Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:31]([O:32][CH3:33])=[CH:30][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([Cl:28])=[CH:22][C:21]=1[Cl:29].[NH:34]1[CH:38]=[CH:37][N:36]=[N:35]1.[OH-].[Na+]>CN(C)C=O>[Cl:29][C:21]1[CH:22]=[C:23]([Cl:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:11]1[C:10]2[C:15](=[CH:16][C:7]3[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:35]4[N:36]=[CH:37][CH:38]=[N:34]4)[C:31]([O:32][CH3:33])=[CH:30][C:8]=3[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Reactant: c1c[nH]nn1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCn5nccn5)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 80 °C
Yield: 21.4 %

Procedure:
A mixture of 0.31 g (0.62 mmol) of 8-(2-chloroethoxy)-4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.36 mL (6.1 mmol) of 1H-1,2,3-triazole and 0.11 g (2.8 mmol) of sodium hydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C. for 4.5 hours, then cooled and poured on to ice. The solid is collected by filtration, washed with water and dried. The two isomers are separated by silica gel flash chromatography, using first 7:3 ethyl acetate/hexane, then a 100:0 to 9:1 gradient of ethyl acetate/methanol. The less polar material, 0.071 g of 4-(2,4-dichloro-5-methoxyphenylamino)-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile, is obtained as yellow solid, mp 285–287° C.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][N:15]2[C:18]([Sn](CCCC)(CCCC)CCCC)=[CH:19][N:20]=[C:14]2[N:13]=1)([O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7])[CH3:3].[Cl:34][C:35]1[N:40]=[C:39](Cl)[CH:38]=[CH:37][N:36]=1>>[Cl:34][C:35]1[N:40]=[C:39]([C:18]2[N:15]3[CH:16]=[CH:17][C:12]([C:2]([CH3:1])([O:4][Si:5]([CH2:10][CH3:11])([CH2:6][CH3:7])[CH2:8][CH3:9])[CH3:3])=[N:13][C:14]3=[N:20][CH:19]=2)[CH:38]=[CH:37][N:36]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(C)(C)O[Si](CC)(CC)CC)ccn12
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1

Procedure:
7-(1-Methyl-1-triethylsilanyloxyethyl)-3-tributylstannyl-imidazo[1,2-α]pyrimidine was reacted with 2,4-dichloropyrimidine by the method of Example 5 to afford 3-(2-chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine as a white solid: δH (400 MHz, CDCl3) 0.70 (6H, q, J 8.0), 1.00 (9H, t, J 8.0), 1.69 (6H, s), 7.57 (1H, d, J 5.5), 7.67 (1H, d, J 7.0), 8.53 (2H, m), 10.07 (1H, d, J 7.0); m/z (ES+) 403 (M++H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[CH3:18])=[CH:5][CH:4]=1.[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:31])[CH3:30])[C:24]=1[N:32]=[C:33]=[O:34])([CH3:22])[CH3:21]>>[CH:20]([C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]([CH3:30])[CH3:31])[C:24]=1[NH:32][C:33](=[O:34])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:19])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[CH3:18])([CH3:21])[CH3:22]
Reactant: Cc1ccc(NCc2ccc(N(C)C)cc2)c(C)c1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: Cc1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)c(C)c1
Yield: 43.4 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using [(4-dimethylaminophenyl)methyl](2,4-dimethylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (1.2 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(2,4-dimethylphenyl)urea (0.78 g) was obtained. melting point: 100° C.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)(O)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1.N1C=CN=C1.S(Cl)([Cl:39])=O>C(#N)C>[F:1][C:2]([F:31])([F:30])[C:3]([Cl:39])([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH3:29])=[CH:23][CH:22]=1)[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=1
Reactant: CCOc1ccc(C(O)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Reactant: O=S(Cl)Cl
Agent: c1c[nH]cn1
Solvent: CC#N
Product: CCOc1ccc(C(Cl)(COCc2cccc(Oc3ccccc3)c2)C(F)(F)F)cc1
Temperature: 0 °C
Yield: 70.8 %

