Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[CH3:8][N:9]([CH2:52][CH:53]=O)[C:10](=[O:51])[C:11]1[CH:50]=[CH:49][CH:48]=[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[CH:19][C:18]=2[C:29]2[CH:34]=[C:33]([C:35](=[O:47])[NH:36][C@@H:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[CH:32]=[CH:31][N:30]=2)=[O:15])[CH:12]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>C(O)C>[CH3:8][N:9]([CH2:52][CH2:53][N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)[C:10](=[O:51])[C:11]1[CH:50]=[CH:49][CH:48]=[C:13]([C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:19][C:18]=2[C:29]2[CH:34]=[C:33]([C:35](=[O:47])[NH:36][C@@H:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[CH2:40][CH2:39][CH2:38]3)[CH:32]=[CH:31][N:30]=2)=[O:15])[CH:12]=1
Reactant: O=C1CNCCN1
Reactant: CN(CC=O)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CN(CCN1CCNC(=O)C1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)N[C@H]3CCCc4ccccc43)ccn2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
This compound was prepared according to the procedure described for the synthesis of Example 187 using piperazin-2-one in place of L-proline-tert-butyl ester. Into a 50-mL round-bottom flask, was placed a solution of (S)—N1-methyl-N1-(2-oxoethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide (100 mg, 0.16 mmol, 1.00 equiv) in ethanol (5 mL), piperazin-2-one (20 mg, 0.20 mmol, 1.20 equiv). This was followed by the addition of acetic acid (20 mg, 0.33 mmol, 2.20 equiv). The mixture was allowed to react with stirring for 1 h at room temperature. To this was added NaBH3CN (22 mg, 0.35 mmol, 2.20 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 7 with sodium bicarbonate (2 mol/L). The resulting solution was extracted with 3×20 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product (120 mg) was purified by Prep-HPLC with the following conditions (1#-Waters 2767-3): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water with 0.05% TFA and CH3CN (20% CH3CN up to 40% in 6 min); Detector, Waters2545 UvDector 254&270 nm. 91.4 mg product was obtained. This resulted in 91.4 mg (54%) of (S)—N1-methyl-N1-(2-(3-oxopiperazin-1-yl)ethyl)-N3-(4-(piperidin-1-yl)-2-(4-(1,2,3,4-tetrahydronaphthalen-1-ylcarbamoyl)pyridin-2-yl)phenyl)isophthalamide as a yellow solid. LCMS (ES, m/z): 714 [M+H]+ H-NMR (300 MHz, CD3OD, ppm): 8.94 (m, 1H), 8.70 (m, 1H), 8.40 (s, 2H), 8.12 (m, 3H), 7.85 (m, 1H), 7.72 (m, 3H), 7.17 (m, 3H), 5.39 (s, 1H), 3.94 (m, 3H), 3.56 (m, 7H), 3.09 (m, 3H), 2.86 (m, 3H), 1.95 (m, 8H).
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14]Br)[CH3:11]>CN(C=O)C>[CH2:10]([O:12][C:13](=[O:16])[CH2:14][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11]
Reactant: Sc1ccccc1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccccc1
Yield: 80.1 %

Procedure:
10.8 g (0.098 mol) of benzenethiol in 70 mL of DMF at 0° C., were treated with 4.31 g (0.108 mol, 1.1 eq) of NaH (55% in oil) over 40 min. 17.19 g (0.103 mol, 1.05 eq) of bromo-acetic acid ethyl ester were added, and stirring was continued over night. The reaction mixture was partitioned between aqueous NH4Cl and EtOAc, dried over Na2SO4, filtered and evaporated, to afford 15.4 g (80%) of phenylsulfanyl-acetic acid ethyl ester as a colorless oil, MS: 197 (MH+).
Reaction SMILES: C[O:2][C:3]1[C:4]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[C:5]([S:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[NH2:12])[CH:6]=[CH:7][CH:8]=1.Cl>CN(C)C=O>[NH2:12][C:11]1[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=1[S:9][C:5]1[C:4]([C:17]2[NH:21][N:20]=[N:19][N:18]=2)=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(Sc2ccccc2N)c1-c1nnn[nH]1
Agent: Cl
Solvent: CN(C)C=O
Product: Nc1ccccc1Sc1cccc(O)c1-c1nnn[nH]1
Temperature: 0 °C
Yield: 35 %

Procedure:
In 14 ml of 1.4M sodium ethylthiolate in N,N-dimethylformamide was dissolved 0.6 g of 2-[3-methoxy-2-(1H-tetrazol-5-yl)phenylthio]aniline (prepared by the process described in Reference Example 7) and the solution was refluxed for 6 hours. To the reaction mixture was added ice-water and the mixture was acidified weakly with diluted hydrochloric acid and extracted with ether. The ether layer was washed with water, dried over magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography using 5% methanol-chloroform as the eluent to give 0.2 g of the title compound as white crystals, m.p. 220°-225° C. (decomp.)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31](Cl)=[O:32])[CH:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([C:43]([CH:45]2[CH2:49][CH2:48][CH2:47][O:46]2)=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:31]([N:40]3[CH2:41][CH2:42][N:37]([C:43]([CH:45]4[CH2:49][CH2:48][CH2:47][O:46]4)=[O:44])[CH2:38][CH2:39]3)=[O:32])[C@H:13]([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:34][CH2:35][CH3:36])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C(C1CCCO1)N1CCNCC1
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(C(=O)C2CCCO2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4-methyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with piperazin-1-yl-(tetrahydro-furan-2-yl)-methanone (Aldrich) to give the title compound. LC-MS: 691.3 [(M+H)+]
Reaction SMILES: Cl.[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2.[Cl:20][CH2:21][C:22]1[S:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:20].[S:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[CH2:21][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)[CH2:7][CH2:6]2
Reactant: ClCc1nc2ccccc2s1
Reactant: Oc1ccc2c(c1)CCC(CN1CCCCC1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2sc(COc3ccc4c(c3)CCC(CN3CCCCC3)C4)nc2c1
Temperature: 60 °C
Reaction time: 7 h
Yield: 50.6 %

