Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:9]3[CH:11]=[C:12]([S:19]([O-:22])(=[O:21])=[O:20])[CH:13]=[C:14]([S:15]([O-:18])(=[O:17])=[O:16])[C:8]=3[CH:7]=[CH:6][C:5]=2[N+:4]([CH2:23][CH2:24][CH2:25][S:26]([O-:29])(=[O:28])=[O:27])=[C:3]1[CH3:30].[Na+:32].[Na+].[CH2:34]1COS(=O)(=O)CC1>>[CH3:1][C:2]1([CH3:31])[C:10]2[C:9]3[CH:11]=[C:12]([S:19]([O-:22])(=[O:20])=[O:21])[CH:13]=[C:14]([S:15]([O-:18])(=[O:16])=[O:17])[C:8]=3[CH:7]=[CH:6][C:5]=2[N+:4]([CH2:23][CH2:24][CH:25]([S:26]([O-:29])(=[O:28])=[O:27])[CH3:34])=[C:3]1[CH3:30].[Na+:32].[Na+:32]
Reactant: O=S1(=O)CCCCO1
Reactant: CC1=[N+](CCCS(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C
Agent: [Na+]
Product: CC1=[N+](CCC(C)S(=O)(=O)[O-])c2ccc3c(S(=O)(=O)[O-])cc(S(=O)(=O)[O-])cc3c2C1(C)C

Procedure:
Compound 4 was prepared analogously to compound 3 (Example 3), except that 1,4-butanesultone is used as a starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=[O:11])[C:7]([NH:13][C:14]([C:16]([O:18]CC)=O)=[O:15])=[CH:6][C:3]=1[C:4]#[N:5].CN(C)C=O.N>O1CCCC1.[Pd]>[Cl:1][C:2]1[CH:9]=[C:8]2[C:7]([NH:13][C:14](=[O:15])[C:16](=[O:18])[N:10]2[OH:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CCOC(=O)C(=O)Nc1cc(C#N)c(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: N#Cc1cc2[nH]c(=O)c(=O)n(O)c2cc1Cl
Yield: 52.6 %

Procedure:
To a solution of 0.6 g (2.0 mmol) 2-chloro-5-ethoxalylamino-4-nitrobenzonitril in 50 ml tetrahydrofuran was added 15 ml dimethylformamide and 0.7 ml 25% aqueous ammonia. The mixture was hydrogenated at atm. pressure by using 0.1 g Pd-C as a catalyst. The catalyst was filtered off, and the filter cake was washed with tetrahydrofuran. The precipitated product was dissolved in 1N aqueous potassium hydroxide. Addition of concentrated hydrochloric acid to pH 1 gave 0.25 g (50%) 7-chloro-6-cyano-1-hydroxyquinoxaline-2,3(1H,4H)-dione. M.p. 320° C. decomp. 1H-NMR (DMSO-d6): 7.6 (1H, s), 7.5 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10]([C:19]([OH:21])=O)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.ClC(OC(C)C)=O.[CH:36]1([NH2:39])[CH2:38][CH2:37]1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[C:10]([C:19]([NH:39][CH:36]3[CH2:38][CH2:37]3)=[O:21])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: NC1CC1
Agent: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1nn(-c2cccc(Br)c2)c2ncccc2c1=O
Yield: 96.7 %

Procedure:
To 1-(3-bromophenyl)-4-oxo-1,4-dihydropyridino[2,3-c]pyridazine-3-carboxylic acid (3.25 g, 9.4 mmol) in dichloromethane (50 mL) was added triethylamine (2.37 g, 23.5 mmol), isopropyl chloroformate (1.49 g, 12.2 mmol), reacted at room temperature for 2 h, cyclopropylamine (0.54 g, 9.4 mmol) was added, reacted at room temperature overnight, extracted with H2O/DCM, organic phase was rotated for dryness to obtain product 3.5 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10](=[O:19])[NH:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:14]=1.[C:20](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]([O:19][CH3:20])=[N:11][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:13][N:14]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(C(F)(F)F)cnc1-c1ccc(F)cc1F
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1nc(C(F)(F)F)cnc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 65.8 %