Procedure:
A solution of 1,1,1-trifluoro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propan-2-ol (0.65 g) and imidazole (0.612 g) were dissolved in dry acetonitrile 30 cm3), and the solution cooled to ca. 0° C. Thionyl chloride (1.21 g) was added dropwise, with stirring. The reaction mixture was allowed to warm to the ambient temperature (ca. 22° C.) and was stirred for a further three hours. Analysis of the reaction mixture by thin layer chromatography and gas liquid chromatography at that time showed no starting tertiary alcohol to be present. The reaction mixture was quenched with water, and a small volume of saturated sodium chloride solution was added. The aqueous mixture was extracted four times with diethyl ether and, finally, once with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulphate and concentrated by evaporation of the solvent under reduced pressure to give an oil. The product was purified by column chromatography on a silica gel support, using n-hexane containing 6% by volume ethyl acetate as eluent, to give 1,1,1-trifluoro-2-chloro-2-(4-ethoxyphenyl)-3-(3-phenoxybenzyloxy)propane (0.48 g) as a colourless oil.
Reaction SMILES: O([CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C1C=CC=CC=1.C1COCC1.[Na].[CH3:31][SH:32]>C(OCC)(=O)C>[CH3:31][S:32][CH:8]=[CH:9][C:10](=[N:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C(=CC(=Nc1ccccc1)Oc1ccccc1)Oc1ccccc1
Reactant: CS
Agent: [Na]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSC=CC(=Nc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.1 %

Procedure:
Phenyl 3-phenoxy-N-phenylacrylimidate (0.30 g) was dissolved to THF (5 ml), sodium salt of methyl mercaptan (0.075 g) was added thereto and stirred for four hours at room temperature. Ethyl acetate (50 ml) was added to the reaction solution, and it was successively washed with water and aqueous saturated of sodium chloride solution, dried over magnesium sulfate (anhydrous), concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain phenyl 3-methylthio-N-phenylacrylimidate (0.20 g) as yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.[F:10][C:11]([F:21])([F:20])[O:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([O:12][C:11]([F:10])([F:20])[F:21])=[CH:14][CH:15]=2)[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: FC(F)(F)Oc1ccc(Nc2cc(Cl)nc(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 93.2 %

Procedure:
A mixture of compound 2,4,6-trichloro-pyrimidine (1 g, 5.63 mmol), 4-trifluromethoxy aniline (1.99 g, 11.24 mmol) and K2CO3 (0.7 g, 6.60 mmol) in 20 mL of ethanol was stirred at room temperature for 15 hours under nitrogen atmosphere. Ethanol was then removed under reduced pressure and water was added. The solid obtained was filtered and dried under vacuum to afford the compound (2,6-dichloro-pyrimidin-4-yl)-(4-trifluoromethoxy-phenyl)-amine (1.7 g, 96%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.C1(CN2CCN(C3SC(C(O)=O)=C(C)N=3)C2=O)CCC1.[NH2:43][CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=1>>[CH:2]1([CH2:1][N:8]2[CH2:12][CH2:11][N:10]([C:13]3[S:14][C:15]([C:19]([NH:43][CH2:44][C:45]4[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=4)=[O:21])=[C:16]([CH3:18])[N:17]=3)[C:9]2=[O:22])[CH2:7][CH2:6][CH2:5]1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: Cc1nc(N2CCN(CC3CCC3)C2=O)sc1C(=O)O
Product: Cc1nc(N2CCN(CC3CCC3)C2=O)sc1C(=O)NCc1cccnc1
Yield: 32 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(cyclobutylmethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 32% yield: mp 136-137° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 8.53-8.41 (m, 2H), 7.63-7.61 (m, 1H), 7.20-7.16 (m, 1H), 6.51-6.17 (m, 1H), 4.60-4.46 (m, 2H), 4.08-3.93 (m, 2H), 3.53-3.41 (m, 2H), 3.39-3.20 (m, 2H), 2.60-2.45 (m, 4H), 2.03-1.98 (m, 2H), 1.88-1.79 (in 2H), 1.74-1.65 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.7, 157.5, 155.5, 153.5, 149.2, 148.7, 135.5, 134.0, 123.5, 116.7, 49.3, 42.5, 42.0, 41.3, 33.7, 26.2, 18.3, 17.2; MS (ES+) m/z 386.3 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[N:6][NH:5][C:4](=[O:11])[C:3]=1[C:12]([O:14]CC)=O.[Na+].[NH2:18][CH2:19][C:20]([O-:22])=[O:21].Cl>COCCO.O>[OH:1][C:2]1[C:7]([CH:8]([CH3:9])[CH3:10])=[N:6][NH:5][C:4](=[O:11])[C:3]=1[C:12]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:14]
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c(C(C)C)n[nH]c1=O
Agent: Cl
Agent: [Na+]
Solvent: COCCO
Solvent: O
Product: CC(C)c1n[nH]c(=O)c(C(=O)NCC(=O)O)c1O
Temperature: 130 °C
Yield: 72 %

