Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[C:3]([NH:5][C:6]1[CH:16]=[CH:15][C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]=1[N+:17]([O-])=O)=[O:4].CCCCCC.C(OCC)(=O)C>C(O)C.[Pt]=O>[NH2:17][C:7]1[CH:8]=[C:9]([CH:15]=[CH:16][C:6]=1[NH:5][C:3](=[O:4])[CH:2]([CH3:20])[CH3:1])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1ccc(NC(=O)C(C)C)c([N+](=O)[O-])c1
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1ccc(NC(=O)C(C)C)c(N)c1
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A sample of ethyl 4-(2-methylpropionylamino)-3-nitrobenzoate (8.0 g, 0.0286 mol) was suspended in ethanol (75 mL) containing platinum oxide (50 mg). The reaction mixture was hydrogenated for 2 h at 35 psi. Thin-layer chromatographic analysis (SiO2, 1:1 hexane:ethyl acetate) showed disappearance of starting material along with the formation of a new lower-running spot (Rf =0.2). The mixture was then filtered through a pad of Celite and the pad washed with fresh ethanol. The filtrate was concentrated and the residue recrystallized from ethyl acetate-hexane. The solid was collected by filtration to give 5.0 g (70%) of ethyl 3-amino-4-(2-methylpropionylamino)benzoate. An analytical sample was prepared by recrystallization twice from ethyl acetate-hexane. The residue was collected by filtration and then dried in vacuo at acetone reflux to give a beige solid, mp 147°-149° C.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1>>[Cl:22][C:23]1[N:28]=[C:27]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:26]=[CH:25][N:24]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Reactant: Clc1ccnc(Cl)n1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)n3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.4) (1.0 g, 2.39 mmol) and 2,4-dichloro-pyrimidine (0.356 g, 2.39 mmol) according to the general procedure IVc. Obtained as an off-white solid (0.49 g, 50%). MS (EI) 404.1 [(M)+]; mp 152° C.
Reaction SMILES: I.[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](SC)=[NH:8].[NH2:11][C:12]1[CH:13]=[CH:14][C:15]2[N:20]([CH:21]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22]3)[CH2:19][CH2:18][S:17][C:16]=2[CH:33]=1>CCO>[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7](=[NH:8])[NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:20]([CH:21]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[CH2:22]3)[CH2:19][CH2:18][S:17][C:16]=2[CH:33]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(N)ccc32)C1
Reactant: CSC(=N)c1cccs1
Agent: I
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(N2CCSc3cc(NC(=N)c4cccs4)ccc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
Methyl thiophene-2-carbimidothioate hydroiodide (0.53 g, 1.874 mmol) was added to a mixture of tert-butyl 3-(7-amino-2H-benzo[b][1,4]thiazin-4(3H)-yl)pyrrolidine-1-carboxylate (0.31 g, 0.937 mmol) in EtOH (20 mL). The mixture was stirred under room temperature overnight. The mixture was quenched with saturated sodium bicarbonate solution (50 mL). The solution was then transferred to a separatory funnel, diluted with water (50 mL), and extracted with CH2Cl2 (2×50 mL). The crude material was subjected to flash chromatography on silica gel (50-90% EtOAc/hexanes). The concentrated fractions afforded a yellow oil (0.29 g, 69%). 1H NMR (CDCl3) δ 7.41 (dd, J=0.9, 5.1 Hz, 1H), 7.38 (d, J=3.6 Hz, 1H), 7.06 (dd, J=3.9, 4.9 Hz, 1H), 6.79-6.76 (m, 2H), 6.68-6.66 (m, 1H), 4.84 (brs, 2H), 4.35-4.23 (m, 1H), 3.74-3.22 (m, 6H), 3.12-3.07 (m, 2H), 2.19-1.99 (m, 2H), 1.47 (s, 9H); ESI-MS (m/z, %): 447, 445 (MH+, 100).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[CH:13]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])C.[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39](B(O)O)[CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1>>[CH3:8][CH:7]([CH3:9])[CH2:6][CH:5]([C:10]1[CH:11]=[C:12]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:29]=2)[CH:13]=[C:14]([C:39]2[CH:38]=[C:37]([C:36]([F:51])([F:50])[F:35])[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=2)[CH:15]=1)[C:4]([OH:34])=[O:3]
Reactant: CCOC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: OB(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(C)CC(C(=O)O)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared from a Suzuki coupling of 4-Methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (intermediate Example 1g) with 3,5-bis-trifluoromethyl-phenylboronic acid under the conditions described in Example 1; 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 0.94-1.01 (m, 6H), 1.54-1.65 (m, 1H), 1.79 (ddd, J=13.82, 7.09, 6.97 Hz, 1H), 2.04-2.15 (m, 1H), 3.85 (t, J=7.70 Hz, 1H), 7.56 (d, J=1.71 Hz, 1H), 7.64 (s, 1H), 7.67 (t, J=1.59 Hz, 1H), 7.73 (s, 4H), 7.90 (s, 1H), 8.02 (s, 2H).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[O:18][C:19]([CH3:22])=[N:20][N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>C(O)C.[Pd]>[CH3:22][C:19]1[O:18][C:17]([CH:14]2[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]2)=[N:21][N:20]=1
Reactant: Cc1nnc(C2CCN(C(=O)OCc3ccccc3)CC2)o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1nnc(C2CCNCC2)o1
Yield: 981.2 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-(5-methyl-1,3,4-oxadiazol-2-yl)piperidine (0.18 g) in ethanol (5 mL) was hydrogenated over 10% palladium on carbon (0.050 g) at a hydrogen pressure of 1 bar for 2 hours. The catalyst was then removed by filtration through diatomaceous earth, the filter cake was washed with ethanol and the solvent evaporated to afford the piperidine as a white crystalline solid (0.98 g); mp 64°-66° C.; NMR (CDCl3): 3.17 (m, 2), 2.98 (m, 1), 2.75 (dr,2, J=2.6, 12.0), 2.51 (s, 3), 2.01 (m, 2), 1.75 (m, 2); MS: m/z=196(M+1+28).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:27]([F:30])([F:29])[F:28])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)=O.[CH3:31][NH2:32].C(O)(=O)C.[H][H]>C(Cl)Cl.[Pd]>[OH:26][CH2:25][CH2:24][NH:23][C:21]([C:13]1[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=2[S:16][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][N:6]1[CH:7]=[C:3]([CH2:1][NH:32][CH3:31])[C:4]([C:27]([F:28])([F:29])[F:30])=[N:5]1)=[O:22]
Reactant: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Reactant: CN
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNCc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 193.5 %