Procedure:
First, 23.3 g of 3-(2,4-difluorophenyl)-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (compound 1-1004) was dissolved in 150 ml of acetone, to which 17.5 g of potassium carbonate and 14.3 g of methyl iodide were added, and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, most of the acetone was distilled out under reduced pressure, and the residue was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography (eluent, hexane/ethyl acetate=19:1), which afforded 16.1 g of 3-(2,4-difluorophenyl)-2-methoxy-6-trifluoromethylpyrazine (m.p., 55.3° C.) as the earlier eluted O-methylated compound and 7.13 g (yield, 29%) of 3-(2,4-difluorophenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-10; m.p., 73.0° C.) as the later eluted desired compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]#[N:16])=[C:13]([NH:17][NH2:18])[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:26]1([CH2:29][C:30](Cl)=[O:31])[CH2:28][CH2:27]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][N:12]=[C:13]([NH:17][NH:18][C:30](=[O:31])[CH2:29][CH:26]2[CH2:28][CH2:27]2)[C:14]=1[C:15]#[N:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1c(OCc2ccccc2)ccnc1NN
Reactant: O=C(Cl)CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(OCc2ccccc2)ccnc1NNC(=O)CC1CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 90.9 %

Procedure:
To a solution of intermediate compound D3 (4.099 g, 17.06 mmol) in dry DCM (112 ml) were added triethylamine (2.76 g, 27.294 mmol) and cyclopropyl-acetyl chloride (3.438 g, 29 mmol). The resulting reaction mixture was stirred at r.t. for 20 min, then concentrated in vacuo to yield intermediate compound D4 (5 g, 91%), which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[C:6]([O:7][C:8]2[C:13]([F:14])=[C:12]([CH3:15])[C:11]([F:16])=[C:10](F)[N:9]=2)=[CH:5][C:4]([C:18]([F:21])([F:20])[F:19])=[N:3]1.[H-].[Na+].[F:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[CH:29][C:30]=1[F:31]>S1(CCCC1)(=O)=O.CCCCC.C(OCC)(=O)C>[F:14][C:13]1[C:8]([O:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:18]([F:21])([F:20])[F:19])[CH:5]=2)=[N:9][C:10]([O:32][C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([F:24])[CH:26]=2)=[C:11]([F:16])[C:12]=1[CH3:15]
Reactant: Cc1c(F)c(F)nc(Oc2cc(C(F)(F)F)nn2C)c1F
Reactant: Oc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=S1(=O)CCCC1
Solvent: CCCCC
Product: Cc1c(F)c(Oc2ccc(F)c(F)c2)nc(Oc2cc(C(F)(F)F)nn2C)c1F
Temperature: 90 °C
Yield: 53.4 %

Procedure:
A mixture of 2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methyl-3,5,6-trifluoropyridine (1.2 g, 4 mmol; see Example 2), 60% sodium hydride (0.2 g, 4 mmol) and 3,4-difluorophenol (0.65 g, 5 mmol) in anhydrous sulfolane (5 ml) is heated to 90° C. overnight. The reaction mixture is diluted with pentane/ethyl acetate (1/1 by volume) and filtered through a bed of silica gel. The filtrate is washed 8 times with water, the organic layer is dried with anhydrous magnesium sulfate, and the solvents are removed in vacuo. The residue is purified by a flash silica gel chromatography using pentane/ethyl acetate in a ratio of 9/1. 0.9 g (53% yield) of the title compound are obtained as a colourless solid, m.p. 93° C.
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C.[Zn]>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[O:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(OCCOc2ccccc2)c1
Agent: [Zn]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(Br)c(OCCOc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
Acetic acid (1.068 mL, 18 mmol) was added to the mixture of 25b (600 mg, 1.8 mmol) and zinc dust (1.157 g, 18.0 mmol) in ethanol (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 4 hrs. The mixture was filtered, the solvent distilled off under reduced pressure and the crude was purified by flash column chromatography to obtain the aniline 25c in 84% yield.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH2:9](O)[CH2:10][C:11]#[CH:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][CH2:11][C:10]#[CH:9])=[CH:4][CH:3]=1
Reactant: C#CCCO
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCCOc1ccc(F)cc1