Procedure:
To a 100 mL round bottom flask was added ethyl 5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinecarboxylate (example 14(a), 55 mg, 0.243 mmol) and Glycine Sodium Salt (59.0 mg, 0.608 mmol) in 2-methoxyethanol (10 ml) and the mixture was refluxed at 130° C. for 2 hours. The mixture was diluted with water (10 ml) and acidified with 1N HCl. The aqueous solution was then extracted with ethyl acetate (40 mL), organics dried over MgSO4, filtered and solvents removed by evaporation. The crude oil was purified by HPLC chromatography (ODS silica, gradient 25-95% acetonitrile/water (0.1% TFA)) to afford the title compound, N-{[5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (45 mg, 0.175 mmol, 71.8% yield), as a white solid. 1H NMR (400 MHz, DMSO-d6) d ppm 15.74 (br. s., 1H), 13.07 (s, 1H), 10.19 (t, J=5.68 Hz, 1H), 4.11 (d, J=5.81 Hz, 2H), 3.14 (sept, J=6.82 Hz, 1H), 1.17 (d, J=6.82 Hz, 6H). MS (ES+) m/e 256 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([CH:7]=O)[C:4]([S:9]([O-:12])(=[O:11])=[O:10])=[CH:3][CH:2]=1.[Na+:13].[CH3:14][C:15]1[CH2:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1.C(N(CC)CC)C>C(O)C>[CH3:14][C:15]1[C:19](=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]=2[S:9]([O-:12])(=[O:11])=[O:10])[C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:16]=1.[Na+:13]
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Reactant: CC1=NN(c2ccccc2)C(=O)C1
Agent: [Na+]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1=NN(c2ccccc2)C(=O)C1=Cc1ccccc1S(=O)(=O)[O-]
Temperature: 25 °C