Procedure:
2-(2-(4-Formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (100 mg, 0.225 mmol), Methylamine (2 M in THF, 0.45 mL, 0.90 mmol) and DCM (3 mL) were treated with acetic acid (13.51 mg, 0.225 mmol) to give pH 4-5 and the solution stirred at RT for 20 min. 10% Pd/C (20 mg) was added as a slurry in DCM and the mixture stirred under 4 barr hydrogen overnight. The mixture was taken into a 20 mL syringe and the residue of the flask washed with MeOH/DCM and also taken into the syringe. The mixture was filtered through a filter tip and concentrated to give a yellow oil (˜200 mg). Purification was achieved on silica eluting with 4% 2 M NH3 in MeOH/DCM and the product obtained as a light yellow glass (74.2 mg, 0.160 mmol, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[Br:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35]O>>[CH3:1][C:2]1[N:6]([CH2:7][C:8]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23][CH2:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[Br:28])=[O:22])[N:20]=3)[CH2:12][CH2:11]2)=[O:9])[N:5]=[C:4]([C:24]([F:27])([F:25])[F:26])[CH:3]=1
Reactant: OCc1ccccc1Br
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C(=O)OCc3ccccc3Br)cs2)CC1

Procedure:
A solution of 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylic acid (III-4, 100 mg) is reacted analogously to Example I-811 with (2-bromophenyl)methanol (49.0 mg). This gives, after chromatographic purification, 2-bromobenzyl 2-(1-{[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-1,3-thiazole-4-carboxylate (123 mg, 89%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:17]([NH:24][CH:6]1[CH2:7][CH2:8][C:3]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([N:2]([CH3:16])[CH3:1])[CH2:4][CH2:5]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CN(C)C1(c2ccccc2)CCC(=O)CC1
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CN(C)C1(c2ccccc2)CCC(NCc2ccccc2)CC1

