Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.Cl.[C:15]([NH:19][NH2:20])([CH3:18])([CH3:17])[CH3:16].O>C(O)C>[C:15]([N:19]1[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:20]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: CC(C)(C)NN
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnn(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 67.6 %

Procedure:
8.51 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt of was suspended in 80 ml of ethanol, and 8.09 g of t-butylhydrazine hydrochloride was then added. The mixture was stirred at 60° C. for 4 hours and then cooled to room temperature. After 50 ml of water was added, the reaction mixture was concentrated to 50 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was recrystallized from hexane to obtain 5.26 g of methyl 1-t-butyl-pyrazole-4-carboxylate.
Reaction SMILES: [C:1](=[S:3])=[S:2].[C:4]1([C:18](=[O:20])[CH3:19])[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1.CC(C)([O-])C.[K+]>O1CCCC1>[O:20]=[C:18]([C:4]1[C:17]2[S:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[S:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)[CH2:19][C:1]([SH:3])=[S:2]
Reactant: CC(=O)c1cccc2c1Sc1ccccc1S2
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CC(=S)S)c1cccc2c1Sc1ccccc1S2

Procedure:
A solution of CS2 (1.55 ml, 25.5 mmol) and 1-thianthren-1-yl-ethanone (6.59 g, 25.5 mmol) in dry tetrahydrofuran (20 ml) was added drop wise to a solution of potassium t-butoxide (5.73 g, 51 mmol) in dry tetrahydrofuran (50 ml) under N2 at 0° C. A red coloration and the formation of a precipitate were observed. The mixture was left under vigorous stirring over the weekend and was then poured onto water (200 ml) and extracted with ether (3×100 ml). The aqueous was acidified with 2N H2SO4 to pH 1 (Whatmann pH paper) and the extracted with ether (3×100 ml). The organic were dried over magnesium sulphate and the solvent was evaporated in vacuo to give the desired product as a dark orange resin (5.00 g, 59%). m/z (LC-MS, ESP), RT=5.11; (M−−1)=333
Reaction SMILES: [N+]([C:4]1[CH:33]=[CH:32][CH:31]=[CH:30][C:5]=1[C:6]([NH:8][CH:9]([C:11]1[N:16]=[N:15][C:14]([NH:17][C:18]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=2)=[N:13][CH:12]=1)[CH3:10])=[O:7])([O-])=O.NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[F:56][C:57]([F:68])([F:67])C1C=CC(C(Cl)=O)=CC=1.C(N(CC)CC)C>O1CCCC1>[F:56][C:57]([F:68])([F:67])[C:32]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH:9]([C:11]2[N:16]=[N:15][C:14]([NH:17][C:18]3[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=3)=[N:13][CH:12]=2)[CH3:10])=[O:7])=[CH:4][CH:33]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3ccccc3[N+](=O)[O-])nn2)cc(OC)c1OC
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(Nc2ncc(C(C)NC(=O)c3ccc(C(F)(F)F)cc3)nn2)cc(OC)c1OC
Yield: 59 %

Procedure:
In a similar manner as described for Intermediate 10, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (295 mg, 0.97 mmol), 4-(trifluoromethyl)benzoyl chloride (0.16 mL, 1.08 mmol), and triethylamine (0.168 mL, 1.20 mmol) in tetrahydrofuran (4 mL) gave 4-(trifluoromethyl)-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)benzamide (284 mg, 59%) as a yellow solid. MS m/z 477 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][OH:21])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([CH2:20][O:21][S:30]([CH3:29])(=[O:32])=[O:31])[C:12](=[O:19])[N:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(-c2cc(CO)c(=O)n(CC(C)C)n2)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC(C)C)n2)cc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.1 %

Procedure:
To an ice-cold solution of 6-(3-fluoro-4-methyl-phenyl)-4-hydroxymethyl-2-isobutyl-2H-pyridazin-3-one (1.08 g, 3.73 mmol) in methylene chloride (20 mL) were added triethylamine (491 mg, 4.85 mmol) and methanesulfonyl chloride (513 mg, 4.48 mmol), and the mixture was stirred for 1 hour. A saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture, and then, the mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from chloroform-hexane to yield the title compound as a colorless crystalline powder (964 mg, 70.4%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([CH3:14])[CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH3:21]I>CN(C=O)C.O>[CH3:21][N:6]([CH2:5][C:4]([CH3:3])([N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)NCC(C)(C)N1CCOCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(CC(C)(C)N1CCOCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 120 h
Yield: 119.5 %