Procedure:
2.1 g of sodium benzaldehyde-2-sulfonate, 1.75 g of 3-methyl-1-phenyl-2-pyrazolin-5-one and 1 g of triethylamine in 20 mL of ethanol were allowed to reflux 5 hours. After cooling to room temperature, the precipitate was filtered off and dried.
Reaction SMILES: [H-].[Na+].[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:29][CH3:30])[C:17]([NH:19][C:20]([CH3:28])([CH2:23][O:24][CH2:25][C:26]#[CH:27])[CH2:21][OH:22])=[O:18])=[CH:10][CH:9]=2)#[CH:4].[CH2:31]1[CH2:35]OC[CH2:32]1.C(Br)C#C>C(OCC)(=O)C.O>[C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH:16]([S:29][CH3:30])[C:17]([NH:19][C:20]([CH3:28])([CH2:21][O:22][CH2:35][C:31]#[CH:32])[CH2:23][O:24][CH2:25][C:26]#[CH:27])=[O:18])=[CH:10][CH:9]=2)#[CH:4]
Reactant: C1CCOC1
Reactant: C#CCOCC(C)(CO)NC(=O)C(Oc1ccc2ncc(C#C)cc2c1)SC
Agent: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOCC(C)(COCC#C)NC(=O)C(Oc1ccc2ncc(C#C)cc2c1)SC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (55% in dispersion in oil) (0.097 g) was added portionwise to a solution of 2-(3-ethynyl-quinolin-6-yloxy)-N-(2-hydroxy-1-methyl-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide (0.4 g) from Example 12b, Stage 3 described above in dry THF (20 ml) at 0° C. The reaction mixture was stirred at room temperature for 0.5 h. Propargyl bromide (0.166 ml) was added dropwise at 0° C. and the resulting mixture was stirred at room temperature for 23 hrs. The reaction mixture was diluted with ethyl acetate and water was added dropwise. The two phases were separated and the aqueous layer was extracted thrice with ethyl acetate. The organic layers were combined, washed once with brine dried over sodium sulphate, filtered and evaporated to give a dark orange oil which was purified by column chromatography (hexane/ethyl acetate 4:2, 1:1) to yield 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-methyl-2-prop-2-ynyloxy-1-prop-2-ynyloxymethyl-ethyl)-2-methylsulfanyl-acetamide as a white solid (m.p.: 95-100° C.). 1H NMR (CDCl3) δ ppm: 8.84 (1H, d); 8.22 (1H, d); 8.04 (1H, d); 7.49 (1H, dd); 7.21 (1H, d); 6.98 (1H, s br); 5.61 (1H, s); 4.19-4.16 (4H, m); 3.82-3.61 (2H, dd); 3.73 (2H, s); 3.29 (1H, s); 2.47-2.43 (2H, m); 2.21 (3H, s); 1.46 (3H, s).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.C(N(CC)CC)C>CO>[F:1][C:2]([F:7])([F:6])[C:3](=[N:5][NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)[NH2:4]
Reactant: COc1ccc(NN)cc1
Reactant: N=C(N)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reaction time: 6 h
Yield: 108.3 %

Procedure:
To a solution of trifluoroacetoamidine (4.24 g, 37.8 mmol) in methanol (20 mL), were added 4-methoxyphenylhydrazine hydrochloride (4.72 g, 27 mmol) and then triethylamine (3.77 mL, 27 mmol) at room temperature. The mixture was stirred for 6 hours. The solvent was removed under reduced pressure. 20 mL of water and 50 mL of ethyl acetate-tetrahydrofuran (9:1) were added to the residue and the organic layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate-tetrahydrofuran (9:1). A combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (6.82 g, 108.2% yield). The residue was used for the next reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:24])=[O:23].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[S:39]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:21][S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)(=[O:23])=[O:24])(=[O:41])=[O:40]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Product: O=S(=O)(Nc1cc(N2CCNCC2)ccc1NS(=O)(=O)c1ccc(F)cc1F)c1ccccc1

Procedure:
2,4-Difluoro-N-[2-[(phenylsulfonyl)amino]-4-(1-piperazinyl)phenyl]benzenesulfonamide was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-piperazinyl)-phenyl}benzenesulfonamide and 2,4-difluorobenzenesulfonylchloride (94 mg, 0.455 mmol) according to general method 3 to give before Boc-deprotection 160 mg of a purple solid. MS (posES-FIA) m/z=Found: 509.1; Calcd 509.11; 1H-NMR δ 77.71-7.46 (m, 6H), 7.25-7.17 (m, 1H), 7.03-6.96 (m, 2H), 6.72 (dd, 1H), 6.44 (d, 1H), 3.20-3.16 (m, 8H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:17][CH2:19][CH2:20][CH2:21][C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]
Reactant: Cc1cc(O)cc(C)c1OCc1ccccc1
Reactant: COC(=O)C(C)(C)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)(C)CCCOc1cc(C)c(OCc2ccccc2)c(C)c1
Yield: 112.1 %

