Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([OH:27])=[O:26].[CH3:28]S(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26]
Reactant: CS(C)=O
Reactant: COc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(Br)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a 2 L flask was added 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (82.5 g, 187 mmol), DMSO (1249 mL), cesium carbonate (67.2 g, 206 mmol) and methyl iodide (23.44 ml, 375 mmol). The mixture was stirred at room temperature for 2 h. To the resulting slurry was added water (500 mL). The mixture became warm and was cooled with an ice/water bath. Stirring was continued an additional 30 min, then filtered and washed with H2O (2 L). The resulting solid was dried under reduced pressure then azeotroped with toluene two times to afford methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (72.3 g, 85% yield) as a tan solid. MS (m/z) 456 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=O)[CH3:6])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4](=[O:21])[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=[S:31])[CH3:6])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)C(C)N1C(=O)COc2ccc([N+](=O)[O-])cc21
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Yield: 68 %

Procedure:
A solution of 2-(6-nitro-3-oxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (185.0 g, 630 mmol) and Lawesson's reagent (279.4 g, 690 mmol) in toluene (1.5 L) was heated to 120° C. for 3 h. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo to give the crude product which was purified by chromatography on silica gel (eluting with 5% EtOAc in petroleum ether) to give 2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (133.0 g, 72%) as a yellow liquid. 1H NMR (CDCl3, 400 MHz): δ 8.02 (dd, J=2.4 Hz, J=8.8 Hz, 1H), 7.85 (d, J=2.4 Hz, 1H), 7.15 (d, J=8.8 Hz, 1H), 6.70 (m, 1H), 5.07 (d, J=15.2 Hz, 2H), 4.28 (q, J=7.2 Hz, 2H), 1.75 (d, J=7.6 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7](=[CH:22][N:23](C)C)[C:8]([C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)=[CH:4][CH:3]=1.[NH2:28]N>C(O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][C:7]2[CH:22]=[N:23][NH:28][C:8]=2[C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CN(C)C=C(Cc1ccc(Cl)cc1)C(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1c1[nH]ncc1Cc1ccc(Cl)cc1
Temperature: 70 °C
Yield: 66.3 %

Procedure:
To a solution of (R)-tert-butyl 2-(2-(4-chlorobenzyl)-3-(dimethylamino)acryloyl)pyrrolidine-1-carboxylate (580 mg, 1.5 mmol) in ethanol (10 mL) was added hydrazine (480 mg, 15 mmol). The resulting solution was heated at 70° C. for 2 h and concentrated in vacuo. Purification of the resulting residue by silica gel column chromatography (hexanes/ethyl acetate gradient, 10-100% EtOAc) afforded (R)-tert-butyl 2-(4-(4-chlorobenzyl)-1H-pyrazol-5-yl)pyrrolidine-1-carboxylate (360 mg, 67%). LCMS: calculated: 365, found (MH+): 366.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[N:12]2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:13]=[N:12]2)[C:8]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)O)c(=O)c2)c1
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: COc1cccc(Oc2cnn(C(CC3CCCC3)C(=O)Nc3ccn(CC(C)(C)O)n3)c(=O)c2)c1
Yield: 10.1 %

