Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9]([NH2:12])(=[O:11])=[O:10])[S:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].Cl>CN(C)C1C=CN=CC=1.CN(C)C=O>[C:22]([O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]=[C:7]([S:9](=[O:11])(=[O:10])[NH2:12])[S:8][C:4]=2[CH:3]=1)(=[O:34])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCC(=O)Oc1ccc2nc(S(N)(=O)=O)sc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-hydroxy-2-benzothiazolesulfonamide (6.9 g., 0.03 mole), triethylamine (4.2 ml., 0.03 mole) and 4-dimethylaminopyridine (100 mg.) in dimethylformamide (30 ml.) is added lauroyl chloride (7 ml.) during a 1/2 hour period. The reaction mixture is stirred for 2 hours at room temperature, poured into ice water and hydrochloric acid, extracted into ether, washed with water, ammonium hydroxide (3 ml. diluted with water) dilute hydrochloric acid and dried over magnesium sulfate. The ether is evaporated at reduced pressure to give 2.2 g of 2-sulfamoyl-6-benzothiazolyl dodecanoate which melts at 112°-114° C. after recrystallization from butyl chloride.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH2:14]([O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30](Br)[CH:29]=2)=[CH:24][CH:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C=O)C.[Cu](I)I>[CH2:14]([O:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[CH:29]=[C:30]([N:1]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4](=[O:5])[C:2]3=[O:3])[CH:31]=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: Brc1cccc(-c2ccc(OCc3ccccc3)cc2)c1
Agent: I[Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1C(=O)N(c2cccc(-c3ccc(OCc4ccccc4)cc3)c2)c2ccccc21
Temperature: 140 °C
Reaction time: 0.5 h

Procedure:
Isatin (0.12 g, 0.81 mmol) in anhydrous DMF (30 mL) was cooled in an ice-bath under nitrogen and treated with sodium hydride (21 mg, 1.1 equivalents). The reaction was stirred in ice for 0.5 hours and then warm ed to room temperature. This solution was then treated with 4-(3-bromophenyl)phenol benzyl ether (Hajduk et al. Am. Chem. Soc. 1997, 119, 5818-5827), (0.16 g, 0.47 mmol) followed by copper iodide (0.32 g, 1.68 mmol). The reaction was heated in an oil-bath at 140° C. After ˜16 hours, the reaction was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (˜75 mL) and filtered. The filtrate was concentrated under reduced pressure to afford a sticky, brown solid which was purified by preparative TLC on silica gel using 25% ethyl acetate in hexanes as the developing solvent. Rf (product)=0.38. Yield =47 mg (25%); MADI-TOF MS 407.02 obs. (405.5 calc.); 1H-NMR (CDCl3) 5.12 (s, 2H), 6.95 (d, 1H, J=8 Hz), 7.06 (d, 2H, J=8.8 Hz), 7.18 (t, 1H, J=7.5 Hz), 7.33-7.47 (m, 7H), 7.53 (d, 2H, J=8.8 Hz), 7.57-7.60 (m, 2H), 7.71 (d, 1H, J=7.5 Hz).
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[H-].[Na+].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20]N(C)C=O>>[CH2:18]([N:5]1[C:4](=[O:6])[CH2:3][CH2:2][C:1]1=[O:7])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH3:20]
Reactant: O=C1CCC(=O)N1
Reactant: CCCCCCCCCBr
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: CCCCCCCCCCN1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Succinimide (0.1 M) dissolved in dry dimethylformamide was treated with sodium hydride (0.1 M) at a temperature of 0° C. Nonyl bromide (0.1 M) was then added and the reaction mixture was stirred at room temperature for three hours. The reaction mixture was concentrated in vacuo and the residue extracted into ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulphate and concentrated in vacuo. The residue obtained was chromatographed over silica gel to afford the desired product. 1HNMR: δ 0.75 (3H, t), 1.10-1.20 (12H, m), 1.35-1.45 (2H, m), 2.55 (4H, s), 3.35 (2H, dd)
Reaction SMILES: C[O:2][C:3](=[O:33])[CH:4]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][CH:24]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:16]([O:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:27][CH:28]=2)[C:3]([OH:33])=[O:2])=[CH:7][CH:8]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)C(Cc1ccc(OCCOCc2ccccc2)cc1)c1ccc(C(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1ccc(C(Cc2ccc(OCCOCc3ccccc3)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To the crude 3-[4-(2-Benzyloxyethoxy)-phenyl]-2-(4-tert-butylphenyl)-propionic acid methyl ester from step d dissolved in 20 mL of THF/MeOH/H2O (3:1:1) was added lithium hydroxide (270 mg, 6.5 mmol) After stirring for 5 hrs at rt, the organic solvents were removed under vacuum and the reaction residue diluted further with water (25 mL). The aqueous mixture was extracted with diethyl ether, made acidic with 1 N HCl and extracted again with ethyl acetate. The ethyl acetate portion was then dried over Na2SO4 and concentrated under vacuum to afford 3-[4-(2-Benzyloxyethoxy)-phenyl]-2-(4-tert-butylphenyl)-propionic acid as a semi-solid mass. (456 mg, 81% over 2 steps)
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=C([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)C#N)[CH3:2].[OH-:17].[K+].Cl.[CH2:20]([OH:22])[CH3:21]>O>[CH2:1]([C:3]1[CH:4]=[C:21]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:20]([OH:17])=[O:22])[CH3:2]
Reactant: CCO
Reactant: [OH-]
Reactant: CCc1cc(C#N)ccc1N1CCCCC1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCc1cc(C(=O)O)ccc1N1CCCCC1