Procedure:
To a suspension of 60% NaH in mineral oil (238 mg, 5.96 mmol) in dry DMF (5 mL) was added dropwise a solution of tert-butyl 2-methyl-2-morpholinopropylcarbamate (770 mg, 2.98 mmol) in dry DMF (5 mL). After 30 min MeI (0.928 mL, 14.9 mmol) was added dropwise. The mixture was stirred at room temperature for 5 d, poured in H2O and extracted with Et2O (30 mL). The organic layer was dried (Na2SO4) and concentrated to yield the desired crude product (970 mg,) as a light yellow oil.
Reaction SMILES: [Cl:1]C1C=C(C=CC=1)C(O[CH:8]1[C:13](=[O:14])[NH:12][C:11]([CH3:15])=[C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[S:9]1)=O.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.Cl>>[ClH:1].[CH3:15][C:11]1[NH:12][C:13](=[O:14])[CH:8]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[S:9][C:10]=1[C:16]1[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=1
Reactant: CC1=C(c2ccncc2)SC(OC(=O)c2cccc(Cl)c2)C(=O)N1
Reactant: C1CCNCC1
Agent: Cl
Product: CC1=C(c2ccncc2)SC(N2CCCCC2)C(=O)N1

Procedure:
2-(3-Chlorobenzoyloxy)-5-methyl-6-(4-pyridinyl)-2H-1,4-thiazin-3(4H)-one and piperidine were reacted. The resultant compound was added with hydrochloric acid and was recrystallized from ethanol to give the titled compound as yellowish brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Si](C)(C)C)=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4].C1C(=O)N([Br:34])C(=O)C1>ClCCl.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:10]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([Br:34])=[CH:14][C:13]=2[F:22])=[N:9][C:8]([CH2:23][NH:24][CH:25]=[O:26])=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ncc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ncc(CNC=O)nc1Nc1ccc(Br)cc1F
Temperature: -30 °C
Reaction time: 3 h
Yield: 80.1 %

Procedure:
To a −30° C. solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-5-formylaminomethyl-pyrazine-2-carboxylic acid methyl ester (1.84 g, 4.89 mmol) in dichloromethane (50 mL) under N2 was added NBS (0.96 g, 5.38 mmol, 1.1 eq.), and the reaction mixture was stirred at −30° C. for 3 h. More NBS (0.96 g, 5.38 mmol, 1.1 eq.) was added, and the reaction mixture was allowed to stand at 0° C. for 18 h. The reaction mixture was diluted with ethyl acetate (250 mL). The organic layer was washed with saturated aqueous solution of sodium bicarbonate, water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was triturated with methanol to afford the desired product as a yellow solid (1.50 g, 80.1%). LCMS (method C): RT=2.51 min, [M+H]+=383/384.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][S:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[CH3:5][S:6][C:7]1[S:11][C:10]([N:12]=[C:1]=[O:2])=[N:9][N:8]=1
Reactant: CSc1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: CSc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methylthio-2-amino-1,3,4-thiadiazole (45 grams) in ethyl acetate (300 ml) is added to the reaction vessel and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen gas to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methylthio-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: Cl.[F:2][C:3]([F:29])([F:28])[C:4]1[CH:5]=[C:6]([CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)[CH2:7][O:8][C@H:9]1[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:30](Cl)(=[O:32])[CH3:31].O>C1COCC1.CCN(CC)CC>[C:30]([N:12]1[CH2:13][CH2:14][C@H:9]([O:8][CH2:7][C:6]2[CH:21]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:23]=[C:4]([C:3]([F:2])([F:28])[F:29])[CH:5]=2)[C@H:10]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11]1)(=[O:32])[CH3:31]
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To a solution of the compound (0.15 g) obtained in Example 1 in THF (5.0 ml), Et3N (0.15 ml) was added, acetyl chloride (0.040 ml) was added at 0° C., and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and then the product was extracted with ethyl acetate. The organic layer was washed with an aqueous 10% citric acid solution and saturated brine, dried, and then the solvent was evaporated under reduced pressure. The obtained residue was isolated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1→1:0) to obtain the title compound as colorless oil (0.10 g, 66%).
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:13]([CH3:16])=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:22][C:2]2[C:3]3[N:4]([C:13]([CH3:16])=[CH:14][N:15]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=3)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Cc1cnc2c(Cl)nc3ccc(Cl)cc3n12
Reactant: NC1CCCC1
Product: Cc1cnc2c(NC3CCCC3)nc3ccc(Cl)cc3n12

