Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[S:9]([CH2:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([O:37]CC)=[O:36])[CH:29]=[CH:28]4)=[CH:21][CH:20]=2)=[C:15]([CH:40]([CH3:42])[CH3:41])[O:14][N:13]=1)=[O:10].O1CCCC1.[OH-].[Na+].Cl>CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[S:9]([CH2:11][C:12]1[C:16]([CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:26]=[C:27]4[C:32](=[CH:33][CH:34]=3)[N:31]=[C:30]([C:35]([OH:37])=[O:36])[CH:29]=[CH:28]4)=[CH:23][CH:24]=2)=[C:15]([CH:40]([CH3:42])[CH3:41])[O:14][N:13]=1)=[O:10]
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(CS(=O)c5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1onc(CS(=O)c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3nc(C(=O)O)ccc3c2)cc1
Temperature: 90 °C
Yield: 100.8 %

Procedure:
To a solution of ethyl 6-[4-({[3-{[(2,6-dichlorophenyl)sulfinyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylate (6 mg, 0.01 mmol) in 1:1 tetrahydrofuran:methanol (0.5 mL) was added 1 N sodium hydroxide (0.020 mL, 0.020 mmol). The solution was heated in a microwave reactor at 90° C. for approximately 10 minutes and then 1 N hydrochloric acid (0.020 mL, 0.020 mmol) was added. The solution was concentrated and then dichloromethane and water were added. The layers were separated and the organic layer was dried over magnesium sulfate and concentrated to afford 6-[4-({[3-{[(2,6-dichlorophenyl)sulfinyl]methyl}-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-2-quinolinecarboxylic acid (6 mg, 100%). 1H-NMR (400 MHz, CDCl3) δ 8.38 (d, J=8 Hz, 1H), 8.23 (d, J=8 Hz, 2H), 8.04-8.01 (m, 2H), 7.68 (d, J=9 Hz, 2H), 7.31 (s, 3H), 7.07 (d, J=9 Hz, 2H), 5.14-4.99 (m, 2H), 4.84-4.59 (m, 2H), 3.24 (septet, J=7 Hz, 1H), 1.35 (d, J=7 Hz, 6H). LRMS (APCI) m/z 595 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:40])[CH2:4][N:5]([S:29](=[O:39])(=[O:38])[NH:30]C(OC(C)(C)C)=O)[C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:40])[CH2:4][N:5]([S:29](=[O:38])(=[O:39])[NH2:30])[C:6]1[CH:11]=[CH:10][C:9]([S:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)(=[O:14])=[O:13])=[CH:8][C:7]=1[O:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)CN(c1ccc(S(=O)(=O)c2ccccc2)cc1OCc1ccccc1)S(=O)(=O)NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN(c1ccc(S(=O)(=O)c2ccccc2)cc1OCc1ccccc1)S(N)(=O)=O

Procedure:
A solution of N-(t-butoxycarbonylsulfamoyl)-N-(4-benzenesulfonyl-2-benzyloxyphenyl)glycine methyl ester (620 mg, 1.05 mmol) in 10 mL TFA/CH2Cl2 (1:1) is stirred at RT for 30 min. The solvent is removed under reduced pressure and the residue is redissolved in CH2Cl2 and restripped (4×). The residual oil is chromatographed on a Biotage 40M column using CH2Cl2/EtOAc (90:10) as eluent to afford the title compound: 1H NMR (CDCl3) δ 7.87 (m, 2H), 7.72 (d, J=8.2 Hz, 1H), 7.60 (m, 2H), 7.50 (m, 3H), 7.41 (m, 5H), 5.18 (s, 2H), 4.92 (br s, 2H), 4.32 (s, 2H), 3.87 (s, 3H); MS (M−1)−=489.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH:8]=[CH:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C(OC(Cl)=O)C.C(N(CC)CC)C.[CH:28]([NH2:31])([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6](=[O:7])[CH:8]=[CH:9][C:10]([NH:31][CH:28]([CH3:30])[CH3:29])=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)C=CC(=O)c1ccc(Cl)cc1
Reactant: CC(C)N
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)NC(=O)C=CC(=O)c1ccc(Cl)cc1

