:5]([CH2:6][C:7]([N:9]2[CH2:13][C@H:12]([NH:14][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[CH:22][CH:23]=2)=[O:16])=[O:8])=[CH:4][N:3]=[CH:2]1
Reactant: O=Cc1ccccc1
Reactant: N[C@@H]1C[C@@H](C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)N(C(=O)Cc2cnc[nH]2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](NCc2ccccc2)CN1C(=O)Cc1cnc[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.3 %

Procedure:
A flask was charged with (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-amino-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (150 mg, 0.302 mmol), benzaldehyde (0.031 mL, 0.30 mmol), methylene chloride (5 mL), acetic acid (0.140 mL, 2.45 mmol) and sodium triacetoxyborohydride (22 mg, 0.45 mmol). The reaction mixture was stirred at ambient temperature for 16 hours and then diluted with 2N sodium hydroxide (10 mL). The dilution was extracted with ethyl acetate (20 mL) and the extract was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. Product was purified from the residue by reverse phase HPLC to give Compound 173, (2S,4R)-1-(2-(1H-imidazol-5-yl)acetyl)-4-(benzylamino)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (47 mg, 0.091 mmol, 30%), as an off-white solid. 1H-NMR (400 MHz, DMSO-D6): 11.94 (s, 1H), 10.09 (s, 1H), 7.60 (d, 2H), 7.34-7.28 (m, 4H), 7.25-7.17 (m, 3H), 7.03-6.96 (m, 6H), 4.48 (t, 1H), 3.60-3.32 (m, 7H), 2.12-1.99 (m, 2H). MS (EI) for C29H28FN5O3. found 513.9 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5](=[O:29])[NH:6][C@@H:7]1[CH2:28][C:10]2[N:11]([CH2:20][C:21]3[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:12]3[CH:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][C:17]=3[C:9]=2[CH2:8]1)([CH3:3])[CH3:2].O.[C:31]([OH:35])(=[O:34])[CH:32]=O>CCO>[C:18]([C:15]1[CH:14]=[CH:13][C:12]2[N:11]([CH2:20][C:21]3[C:22]([NH:27][CH2:32][C:31]([OH:35])=[O:34])=[N:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH2:28][C@@H:7]([NH:6][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[O:29])[CH2:8][C:9]=3[C:17]=2[CH:16]=1)#[N:19]
Reactant: O=CC(=O)O
Reactant: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3N)c3ccc(C#N)cc23)C1
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)N[C@H]1Cc2c(n(Cc3cccnc3NCC(=O)O)c3ccc(C#N)cc23)C1
Temperature: 75 °C
Reaction time: 18 h
Yield: 65.3 %

Procedure:
Dissolve [(S)-4-(2-amino-pyridin-3-ylmethyl)-7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-carbamic acid isopropyl ester (253 mg, 0.650 mmol) in EtOH (25 mL). Add 3 Å molecular sieves and glyoxylic acid monohydrate (239 mg, 2.60 mmol), then stir at 40-110° C. for 18 h under hydrogen (60 psi, 4.08 bar). Filter the reaction through a pad of diatomaceous earth and wash the catalyst/sieves with THF (50 mL). Combine the filtrate and concentrate in vacuo to a yellow oil. Triturate with water (30 mL) and sonicate the resulting aqueous slurry for 5 min. Filter off a tan solid and dry in vacuo. Triturate the solid with Et2O (5 mL) and sonicate the slurry for 30 min. Filter to obtain 190 mg (65%) of the product as a tan solid. LCMS 100% @ 3.99 min m/z 448 (M+H), 446 (M−H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:18]=1.Cl.N1C=CC=CC=1>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:18]=1
Reactant: COc1ccc(-c2cc3cc(F)ccc3o2)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc(-c2cc3cc(F)ccc3o2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 13 %