Procedure:
By reaction of 2,3,6-trichloroquinoxaline with propargylamine, following a procedure that is similar to that described in example 2, there is obtained 8-chloro-1-methylimidazo[1,2-a]quinoxaline-4(5H)-one (m.p. >300° C.) and, subsequently, 4,8-dichloro-1-methylimidazo[1,2-a] quinoxaline. By reacting this product with cyclopentylamine according to the method described in example 3, there is obtained 4-cyclopentylamino-8chloro-1-methylimidazo[1,2-a]quinoxaline. m.p. (DSC)=130.5° C.(onset); IR (KBr): 3421, 2954, 1555 cm-1 ; 1H-NMR (CDCl3): δ7.95 (1H,d, J=2 Hz), 7.6 (1H,d, J=9 Hz), 7.35÷7.15 (2H,m), 6.1 (1H,d), 4.5 (1H,s), 2.8 (3H,s), 2.4÷2.05 (4H,m), 2.0÷1.3 (4H,m); UV (EtOH): λmax =227, 251, 276, 305, 336 nm. Elementary analysis for C16H17ClN4 (m.w. 300.79): calcd. C 63.89, H 5.70, N 18.63%; found C 63.79, H 5.79, N 18.58%.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([NH:10][C:11]2[C:26]([F:27])=[CH:25][C:14]([O:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](C(N)=O)[CH:17]=3)=[C:13]([F:28])[CH:12]=2)=[O:9])[C:4](=[O:29])[N:3]1[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O.C(OI(C1C=CC=CC=1)OC(=O)C)(=O)C.CC#[N:54]>CCOC(C)=O>[NH2:54][C:18]1[CH:17]=[C:16]([O:15][C:14]2[C:13]([F:28])=[CH:12][C:11]([NH:10][C:8]([C:5]3[C:4](=[O:29])[N:3]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:2]([CH3:1])[C:6]=3[CH3:7])=[O:9])=[C:26]([F:27])[CH:25]=2)[CH:21]=[CH:20][N:19]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(N)c3)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a solution of 4-(4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)-2,5-difluorophenoxy)picolinamide (80 mg, 0.17 mmol) in EtOAc (2 mL), CH3CN (2 mL), and H2O (1 mL) was added PhI(OAc)2 (70 mg, 1.2 mmol). The reaction was stirred at 0° C. for 30 minutes, then warmed up to rt and continued to stir for 8 hours. The mixture was filtered through a CELITE® pad, which was washed with EtOAc (30 mL). The filtrate was concentrated in vacuo and the residue was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=20/1) to afford the tile compound as a white solid (51 mg, 68%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.CN(C)P(N(C)C)(N(C)C)=O.C(NC(C)C)(C)C.[Li].Br[CH2:47][CH2:48][Cl:49].Cl>C1COCC1>[Cl:49][CH2:48][CH2:47][C:16]1([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14][CH:13]([C:23]([O:25][CH3:26])=[O:24])[CH2:18][CH2:17]1
Reactant: COC(=O)C1CCC(C(=O)OC)CC1
Reactant: ClCCBr
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: COC(=O)C1CCC(CCCl)(C(=O)OC)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
To a solution of diisopropylamine (88 mL, 0.62 mol) in anhydrous THF (500 mL) was added n-butyl lithium (240 mL, 0.6 mol, 2.5 M solution in hexane) over 20 minutes at −78° C. The mixture was stirred at 0° C. under nitrogen for 30 min. To a mixture of dimethyl cyclohexane-1,4-dicarboxylate (100 g, 0.5 mol) and hexamethylphosphoramide (360 mL, 2 mol) in anhydrous THF (800 mL) was added lithium diisopropylamine (freshly prepared above) over 30 min at −40° C. After stirring for 1 h at this temperature, 1-bromo-2-chloroethane (42 mL, 0.5 mol) was added over 1 h. The mixture was stirred for 3 h at −78° C., then warmed to room temperature and stirred overnight. To the reaction mixture was added aqueous hydrochloric acid (3 N, 420 mL) and the mixture was stirred for 10 min. The solvent was removed by evaporation under reduced pressure. The aqueous layer was extracted with ethyl acetate (3×200 mL), and the combined extracts were washed with brine (2×300 mL) and dried over sodium sulfate. Concentration under reduced pressure afforded dimethyl 1-(2-chloroethyl)cyclohexane-1,4-dicarboxylate (116 g, 88% yield), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 3.72 (s, 3H), 3.65 (s, 3H), 3.46-3.42 (m, 2H), 2.33-2.21 (m, 3H), 2.05-1.85 (m, 4H), 1.58-1.42 (m, 2H), 1.25-1.15 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])[N:3]=1.Cl.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([NH:25][C:26]2[N:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][CH:27]=2)[CH2:20]1.C(N(CC)C(C)C)(C)C>CS(C)=O>[C:32]([C:29]1[CH:28]=[CH:27][C:26]([NH:25][CH:21]2[CH2:22][CH2:23][CH2:24][N:19]([C:2]3[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([C:10]4[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=4[Cl:17])[N:3]=3)[CH2:20]2)=[N:31][CH:30]=1)#[N:33]
Reactant: N#Cc1ccc(NC2CCCNC2)nc1
Reactant: N#Cc1ccc(-c2ccc(Cl)cc2Cl)nc1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: N#Cc1ccc(NC2CCCN(c3nc(-c4ccc(Cl)cc4Cl)ccc3C#N)C2)nc1
Temperature: 120 °C