Procedure:
3-Ethyl-4-(1-piperidinyl)benzonitrile (D8) (817 mg, 3.82 mmol) and potassium hydroxide (2.14 g, 38.2 mmol) in ethanol (35 mL) and water (8 mL) were heated to 90° C. (block temperature) for 9 h. Further potassium hydroxide (2.14 g, 38.2 mmol) and water (8 mL) were added and the reaction heated for a further 18 h. The reaction was allowed to cool and was neutralised with aqueous HCl. A white solid was separated by filtration and an attempt was made to purify the filtrate by SCX cartridge, but this failed. Both the solid and product of SCX were combined, methanol added and then the mixture acidified with acetic acid. The mixture was filtered to obtain the filtrate, which was then trapped on SCX cartridge, washed with methanol and eluted with 2M ammonia in methanol. On test scale this gave the title compound as a white solid (96 mg, 0.41 mmol) and on the remaining material gave a colourless oil (563 mg, 2.41 mmol). MS (ES): C14H19NO2 requires 233; found 234 (MH+).
Reaction SMILES: [CH:1]1([O:7][C:8]2[CH:9]=[C:10]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][N:30]([CH2:38][C@H:39]([OH:49])[C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-])=O)=[CH:42][CH:41]=4)[C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:23][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl-].[NH4+].C(OCC)(=O)C>O.C(O)C.[Fe]>[NH2:46][C:43]1[CH:42]=[CH:41][C:40]([C@@H:39]([OH:49])[CH2:38][N:30]([CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:10]3[CH:11]=[CH:12][C:13]([C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[O:15])=[C:8]([O:7][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]4)[CH:9]=3)=[CH:22][CH:23]=2)[C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[CH:45][CH:44]=1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCCc1ccc(-c2ccc(C(=O)NS(C)(=O)=O)c(OC3CCCCC3)c2)cc1)C[C@H](O)c1ccc(N)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67.4 %

Procedure:
A mixture of tert-butyl [3-[3′-(cyclohexyloxy)-4′-[[(methylsulfonyl)amino]carbonyl]-4-biphenylyl]propyl][(2R)-2-hydroxy-2-(4-nitrophenyl)ethyl]carbamate (200 mg), iron powder (48.2 mg) and ammonium chloride (7.7 mg) in water (1.0 ml) and ethanol (3.0 ml) was stirred 80° C. for 1 hour. After cooling to room temperature, ethyl acetate (15 ml) was added to the reaction mixture and iron powder was removed by filtration through a Celite cake. The filtrate was washed with water and brine and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave a crude product which was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give tert-butyl [(2R)-2-(4-aminophenyl)-2-hydroxyethyl][3-[3′-[cyclohexyloxy]-4′-[[(methylsulfonyl)-amino]carbonyl]-4-biphenylyl]propyl]carbamate (129 mg) as a white solid (foam).
Reaction SMILES: Cl.[C:2](=[N:5][OH:6])([NH2:4])[CH3:3].[H-].[Na+].[I:9][C:10]1[CH:20]=[CH:19][C:13]([C:14](OCC)=O)=[CH:12][CH:11]=1>O1CCCC1>[CH3:3][C:2]1[N:4]=[C:14]([C:13]2[CH:19]=[CH:20][C:10]([I:9])=[CH:11][CH:12]=2)[O:6][N:5]=1
Reactant: CC(N)=NO
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2ccc(I)cc2)n1
Temperature: 65 °C
Yield: 29 %