Procedure:
Compound 83 was treated with Pyridine HCl (5 g) and heated to 200° C. After 1 hr, the reaction was cooled and diluted with water. The aqueous layer was extracted with EtOAc, dried over MgSO4, filtered and concentrated to give a solid (0.11 g, 13%); Mp=202-204° C.; 1NMR (DMSO-d6) δ 9.92 (br s, 1 H), 7.73 (d, 2 H, J=8.7 Hz), 7.58 (dd, 1 H, J=8.7 Hz, 4.4 Hz), 7.39 (dd, 1 H, J=8.8 Hz, 2.5 Hz), 7.17 (d, 1 H, J=1.0 Hz), 7.10-7.06 (m, 1 H), 6.88 (d, 2 H, J=8.8 Hz); MS 227 [M−H]−
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[C:4]([S:25][CH2:26][CH2:27]I)[CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]2[N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[CH2:27][CH2:26][S:25][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCI)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(F)c([N+](=O)[O-])cc32)CC1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl 4-(4-fluoro-2-(2-iodoethylthio)-5-nitrophenylamino)piperidine-1-carboxylate (394 mg, 0.750 mmol) in DMF (5 mL) was added potassium carbonate (207 mg, 1.500 mmol), and the resulting mixture was stirred at 60° C. for 2 hours and then at 90° C. overnight. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with saturated sodium carbonate (3×), water, and brine. The organic phase was dried, filtered, concentrated, and then chromatographed using 1:9 ethyl acetate:hexanes giving the desired product (193 mg, 64.7%) as a red foam. 1H NMR (DMSO-d6) δ 7.42 (d, J=6.6 Hz, 1H), 7.30 (d, J=11.7 Hz, 1H), 4.10-3.95 (m, 2H), 3.91-3.79 (m, 1H), 3.41-3.36 (m, 2H), 3.13-3.09 (m, 2H), 2.99-2.78 (m, 2H), 1.73-1.63 (m, 2H), 1.63-1.51 (m, 2H), 1.41 (s, 9H); ESI-MS (m/z, %): 420 (MNa+, 52), 398 (MH+, 35), 342 (100), 298 (64).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][S:10]1(=[O:19])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:39][CH2:40][CH2:41]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>>[Br:39][CH2:40][CH2:41][N:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[S:10]1(=[O:18])=[O:19]
Reactant: O=S1(=O)Nc2ccccc2N1c1ccc(F)cc1Cl
Reactant: OCCBr
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=S1(=O)N(CCBr)c2ccccc2N1c1ccc(F)cc1Cl

Procedure:
1-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (made analogously as in general procedure I, 0.33 g, 1.1 mmol) was treated with triphenylphosphine (0.36 g, 1.4 mmol), 2-bromo ethanol (0.16 g, 1.4 mmol), and diisopropylazodicarboxylate (0.28 g, 1.4 mmol) to provide 0.30 g of 1-(2-bromoethyl)-3-(2-chloro-4-fluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide. HRMS: calculated for C14H11BrClFN2O2S, 403.93971; found (EI, M+), 403.9386
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][Cl:15].C(N(CC)CC)C>C(O)C>[Cl:15][CH2:14][CH2:13][CH2:12][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2nccn12
Reactant: ClCCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: ClCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 72.1 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (5.02 g, 33.4 mmoles) and 1-bromo-3-chloropropane (5.26 g, 33.4 mmoles) in ethanol (100 ml) was added triethylamine (4.66 ml, 33.4 mmoles) and the mixture was stirred at room temperature for 17 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 5.46 g of the desired product (72.0%, light brown oily product).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[H-].[Na+].F[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=1>CN(C=O)C.O>[N:1]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: COC(=O)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2cnc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of (2.3 g, 19.46 mmol) 1H-benzimidazole in DMF (80 mL) at 0° C. was added sodium hydride (0.78 g, 19.46 mol, 60 wt. %) and the reaction mixture was stirred at 0° C. for 30 minutes, then at room temperature for 1 hour. Methyl 4-fluorobenzoate (3.0 g, 19.46 mmol) was then added and the reaction mixture was heated at 85° C. for 24 h. The reaction mixture was cooled to room temperature, diluted with water (300 mL) and extracted with dichloromethane (4×250 mL). The combined organic layers were washed with water (2×250 mL), saturated aqueous sodium chloride (200 mL), dried (magnesium sulfate) and the solvent removed in vacuo to give a crude oil. Purification by flash column chromatography (silica, ethyl acetate:hexanes 2:10) provided 3.7 g (76%) of methyl 4-(1H-benzimidazol-1-yl)benzoate as a white solid. To a solution of methyl 4-(1H-benzimidazol-1-yl)benzoate (3.7 g, 14.7 mmol) dissolved in THF/MeOH (1:1, 90 mL) was added 1.0 M aqueous NaOH (0.587 g, 14.67 mmol) and the reaction mixture was allowed to stir for 12 h at room temperature and the solvent removed in vacuo. The residue was diluted with water (100 mL), cooled to 0° C., and the pH was adjusted to 6.0 with 1.0 N aqueous HCl. The resulting precipitate was filtered and dried to afford 3.4 g (96%) of 4-(1H-benzimidazol-1-yl)benzoic acid as a white solid. MS [239.0 m/e (M+H)].
Reaction SMILES: [CH2:1]1[C:6]2([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH:3]([OH:12])[CH2:2]1.O[C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C@:24]1([CH3:30])[CH2:28][O:27][C:26](=[O:29])[NH:25]1)[CH:18]=[CH:17]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O1CCCC1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:30][C@@:24]1([C:19]2[CH:18]=[CH:17][C:16]3[C:21](=[CH:22][CH:23]=[C:14]([O:12][CH:3]4[CH2:2][CH2:1][C:6]5([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]5)[CH2:5][CH2:4]4)[CH:15]=3)[CH:20]=2)[CH2:28][O:27][C:26](=[O:29])[NH:25]1
Reactant: C[C@@]1(c2ccc3cc(O)ccc3c2)COC(=O)N1
Reactant: OC1CCC2(CCCCC2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@]1(c2ccc3cc(OC4CCC5(CCCCC5)CC4)ccc3c2)COC(=O)N1
Yield: 100.1 %