Procedure:
2.00 g 4-dimethylamino-4-phenyl-cyclohexanone were dissolved in 30 ml analytical grade tetrahydrofuran, and 986 mg benzylamine followed by 794 μl glacial acetic acid were added, while stirring in an ice-bath. 2.72 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred for approx. 65 hours. For working up, 15 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 25 ml diethyl ether each time. The combined organic phases were then washed twice with 20 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained was chromatographed over silica gel with diethyl ether with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 844 mg of the nonpolar diastereoisomer of N′-benzyl-N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine were obtained, and were converted into 843 mg of the corresponding hydrochloride by dissolving in 6.8 ml 2-butanone and addition of 27.1 μl water followed by 381 μl chlorotrimethylsilane and stirring overnight.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]3[O:25][CH2:26][O:27][C:21]=3[CH:20]=2)[C:10]2[C:15]([CH3:16])=[CH:14][S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]4[O:25][CH2:26][O:27][C:21]=4[CH:20]=3)[C:10]3[C:15]([CH3:16])=[CH:14][S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Cc1csc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c12
Reactant: c1cn[nH]c1
Product: Cc1csc2nc(-n3cccn3)nc(NCc3ccc4c(c3)OCO4)c12

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-methyl-4-(3,4-methylenedioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:21][CH2:20][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:18][CH2:17]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH3:35]I.O>C1COCC1>[CH3:35][N:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]3[C:16]4([CH2:17][CH2:18][N:19]([C:22]5[CH:31]=[N:30][C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[N:23]=5)[CH2:20][CH2:21]4)[CH2:15][CH2:14][CH2:13][C:12]3=[O:32])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CI
Reactant: O=C1CCCC2(CCN(c3cnc4ccccc4n3)CC2)N1Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccc2c(CN3C(=O)CCCC34CCN(c3cnc5ccccc5n3)CC4)cccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 50 %

Procedure:
The title compound was synthesized from 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (prepared according to method G) via methylation as follows: NaH (7 mg, 0.18 mmol, 60% in mineral oil) was added to an ice-cold solution of 1-((1H-indol-4-yl)methyl)-9-(quinoxalin-2-yl)-1,9-diazaspiro[5.5]undecan-2-one (synthesized according to method G) (25 mg, 0.06 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 10 min. The mixture was cooled to 0° C., methyl iodide (26 mg, 0.18 mmol) was added at 0° C. and stirring was continued at 0° C. for 1 h. Then the mixture was allowed to warm to rt over a period of 1 h. The mixture was poured into water and the solution was extracted twice with ethyl acetate. The combined organic layers were washed with water and brine, filtered and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure. The product was purified by preparative reversed phase HPLC (column Zorbax eclipseXDB C18 21.2×150 mm 5 ♀m, flow 20 mL/min, eluent: gradient water/acetonitrile) to yield the title compound (13 mg, 50%). [1H NMR (300 MHz, CDCl3) ♀ ppm 8.49 (s, 1H), 7.88 (d, 1H), 7.68-7.50 (m, 2H), 7.45-7.35 (m, 1H), 7.21-7.08 (m, 2H), 6.95 (d, 1H), 6.73 (d, 1H), 6.35 (d, 1H), 4.98 (s, 2H), 4.40 (d, 2H), 3.78 (s, 3H), 3.15 (t, 2H), 2.68 (t, 2H), 2.25-2.05 (m, 4H), 2.00-1.85 (m, 2H), 1.80-1.70 (m, 2H); LCMS RtF=1.50 min, [M+H]+=440.0].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](O)=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:27])=O>CCCCCC>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:27])=[C:14]([C:19]#[N:20])[CH:15]=[N:16]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c(O)c(C#N)cnc2cc1OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CCCCCC
Product: COc1cc2c(Cl)c(C#N)cnc2cc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
A total of 500 mg (1.63 mM) of 7-benzyloxy-4hydroxy-6-methoxy-quinoline-3-carbonitrile was taken up into 3 ml of oxalyl chloride (2M in CHCl3) and allowed to stand for 15 min followed by refluxing for 1 h. The solution was allowed to cool and then diluted with 300 mg of hexane to give a green solid. The solid was isolated and washed with excess hexane and dried under vacuum at 40° C. to yield 586 mg of 7-benzyloxy-4-chloro-6-methoxy-quinoline-3-carbonitrile as the hydrogen chloride salt. This compound was taken immediately on for the next step.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][NH:9][C:8]2=O)(=[O:3])[CH3:2].S(Cl)([Cl:18])=O>>[ClH:18].[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[CH:10][N:9]=[C:8]2[Cl:18])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc2nc[nH]c(=O)c2c1
Product: CC(=O)Oc1ccc2ncnc(Cl)c2c1
Product: Cl