Procedure:
The precursor 4-(4-chlorophenyl)-N-(1-methylethyl)-4-oxo-2-butenamide (7A) was prepared by the procedure shown in the previous examples by treating 1A with ethylchloroformate and triethylamine in toluene at 0°, then adding at 0° a solution of isopropylamine in toluene. 7A was obtained as a solid, m.p.: 162°-163°. It was converted to 7 by treatment with hydrogen perioxide, by the procedure described in Example 1, 7 being obtained as a solid, m.p.: 128-129°.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N+:3]=1[O-:9].[N+:10]([O-])([OH:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][N+:3]=1[O-:9]
Reactant: Cc1ccc[n+]([O-])c1C
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1c([N+](=O)[O-])cc[n+]([O-])c1C
Reaction time: 24 h

Procedure:
A solution of 183 mg (1.49 mmol) of 2,3-dimethylpyridine 1-oxide in 0.6 ml of conc. sulphuric acid is treated while coollng with ice with 0.2 ml of 65% nitric acid (d=1.4). The reaction mixture is stirred at 9° for 24 hours and poured on to a mixture of ice and sodium carbonate, whereupon the resulting mixture is extracted with methylene chloride and the methylene chloride phase is dried and evaporated. The residue crystallized from ethanol/n-pentane, gives 2,3-dimethyl-4-nitropyridine 1-oxide of melting point 99°-102°.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[Br:23][C:24]1[S:28][C:27]([S:29](Cl)(=[O:31])=[O:30])=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl>[Br:23][C:24]1[S:28][C:27]([S:29]([N:18]2[CH2:19][CH2:20][N:15]([C:12]3[CH:11]=[CH:10][C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:1])([F:21])[F:22])=[CH:14][CH:13]=3)[CH2:16][CH2:17]2)(=[O:31])=[O:30])=[CH:26][CH:25]=1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccc(Br)s1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 0.25 h

Procedure:
A 100-mL round-bottomed was charged with 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol (0.54 g, 1.65 mmol, published PCT patent application no. WO 2006/094842), 10 mL of CH2Cl2, and 5-bromo-2-thiophenesulfonyl chloride (0.43 g, 1.65 mmol, Sigma-Aldrich, St. Louis, Mo.). To this was added triethylamine (0.28 mL, 2.06 mmol). After 15 min at room temperature, the mixture was diluted with 10 mL of CH2Cl2 and filtered. The filtrate was concentrated and purified by column chromatography on silica gel (0-50% EtOAc in hexanes) to give 2-(4-(4-((5-bromo-2-thiophenyl)sulfonyl)-1-piperazinyl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.83 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[C:18]([NH:20][CH2:21][O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=[CH:16][N:15]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=[O:36]>ClCCl>[Cl:33][CH:34]([Cl:38])[C:35]([N:20]([C:18]1[CH:17]=[CH:16][N:15]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:19]=1)[CH2:21][O:22][CH:23]([CH3:25])[CH3:24])=[O:36]
Reactant: CC(C)OCNc1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OCN(C(=O)C(Cl)Cl)c1ccnc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-(2,6-Dichlorophenyl)isoxazol-5-yl)-N-(isopropoxymethyl)pyridin-4-amine (269 mg, 0.58 mmol) was dissolved in anhydrous dichloromethane with triethylamine (100 μL, 0.70 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (70 μL, 0.70 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 99:1 dichloromethane:methanol to yield 2,2-dichloro-N-(2-(3-(2,6-dichlorophenyl)isoxazol-5-yl)pyridin-4-yl)-N-(isopropoxymethyl)acetamide (Cpd. No. 4). 1H NMR (CDCl3): 8.81 (d, 1H), 8.02 (s, 1H), 7.51-7.32 (m, 3H), 7.12 (s, 1H), 6.23 (s, 1H), 5.21 (s, 2H), 6.00 (s, 1H), 3.90 (m, 1H), 3.10 ppm (m, 6H). MW=489 confirmed by LC-MS, tr=14.57 min (Method Y) MH+=487-491.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:20])[F:21])[CH:13]=2)=[O:9])[CH:5]=[CH:4][N:3]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1nccc(C(=O)NCc2cccc(OC(F)(F)F)c2)n1
Product: CC(=O)Nc1nccc(C(=O)NCc2cccc(OC(F)(F)F)c2)n1