Procedure:
60 mg (0.21 mmol) of 2-chloro-6-(2,4-dichlorophenyl)pyridine-3-carbonitrile, 63 mg (0.25 mmol) of 6-(piperidin-3-ylamino)pyridine-3-carbonitrile hydrochloride (Example 10A) and 0.184 ml (1.06 mmol) of N,N-diisopropylethylamine were initially charged in 2 ml of DMSO. The mixture was heated at 120° C. in a microwave for 30 min. The crude product was purified by means of preparative HPLC (method 13). 61 mg (64% of theory) of the product were obtained in solid form.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[C:30]([Cl:39])[CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[N:21]=2)=[CH:15][CH:14]=1)(C)(C)C.C(Cl)Cl.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56]>CCOC(C)=O>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[NH2:7][CH2:8][C:9]([CH3:48])([CH3:47])[CH2:10][NH:11][C:12](=[O:46])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[N:25]=[C:24]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][Br:38])=[C:30]([Cl:39])[CH:29]=3)[N:23]=[C:22]([O:40][CH2:41][C:42]([F:43])([F:44])[F:45])[N:21]=2)=[CH:15][CH:14]=1
Reactant: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(CN)CNC(=O)c1ccc(Nc2nc(NCc3ccc(OCCCBr)c(Cl)c3)nc(OCC(F)(F)F)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.2 %

Procedure:
To a 100 mL round-bottom flask equipped with a stir bar and charged with tert-butyl(3-(4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)-2,2-dimethylpropyl)carbamate (1.655 g, 2.136 mmol) was added CH2Cl2 (5 mL), and then trifluoroacetic acid (2.50 mL, 32.4 mmol). The solution was stirred at room temperature for 2 h. The solution was transferred to a 250 mL separatory funnel and was diluted with EtOAc (75 mL). The solution was washed with sat. aq. NaHCO3 (75 mL). The aq. phase was extracted with EtOAc (2×75 mL). The combined organics were washed with sat. aq. NaCl (50 mL); dried over MgSO4; filtered; then concentrated in vacuo to afford N-(3-amino-2,2-dimethylpropyl)-4-((4-((4-(3-bromopropoxy)-3-chlorobenzyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamide trifluoroacetic acid as a colorless solid (1.52 g, 100%). MS m/z=674.25 (M+1)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([O-])=O.BrC1[CH:21]=[C:20](C(F)(F)F)[N:19]=[C:18](C)[CH:17]=1>>[F:12][C:11]([F:14])([F:13])[C:6]1[CH:5]=[C:4]([N:1]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])c1cc[n+]([O-])c(C(F)(F)F)c1
Reactant: Cc1cc(Br)cc(C(F)(F)F)n1
Product: FC(F)(F)c1cc(N2CCNCC2)ccn1