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 1 which is concerned with the preparation of starting materials, 6-acetoxyquinazolin-4-one was reacted with thionyl chloride to give 6-acetoxy-4-chloroquinazoline hydrochloride which was used without further purification.
Reaction SMILES: [CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH2:7].[N:19]1[CH:24]=[CH:23][CH:22]=[N:21][C:20]=1[C:25]1[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1.C(N(CC)CC)C.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl>C(Cl)Cl>[CH3:1][C@:2]1([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][N:10]=2)[CH2:6][CH2:5][CH2:4][C@@H:3]1[NH:7][C:31]([C:26]1[C:25]([C:20]2[N:19]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:30][CH:29]=[CH:28][N:27]=1)=[O:32]
Reactant: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1N
Reactant: O=C(O)c1ncccc1-c1ncccn1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(Nc2cnc(C(F)(F)F)cn2)CCC[C@@H]1NC(=O)c1ncccc1-c1ncccn1

Procedure:
A solution of (1S,2S)-1-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine (Intermediate 25; 50 mg, 0.192 mmol), 3-(pyrimidin-2-yl)pyridine-2-carboxylic acid (CAS number 1228431-21-7; 46 mg, 0.231 mmol), triethylamine (80 ul, 0.576 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (34 mg, 0.250 mmol) and EDC (48 mg, 0.250 mmol) in DCM (5 ml) was stirred at room temperature for 18 hours. The reaction was partitioned between DCM (20 ml) and a saturated solution of sodium bicarbonate (10 ml). The aqueous layer was further extracted with DCM (20 ml) and the combined organics were filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.BrC(OC)=O.[CH3:24][NH:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[Na+].[Cl-]>O1CCCC1.N1C=CC=CC=1>[CH3:24][N:25]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: CNC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Agent: COC(=O)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.5 Grams of 6-(3-carboxy)propoxycarbostyril and 1.8 ml of pyridine are added to 50 ml of tetrahydrofuran, and then 1.0 ml of methyl bromoformate is added dropwise to said solution under external ice cooling and agitation while maintaining the internal temperature at 5°-15° C. after addition, the mixture is further agitated at room temperature for 1 hour and then added with 1.2 g of N-methylcyclohexylamine, followed by additional 3-hour agitation. The reaction solution is poured into 200 ml of saturated NaCl solution and the precipitated crystals are filtered out and washed with water. The obtained crude crystals are recrystallized from chloroform-ethanol to obtain 2.3 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]carbostyril in the form of colorless needle-like crystals with m.p. of 184.5°-186° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH2:14])[NH:10][C:9]=2[CH:8]=[C:7]([C:15]#[N:16])[CH:6]=1)=[O:4].O.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28](O)=[O:29])[N:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([NH:14][C:28]([C:20]3[N:19]=[CH:18][C:27]4[C:22]([CH:21]=3)=[CH:23][CH:24]=[CH:25][CH:26]=4)=[O:29])[NH:10][C:9]=2[CH:8]=[C:7]([C:15]#[N:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(C#N)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C#N)cc2[nH]c(NC(=O)c3cc4ccccc4cn3)nc12