Procedure:
The title compound is prepared from 2-amino-N-(3-(trifluoromethoxy)benzyl)pyrimidine-4-carboxamide (15 mg, 0.05 mmol, Step-1) and acetyl chloride (11 mg, 0.14 mmol) according to the procedure similar to that described in Step-2 of Example 8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=4[C:27]#[N:28])=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1ccccc1O
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccccc4C#N)ncnc32)CC1

Procedure:
4-[4-(2-Cyano-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester was prepared according to General Procedure B by the reaction of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19) with 2-hydroxybenzonitrile (available from Alfa Aesar, Ward Hill, Mass., USA) in dimethylformamide. 1H NMR (400 MHz, DMSO-d6) δ 1.43 (s, 9H), 1.98-2.08 (m, 4H), 2.98-3.08 (m, 2H), 4.08-4.11 (m, 2H), 5.01-5.06 (m, 1H), 7.55-7.59 (m, 1H), 7.63-7.65 (m, 1H), 7.85-7.90 (m, 1H), 8.02-8.04 (m, 1H), 8.47 (s, 1H), 8.58 (s, 1H). Mass spectrum MH+=421.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7](OC(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8].[CH3:14][NH:15][CH3:16].O1CCCC1>>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([N:15]([CH3:16])[CH3:14])=[O:8]
Reactant: CNC
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cc(Br)ccc1N
Temperature: 60 °C
Yield: 78.6 %

Procedure:
Into a 350 ml round bottomed pressure tube were added 5-bromoisatoic anhydride (15.0 g, 62.0 mmol) and 2 M dimethylamine in tetrahydrofuran (90 ml, 180 mmol). The vial was sealed and heated in an oil bath at 60° C. for 1 hour, then the mixture was concentrated to dryness. The residue was dissolved in dichloromethane (100 ml). The organic layer washed with saturated, aqueous sodium bicarbonate solution (25 ml), washed with water (25 ml), dried over sodium sulfate, filtered, and concentrated to obtain a yellow powder. The powder was re-crystallized from ether to obtain 11.8 g (78.6%) of 2-amino-5-bromo-N,N-dimethyl-benzamide. 1H-NMR (250 MHz, CDCl3) δ 7.20 (dd, J=8.5, 2.5 Hz, 1H), 7.10 (d, J=2.5 Hz, 1H), 6.65 (d, J=8.7 Hz, 1H), 5.34 (s, 2H), 2.91 (s, 6H); MS m/z 243.1, 245.1 (M+H+).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH:12]=[CH:11]3)[CH2:8]1)(=[O:4])=[O:3].[H][H]>O1CCOCC1.[C].[Pd]>[CH3:1][S:2]([O:5][CH2:6][CH:7]1[O:19][C:18]2[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:20])[CH2:12][CH2:11]3)[CH2:8]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCC1Cc2c(ccc3[nH]c(=O)ccc23)O1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CS(=O)(=O)OCC1Cc2c(ccc3c2CCC(=O)N3)O1
Yield: 84.8 %