Procedure:
To a solution of 4-fluorophenol (5.00 g, 44.6 mmol), 3-butyn-1-ol (3.38 ml, 44.6 mmol) and triphenylphosphine (17.5 g, 66.9 mmol) in tetrahydrofuran (100 ml) was added diethyl azodicarboxylate (11.7 g, 66.9 mmol) with stirring under ice-cooling, and then the resulting mixture was stirred at room temperature for 18 hours. After stirring, the reaction mixture was evaporated in vacuo, and to the residue were added hexane (200 ml) and ethyl acetate (20 ml). The precipitate separated out was filtered off, and the filtrate was evaporated in vacuo. The residue obtained was purified by flash chromatography on a silica gel column using hexane as the eluent to afford the title compound.
Reaction SMILES: NN.CC([N:7]([CH2:11][CH2:12][CH:13]([N:20]1C(=O)C2C(=CC=CC=2)C1=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8](=[O:10])[O-:9])(C)C>C1COCC1.CO>[NH2:20][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][CH2:11][NH:7][C:8](=[O:10])[O:9][C:14]([CH3:19])([CH3:15])[CH3:13]
Reactant: CC(C)(C)N(CCC(c1ccccc1)N1C(=O)c2ccccc2C1=O)C(=O)[O-]
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 151.8 %

Procedure:
NH2NH2 (1.8 mL, 57.7 mmol) was added to a THF/MeOH (1:1, 30 mL) solution of 1,1-dimethylethyl[3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-phenylpropyl]carbamate (2.2 g, 5.79 mmol) and stirred at 50° C. in a sealed system. After 12 hours, the solids were filtered, washing with methanol. The filtrate was concentrated and purified by column chromatography using 5% MeOH in CHCl3 containing 1% NH4OH to give the title compound (1.1 g, 76%) as a white solid: LC-MS (ES) m/z=251 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([CH3:10])([CH2:8][OH:9])[CH3:7])(=[O:3])[OH:2].[C:11]1(C)[CH:16]=[CH:15][C:14](S(O)(=O)=O)=[CH:13][CH:12]=1>C(O)CCCCC>[C:1](=[O:2])([O:4][CH2:5][C:6]([CH3:10])([CH3:7])[CH2:8][OH:9])[O:3][CH2:15][CH2:16][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(CO)COC(=O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)OCC(C)(C)CO
Temperature: 100 °C

Procedure:
3.9 g of neopentyl glycol carbonate was dissolved in 5.0 g of n-hexanol and0.075 g of p-toluenesulfonic acid was added to the solution. The mixture was heated at 100° C. for 20 minutes. After the reaction, the mixture was evaporated in vacuo to remove unreacted n-hexanol and then filtered to remove unreacted neopentyl glycol carbonate. n-Hexyl 2,2-dimethyl-3-hydroxypropyl carbonate was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:27]3[N:23]([C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:50])[N:40]([CH:47]([CH3:49])[CH3:48])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:19]2=[O:51])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:52][Si]([N-][Si](C)(C)C)(C)C.[K+].CI>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:27]3[N:23]([C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[N:25][N:26]=3)[C:22]3[CH:34]=[CH:35][CH:36]=[CH:37][C:21]=3[N:20]([CH2:38][C:39](=[O:50])[N:40]([CH:47]([CH3:48])[CH3:49])[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:19]2=[O:51])=[CH:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)N(C(=O)CN1C(=O)C(Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CI
Product: CC(C)N(C(=O)CN1C(=O)C(C)(Cc2cn(C(=O)OC(C)(C)C)c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21)c1ccccc1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 33.3 %