Procedure:
A mixture of 11.3 g (49.6 mmol) of 3,5-dimethyl-4-(phenylmethoxy)phenol (Example G), 13.3 g (1.2×49.6 mmol) of 5-bromo-2,2-dimethylvaleric acid, methyl ester (U.S. Pat. No. 4,665,226) and 8.2 g (1.2×49.6 mmol) of anhydrous potassium carbonate in 300 mL of acetonitrile is stirred at reflux for 18 hours. The reaction flask and inorganic residue are washed with fresh acetonitrile and the solvent is removed. A diethyl ether solution of the residual product is washed with 50 mL of 2N potassium hydroxide solution, brine, dried and evaporated leaving 20.6 g of the product as a pale yellow oil. Distillation through a short path apparatus affords 15.4 g of the title compound; bp 190°-194° C./0.1 mm (230°-240° C).
Reaction SMILES: [Cl-].[CH:2]1([S:5]([NH:8][C:9]([C@@:11]2([NH3+:16])[CH2:13][C@H:12]2[CH:14]=[CH2:15])=[O:10])(=[O:7])=[O:6])[CH2:4][CH2:3]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([C@@H:45]1[NH:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][C:62]2[CH:70]=[C:58]([CH:59]=[CH:60][CH:61]=2)[C:57]2=[CH:71][C:53](=[CH:54][CH:55]=[CH:56]2)[CH2:52][O:51][C@H:50]2[CH2:72][N:47]([C@H:48]([C:73](O)=[O:74])[CH2:49]2)[C:46]1=[O:76])([CH3:44])([CH3:43])[CH3:42].CCN(C(C)C)C(C)C>CN(C=O)C>[C:41]([C@@H:45]1[NH:69][CH2:68][CH2:67][CH2:66][CH2:65][CH2:64][CH2:63][C:62]2[CH:70]=[C:58]([CH:59]=[CH:60][CH:61]=2)[C:57]2=[CH:71][C:53](=[CH:54][CH:55]=[CH:56]2)[CH2:52][O:51][C@H:50]2[CH2:72][N:47]([C@H:48]([C:73]([NH:16][C@:11]3([C:9]([NH:8][S:5]([CH:2]4[CH2:4][CH2:3]4)(=[O:7])=[O:6])=[O:10])[CH2:13][C@H:12]3[CH:14]=[CH2:15])=[O:74])[CH2:49]2)[C:46]1=[O:76])([CH3:44])([CH3:42])[CH3:43]
Reactant: CC(C)(C)[C@@H]1NCCCCCCc2cccc(c2)-c2cccc(c2)CO[C@@H]2C[C@@H](C(=O)O)N(C2)C1=O
Reactant: C=C[C@@H]1C[C@]1([NH3+])C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NCCCCCCc1cccc(c1)-c1cccc(c1)CO2)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,2S)-1-{[(cyclopropylsulfonyl)amino]carbonyl}-2-vinylcyclopropanaminium chloride 48 (prepared as described in WO 03/099274) (1.2 eq.) and HATU (1.2 eq.) were added to a 0.1M solution of (9R,11S,14S)-14-tert-butyl-13-oxo-8-oxa-12,15-diazatetracyclo[20.3.1.12,6.19,12]octacosa-1(26),2(28),3,5,22,24-hexaene-11-carboxylic acid 105 in DMF containing DIPEA (4.0 eq.). The reaction mixture was stirred at RT overnight. The reaction mixture was concentrated to dryness, dissolved in DMSO and purified by RP-HPLC (stationary phase: column WATERS XTERRA C18, 5 μm, 19×150. Mobile phase: MeCN/H2O buffered with 0.1% TFA from 30% to 90% of MeCN in 14 minutes, run time 18 minutes). Fractions containing the pure compound were combined and freeze dried to afford compound 142 (TFA salt) as an off white solid (30% over 4 steps). 1H NMR (400 MHz, DMSO-d6, 300 K) δ 10.65 (s, 1H), 8.89 (s, 1H), 8.65-8.49 (bs, 1H), 8.25-8.11 (bs, 1H), 7.62-7.56 (m, 2H), 7.51-7.38 (m, 4H), 7.31 (d, J 7.3, 1H), 7.24 (d, J 7.3, 1H), 5.69-5.53 (m, 1H), 5.24 (d, J 17.2, 1H), 5.14 (d, J 11.9, 1H), 4.71 (d, J 12.4, 1H), 4.61 (d, J 12.4, 1H), 4.31 (bt, 1H), 4.37 (bs, 1H), 4.16 (d, J 8.8, 1H), 4.04 (d, J 11.9, 1H), 3.79 (dd, J 11.5, 3.9, 1H), 3.00-2.91 (m, 1H), 2.91-2.81 (m, 1H), 2.80-2.68 (m, 2H), 2.22 (q, J 17.5, 8.8, 1H), 2.02-1.91 (m, 1H), 1.83-1.69 (m, 2H), 1.68-1.56 (m, 2H), 1.41-1.24 (m, 5H), 1.22-1.02 (m, 13H), 0.91 (t, J 7.3, 4H). MS (ES+) m/z 705 (M+H)+.
Reaction SMILES: CC(C)([O-])C.[Na+].CN(C)C=O.[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.F[C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27]>O>[CH2:12]([O:19][C:21]1[CH:22]=[CH:23][C:24]([N+:29]([O-:31])=[O:30])=[C:25]([CH:28]=1)[NH:26][CH3:27])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CNc1cc(F)ccc1[N+](=O)[O-]
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(OCc2ccccc2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Sodium t-butoxide (865 mg, 9 mmol) was added to a N,N-dimethylformamide (5 mL) solution of benzyl alcohol (0.93 mL, 9 mmol), and the mixture was stirred at room temperature for 30 minutes. Thereafter, 5-fluoro-N-methyl-2-nitroaniline (510 mg, 3 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, and precipitated crystals were collected by filtration. The resulting crystals were washed with water, and dried at 50° C., thereby obtaining 710 mg of orange, powdery 5-benzyloxy-N-methyl-2-nitroaniline (yield: 92%).
Reaction SMILES: [CH3:1][C:2]([NH:10][C:11]([C:13]1[S:36][C:16]2[NH:17][N:18]=[C:19]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][N:29]4[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:24][CH:23]=3)[C:15]=2[CH:14]=1)=[O:12])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3].C(N(C(C)C)CC)(C)C.Cl[C:47]([O:49][CH2:50][CH3:51])=[O:48]>C1COCC1>[CH2:50]([O:49][C:47]([N:17]1[C:16]2[S:36][C:13]([C:11](=[O:12])[NH:10][C:2]([CH3:1])([C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH3:3])=[CH:14][C:15]=2[C:19]([NH:20][C:21](=[O:35])[C:22]2[CH:23]=[CH:24][C:25]([CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:26][CH:27]=2)=[N:18]1)=[O:48])[CH3:51]
Reactant: CCOC(=O)Cl
Reactant: CC(C)(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCCC4)cc3)n[nH]c2s1)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)n1nc(NC(=O)c2ccc(CN3CCCCC3)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Reaction time: 0.08 h