Procedure:
The compound obtained in Example 157 (0.85 g, 2.88 mmol) dissolved in dioxane (50 ml) was combined with 10% palladium-carbon (1.55 g), then stirred in the stream of hydrogen at 60° for 16 hours. From the reaction mixture, palladium-carbon was filtered off. The filtrate was condensed under reduced pressure, and the reside was washed with ether. 0.726 g of the tile compound was obtained as pale brown crystals (84.8%). They were recrystallized from a solvent mixture of chloroform--methanol--ether to obtain colorless prisms of the title compound (mp.: 209°-210° C. (dec.)).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[CH3:15][C:16]1[C:20]([CH3:21])=[C:19]([NH2:22])[O:18][N:17]=1.N1C=CC=CC=1>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH3:15][C:16]1[C:20]([CH3:21])=[C:19]([NH:22][S:11]([C:3]2[C:4]3[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=3[S:6][C:2]=2[CH3:1])(=[O:13])=[O:12])[O:18][N:17]=1
Reactant: Cc1sc2ccccc2c1S(=O)(=O)Cl
Reactant: Cc1noc(N)c1C
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1noc(NS(=O)(=O)c2c(C)sc3ccccc23)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Methylbenzo[b]thiophene-3-sulfonyl chloride (1.7 mmoles, 0.41 g) was added to a solution of 3,4-dimethyl-5-aminoisoxazole (0.75 mmoles, 84 mg), 4-dimethylaminopyridine (DMAP; 50 mg) and pyridine (5 ml) at ambient temperature. After 24 h, the reaction mixture was diluted with ethyl acetate (50 ml) and washed with 2% HCl (3×50 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a brown-orange solid, which was dissolved in a solution of methanol (10 ml) and NaOH (60 mg). The solution was stirred 1 h at ambient temperature, then the methanol was evaporated and the resulting residue was diluted with 2% HCl (50 ml), and extracted with ethyl acetate (75 ml). The organic phase was dried (MgSO4), filtered and concentrated to collect a tan solid. Recrystallization from chloroform and hexanes resulted in 93 mg (38%) of N-(3,4-dimethyl-5-isoxazolyl)-2-methylbenzo[b]thiophene-3-sulfonamide as light yellow crystals, m.p. 174-176° C.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12]C)[CH:8]=2)[N:3]=1.[C:14]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([Cl:26])[CH:18]=1)([OH:16])=[O:15]>>[Cl:26][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][C:20]=1[C:2]1[N:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1)[C:14]([OH:16])=[O:15]
Reactant: COc1ccc2nc(Cl)ncc2c1
Reactant: O=C(O)c1ccc(B(O)O)c(Cl)c1
Product: O=C(O)c1ccc(-c2ncc3cc(O)ccc3n2)c(Cl)c1

Procedure:
Prepared according to Scheme 6, B conditions, starting from Intermediate 8 and 4-carboxy-2-chlorophenylboronic acid. 1H NMR (DMSO-d6 400 MHz): δ 10.60 (brs, 1H), 9.56 (s, 1H), 8.10-7.89 (m, 4H), 7.62 (dd, J=9.2, 2.8 Hz, 1H), 7.38 (d, J=2.8 Hz, 1H). MS (ESI): m/z 300.8 [M+H]+.
Reaction SMILES: [CH2:1]([CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>C(O)(=O)C.O>[CH2:1]([CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=[O:22])[CH2:17]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCC1CCCC(O)C1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCCCCCCCCCCCC1CCCC(=O)C1
Temperature: 60 °C

Procedure:
A solution of 25 g (80 mmol) of 3-pentadecylcyclohexanol in 190 ml of glacial acetic acid was cooled to about 0° C., with stirring, and a solution of 8.33 g (31.8 mmol) of sodium dichromate in 14 ml of glacial acetic acid and 5 ml of water was added dropwise over 4.5 hours at a temperature below 10° C. The reaction mixture was heated to 60° C. for one hour and vacuum stripped to remove acetic acid. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate solution and water and dried over sodium sulfate. Upon vacuum stripping of the solvent, the desired 3-pentadecylcyclohexanone was obtained as a waxy solid, m.p. 41° C. The yield was 23 g (92% of theoretical).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34].C(=O)(O)[O-].[Na+]>CN(C)C=O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:24])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:28][CH2:29][O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:21][CH:22]=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Reactant: COCCOCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COCCOCCOc1ccc(C[C@H](NC(=O)OCc2ccccc2)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
6.59 g (20 mmol) of N-benzyloxycarbonyl-tyrosine-methyl ester is dissolved in 25 ml of anhydrous N,N-dimethylformamide and mixed at 0° C. under argon with 0.81 g (20.5 mmol) of sodium hydride dispersion (60% in mineral oil). The batch is allowed to stir for 10 minutes, then 3.75 g (20.5 mmol) of 1-bromo-2-(2-methoxyethoxy)-ethane is added, the reaction temperature is allowed to increase to room temperature and stirred for another three hours. For working-up, the batch is taken up in toluene and shaken out several times against aqueous sodium bicarbonate solution. The organic phase is separated, dried on magnesium sulfate, filtered and concentrated by evaporation. The oily residue is chromatographed for purification on silica gel with hexane/diethyl ether/triethylamine.
Reaction SMILES: Cl[C:2]1[C:3](=[O:16])[N:4]([CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][O:12][CH3:13])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[NH:23][CH2:22][CH2:21]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:23]2[C:24]3[C:20](=[CH:19][C:18]([Cl:17])=[CH:26][C:25]=3[Cl:27])[CH2:21][CH2:22]2)[C:3](=[O:16])[N:4]([CH:9]([CH2:14][CH3:15])[CH2:10][CH2:11][O:12][CH3:13])[CH:5]=1
Reactant: Clc1cc(Cl)c2c(c1)CCN2
Reactant: CCC(CCOC)n1cc(Cl)nc(Cl)c1=O
Product: CCC(CCOC)n1cc(Cl)nc(N2CCc3cc(Cl)cc(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-(1-ethyl-3-methoxypropyl)-2(1H)-pyrazinone and 5,7-dichloroindoline as the starting materials. mp 95-97° C.; 1H NMR (300 MHz, CDCl3): δ 7.16 (d, J=2.2 Hz, 1 H), 7.09 (d, J=1.8 Hz, 1 H), 6.78 (s, 1 H), 4.89-4.82 (m, 1 H), 4.32 (t, J=8.1 Hz, 2 H), 3.39-3.27 (m, 2 H), 3.25 (s, 3 H), 3.11 (t, J=7.9 Hz, 2 H), 2.01-1.93 (m, 2 H), 1.84-1.72 (m, 2 H), 0.86 (t, J=7.5 Hz, 3 H); HRMS (ESI) calcd for C18H21N3O2Cl3 (M+H)+: 416.0699; found m/z 416.0717.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]2[CH:16]=[C:15]([C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)[CH:14]=[C:13]3[C:9]=2[CH:10]=[N:11][N:12]3S(C2C=CC=CC=2)(=O)=O)=[N:5][N:4]=1.[CH3:35][S:36]([O-:38])=[O:37].[Na+].[OH-].[Na+].Cl>C(O)C.C(O)(C)C>[NH:21]1[C:22]2[C:18](=[C:17]([C:15]3[CH:14]=[C:13]4[C:9]([CH:10]=[N:11][NH:12]4)=[C:8]([C:6]4[O:7][C:3]([CH2:2][S:36]([CH3:35])(=[O:38])=[O:37])=[N:4][N:5]=4)[CH:16]=3)[CH:25]=[CH:24][CH:23]=2)[CH:19]=[CH:20]1
Reactant: O=S(=O)(c1ccccc1)n1ncc2c(-c3nnc(CCl)o3)cc(-c3cccc4[nH]ccc34)cc21
Reactant: CS(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCO
Product: CS(=O)(=O)Cc1nnc(-c2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)o1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 12.5 %

Procedure:
4-[5-(Chloromethyl)-1,3,4-oxadiazol-2-yl]-6-(1H-indol-4-yl)-1-(phenylsulfonyl)-1H-indazole (50 mg, 0.102 mmol) and sodium methanesulfinate (10.42 mg, 0.102 mmol) in ethanol (0.8 ml) were heated under microwave irradiation to 100° C. for 30 mins then 150° C. for 30 min, followed by 150° C. for a further 30 mins. Additional sodium methanesulfinate (10.42 mg, 0.102 mmol) was added and the reaction heated to 150° C. for a further 30 mins. The solvent was removed and the resultant beige solid treated with isopropanol (1 ml) and 2M aqueous sodium hydroxide (1.003 ml, 2.006 mmol) and stirred at 20° C. for 20 h. The mixture was neutralised with 2M aqueous hydrogen chloride, evaporated to dryness and azeotroped with isopropanol (2 ml). The residue was partitioned between dichloromethane (5 ml) and water (5 ml) and shaken vigorously. The aqueous phase was pipetted off, then the heterogeneous solution was treated with methanol (5 ml), absorbed onto Florisil and the solvents removed. The Florisil was placed on top of a silica cartridge (10 g) and eluted with 0-3% methanol/dichloromethane. Appropriate fractions were combined and concentrated to give a beige solid, 16 mg. Further purification by Mass Directed Automated Preparative HPLC afforded the title compound as a white solid (5 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([OH:16])=O)=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1.[N:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH2:25])=[CH:20][CH:19]=1>>[OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[S:9][C:10]([C:14]([NH:25][CH2:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[O:16])=[C:11]([CH3:13])[N:12]=2)[C:4](=[O:17])[CH:3]=1
Reactant: NCc1ccncc1
Reactant: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)O
Product: Cc1nc(-n2ccc(O)cc2=O)sc1C(=O)NCc1ccncc1
Yield: 46 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-hydroxy-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid in place of 4-methyl-2-(2-oxo-4-phenylpyridin-1(2H)-yl)thiazole-5-carboxylic acid to react with pyridin-4-ylmethanamine, the title compound was obtained as a colorless solid in 46% yield: mp 275-278° C. (dichloromethane/methanol); 1H NMR (300 MHz, DMSO-d6) δ 11.59 (br s, 1H), 8.88-8.78 (m, 1H), 8.58 (t, J=8.9 Hz, 1H), 8.47-8.44 (m, 2H), 7.26-7.23 (m, 2H), 6.27-6.22 (m, 1H), 5.85-5.80 (m, 1H), 4.44-4.30 (m, 2H), 2.56 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 167.9, 162.2, 161.6, 154.2, 150.6, 149.9, 148.8, 132.6, 123.2, 122.6, 104.4, 98.0, 42.2, 17.5; MS (ES+) m/z 343.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[Se:4][C:3]=1[C:11]#[N:12].C([OH:15])C>[OH-].[Na+]>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[Se:4][C:3]=1[C:11]([NH2:12])=[O:15]
Reactant: CCO
Reactant: N#Cc1[se]c2ncccc2c1N
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1[se]c2ncccc2c1N
Temperature: 7.5 °C
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a suspension of 3-aminoselenopheno[2,3-b]pyridine-2-carbonitrile (1.0 g) in aqueous sodium hydroxide solution (20 mL, 10%) was added ethanol (20 mL) and the mixture refluxed for 45 min. Ethanol was distilled off under vacuum (appr. 25 mL) and the mixture was allowed to cool to 5-10° C. The separated crystals and the solution was poured into ice cooled water and stirred for 15 min. The solid was filtered off, washed with cold water and dried to give the product as a pale yellow color solid (0.53 g, 50%), mp 256-260° C. 1H NMR (400 MHz, DMSO-d6): δ 8.60 (1H, d, J=3.6 Hz, H-6), 8.37 (1H, d, J=7.6 Hz, H-4), 7.47 (1H, dd, J=8.0, 4.8 Hz, H-5), 7.32 (2H, s, —CONH2), 7.09 (2H, s, —NH2); LC-MS (negative ion mode): m/z 238, 241 (M−H)−.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH3:13])[S:10](=[O:12])(=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]([OH:17])=O.S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:13][N:9]1[C:8](=[O:14])[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([C:15]([Cl:20])=[O:17])[C:2]=2[CH3:1])[S:10]1(=[O:12])=[O:11]
Reactant: Cc1c(C(=O)O)ccc2c1C(=O)N(C)S2(=O)=O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)Cl)ccc2c1C(=O)N(C)S2(=O)=O
Temperature: 80 °C
Yield: 74 %

Procedure:
3.8 g (14.9 mmol) of 4,N-dimethyl-1,1,3-trioxo-2,3-dihydro-1λ6 benz[d]isothiazole-5-carboxylic acid are suspended in 100 ml of toluene, and the mixture is heated to 80° C. and 3.5 g (29.8 mmol) of thionyl chloride are added dropwise. After refluxing for two hours, the solution is decanted hot and the reaction mixture is concentrated on a rotary evaporator. Yield: 74% of theory, m.p.: 149°-150° C.