Procedure:
The mixture of spiro[5.5]undecan-3-ol (166.0 mg, 0.0009866 mol), (R)-4-(6-hydroxynaphthalen-2-yl)-4-methyloxazolidin-2-one (200.0 mg, 0.0008222 mol), and triphenylphosphine (259 mg, 0.000987 mol) in tetrahydrofuran (7 mL, 0.08 mol) was heated to reflux, and diisopropyl azodicarboxylate (0.194 mL, 0.000987 mol) was added dropwise and was stirred and refluxed for overnight. The mixture was taken up into methylene chloride and subjected to chromatography purification with EtOAc/hexane (10:90 to 80:20) to give product (4R)-4-methyl-4-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)oxazolidin-2-one as a white solid (324 mg, 100%). LCMS Rf=2.34 min 394.45 ([M+1]+, 100%).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[CH:6]=[CH:5][N:4]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Cl)=[CH:18][CH:17]=1>ClCCl.O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:12]2[CH:13]=[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)[CH:10]=[N:11]2)=[CH:18][CH:17]=1
Reactant: CSc1nccc(-c2cn[nH]c2)n1
Reactant: COc1ccc(CCl)cc1
Solvent: ClCCl
Solvent: O
Product: COc1ccc(Cn2cc(-c3ccnc(SC)n3)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(methylthio)-4-(1H-pyrazol-4-yl)pyrimidine (200 mg, 1 mmol) in dichloromethane (3 mL) and H2O (1 mL) was added 4-methoxybenzylchloride (200 mg, 1.28 mmol) at 0° C. The mixture was stirred at RT overnight. The organic layer was separated, washed with brine and concentrated in vacuo to give crude 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(methylthio)pyrimidine. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.50, (d, J=5.4 Hz, 1H), 8.16 (s, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 5.30 (s, 2H), 3.72 (s, 3H), 2.51 (s, 3H); MS (ESI) m/z: 313 (M+H+).
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[OH:21])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:25])(=[O:24])[CH2:5][CH2:4]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34].C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][O:2][CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:16]3[CH:17]=[N:18][N:19]([CH2:22][CH3:23])[C:20]=3[O:21][C:33](=[O:35])[CH3:34])=[O:15])[C:11]=2[CH3:13])[S:6](=[O:24])(=[O:25])[CH2:5][CH2:4]1
Reactant: CC(=O)Cl
Reactant: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1ncc(C(=O)c2ccc3c(c2C)C(OC)CCS3(=O)=O)c1OC(C)=O
Yield: 73 %