Procedure:
The compound can be prepared from 4-Nitro-2-trifluoromethyl-pyridine 1-oxide [147149-97-1] in analogy to the procedure used for the preparation of 4-Bromo-2-methyl-6-trifluoromethyl-pyridine [615579-78-1] (WO03087056). MS (m/e): 227 (M+H+, 100%)
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:22](B(O)O)=[CH:21][N:20]([C:26]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)=[CH:14][CH:13]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1(C)C=CC=CC=1>[F:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:22]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)=[CH:21][N:20]([C:26]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:17]=1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Reactant: Brc1ccc2nccn2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2-c2ccc3nccn3c2)cc1
Temperature: 25 °C
Yield: 80 %

Procedure:
2.2 g 6-bromoimidazo[1,2-a]pyridine, 6 g 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25), and 647 mg tetrakistriphenyl phosphine palladium were heated in a solution mixture of 30 mL ethanol, 30 mL toluene and 17 mL of 2 N aqueous sodium carbonate at 80° C. for 2 hours in a stream of nitrogen. The reaction solution was cooled to room temperature, ethyl acetate was added thereto, and the organic layer was dried over magnesium sulfate. After filtration, the organic solvent was evaporated, and the residue was dissolved in dichloromethane and purified by NH silica gel (hexane/ethylacetate). The resulting solid was recrystallized from ethyl acetate/hexane, to give 4.65 g of the title compound as colorless crystals.
Reaction SMILES: [CH3:1][N:2]([CH:9]=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:11](OCCCC)=[CH2:12].ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl>O1CCOCC1>[CH3:1][N:2]([C:9]([CH:11]=[CH2:12])=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CN(C=O)c1ccccc1
Reactant: C=COCCCC
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: C=CC(=O)N(C)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methylformanilide (30 g), butyl vinyl ether (22.2 g) in 25 ml of 1,4-dioxane under stirring at 10–15° C., a solution of bis-trichloromethylcarbonate (28.3 g) in 50 ml of 1,4-dioxane is added dropwise in 90 min. The reaction mixture is kept under stirring at room temperature overnight, then the solvent is evaporated under reduced pressure. Toluene (50 ml) and water (200 ml) are added, the mixture is cooled at about 5–10° C. and the pH is corrected to about 7 by adding sodium hydroxide 15% aqueous solution (30 ml). After separation of the phases, the aqueous layer is extracted twice with toluene (50 ml×2) and the combined organic layers are washed with water (50 ml) and evaporated under reduced pressure. The obtained residue (32.3 g, containing, according to HPLC assay, 28.7 g of pure product, 81% molar yield) is used for the next step of the synthesis without any further purification.
Reaction SMILES: C(ON=O)CC(C)C.[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1N.NC1C=CC=CC=1.CCCCCC.CCOCC.[S:35]1[CH:39]=[CH:38][CH:37]=[CH:36]1>>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[C:36]1[S:35][CH:39]=[CH:38][CH:37]=1
Reactant: Nc1ccccc1Br
Reactant: c1ccsc1
Agent: CC(C)CCON=O
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Nc1ccccc1
Product: Brc1ccccc1-c1cccs1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 34 %

Procedure:
A solution of 8.8 mL of isoamylnitrite (65.5 mmol) in 85 mL of thiophene under a nitrogen atmosphere was heated to 50° C. and treated dropwise with a solution of 7.5 g of 2-bromoaniline (43.5 mmol) dissolved in 20 mL of thiophene. After addition was complete, the temperature was raised to 90° C. After 90 minutes, no starting aniline was observed by thin layer chromatography (hexane/ether;100:5). The reaction mixture volume was reduced by atmospheric distillation. The residue was dissolved in ether and the organic layer was washed twice with water, dried over magnesium sulfate and evaporated under vacuum. The residue was dissolved in n-hexane/ether (100:5) and passed over silica gel, eluting with n-hexane/ether (100:5) to give 3.5 g (14.6 mmol, 34%) of the product, 1H NMR (200 MHz, CDCl3): 7.11 (m, 1H), 7.16 (dd, 1H), 7.27 (m, 2H), 7.37 (dd, 1H), 7.42 (dd, 1H), 7.66 (dd, 1H).