Procedure:
0.28 g (1.3 mmol) of 2-amino-6-cyano-1H-benzoimidazole-4-carboxylic acid methyl ester was added to a mixture of 0.22 g (1.3 mmol) of isoquinoline-3-carboxylic acid monohydrate, 0.49 g (1.3 mmol) of HBTU, 3 mL of DMF and 1 mL of DIEA to produce 6-cyano-2-[(isoquinoline-3-carbonyl)-amino]-1H-benzoimidazole-4-carboxylic acid methyl ester, according to General Procedure A. LCMS: 373.0 (M+1)+.
Reaction SMILES: [H-].[Na+:2].[C:3]([C:11]1[C:15]2=[C:16]([C:21]([OH:23])=[O:22])[C:17]([OH:20])=[CH:18][CH:19]=[C:14]2[O:13][C:12]=1[C:24]([F:27])([F:26])[F:25])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:28][O:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[N:33]=[C:32](S(C)(=O)=O)[N:31]=1.O>CN(C)C=O>[C:3]([C:11]1[C:15]2=[C:16]([C:21]([O-:23])=[O:22])[C:17]([O:20][C:32]3[N:33]=[C:34]([O:36][CH3:37])[CH:35]=[C:30]([O:29][CH3:28])[N:31]=3)=[CH:18][CH:19]=[C:14]2[O:13][C:12]=1[C:24]([F:27])([F:25])[F:26])(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1.[Na+:2]
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: O=C(O)c1c(O)ccc2oc(C(F)(F)F)c(C(=O)c3ccccc3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Oc2ccc3oc(C(F)(F)F)c(C(=O)c4ccccc4)c3c2C(=O)[O-])n1
Reaction time: 1 h
Yield: 40.5 %

Procedure:
While stirring 0.35 g of sodium hydride in 30 ml of N,N-dimethylformamide at room temperature, 1.73 g of 3-benzoyl-5-hydroxy-2-trifluoromethylbenzofuran-4-carboxylic acid was gradually added thereto. After completion of the addition, the mixture was further stirred for one hour. While stirring this mixture at room temperature, 1.08 g of 4,6-dimethoxy-2-methylsulfonylpyrimidine was added thereto, and then the mixture was stirred at 70° C. for 3 hours. The mixture was returned to room temperature and poured into water. Precipitated crystals were separated by filtration and washed with water and acetone to obtain 1.02 g (yield: 40.5%) of the desired compound.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([O:27]C)=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1.[OH-].[Na+]>CO.O>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:19]([N:20]([CH:22]([CH3:24])[CH3:23])[CH3:21])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25]([OH:27])=[O:26])[CH:16]=4)[N:11]=3)=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]nnc4c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]nnc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of methyl 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (140 mg, 0.37 mmol) in methanol (25 mL) and water (5 mL) was added sodium hydroxide (45 mg, 1.11 mmol) with stirring for overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (20 mL), and adjusted to pH 5 with HCl (3N) to give the precipitate, which was collected by filtration to afford 2-(1H-benzo[d][1,2,3]triazol-5-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (110 mg, 82%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Cl)[CH:9]=1>CN(C)C=O>[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([N:1]=[N+:2]=[N-:3])[CH:9]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1ccnc(Cl)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(N)ccn1
Temperature: 110 °C
Reaction time: 10 h
Yield: 87.1 %

Procedure:
Sodium azide (1.31 g) and ammonium chloride (1.07 g) were added to a solution of 4-amino-2-chloropyridine (2 g) in dimethylformamide (20 ml) and the mixture was stirred at 110° C. for 10 hours. After the insoluble material was filtered off, the filtrate was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography to give 1.83 g of 4-amino-2-azidopyridine, melting point 220° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[CH3:25][O:26][C:27]([C:29]1[CH:30]=[N:31][C:32](Cl)=[N:33][CH:34]=1)=[O:28]>>[CH3:25][O:26][C:27]([C:29]1[CH:30]=[N:31][C:32]([O:9][CH2:8][C:6]2[CH:5]=[CH:4][C:3]([CH:10]([CH3:24])[C:11]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([Cl:23])[CH:18]=3)([OH:16])[C:12]([F:15])([F:14])[F:13])=[C:2]([Cl:1])[CH:7]=2)=[N:33][CH:34]=1)=[O:28]
Reactant: COC(=O)c1cnc(Cl)nc1
Reactant: CC(c1ccc(CO)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1cnc(OCc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)nc1

Procedure:
The title compound was prepared in analogy to Example 93, step 7 from 3-(2-chloro-4-hydroxymethyl-phenyl)-2-(2-chloro-pyridin-4-yl)-1,1,1-trifluoro-butan-2-ol (obtained in Example 120, step 1) by alkylation with methyl-2-chloropyrimidine-5-carboxylate [CAS Reg. No. 287714-35-6]. MS (m/e)=516.1 [MH+].