Procedure:
Using the method described in Example 1, 3-cyclopentyl-2-[4-(3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid (Intermediate 25) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-2-[4-(3-methoxy-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionamide as an off-white solid (14.6 mg, 10.1%); ES+-HRMS m/e calcd for C26H33N5O5 [M+Na+] 518.2374 found 518.2378. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.09 (m, 1H), 1.21-1.74 (m, 8H), 1.91 (m, 1H), 2.27 (m, 1H), 3.78 (s, 3H), 3.89 (s, 2H), 4.67 (s, 1H), 5.45 (m., 1H), 5.78 (br.s., 1H), 6.40 (s, 1H), 6.81-6.98 (m, 3H), 7.37-7.49 (m, 1H), 7.52 (d, J=2.1 Hz, 1H), 8.11 (d, J=2.4 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].CO[CH2:24][Cl:25]>C(=S)=S.Cl[Ti](Cl)(Cl)Cl>[Cl:25][CH2:24][C:6]1[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:14]=3)[CH2:9][C:8]=2[CH:7]=1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Reactant: COCCl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: S=C=S
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)c(CCl)cc1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3,6-di-t-butylfluorene (2.00 g, 7.19 mmol) and chloromethyl methyl ether (2.5 ml) in CS2 (15 ml) was added at 0° C. a solution of TiCl4 (0.4 ml) in CS2 (5 ml). The reaction mixture was stirred for 3 hours at room temperature. The mixture was poured into ice water and extracted with ether. The ether extract was dried over sodium sulfate and evaporated under vacuum to leave a residue, which was purified by column chromatography (hexane/CH2Cl2=10/1) and crystallization from hot heptanes. The product provided 2-chloromethyl-3,6-di-t-butylfluorene (yield 0.75 g). 1H NMR (CDCl3): δ 7.80 and 7.78 (each d, 1H, 4,5-H), 7.47 (d, 1H, J=8.1 Hz, H8), 7.34 (dd, 1H, J=8.1 Hz, J=1.5 Hz, H7), 7.31 (d, 1H, 1H, J=1.5 Hz, H1), 4.72 (s, 2H, CH2Cl), 3.87 (s, 2H, H9), 1.41 (s, 18H, t-Bu) and 2,7-dichloromethyl-3,6-di-t-butylfluorene (yield 0.63 g). 1H NMR (CDCl3): δ 7.87 (br s, 2H, 4,5-H), 7.34 (br s, 2H, 1,8-H), 4.75 (s, 4H, CH2Cl), 3.95 (s, 2H, H9), 1.42 (s, 18H, t-Bu) as indicated by the following reaction:
Reaction SMILES: [CH2:1]([C:10]1([OH:24])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]1[NH:19][CH2:20][CH2:21][CH2:22]O)[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1.S(Cl)([Cl:27])=O>>[CH2:1]([C:10]1([OH:24])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]1[NH:19][CH2:20][CH2:21][CH2:22][Cl:27])[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cccc(CC2(O)C(NCCCO)=Nc3ccccc32)c1
Product: COc1cccc(CC2(O)C(NCCCCl)=Nc3ccccc32)c1

Procedure:
Reaction of 3-(m-anisyl)-2-(3-hydroxypropylamino)-3H-indol-3-ol with thionylchloride by a procedure analogous to that described in Example 2 gives 3-(m-anisyl)-2-(3-chloropropylamino)-3H-indol-3-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([O-:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1.[Na+].I[C:23]1[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=1[C:25]([O:27][CH3:28])=[O:26]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[CH:14]=[C:13]([S:18]([C:23]2[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=2[C:25]([O:27][CH3:28])=[O:26])(=[O:20])=[O:19])[CH:12]=[CH:11]3)=[CH:4][CH:3]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: COC(=O)c1ccccc1I
Agent: [Na+]
Product: COC(=O)c1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Yield: 57.8 %

Procedure:
The title compound was prepared from sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate (2.2 g, 7.13 mmol) and methyl 2-iodobenzoate (1.06 mL, 7.0 mmol) according to the methods of Example 6 Step 4. Purification by flash column chromatography eluting with a 20-50% ethyl acetate/isohexane gradient gave methyl 2-{[6-(4-fluorophenyl)-2-naphthyl]sulfonyl}benzoate (1.7 g, 58%). 1H NMR (500 MHz, CDCl3) δ 8.58 (1H, s), 8.25-8.16 (1H, m), 8.06 (1H, d, J=8.5 Hz), 8.01 (1H, s), 8.00-7.92 (2H, m), 7.81 (1H, dd, J=1.7, 8.5 Hz), 7.71-7.54 (5H, m), 7.23-7.13 (2H, m), 3.96 (3H, s); m/z (ES+) 421 [MH+].
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])#[N:2].C(O)[CH2:12][CH2:13][CH2:14][OH:15].C(#N)C=C>>[C:14]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][C:1]#[N:2])(=[O:15])[CH:13]=[CH2:12]
Reactant: OCCCCO
Reactant: N#CCCOCCCCO
Solvent: C=CC#N
Product: C=CC(=O)OCCCCOCCC#N

Procedure:
Following the procedures described in Example 1, 4-(2-cyanoethoxy)-1-butanol (bp 148°-152° C./4.5 mm Hg) is prepared from 1,4-butanediol and acrylonitrile, acrylation of which gives the desired product.
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([CH3:9])([CH3:8])[CH3:7].[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([OH:33])[CH:31]=2)[CH:26]=[N:25]1.O>CN(C)C=O>[O:33]([C:30]1[CH:31]=[C:32]2[C:27]([CH:26]=[N:25][NH:24]2)=[CH:28][CH:29]=1)[Si:10]([C:6]([CH3:9])([CH3:8])[CH3:7])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Oc1ccc2cn[nH]c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2cn[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.6 %

Procedure:
Imidazole (3.0 g, manufactured by Kanto Chemical Co., Inc.) and t-butylchlorodiphenylsilane (12.1 g, manufactured by Tokyo Chemical Industry Co., Ltd.) were added to a solution of 1H-indazol-6-ol (3.0 g) synthesized according to the literature (L. F. Fieser, J. Am. Chem. Soc., 1926, 48, 1097-1107) in N,N-dimethylformamide (100 mL, manufactured by Kanto Chemical Co., Inc.), and the mixture was stirred for 3 hours at room temperature. Water (200 mL) was added to the reaction solution, and the mixture was extracted with diethyl ether (3×200 mL), washed with brine (400 mL), and dried (MgSO4). The solvent was then evaporated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1), to give 7.3 g of the title compound. LC-MS: HPLC retention time 2.05 minutes, m/z 373 (M+H), condition C-1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:19](=[O:20])[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]([CH3:11])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(C(C)(C)C)cc1N
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Yield: 29.8 %

Procedure:
According to the procedure described in Example 161C, 3-tert-butyl-1-methyl-1H-pyrazol-5-amine (1.0 g, 6.5 mmol), and K2CO3 (1.17 g, 8.5 mmol) in THF (15 mL) were reacted with phenyl chloroformate (1.12 g, 7.2 mmol). The crude product was purified by silica gel chromatography with 0-50% EtOAc/hexane gradient to afford phenyl 3-tert-butyl-1-methyl-1H-pyrazol-5-ylcarbamate as solid (0.53 g, 31%). 1H NMR (300 MHz, DMSO-d6) δ 10.2 (s, 1H), 7.43 (m, 2H), 7.25 (m, 3H), 6.06 (s, 1H), 3.66 (s, 3H), 1.25 (s, 9H); LC-MS (ESI) m/z 274 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27]1([CH:33]=[CH:34][C:35](Cl)=[O:36])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([N:16]2[CH:20]=[CH:19][N:18]=[CH:17]2)[C:9]2[CH:10]=[CH:11][C:12]([NH:15][C:35](=[O:36])[CH:34]=[CH:33][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(C=Cc1ccccc1)Nc1ccc(C(c2ccc(Cl)cc2)n2ccnc2)cc1
Yield: 83.8 %

Procedure:
To a stirred and cooled (0° C.) mixture of 14.6 parts of 4-[(4-chlorophenyl)(1H-imidazol-1-yl)methyl]benzenamine, 60.9 parts of benzene and 6.86 parts of pyridine was added a solution of 10.6 parts of 3-phenyl-2-propenoyl chloride in 17.4 parts of benzene under a nitrogen atmosphere. After stirring overnight at room temperature, the reaction mixture was basified and extracted with ethyl acetate. The extract was washed with water, dried, filtered and evaporated. The residue was crystallized from dichloromethane. The product was filtered off and dried, yielding 17.7 parts (83.8%) of N-[4-[(4-chlorophenyl) (1H-imidazol-1-yl)methyl]phenyl]-3-phenyl-2-propenamide; top. 244° C.(interm. 50).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10]N.[CH3:12][N:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.Cl>C(O)C>[CH3:2][O:3][C:4]1[C:5]2[NH:10][C:16]3[CH2:17][CH2:18][N:13]([CH3:12])[CH2:14][C:15]=3[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: COc1ccccc1NN
Reactant: CN1CCC(=O)CC1
Agent: Cl
Solvent: CCO
Product: COc1cccc2c3c([nH]c12)CCN(C)C3
Temperature: 80 °C
Yield: 30.3 %

Procedure:
To a stirred solution of (2-methoxyphenyl)hydrazine hydrochloride (5 g, 0.0286 mol) and 1-methyl-4-piperidone (2.83 mL, 0.0229 mol) in ethanol (50 mL) was added ethanolic hydrochloric acid (5 mL). The reaction mixture was heated at 80° C. for 2 h. After completion, the reaction mixture was cooled to RT and solvent removed under reduced pressure. The residue was basified with 10% sodium hydroxide solution and extracted with EtOAc (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel column chromatography (6% MeOH:DCM) to yield 6-methoxy-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (1.5 g, 24% yield).
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23](=[O:26])(=[O:25])[NH2:24])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2].[CH2:30]([N:32]=[C:33]=[S:34])[CH3:31]>>[CH2:1]([C:3]1[C:4](=[O:29])[N:5]([C:9]([NH:11][CH2:12][CH:13]2[C:22]3[C:17](=[CH:18][C:19]([O:27][CH3:28])=[C:20]([S:23]([NH:24][C:33]([NH:32][CH2:30][CH3:31])=[S:34])(=[O:25])=[O:26])[CH:21]=3)[O:16][CH2:15][CH2:14]2)=[O:10])[CH2:6][C:7]=1[CH3:8])[CH3:2]
Reactant: CCC1=C(C)CN(C(=O)NCC2CCOc3cc(OC)c(S(N)(=O)=O)cc32)C1=O
Reactant: CCN=C=S
Product: CCNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OCCC2CNC(=O)N1CC(C)=C(CC)C1=O

Procedure:
4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido)methyl)-6-(ethylaminothiocarbonylaminosulfonyl)-7-methoxychroman ##STR48## 4-((3-Ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-(ethylaminothio-carbonylaminosulfonyl)-7-methoxychroman is prepared analogously to Example 14 from 4-((3-ethyl-4-methyl-2-oxo-3-pyrroline-1-carboxamido) methyl)-6-sulfamoyl-7-methoxychroman and ethyl isothiocyanate. Melting point: 147° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]23[O:16][CH2:15][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:11][O:10]3)=[CH:5][CH:4]=1)#[CH:2].[CH3:20][N:21]=[C:22]=[S:23].CNC(=O)C#CC1C=CC(C23OCC(CCC)(CO2)CO3)=CC=1>>[CH3:20][NH:21][C:22](=[S:23])[C:2]#[C:1][C:3]1[CH:4]=[CH:5][C:6]([C:9]23[O:10][CH2:11][C:12]([CH2:17][CH2:18][CH3:19])([CH2:13][O:14]2)[CH2:15][O:16]3)=[CH:7][CH:8]=1
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Reactant: CN=C=S
Agent: CCCC12COC(c3ccc(C#CC(=O)NC)cc3)(OC1)OC2
Product: CCCC12COC(c3ccc(C#CC(=S)NC)cc3)(OC1)OC2

Procedure:
N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-yn-thioamide was prepared from 1-(4ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane and methyl isothiocyanate in a manner analogous to the synthesis of N-Methyl-3-[4-(4-n-propyl-2,6,7-trioxabicyclo[2,2,2]oct-1-yl)phenyl]-prop-2-ynamide.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[CH2:16](Br)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:5]([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:4]=2[CH:3]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCCCCCBr
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Yield: 85 %

Procedure:
This compound was prepared from 2,7-dibromofluorene and n-octyl bromide, using a similar procedure as described in Example III. The product was obtained in an 85% yield as colorless crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24]C(OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35]CC1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1.Cl>>[ClH:35].[CH3:44][O:43][C:40]1[CH:41]=[CH:42][C:24]([CH2:23][S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]([NH:15][C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[N:13][CH:12]=2)=[CH:38][CH:39]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: COc1ccc(CCl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: COc1ccc(CSc2cnc(Nc3nc(C)cs3)c(OCc3ccccc3)c2)cc1
Yield: 77.6 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-(chloromethyl)-4-methoxybenzene (0.023 mL, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(4-methoxybenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (64.1 mg, 78.3% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 7.82 (d, 1H), 7.60-7.54 (m, 3H), 7.45-7.34 (m, 3H), 7.13 (m, 2H), 6.82 (m, 3H), 5.30 (s, 2H), 4.14 (s, 2H), 3.70 (s, 3H), 2.30 (d, 3H); Mass spectrum (apci) m/z=450.0 (M+H-HCl).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2[CH2:3]1.[C:13]1([C:19]2[C:23]([CH:24]=O)=[CH:22][NH:21][N:20]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1CCCCC1.CC(O)C>[O:1]=[C:2]1[NH:6][C:5]2[S:7][C:8]([C:10]([NH2:12])=[O:11])=[CH:9][C:4]=2/[C:3]/1=[CH:24]/[C:23]1[C:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[N:20][NH:21][CH:22]=1
Reactant: NC(=O)c1cc2c(s1)NC(=O)C2
Reactant: O=Cc1c[nH]nc1-c1ccccc1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: NC(=O)c1cc2c(s1)NC(=O)/C2=C\c1c[nH]nc1-c1ccccc1
Temperature: 75 °C
Yield: 45.5 %

Procedure:
5,6-Dihydro-5-oxo-4H-thieno[2,3-b]pyrrole-2-carboxamide (30 mg, 0.17 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (2 ml). 3-Phenyl-1H-pyrazole-4-carboxaldehyde (0.18 mmol, 31 mg) was added in one portion and the mixture heated at 75° C. for 1 hour. The reaction mixture was poured into an ice/water mixture (2 ml) and the precipitated solid was collected by filtration and washed with water to give 26 mg of (Z)-5,6-dihydro-5-oxo-4-[(3-phenyl-1H-pyrazol-4-yl)methylene]-4H-thieno[2,3-b]pyrrole-2-carboxamide as a yellow/brown solid. MS(ES): m/e 337 [M+H].
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[OH-].[Na+].[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C(=O)O)ccc1OCc1ccccc1
Reaction time: 1 h
Yield: 57 %

Procedure:
To a suspension of 4-hydroxy-3-methoxybenzoic acid (25 g, 0.15 mole) in ethanol (150 ml), 2N NaOH aq. (74.3 g, 0.15 mole) and benzyl chloride (56.5 g, 0.45 mole) were added, continued to stir for 1 hour under reflux. Then, 5N NaOH aq. (150 ml) was added dropwise with stirring under reflux, and continued to stir for 1 hour under reflux. After reaction, the solvent was removed, and H2O was added to the residue and acidified with conc. hydrochloric acid to make pH 1. The precipitate was filtered, washed with H2O and dried to give 22.1 g of 4-benzyloxy-3-methoxybenzoic acid as pale yellow crystals having a m.p. of 171°-172.5° C.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=O)[CH2:12]3)([O:3][CH3:4])=[O:2].Cl.[NH2:28][OH:29].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C@:14]([OH:25])([CH2:15][C@@H:16]([OH:24])[CH2:17][CH2:18]1)[C:13](=[N:28][OH:29])[CH2:12]3)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=O)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC(=NO)[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C

Procedure:
A suspension of 17β-Carbomethoxy-6-oxo-3β,5α-dihydroxy-androstane, 8 g, as prepared in example 17, hydroxylamine hydrochloride (12 g) and sodium acetate trihydrate (16 g) in ethanol (100 mL) is heated at reflux for 1 h. The reaction mixture is cooled to ambient temperature and filtered to afford 17β-carbomethoxy-6-oximino-3β,5α-dihydroxyandrostane as a white solid, mp 234°-237° C. dec. Anal. Calcd. for C21H33NO5.H2O: C, 63.34; H, 8.88; N, 3.53. Found: C, 62.91; H, 8.98; N, 3.27.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:24]=[CH:23][C:14]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]2)=[CH:13][CH:12]=1.[Cl:25][CH2:26][CH2:27][CH2:28][S:29](Cl)(=[O:31])=[O:30].N1C=CC=CC=1>C1COCC1.C([O-])(O)=O.[Na+]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([NH:22][S:29]([CH2:28][CH2:27][CH2:26][Cl:25])(=[O:31])=[O:30])[CH2:20][CH2:21]2)=[CH:23][CH:24]=1
Reactant: NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(CCCCl)NC1CCN(Cc2ccc([C@H]3COc4ccccc4O3)cc2)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of compound 217 (535 mg, 1.65 mmol) in THF (10 mL) is added 3-chloro-propane-1-sulfonyl chloride (0.40 mL, 3.3 mmol) and pyridine (0.27 mL). After 18 h, the mixture is diluted with saturated NaHCO3 and extracted with EtOAc. The organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by flash chromatography eluting with a gradient of 0-10% MeOH in DCM to provide 3-chloro-propane-1-sulfonic acid {1-[(S)-4-(2,3-dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-piperidin-4-yl}-amide. LC/MS method 1: ES+ m/z 465.2 [M]+, Rt=0.68 min).