Procedure:
4-Methoxy-5-methyl-6-(1-ethyl-5-hydroxypyrazol-4-yl) carbonylthiochroman-1,1-dioxide was used as a starting material (XIH). And, 0.40 g (1.1 mmol) thereof was dissolved in 4 ml of methylene chloride, and 0.22 g (2.2 mmol) of triethylamine as a base and 0.17 g (2.2 mmol) of acetyl chloride as a reaction reagent (XII) were added. The resultant mixture was allowed to react at room temperature for 8 hours. A saturated sodium carbonate aqueous solution was added to the reaction mixture, the reaction mixture was extracted with ethyl acetate, and its organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resultant oil was purified with flush column chromatography (Wako Gel C-300: hexane/ethyl acetate=1:2) to give 0.33 g (yield 73%) of 4-methoxy-5-methyl-6-(1-ethyl-5-acetoxypyrazol-4-yl)carbonylthiochroman-1,1-dioxide (Compound No. 51) as an end compound which comes under the general formula (XI). Table 18 shows the structures of the starting material (XIH) and the reaction reagent (XII), and the structure and the yield of the end product (XI).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8](N(C)C)(=[O:10])=[O:9])=[C:6]([OH:14])[C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[O:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.[C:25](C1OC2C(S(C)(=O)=O)=C(Cl)C=CC=2N=1)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:15][C:16]2[C:19](=[O:20])[C:18](=[O:21])[C:17]=2[O:22][CH2:23][CH3:24])=[C:6]([OH:14])[C:7]=1[S:8]([CH3:25])(=[O:10])=[O:9]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(C)(=O)=O)c2o1
Reactant: CCOc1c(Nc2ccc(Cl)c(S(=O)(=O)N(C)C)c2O)c(=O)c1=O
Product: CCOc1c(Nc2ccc(Cl)c(S(C)(=O)=O)c2O)c(=O)c1=O

Procedure:
The title compound is prepared analogously to 6-chloro-3-(2-ethoxy-3,4-dioxo-cyclobut-1-enylamino)-2-hydroxy-N,N-dimethyl-benzenesulfonamide (Ex. 3 step 2) by replacing 2-tert-butyl-6-chloro-benzooxazole-7-sulfonic acid dimethylamide (Ex. 3 step 2) with 2-tert-Butyl-6-chloro-7-methanesulfonyl-benzooxazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:13])[C:10]=1[O:11][CH3:12])[C:5]([Cl:23])=[O:6]
Reactant: COc1c(Cl)cc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(=O)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3,5-dichloro-4-methoxybenzoic acid (8.81 g), toluene (170 mL), N,N-dimethylformamide (5 droplets) and thionyl chloride (6.0 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and then used for the synthesis of (c).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:42][CH3:43])=[CH:26]3)=[N:23][CH:24]=2)=[CH:15][CH:14]=1>ClCCl.CN(C=O)C.ClCCl>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[N:23][C:22]([N:25]3[C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:34]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)=[O:35])[CH:32]=4)[C:27]([S:42]([CH3:43])=[O:6])=[CH:26]3)=[N:21][CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cn(-c2ncc(-c3ccc(O)cc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CS(=O)c1cn(-c2ncc(-c3ccc(O)cc3)cn2)c2cc(C(=O)N3CCOCC3)ccc12
Reaction time: 1 h