Procedure:
Acetamidoxime hydrochloride (1.5 g) was added portionwise to an ice-cooled suspension of sodium hydride (1.18 g of a 60% dispersion in oil) in dry tetrahydrofuran (40 ml) under an atmosphere of argon. Molecular sieve type 4A (8-12 mesh) were added followed by a solution of ethyl 4-iodobenzoate (3.73 g) in tetrahydrofuran (10 ml). The mixture was heated at 65° C. for 3 hours. The mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic extract was separated, washed with saturated brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatgraphy on silica gel using a 70:30 (v/v) mixture of ethyl acetate/hexane as eluent to give 3-methyl-5-(4-iodophenyl)-1,2,4-oxadiazole as a solid (1.12 g), m.p. 136°-7° C.; microanalysis, found: C, 38.2; H, 2.5; H, 9.5%; C9H7IN2O requires: C, 37.8; H, 2.47; N, 9.79%; NMR: 2.41(3H,s), 7.84(2H,d) and 8.02(2H,d); m/z 287(M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([F:15])([F:14])([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>C(O)C.[Pd]>[F:11][S:10]([F:12])([F:13])([F:14])([F:15])[C:6]1[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(S(F)(F)(F)(F)F)c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc(S(F)(F)(F)(F)F)c1

Procedure:
2 g (8 mmol) of 3-nitropentafluorosulfanylbenzene (CAS # 2613-26-5) were dissolved in 20 ml of ethanol, admixed with 0.1 g of palladium on carbon (10%) and hydrogenated at 5.5 bar until the hydrogen uptake had ended. Subsequently, the reaction mixture was filtered and concentrated under reduced pressure. Molecular weight 219.01 (C6H6F5NS); retention time Rt=1.74 min. [C]; MS (ESI): 261.07 (MH++CH3CN).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:2].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[S:32])[NH2:18])=[CH:15][CH:16]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:23]
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Reactant: S
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOC(=O)C(Cc1ccc(C(N)=S)cc1)(NC(C)=O)C(=O)OCC
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a solution of 10.0 g (30 mmoles) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester and 3.5 g (35 mmoles) of triethylamine in 250 ml of pyridine, hydrogen sulfide gas is introduced until the solution is saturated. The reaction mixture is then stirred at 25° for 18 hours, followed by evaporation of the solvent. The residue is slurried with 50 ml of carbon disulfide for 1 hour and the resulting crystalline solid recovered by filtration to yield 8.7 g (24 mmoles, 80%) of N-acetyl-α-ethoxycarbonyl-4-thiocarbamoylphenylalanine ethyl ester, m.p. 168°-172°.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O)C.S(=O)(=O)(O)O.OO.[C:21]([OH:24])(=[O:23])[CH3:22]>>[CH2:5]([C:4]1[CH:3]=[CH:11][CH:10]=[C:9]2[NH:8][C:7](=[O:12])[O:24][C:21](=[O:23])[C:22]=12)[CH3:6]
Reactant: CCc1ccc2c(c1)C(=O)C(=O)N2
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Agent: OO
Product: CCc1cccc2[nH]c(=O)oc(=O)c12
Temperature: 25 °C

Procedure:
5-Ethylisatin (70 g), acetic acid (200 ml) and concentrated sulfuric acid (0.8 ml) were charged in a 500 ml two-necked flask, followed by stirring at room temperature. Then, 50 ml of aqueous 30% hydrogen peroxide was added dropwise and, after stirring at 60° to 65° C. for additional one hour, the mixture was cooled. The deposited solid was filtered, washed with water and dried under vacuum to obtain 6-ethylisatoic anhydride. Crude yield: 35 g
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH2:17])[CH3:16])=[CH:11][CH:10]=1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>ClCCl>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([NH:17][C:18](=[O:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC(N)c1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)NC(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 90.9 %

Procedure:
Triethylamine (2.8 mL) was dropped to the solution of 1-(4-bromophenyl)ethanamine (2.0 g, 10.0 mmol), and acetic anhydride (1.53 g, 15.0 mmol) in dichloromethane (30 mL) at room temperature. Then the mixture was stirred at room temperature for 12 hours. The mixture was washed with sodium hydroxide solution (40 mL, 0.5M) and water (40 mL). The organic phase was dried over sodium sulfate and filtered. The filtrate was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=1:5) to give N-(1-(4-bromophenyl)ethyl)acetamide (2.2 g, 91%) as a white solid. 1H NMR (300 MHz, d6-DMSO): δ 8.27 (d, J=4.8 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.01 (d, J=8.4 Hz, 1H), 4.94 (m, 1H), 2.12 (s, 3H), 1.45 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH2:1]([N:13]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].[CH3:42][O:43][C:44]1[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=1.[N:51]([O-])=O.[Na+]>O1CCCC1.O.CO>[CH2:28]([N:13]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[S:14]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:27])=[C:19]([N:51]=[N:50][C:47]2[CH:48]=[CH:49][C:44]([O:43][CH3:42])=[CH:45][CH:46]=2)[CH:18]=1)(=[O:16])=[O:15])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: O=N[O-]
Reactant: CCCCCCCCCCCCN(CCCCCCCCCCCC)S(=O)(=O)c1ccc(O)c2ccccc12
Reactant: COc1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCN(CCCCCCCCCCCC)S(=O)(=O)c1cc(N=Nc2ccc(OC)cc2)c(O)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.9 %

Procedure:
A solution of 30.7 g (0.027 mole) crude 4-(N,N-didodecylsulfamyl)-1-naphthol in a mixture of 100 ml tetrahydrofuran, 100 ml methanol, and 4.2 ml 50% sodium hydroxide solution was cooled in an ice-acetone bath and treated with a diazonium salt solution prepared from 3.30 g (0.027 mole) p-anisidine in 20 ml water containing 4.5 ml concentrated hydrochloric acid and 1.85 g (0.027 mole) sodium nitrite in 5 ml of water. The mixture was stirred at 0°-10° C. for 2 hr., allowed to warm to room temperature, and filtered to give 14.6 g of red brown solid. This solid was recrystallized from hexane to give 8.2 g of a bright red powder, m.p. 100°-102° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH2:34])[N:18]=[C:17]([CH:35]3[CH2:37][CH2:36]3)[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[S:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[S:43](Cl)(=[O:45])=[O:44]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][CH2:33][NH:34][S:43]([C:39]3[S:38][CH:42]=[CH:41][CH:40]=3)(=[O:45])=[O:44])[N:18]=[C:17]([CH:35]3[CH2:37][CH2:36]3)[N:16]=2)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCCN
Reactant: O=S(=O)(Cl)c1cccs1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C2CC2)nc1OCCCNS(=O)(=O)c1cccs1

Procedure:
According to the procedure described in Example 4a) 200 mg p-tert.-butyl-N-[6-(3-aminopropoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide was reacted with thiophene-2-sulfonylchloride to give 144 mg p-tert.-butyl-N-[6-(3-(2-thiophene-sulfonylamino)-propoxy)-5-(o-methoxyphenoxy)-2-cyclopropyl-4-pyrimidinyl]benzene-sulfonamide. LC-MS: tR=6.06 min, [M+1]+=673.20, [M−1]−=671.24.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][CH2:9][NH2:10])[CH3:3].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28](S(C)(=O)=O)[N:27]=2)=[CH:22][CH:21]=1>CN(C)C(=O)C>[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([NH:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:2]([CH3:3])[CH3:1])[N:27]=2)=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)c1nccc(-c2ccc(C(=O)Nc3ccccc3N)cc2)n1
Reactant: CN(C)CCOCCCN
Solvent: CC(=O)N(C)C
Product: CN(C)CCOCCCNc1nccc(-c2ccc(C(=O)Nc3ccccc3N)cc2)n1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of dimethylaminoethoxypropylamine (2.02 mg, 12.5 μmol) in N,N-dimethylacetamide (125 μl), was added a solution of N-(2-aminophenyl)-4-[2-(methylsulfonyl)pyrimidin-4-yl]benzamide (Method 62, 2.2 mg, 5 mop in N,N-dimethylacetamide (100 μl). The reaction mixture was heated to 50° C. and agitated for a period of 16 hours, before being evaporated to dryness to give the title compound; Mass Spectrum: M+H+ 435.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][C:7]#[N:8])=[O:5].C([O-])(=O)C.[NH4+].C(O)(=O)C.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31](=O)[CH3:32])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1>C1C=CC=CC=1.O>[C:7](/[C:6](=[C:31](/[C:28]1[CH:27]=[CH:26][C:25]([N:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)=[CH:30][CH:29]=1)\[CH3:32])/[C:4]([O:3][CH2:2][CH3:1])=[O:5])#[N:8]
Reactant: CC(=O)c1ccc(N2CCN(C)CC2)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)/C(C#N)=C(/C)c1ccc(N2CCN(C)CC2)cc1
Temperature: 137.5 °C
Reaction time: 36 h
Yield: 31.9 %

Procedure:
Ethyl cyano acetate (3.12 g, 27.6 mmol), ammonium acetate (123 mg, 1.76 mmol), acetic acid (0.2 ml, 3.5 mmol) were added successively to a stirred solution of 1-(4-(4-methylpiperazin-1-yl)phenyl)ethanone (5.0 g, 23 mmol) in benzene (25 ml) and stirred for 36 h at 135-140° C. The reaction mixture was poured into water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the crude product. This was purified by column chromatography using 2% methanol in CHCl3 as eluent to afford (Z)-ethyl 2-cyano-3-(4-(4-methylpiperazin-1-yl)phenyl)but-2-enoate as yellow liquid 2.30 g (32.4%).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH3:8])=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[NH2:42][CH2:43][C:44]1[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=1[CH3:50]>O.ClCCl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]([C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:42][CH2:43][C:44]3[C:45]([OH:52])=[N:46][C:47]([CH3:51])=[CH:48][C:49]=3[CH3:50])=[O:15])=[CH:16][CH:17]=2)[CH3:8])=[CH:18][CH:19]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(Oc1ccc(F)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3ccc(F)cc3)cc2)c(O)n1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
A mixture of 4-(1-(4-fluorophenoxy)ethyl)benzoic acid (260 mg, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (382 mg, 2 mmol), N-hydroxybenzotriazole (270 mg, 2 mmol), triethylamine (0.3 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1 mmol) was added. The mixture was stirred at 25° C. for 12 hours. To the mixture, water (20 mL) was added and the mixture was extracted with dichloromethane (30 mL×3). The combined organic phase was dried by sodium sulfate and then filtered. The filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=20:1) to give 4-(1-(4-fluorophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (Compound I-46) (115 mg, 29%). LRMS (M+H+) m/z: calcd 394.17. found 394. HPLC purity (214 nm): 94%. 1H NMR (300 MHz, d6-DMSO): δ 11.44 (s, 1H), 8.30 (t, J=5.1 Hz, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.41 (d, J=8.4 Hz, 2H), 7.04-6.85 (m, 4H), 5.83 (s, 1H), 5.47 (q, J=6.6 Hz, 1H), 4.26 (d, J=5.1 Hz, 2H), 2.16 (s, 3H), 2.10 (s, 3H), 1.52 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:8]([OH:10])[CH3:9])[S:5][C:6]=1[CH3:7].[Br:11][CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>C(#N)C>[Br-:11].[CH3:1][C:2]1[N+:3]([CH2:12][C:13](=[O:14])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([CH:8]([OH:10])[CH3:9])[S:5][C:6]=1[CH3:7]
Reactant: Cc1nc(C(C)O)sc1C
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: Cc1sc(C(C)O)[n+](CC(=O)c2ccccc2)c1C
Product: [Br-]
Reaction time: 1 h
Yield: 33.7 %

Procedure:
1-(4,5-dimethyl-2-thiazolyl)ethanol (0.24 g, 1.5 mmole), 2-bromo-1-phenyl-1-ethanone (0.3 g, 1.5 mmole) and acetonitrile (0.1 mL) were heated at 45° C. with stirring for 1 hr, then stored at 37° C. for 20 hr, and at 25° C. for 26 hr. The partially solidified mixture was washed with ether and acetonitrile-ether to give 0.25 g of crude product which was recrystalized from acetonitrile-ether to give 0.18 g of the title compound, mp 174–176° C. Calcd for C15H18NO2SBr: C, 50.57; H, 5.09; N 3.93. Found, C, 50.37; H, 5.09; N, 3.88.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13]N=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH:33]([S:36](Cl)(=[O:38])=[O:37])([CH3:35])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][CH:2]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][N:30]([S:36]([CH:33]([CH3:35])[CH3:34])(=[O:38])=[O:37])[CH2:29][CH2:28]2)[N:10]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)S(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1ccc(NC2CCN(S(=O)(=O)C(C)C)CC2)nc1N

Procedure:
The title compound was prepared from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt (Example 22) and isopropyl sulfonyl chloride (Aldrich 97%) using the procedure described in Example 24. HRMS, observed: 451.1814, Calcd for (M+H)+: 451.1810.