Procedure:
To a solution of 3-(4-Piperidin-1-ylmethyl-benzoylamino)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (1-methyl-1-phenyl-ethyl)-amide (500 mg, 1 mmol) in anhydrous THF (20 mL), diisopropylethylamine (1.027 ml, 6 mmol) was added dropwise at room temperature. The reaction was stirred for 5 minutes, and then ethyl chloroformate (130 mg, 0.115 mL, 1.2 mmol) wais also added dropwise. After stirring for 1 hour, the solvent was evaporated, the crude taken up with dichloromethane washed thoroughly with water, brine and dried with sodium sulfate. After filtration and evaporation the crude was triturated with ethyl ether to give the title compound as white solid.
Reaction SMILES: Cl.[NH:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[CH:4]1.[C:15]([Cl:20])(=[O:19])[CH2:16][CH2:17][CH3:18]>>[ClH:20].[C:15]([N:2]=[C:3]1[CH:8]=[CH:7][N:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:5]=[CH:4]1)(=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CCCC(=O)Cl
Agent: Cl
Product: CCCC(=O)N=c1ccn(-c2ccccc2)nc1
Yield: 72 %

Procedure:
5.0 g (24.1 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 50 ml of butyryl chloride were refluxed for 15 hours, while stirring. The mixture was cooled and then filtered under suction, and the residue was washed with acetone and recrystallized from isopropanol. 4.8 g (72% of theory) of 4-butyrylimino-1,4-dihydro-1-phenylpyridazine hydrochloride were isolated as pale beige crystals of melting point 205°-208° C.