Procedure:
To a solution of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indole-1-carboxylic acid tert-butyl ester (100 mg, 0.147 mmol) in DMF (2 mL) at −5° C. was added KHMDS (0.5M in THF, 322 μL, 0.161 mmol). The solution was stirred at −5° C. for 20 minutes and methyl iodide (10 μL, 0.161 mmol) was added. The reaction was stirred at room temperature for 24 hours, was diluted with EtOAc and the organic solution was washed with brine (3×). The organic solution was dried (Na2SO4), filtered and concentrated. The residue was purified by preparative chromatography (2×) eluting with 50% EtOAc in hexanes to provide 34 mg of 3-{6-[(isopropyl-phenyl-carbamoyl)-methyl]-4-methyl-5-oxo-1-phenyl-5,6-dihydro-4H-2,3,6,10b-tetraaza-benzo[e]azulen-4-ylmethyl}-indole-1-carboxylic acid tert-butyl ester. 1H NMR (CD2Cl2) δ 8.05 (d, 1H), 7.67 (d, 1H), 7.36-7.54 (m, 10H), 7.08-7.30 (m, 6H), 6.90 (d, 1H), 5.02 (m, 1H), 4.29 (d, 1H), 4.11 (m, 1H), 2.78 (s, 2H), 1.80 (s, 3H), 1.64 (s, 9H), 1.10 (m, 6H); MS 695.3 (M+1).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([O:12]CC)=O)=[N:4]1)[CH3:2].[OH-].[NH4+:16]>>[CH2:1]([N:3]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([C:10]([NH2:16])=[O:12])=[N:4]1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(CC)n1
Reactant: [NH4+]
Agent: [OH-]
Product: CCc1cc(C(N)=O)nn1CC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl 1,5-diethyl-1H-pyrazole-3-carboxylate (29.4 g, 0.50 mol) and ammonium hydroxide (150 mL of 30%) was stirred overnight at ambient temperature. An analysis by thin layer chromatography (TLC) indicated the reaction was incomplete. The reaction was then heated for 14 hours at 125° C. in a pressure vessel, allowed to cool to ambient temperature, and cooled to 0° C. A precipitate formed, was isolated by filtration, and washed with cold hexanes to provide 8.3 g of 1,5-diethyl-1H-pyrazole-3-carboxamide as a white solid, mp 129-131° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:8][N:7]=1)=O)C.[CH2:34]([NH2:36])[CH3:35]>C(O)C>[CH2:34]([NH:36][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[C:15]([Br:17])[C:14]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:13][C:12]=2[O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[O:8][N:7]=1)=[O:3])[CH3:35]
Reactant: CCN
Reactant: CCOC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Solvent: CCO
Product: CCNC(=O)c1cc(-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)on1
Temperature: 80 °C

Procedure:
5-(2,4-bis-benzyloxy-5-bromo-phenyl)-isoxazole-3-carboxylic acid ethyl ester was suspended in ethanol and ethylamine (2M in methanol, 3 eq), the resulting yellow suspension was heated to reflux (80° C.) under nitrogen, at which point the reagents went into solution. This was heated for 14 hours, then left to cool to ambient temperature. A white precipitate formed, which was filtered off and washed with further ethanol before being dried in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.Cl.Cl.[CH3:15][NH:16][NH:17][CH3:18].CCN(CC)CC.Cl>CCO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:7])[N:17]([CH3:18])[N:16]([CH3:15])[C:9]2=[O:8]
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Reactant: CNNC
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2ccc(Br)cc2c(=O)n1C
Yield: 43.5 %