Procedure:
m-Chloroperoxybenzoic acid (134 mg, 0.5022 mmol, 0.8 eq) was added at 0° C. to a stirred solution of 86a) (280 mg, 0.6278 mmol, 1.0 eq) in dichloromethane/DMF (10:1; 22 mL) and the solution was stirred for 1 h at this temperature. The reaction mixture was then diluted with dichloromethane (20 mL), washed with saturated sodium hydrogen carbonate solution and brine, and dried over anhydrous sodium sulfate. The solvents were removed under vacuum and the residue was purified by preparative TLC using ethyl acetate as eluent. White solid. Yield: 65 mg (21% of theory)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[OH:10])[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:18][CH3:19]>CC(C)=O>[CH2:18]([O:10][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[NH:1][CH:2]=[CH:3]2)[CH3:19]
Reactant: CCI
Reactant: Oc1cccc2cc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1H-indol-7-ol (500 mg, 3.75 mmol) in acetone (10 mL) at r.t. was added potassium carbonate (3.11 g, 22.5 mmol), followed by iodoethane (0.45 mL, 5.63 mol). The mixture was stirred at r.t. for 16 h then solvent removed under reduced pressure. The crude product thus obtained was purified by chromatography over silica gel to afford 7-ethoxy-1H-indole: 1H NMR (400 MHz, MeOD) δ ppm 1.51 (t, J=6.95 Hz, 3H), 4.22 (q, J=6.91 Hz, 2H), 6.42 (d, J=3.03 Hz, 1H), 6.63 (d, J=7.58 Hz, 1H), 6.92 (t, J=7.83 Hz, 1H), 7.04-7.23 (m, 2H); MS (ES+): m/z 162.20 (MH+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:22][C:23]1[NH:24][CH:25]=[CH:26][N:27]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[F:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:24]3[CH:25]=[CH:26][N:27]=[C:23]3[CH3:22])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCCc1oc(Cl)nc1-c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCc1oc(-n2ccnc2C)nc1-c1ccc(F)cc1

Procedure:
Ethyl 2-chloro-4-(4-fluorophenyl)-5-oxazolebutanoate (3.11 g), 2-methylimidazole (2.46 g), potassium carbonate (4.15 g) and N,N-dimethylformamide (25 ml) was stirred at 120-130° C. for 2 hours. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (150 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer was concentrated, the residue was subjected to silica gel column chromatography, and ethyl 4-(4-fluorophenyl)-2-(2-methyl-1-imidazolyl)-5-oxazolebutanoate was obtained as an oil (3.47 g, 57%) from an ethyl acetate-hexane (1:1, v/v)-eluted fraction. Conversion to the hydrochloride and the subsequent recrystallization from hexane-ethylacetate gave pale yellow prisms. Melting point 140-145° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([OH:21])=[O:20])=[CH:5][CH:4]=1.[CH:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[C:24](O)[CH:23]=1.CCN=C=NCCCN(C)C.Cl.O>CN(C1C=CN=CC=1)C.C1COCC1>[CH3:1][O:2][C:3]1[C:15]2[N:14]([CH3:16])[C:13]3[C:12](=[O:17])[N:11]([CH3:18])[CH2:10][CH2:9][C:8]=3[C:7]=2[C:6]([C:19]([O:21][C:24]2[CH:23]=[CH:22][C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=2)=[O:20])=[CH:5][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(C(=O)O)c2c3c(n(C)c12)C(=O)N(C)CC3
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3c(n(C)c12)C(=O)N(C)CC3

Procedure:
A solution of 8-methoxy-2,9-dimethyl-1-oxo-1,2,3,4-tetrahydro-β-carboline-5-carboxylic acid (from step 5) (1 mmol), p-nitrophenol (1.5 mmol), EDCl (1.5 mmol) and DMAP (0.1 mmol) in dry THF was stirred at r.t. for 18 h. Minimum water was then added and the precipitated p-nitrophenylester was filtered and washed with water and dried (50-60%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCOCC1.[NH2:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37]>C(Cl)Cl>[C:1]([NH:16][CH2:17][CH2:18][O:19][C:20]1[C:30]2[CH2:29][CH2:28][N:27]([C:31](=[O:36])[C:32]([F:33])([F:35])[F:34])[CH2:26][CH2:25][C:24]=2[CH:23]=[CH:22][C:21]=1[Cl:37])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2
Solvent: ClCCl
Solvent: C1COCCN1
Product: O=C(NCCOc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)c1ccccc1

Procedure:
Combine benzoyl chloride (19.3 mg, 0.137 mmol), PS-morpholine (109 mg, 0.272 mmol), 6-(2-amino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (46 mg, 0.137 mmol) in DCM (1.5 mL) and stir at ambient temperature for 16 h. Filter the resin, wash with DCM and concentrate in vacuo. Purify by reverse phase HPLC (10-95% of solvent B in 12.8 min, 25 mL/min; solvent A: water, 0.1% trifluoroacetic acid; solvent B: acetonitrile, 0.1% trifluoroacetic acid; column: YMC SH-341-5, S-5μm, 12 nm, 100×20 mm) to give 6-(2-benzoylamino-ethoxy)-7-chloro-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine.