Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].C[O-].[Na+].C([O:10][C:11](=O)[CH:12]([C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:13](OCC)=[O:14])C.Cl>CO.O>[OH:10][C:11]1[C:12]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)=[C:13]([OH:14])[N:4]=[C:2]([SH:3])[N:1]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(C)cc1
Reactant: NC(N)=S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2c(O)nc(S)nc2O)cc1
Yield: 41 %

Procedure:
To a solution of thiourea (13.69 g) in methanol (150 ml) is added a 28% solution of sodium methoxide in methanol (34.70 g) at 60° C., and thereto is further added (4-methylphenyl)malonic acid diethyl ester (32.62 g) at the same temperature. The reaction solution is refluxed for 8 hours. After cooling, water is added to the reaction solution, and the pH value of the solution is adjusted to pH 1 with hydrochloric acid under ice-cooing. The precipitated crystals are collected by filtration, and the residue is washed and dried to give 4,6-dihydroxy-2-mercapto-5-(4-methylphenyl)pyrimidine (12.53 g) as a crystal.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[CH:10]3)[CH2:3][CH2:2]1.CN([CH2:19][C:20]1[C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[NH:22][CH:21]=1)C>>[NH:12]1[C:13]2[C:9](=[CH:8][C:7]([C:4]3[CH2:3][CH2:2][N:1]([CH2:19][C:20]4[C:28]5[C:23](=[N:24][CH:25]=[CH:26][CH:27]=5)[NH:22][CH:21]=4)[CH2:6][CH:5]=3)=[CH:15][CH:14]=2)[CH:10]=[CH:11]1
Reactant: C1=C(c2ccc3[nH]ccc3c2)CCNC1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Product: C1=C(c2ccc3[nH]ccc3c2)CCN(Cc2c[nH]c3ncccc23)C1
Yield: 35 %

Procedure:
5-(1,2,3,6-Tetrahydropyridin-4-yl)-1H-indole (200 mg, 1.0 mmol) and 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (177 mg, 1.01 mmol) were coupled as described in Example 4 to give a solid which was purified by flash chromatography, eluting with 10% methanol in dichloromethane containing 1% ammonia. Recrystallisation from methanol gave the title compound (115 mg, 35%) as a tan solid, m.p. 187°-189° C.; (Found: C, 73.78; H, 6.34; N, 16.13. C21H20N4.0.75 H2O requires C, 73.77; H, 6.34; N, 16.39%); δH (DMSO-d6) 2.68 (2H, m, tetrahydropyridinyl H), 3.10 (2H, s, tetrahydropyridinyl H), 3.18 (1H, d, J 4.4 Hz, tetrahydropyridinyl H), (other tetrahydropyridinyl H obscured by solvent at 3.30), 3.74 (2H, s, ArCH2N), 6.02 (1H, m, CH=CR), 6.40 (1H, s, ArH), 7.04 (1H, dd, J 7.5, 3.2 Hz, 5-H), 7.20 (1H, d, J 8.2 Hz, ArH), 7.32 (2H, m, ArH), 7.40 (1H, s, ArH), 7.52 (1H, s, ArH), 8.04 (1H, d, J 7.5 Hz, 4-H), 8.18 (1H, d, J 3.2 Hz, 6-H), 11.00 (1H, br s, NH), and 11.48 (1H, br s, NH); m/z (CI+, NH3) 329 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH:24]=O)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][C:12]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([CH2:23][CH2:24][N:34]4[CH2:38][CH2:37][CH2:36][CH2:35]4)=[CH:22][C:17]3=[N:16][CH:15]=2)=[O:13])[N:4]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=2)[N:3]=1
Reactant: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CC=O)ccn45)cccc32)n1
Reactant: C1CCNC1
Product: Cc1cccc(Cn2nc(C)c3c(NC(=O)c4cnc5cc(CCN6CCCC6)ccn45)cccc32)n1

Procedure:
Prepared according to procedure of Example 72 from N-(3-methyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide (Example 72, Steps A-B) and pyrrolidine. MS (ES+APCI) m/z=494 (M+H) detected.
Reaction SMILES: [CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2].Cl[CH2:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([CH:3]1[C:8]([C:9]2[CH:24]=[CH:23][C:12]3[N:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:27][C:28]5[N:33]=[CH:32][CH:31]=[CH:30][N:29]=5)=[CH:18][CH:17]=4)[O:15][C:11]=3[CH:10]=2)=[N:7][NH:6][C:5](=[O:25])[CH2:4]1)[CH3:2]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1
Reactant: ClCc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCc4ncccn4)cc3)oc2c1

Procedure:
40 mg (119 μmol) 5-ethyl-6-[2-(4-hydroxy-phenyl)-benzoxazol-6-yl]-4,5-dihydro-2H-pyridazin-3-one, 23.5 mg (142 μmol) 2-(chloromethyl)-pyrimidine, 50 mg (362 μmol) potassium carbonate and 2 ml DMF are together heated to 80° C. for 2.5 h. Then the mixture is extracted with 10% sodium carbonate solution and EA. The org. phase is washed with sat. saline solution, dried on sodium sulphate and then the solv. is totally eliminated i.V. The residue is recrystallised from cyclohexane/EA.
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[NH:14][CH2:13]3)=[O:5])[CH3:2].[H-].[Na+].CI.[C:32](OCC)(=O)C>CN(C=O)C>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]2[C@H:12]3[C@H:22]([CH2:23][CH2:24][C@:7]12[CH3:8])[C@:20]1([CH3:21])[C:15](=[CH:16][C:17](=[O:25])[CH2:18][CH2:19]1)[N:14]([CH3:32])[CH2:13]3)=[O:5])[CH3:27]
Reactant: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CNC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCN(CC)C(=O)[C@H]1CC[C@H]2[C@@H]3CN(C)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.5 h

Procedure:
To a solution of 17β-N,N-diethylcarbamoyl-6-azaandrost-4-en-3-one (24 mg, 0.065 mmol) in DMF (2 mL) at room temperature is added NaH (16 mg, 80% oil dispersion, 0.5 mmol) and, after 30 min, methyl iodide (50 μL, excess). After stirring for 30 min ethyl acetate (30 mL) is added, the solution washed with H2O and saturated aqueous NACl, dried over MgSO4, concentrated and flash chromatographed on silica gel (100% ethyl acetate to 5% methanol/chloroform) to give 17β-N,N-diethylcarbamoyl-6-methyl-6-azaandrost-4-ene-3-one as a white solid; yield 19 mg (76%). This material is then recrystallized from hexanes/methylene chloride to give 14 mg pure white solid; m.p. 158°-159° C. Anal. Calcd. for C24H38N2O2 ; C, 74.57; H, 9.91; N, 7.25. Found: C, 74.38; H, 9.84; N, 7.18.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21](OCC)=[O:22])[N:9]=1>C(CN)O>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:10]([CH2:20][C:21]([NH:10][CH2:20][CH2:21][OH:22])=[O:22])[N:9]=1
Reactant: CCOC(=O)Cn1nc(-c2ccccc2O)nc1-c1ccccc1O
Solvent: NCCO
Product: O=C(Cn1nc(-c2ccccc2O)nc1-c1ccccc1O)NCCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.0 g of ethyl [3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]acetate (Example 2) are dissolved in 10 ml of ethanolamine and stirred at room temperature for 2 h. The mixture is concentrated to dryness in vacuo and the residue is crystallized from isopropanol. After drying, 2-[3,5-bis(2-hydroxyphenyl)-[1,2,4]triazol-1-yl]-N-(2-hydroxyethyl)acetamide remains as colorless crystals of m.p. 208-211° C.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[N+:22]([O-])([O-:24])=[O:23].[K+]>S(=O)(=O)(O)O>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:22]([O-:24])=[O:23])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1c(F)c(F)c([N+](=O)[O-])c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 0 °C
Yield: 69.4 %

Procedure:
To a solution of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (490 mg) in concentrated sulfuric acid (5 ml) was added potassium nitrate (235 mg) below 5° C. under stirring portionwise. After stirring for 45 minutes, the reaction mixture was poured into ice water (25 ml) and the resulting precipitate was collected by filtration, washed with cold water sufficiently, recrystallized from a solution of dichloromethane-methanol (1:1) to give the title compound (392 mg) as yellow prisms, mp 215.5°-221° C. (decompd.).
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11](OC(=O)C)(=[O:13])[CH3:12].N1C=CC=CC=1>O>[C:11]([O:10][CH2:1]/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCC/C=C\CO
Solvent: O
Solvent: c1ccncc1
Product: CCCCCC/C=C\COC(C)=O

Procedure:
Cis-2-nonenol (2.9 g, 0.03 mole), acetic anhydride (3.1 g, 0.045 mole) and pyridine (15 ml) is heated at reflux for 3 hours. The solution is cooled and diluted with water. The organic layer is separated and washed successively with 3% sulfuric acid, and water. The solution is dried over sodium sulfate and distilled under vacuum to yield cis-2-nonenyl acetate, b.p. 58° - 62°C/0.1 mm.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C:4](=[CH:8][CH:9]([CH3:11])[CH3:10])[C:5]([OH:7])=[O:6].[C:13]([OH:16])(=[S:15])[CH3:14]>>[C:13]([S:15][CH:8]([CH:4]([CH2:3][CH:2]([CH3:12])[CH3:1])[C:5]([OH:7])=[O:6])[CH:9]([CH3:11])[CH3:10])(=[O:16])[CH3:14]
Reactant: CC(O)=S
Reactant: CC(C)C=C(CC(C)C)C(=O)O
Product: CC(=O)SC(C(C)C)C(CC(C)C)C(=O)O

Procedure:
E and Z 2-(2-methylpropyl)-4-methyl-pent-2-enoic acid (7 g) in thioacetic acid (50 ml) was heated at 100° C. under reflux for 72 h. The excess thioacetic acid was removed in vacuo and the residue dissolved in dichloromethane which was extracted with aqueous saturated sodium hydrogen carbonate (3×200 ml). The aqueous phase was separated, acidified to pH1 with concentrated hydrochloric acid and extracted with fresh dichloromethane. The organic extract was dried over sodium sulphate and concentrated in vacuo to a gum which was chromatographed on silica in 15% ethyl acetate in dichloromethane to afford 2-(RS)-(1-(RS)-S-Acetyl mercapto-2-methylpropyl)-4-methyl pentanoic acid (2.0 g) as a colourless oil δ(CDCl3) 0.86-1.08 (12H, m, 2×CH(CH3)2); 1.32-1.46 (1H, m, CH); 1.48-1.78 (2H, m, CH2); 1.92-2.12 (1H, m, CH); 2.36 and 2.39 (3H, each s, CH3COS); 2.65 and 2.9 (1H, each m, CH); 3.65 and 3.78 (1H, each m, CHS).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C@@:9]3([CH3:14])[C:11]([CH3:13])([CH3:12])[C@H:6]([CH2:7][CH2:8]3)[C:5]=2[C:4](=[O:15])[NH:3]1.Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21]>CN(C)C=O>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][CH:26]=[CH:27][C:18]=1[CH2:17][N:3]1[C:4](=[O:15])[C:5]2[C@@H:6]3[C:11]([CH3:12])([CH3:13])[C@@:9]([CH3:14])([CH2:8][CH2:7]3)[C:10]=2[N:2]1[CH3:1]
Reactant: Cn1[nH]c(=O)c2c1[C@]1(C)CC[C@H]2C1(C)C
Reactant: COC(=O)c1ccccc1CBr
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1Cn1c(=O)c2c(n1C)[C@]1(C)CC[C@H]2C1(C)C
Yield: 57.2 %

Procedure:
A solution of (4S,7R)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 19; 300 mg, 1.5 mmol) and methyl 2-bromomethyl-benzoate (370 mg, 1.6 mmol) in dimethylformamide (15 mL) was heated at ˜100° C. for 2 days. The reaction mixture was allowed to cool and the solvent was evaporated. The residue was taken up in dichloromethane and purified on a Biotage 40S system, eluting with 0-2% methanol/dichloromethane to give 2-((4S,7R)-1,7,8,8-tetramethyl-3-oxo-1,3,4,5,6,7-hexahydro-4,7-methano-indazol-2-ylmethyl)-benzoic acid methyl ester (304 mg, 59%) as an orange oil. 1H NMR indicated that it contained minor impurities. It was used in the next step without further purification.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)([CH2:9][CH2:10][C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[O:4][C:3]1=[O:25].[SH:26][C:27]1[S:28][CH:29]=[CH:30][N:31]=1.C(N(CC)CC)C>CN(C=O)C>[CH:20]1([C:5]2([CH2:9][CH2:10][C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[O:4][C:3](=[O:25])[C:2]([S:26][C:27]3[S:28][CH:29]=[CH:30][N:31]=3)=[C:7]([OH:8])[CH2:6]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1CC(CCC#Cc2cccc(O)c2)(C2CCCC2)OC(=O)C1Cl
Reactant: Sc1nccs1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1OC(CCC#Cc2cccc(O)c2)(C2CCCC2)CC(O)=C1Sc1nccs1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 10.6 %

Procedure:
To a solution of 3-chloro-6-cyclopentyl-6-[4-(3-hydroxy-phenyl)-but-3-ynyl]-dihydro-pyran-2,4-dione (216 mg, 0.6 mmol) from Step 5 below and 2-mercaptothiazole (141 mg, 1.2 mmol) in DMF (6 mL) was added triethylamine (0.15 mL, 1.2 mmol). The reaction was stirred at 50° C. for 2.5 hours and then quenched with 10 mL of saturated ammonium chloride. The mixture was further acidified to a pH of 1–2 with 1 N HCl. To this mixture was added 10 mL CH2Cl2 and the layers were separated. The aqueous was extracted with 2×10 mL CH2Cl2, and the organic layers were combined. After drying the organic layer over MgSO4, the solids were filtered away and the liquid was concentrated to an oil. The oil was chromatographed on silica to yield the desired product (28 mg, 11% yield).
Reaction SMILES: C1(C[O:8][C:9](=[O:22])/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)C=CC=CC=1>[Pd].CCO>[CH3:21][C:18]([C:15]1[CH:14]=[CH:13][C:12]([CH2:11][CH2:10][C:9]([OH:22])=[O:8])=[CH:17][CH:16]=1)([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)c1ccc(CCC(=O)O)cc1
Yield: 97.3 %

Procedure:
A stirring solution of (E)-3-[4-(1,1-dimethylethyl)phenyl]-2-propenoic acid phenylmethyl ester (2.04 g, 6.93 mmol) in 136 mL of abs. EtOH in the presence of 377 mg of 10% Pd/C was hydrogenated at room temperature at atmospheric pressure. After removing the catalyst by filtration through a pad of celite, the filtrate was concentrated to give 4-(1,1-dimethylethyl)benzenepropanoic acid, (1.39 g, 6.74 mmol) in 97% yield, m.p. 110°-113° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.C1(C)C=CC=C(O[C:16](=[NH:20])[NH:17][C:18]#[N:19])C=1>C(O)(C)C>[C:16]([NH:17][C:18]([NH:1][CH2:2][CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1)=[NH:19])#[N:20]
Reactant: NCCc1c[nH]cn1
Reactant: Cc1cccc(OC(=N)NC#N)c1
Solvent: CC(C)O
Product: N#CNC(=N)NCCc1c[nH]cn1

Procedure:
3.62 g. histamine (0.0300 mole) and 5.26 g. (0.0300 mole) O-m-tolyl-N-cyanoisourea are combined in 75 ml. of isopropanol. The mixture is heated 25 minutes to reflux and refluxed 70 minutes. The reaction solution is cooled and stripped to a light orange oil, triturated in benzene, decanted, and the residue is recrystallized from MeOH/CH3CN to obtain N-cyano-N'-[2-(4-imidazolyl)ethyl] guanidine having a m.p. of 152°-154° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O-:10])=[O:9])[N:6]=1.[K+].[CH2:13](O)[CH:14]([CH3:16])[CH3:15].Cl.C(=O)([O-])[O-].[K+].[K+]>O.O1CCOCC1>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[O:11])[C:8]([O:10][CH2:13][CH:14]([CH3:16])[CH3:15])=[O:9])[N:6]=1
Reactant: Nc1nc(C(=O)C(=O)[O-])cs1
Reactant: CC(C)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)COC(=O)C(=O)c1csc(N)n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture comprising 10 g of potassium 2-aminothiazol-4-ylglyoxylate, 15 g of isobutyl alcohol and 50 ml of a 4N dioxane solution of hydrogen chloride was stirred at room temperature for 2 days. The reaction mixture was poured into water and neutralized with potassium carbonate, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the ethyl acetate was evaporated off under reduced pressure, giving the desired compound as a pale yellow powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[C:9]([O:30][CH3:31])=[CH:10][C:11]([O:28][CH3:29])=[C:12]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:13]=1)=[O:7].Cl.[NH:33]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[C:36](=[O:43])[NH:35][C:34]1=[O:44].[I-].[Na+].C(N(CC)CC)C>CN(C=O)C>[O:44]=[C:34]1[NH:35][C:36](=[O:43])[C:37]2([CH2:42][CH2:41][N:40]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]3[C:9]([O:30][CH3:31])=[CH:10][C:11]([O:28][CH3:29])=[C:12]([NH:14][S:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=4)(=[O:17])=[O:16])[CH:13]=3)=[O:7])[CH2:39][CH2:38]2)[NH:33]1
Reactant: O=C1NC(=O)C2(CCNCC2)N1
Reactant: COc1cc(OC)c(C(=O)CCCCCl)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(OC)c(C(=O)CCCCN2CCC3(CC2)NC(=O)NC3=O)cc1NS(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 115 °C
Yield: 38.2 %

Procedure:
A mixture of N-[5-(5-chloropentanoyl)-2,4-dimethoxyphenyl]-4-trifluoromethylbenzenesulfonamide (0.8 g, 1.7 mmol), prepared as in Example 14, 1,3,8-triazaspiro[4.5]decane-2,4-dione hydrochloride (0.55 g, 2.7 mmol), prepared as in Example 16, sodium iodide (0.4 g, 2.7 mmol), triethylamine (0.5 g, 5 mmol) in DMF (approximately 5 mL) was heated 16 hours at 115° C. The mixture was concentrated and the residue was stirred with water and the solids were collected, dried and purified by column chromatography eluting with methylene chloride/methanol+ammonium hydroxide (95:5) to give N-{5-[5-(2,4-dioxo -1,3,8-triazaspiro[4.5]dec-8-yl)pentanoyl]-2,4-dimethoxyphenyl}-4-trifluoromethylbenzenesulfonamide (0.4 g, 0.65 mmol), m.p. 226° C. The free base was recrystallized from a solution of hydrogen chloride in ethanol to give N-{5-[5-(2,4-dioxo-1,3,8-triazaspiro[4.5]dec-8-yl)pentanoyl]-2,4-dimethoxyphenyl}-4-trifluoromethylbenzenesulfonamide hydrochloride (0.37 g, 0.57 mmol), m.p. 277°-278° C. (dec).
Reaction SMILES: [NH2:1][C:2]1[C:12]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:20][S:21]([NH:1][C:2]1[C:12]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccccc1)C(=O)CCO2
Yield: 81.1 %

Procedure:
In 200 ml of pyridine was dissolved 25.5 g of 7-amino-2,3-dihydro-6-phenoxy-4H-1-benzopyran-4-one. To the solution being maintained at 20°-25° C. was dropwise added 12.6 g of methanesulfonyl chloride. The mixture was subjected to reaction for 12 hours at the same temperature. The solvent was removed by distillation under reduced pressure. The residue was dissolved in 200 ml of ethyl acetate. The solution was extracted with two 500-ml portions of a 1N aqueous sodium hydroxide solution. The extracts (the aqueous layers) were combined, adjusted to pH 4 with 4N hydrochloric acid, and extracted with two 300-ml portions of ethyl acetate. The extracts (the organic layers) were combined, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystal was recrystallized from methanol to obtain 27.0 g (yield: 81.1%) of 2,3-dihydro-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: Cl.[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH2:15])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[O:2]1[C:6]2([CH2:11][CH2:10][CH:9]([CH:12]([NH:15][C:16](=[O:18])[CH3:17])[CH2:13][CH3:14])[CH2:8][CH2:7]2)[O:5][CH2:4][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CCC(N)C1CCC2(CC1)OCCO2
Agent: Cl
Solvent: ClCCl
Product: CCC(NC(C)=O)C1CCC2(CC1)OCCO2
Temperature: 0 °C

Procedure:
Into a 50 mL round-bottom flask were placed a solution of 1-1,4-dioxaspiro[4.5]decan-8-ylpropan-1-amine hydrochloride (as prepared in Example 104 Step B) (50 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (10 mL) and TEA (42.8 mg, 0.42 mmol, 2.00 equiv). This was followed by the addition of acetyl chloride (19.8 mg, 0.25 mmol, 1.20 equiv) dropwise with stirring at 0° C. The resulting solution was stirred overnight at room temperature. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 2×20 ml, of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the title compound as a yellow oil.
Reaction SMILES: [C:1]12([O:18][CH2:17][CH2:16][O:15]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([C:11](OC)=[O:12])[CH2:2]2.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1.C(Cl)Cl>[C:1]12([O:15][CH2:16][CH2:17][O:18]1)[C:10]1[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:4][C@@H:3]([CH:11]=[O:12])[CH2:2]2
Reactant: COC(=O)[C@@H]1Cc2ccccc2C2(C1)OCCO2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C[C@@H]1Cc2ccccc2C2(C1)OCCO2
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-methyl 3′,4′-dihydro-2′H-spiro[[1,3]dioxolane-2,1′-naphthalene]-3′-carboxylate (4.7 g, 18.93 mmol) in toluene (50 mL) and CH2Cl2 (12.50 mL) to these solution of DIBAL-H (Diisobutylaluminum hydride) (22.72 mL, 22.72 mmol) was added drop-wise at −78° C. under argon, and the mixture was stirred for 2 h at this temperature.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][S:19]([C:22]2[S:23][C:24]([Cl:27])=[CH:25][CH:26]=2)(=[O:21])=[O:20])=[O:17])=[CH:11][C:10]=1[CH3:28]
Reactant: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NC(=O)NS(=O)(=O)c2ccc(Cl)s2)ccc1N
Reaction time: 1.5 h
Yield: 136.7 %

Procedure:
To a chilled solution of N-{4-[(tert-butoxy)carbonylamino]-3-methylphenyl}{[(5-chloro(2-thienyl))sulfonyl]amino}carboxamide (0.246 g, 0.55 mmol) in CH2Cl2 (5 mL) was added neat TFA (1.1 mL). The reaction mixture was stirred cold for 1.5 hr, concentrated in vacuo, azeotroped with heptane and dried to give N-(4-amino-3-methylphenyl) {[(5-chloro(2-thienyl))sulfonyl]amino}-carboxamide (0.26 g) as the mono TFA salt. ES-MS (M+H)+=346.
Reaction SMILES: [SH-:1].[Na+].Cl[C:4]1[N:9]2[N:10]=[N:11][N:12]=[C:8]2[N:7]=[C:6]([CH3:13])[CH:5]=1.Cl>O>[SH:1][C:4]1[N:9]2[N:10]=[N:11][N:12]=[C:8]2[N:7]=[C:6]([CH3:13])[CH:5]=1
Reactant: Cc1cc(Cl)n2nnnc2n1
Reactant: [SH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nnnc2n1
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 93.4 %

Procedure:
To a solution of 108 g (1.35 mole) of sodium hydrosulfide dissolved in 4 liters of water, 70 g (0.41 mole) of 7-chloro-5-methyltetrazolo[1,5-a]pyrimidine was added and the mixture was heated to 60° C. and stirred for 2.5 hours. The pH of the mixture was adjusted to about 1 with 2N hydrochloric acid under ice-cooling and stirring. The precipitates were collected by filtration and washed with water, isopropanol and then ether, followed by drying, to obtain 64 g of the title compound (Yield: 93%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.Cl([O-])(=O)(=O)=O.[Li+]>>[F:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH2:5][CH2:4]2)=[CH:22][CH:21]=1
Reactant: O=C(OCc1ccccc1)N1CCC2(CC1)CO2
Reactant: Nc1ccc(F)cc1
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Product: O=C(OCc1ccccc1)N1CCC(O)(CNc2ccc(F)cc2)CC1

Procedure:
The object product (2.8 g, 98%) was obtained in the same manner as in Example 24(1) and using benzyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (1.98 g), 4-fluoroaniline (889 mg) and lithium perchlorate (960 mg).