Procedure:
A suspension of 4-bromophthalic anhydride (1.0 g) in EtOH (10 mL) was treated with 1,2,-dimethylhydrazine dihydrochloride (650 mg) and NEt3 (1.35 mL) and heated at reflux during 16 h. The reaction mixture was cooled and diluted into 0.1M HCl (100 mL). The resμLting white solid was collected by filtration, washed with water, and dried in vacuo to give 6-bromo-2,3-dimethyl-2,3-dihydrophthalazine-1,4-dione (516 mg), m.p. 207-209.
Reaction SMILES: CN1CCCCC1.[CH3:8][NH:9][O:10][CH3:11].[CH3:12][N:13]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@H:14]([C:36]([OH:38])=O)[CH2:15][S:16][C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.ClC(OCC(C)C)=O>ClCCl>[CH3:12][N:13]([C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])[C@@H:14]([CH2:15][S:16][C:17]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]([N:9]([O:10][CH3:11])[CH3:8])=[O:38]
Reactant: CN(C(=O)OC(C)(C)C)[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: CNOC
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N(C)C(=O)OC(C)(C)C
Temperature: 20 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
1.96 cm3 of N-methylpiperidine are added, at a temperature in the region of 0° C., to a suspension of 1.57 g of N,O-dimethylhydroxylamine in 10 cm3 of dichloromethane. This solution is added to the reaction mixture containing 7.8 g of N-methyl-N-tert-butoxycarbonyl-S-triphenylmethyl-L-cysteine, 1.96 cm3 of N-methylpiperidine and 2.08 cm3 of isobutyl chloroformate in 20 cm3 of dichloromethane at a temperature in the region of -8° C. The reaction mixture is stirred for 2 hours at a temperature in the region of 20° C. and then washed with a 10% (w/v) aqueous citric acid solution, then with a 2% (w/v) aqueous sodium hydroxide solution and finally with a saturated sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and concentrated under reduced pressure. The thick red oil obtained is purified by chromatography on silica [eluent: dichloromethane/ethyl acetate (95/5 by volume)]. 4.2 g of N-(N-methyl-2(R)-tert-butoxycarbonylamino-3-(triphenylmethylthio)propionyl)-N,O-dimethylhydroxyl-amine are obtained in the form of a red oil, the characteristics of which are the following:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:15]([OH:16])([CH3:17])[CH3:14])=[N:3][CH:4]=1
Reactant: CC(C)=O
Reactant: Brc1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CC(C)(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
2,5-Dibromopyridine (1.04 g, 4.39 mmol) was dissolved in toluene (22 mL) in a 100 mL round-bottomed flask. The mixture was cooled to −78° C. n-Butyllithium (3.02 mL, 4.83 mmol) was added dropwise. The mixture was stirred 30 min, followed by the addition of acetone (2 mL). The mixture was stirred 40 min and then let warm to rt. The mixture was washed with ammonium chloride (5% aq, 50 mL), water (50 mL) and then brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by Biotage (16% ethyl acetate in hexanes). Concentration of the desired fractions afforded the product (0.82 g, 3.78 mmol, 86% yield). MS (ESI) m/z 216.0 [M]+, 218.1 [M+2]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[CH:6][CH:5]=[C:4]([CH3:18])[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[S:28])=[CH:22][CH:21]=1.C1(C)C=CC=CC=1>CCOCC>[Cl:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=2)=[S:28])=[N:3][C:4]([CH3:18])=[CH:5][CH:6]=1
Reactant: Cc1ccc(OCc2c(F)cccc2Cl)c(N)n1
Reactant: S=C=Nc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Cc1ccc(OCc2c(F)cccc2Cl)c(NC(=S)Nc2ccc(Cl)cc2)n1

Procedure:
A mixture of 2-amino-3-(2-chloro-6-fluorobenzyloxy)-6-methylpyridine (2.0 g, 0.0075 mol), 4-chlorophenyl isothiocyanate (1.53 g, 0.0089 mol) and toluene (10 ml) was heated under reflux for 2 hours, then cooled and diluted with ether to induce crystallisation of the product, which was triturated with ethanol. Yield 2.6 g (82%), m.p. 204°-205 ° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[N:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)=[CH:12][CH:13]=1
Reactant: OCCN1CCNCC1
Reactant: Fc1ccc(-c2nc3ccc(Cl)nn3c2-c2ccnnc2)cc1
Solvent: CCCCCO
Product: OCCN1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnnc4)n3n2)CC1
Temperature: 130 °C

Procedure:
The mixture of 0.26 g (0.8 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine and 0.425 g (3.2 mmol) of 2-hydroxyethylpiperazine in 4 ml of pentanol is heated in a sealed tube at 130° C. for 32 hours.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[C:20]([NH:24][S:25]([C:28]1[C:29]([C:34]2[CH:39]=[CH:38][C:37]([NH2:40])=[C:36]([F:41])[CH:35]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[C:34]1[CH:39]=[CH:38][C:37]([NH:40][C:15]([CH2:14][C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=3)[S:10][CH:11]=2)=[O:17])=[C:36]([F:41])[CH:35]=1)(=[O:27])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)c(F)c1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)Cc2csc(NC(=O)c3ccc(Cl)cc3)n2)c(F)c1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 4′-amino-3′-fluoro-biphenyl-2-sulfonic acid tert-butylamide (CAS 209919-51-7, prepared according to B.-Y. Zhu et al., patent application WO 2000071515) to give N-{4-[(2′-tert-butylsulfamoyl-3-fluoro-biphenyl-4-ylcarbamoyl)-methyl]-thiazol-2-yl}-4-chloro-benzamide, using general procedure C. White amorphous solid. MS 601.3 ([M+H]+)
Reaction SMILES: [C:1]([O:9][CH3:10])(=[O:8])/[CH:2]=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[Cl-].[Cl-].C([Al+2])C.[CH:16]([S:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:17]>ClCCCl.CCCCCC>[C:19]1([S:18][CH:16]2[CH2:17][CH:3]([C:4]([O:6][CH3:7])=[O:5])[CH:2]2[C:1]([O:9][CH3:10])=[O:8])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C=CSc1ccccc1
Reactant: COC(=O)/C=C/C(=O)OC
Agent: CC[Al+2]
Agent: [Cl-]
Solvent: CCCCCC
Solvent: ClCCCl
Product: COC(=O)C1CC(Sc2ccccc2)C1C(=O)OC
Temperature: 25 °C

Procedure:
To a solution of 1.06 g (7.34 mmol) of dimethyl fumarate in 20 mL of dry 1,2-dichloroethane under nitrogen atmosphere, was added with stirring, 7.34 mmol of a 1.0 M solution of ethylaluminum dichloride in hexane. The resultant yellow solution was heated to reflux and a solution of 1.0 g (7.34 mmol) of phenyl vinyl sulfide in 4 mL of dry 1,2-dichloroethane was added dropwise, via syringe, over a period of 20 minutes. The reaction mixture was allowed to stir at reflux for 3 h. After cooling to ambient temperature, the reaction was quenched carefully with 100 mL of 1.0 N hydrochloric acid solution and the reaction mixture was extracted with 3×50 mL of ethyl acetate. The organic extract was washed with 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated to a viscous orange oil. The oil (1.56 g) was chromatographed on silica gel (25 g) eluted with 300 mL of 3% ethyl acetate in 1,2-dichloroethane. The resultant yellow oil was purified by bulb-to-bulb distillation to give the title compound as a yellow oil; b.p 120° C. (0.05 mm Hg); EI-MS, m/e (relative intensity): 280 (M+, 18), 136 (100), 91 (13); 1H NMR (CDCl3) δ 2.20 (q, 1H), 2.61 (m, 1H), 3.22 (q, 1H), 3.34 (t, 1H), 3.66 (s, 3H), 3.67 (s, 3H), 3.87 (m, 1H), 7.30 (m, 5H).