Procedure:
To a solution of 6-hydroxy-2-piperidinomethyltetralin hydrochloride (205 mg, Reference Example 19) and 2-chloromethylbenzothiazole (183 mg) in DMF (10 ml) was added potassium carbonate (327 mg) and the reaction mixture was stirred at room temperature for 4 days and further at 60° C. for 7 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by silica gel column chromatography (eluent: ethyl acetate: methanol=10:1), alumina column chromatography (eluent: ethyl acetate: hexane=1:4) and converted into its hydrochloride, which was recrystallized from methanol-ethyl acetate to obtain the titled compound (158 mg).
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18](S(C)(=O)=O)[N:17]=3)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.[NH2:30][NH2:31]>>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:30][NH2:31])[N:17]=3)[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2
Reactant: CS(=O)(=O)c1nccc(Nc2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Reactant: NN
Product: NNc1nccc(Nc2cc(-c3cc4ccccc4s3)c3[nH]ncc3c2)n1
Yield: 22.3 %

Procedure:
(7-Benzo[b]thiophen-2-yl-1H-indazol-5-yl)-(2-methanesulfonyl-pyrimidin-4-yl)-amine (Preparation #8, 20 mg, 0.048 mmol) was treated with hydrazine (0.4 mL, 12.2 mmol) at ambient temperature for about 5 hours. A solid was filtered off and was further purified by trituration in dichloromethane followed by filtration to yield (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-(2-hydrazino-pyrimidin-4-yl)-amine (4 mg, 23% yield); LC/MS (method f) Rt 6.0 min; m/z (ESI−): (M−H)+ 371.7.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:36])([F:35])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][OH:34])[CH:28]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[O:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[F:36][C:7]([F:6])([F:35])[C:8]1[CH:9]=[C:10]([NH:14][C:15]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C:27]4[CH:32]=[CH:31][N:30]=[C:29]([CH2:33][O:34][S:2]([CH3:1])(=[O:4])=[O:3])[CH:28]=4)=[CH:23][CH:24]=3)[CH:19]=[CH:18]2)=[O:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)n1ccc2cc(Oc3ccnc(CO)c3)ccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cc(Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)ccn1

Procedure:
Methanesulfonyl chloride (0.2 mL, 2.46 mmol) is added to a solution of 5-(2-hydroxymethyl-pyridin-4-yloxy)-indole-1-carboxylic acid (3-trifluoromethylphenyl)-amide, Example 25-D, (700 mg, 1.64 mmol) and triethylamine (0.7 mL, 4.92 mmol) in DCM (50 mL) at rt. After 1 h the reaction is partitioned between DCM and saturated aqueous NaHCO3. Organic layer is removed, dried over anhydrous Na2SO4, concentrated and then separated via FCC (EtOAc/heptanes 2:4 to EtOAc/heptanes 9:1) to give the title compound. MS (ESI) m/z 506.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32]C)=[O:31])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([OH:32])=[O:31])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][C:21]2[C:26]([Cl:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=2[Cl:29])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(OCCOc2c(Cl)cc(C)cc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(Cl)c(OCCOc2ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc2)c(Cl)c1

Procedure:
Methyl N-(tert-butoxycarbonyl)-O-[2-(2,6-dichloro-4-methylphenoxy)ethyl]tyrosinate from the previous step (1 eq.) was dissolved in a 2:1 (v/v) THF:MeOH solution (0.07 M). To this was then added lithium hydroxide (1.0 M aqueous solution, 5 eq.) and the resulting solution was stirred at RT for 16 h. The volatiles were then removed in vacuo. Following careful acidification of the resulting residue with 10% aq. HCl, the mixture was extracted with EtOAc. The combined organic extracts were washed with H2O and brine, dried over MgSO4 and filtered. Concentration of the filtrate in vacuo afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38]Br)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:49]1[C:57]2[C:52](=[CH:53][C:54](B3OC(C)(C)C(C)(C)O3)=[CH:55][CH:56]=2)[CH2:51][CH2:50]1.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@H:12]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([CH2:38][C:54]3[CH:53]=[C:52]4[C:57](=[CH:56][CH:55]=3)[CH2:49][CH2:50][CH2:51]4)[CH:32]=2)[O:11][C@@H:10]1[CH2:40][O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc3c(c2)CCC3)OC1(C)C
Reactant: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Clc1ccc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc1Cc1ccc2c(c1)CCC2
Temperature: 100 °C
Yield: 69.4 %

Procedure:
To a solution of (2R,3R,4R,5S,6S)-3,4,5-tris(benzyloxy)-2-(benzyloxymethyl)-6-(3-(bromomethyl)-4-chlorophenyl)-tetrahydro-2H-pyran (106) (580 mg, 0.8 mmole) in toluene/EtOH (9 mL/8 mL) were added 2-(2,3-dihydro-1H-inden-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (121) (400 mg, 1.6 mmol), tetrakis(triphenylphosphin)palladium (180 mg, 0.16 mmol), and Cs2CO3 (2.1 g, 2.32 mmol) at room temperature. The mixture was stirred at 100° C. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography to provide the title compound (425 mg, 70%).
Reaction SMILES: [OH-:1].[Na+].BrBr.[CH3:5][C:6]1[O:10][C:9]([CH:11]=[O:12])=[CH:8][CH:7]=1>O>[CH3:5][C:6]1[O:10][C:9]([C:11]([OH:1])=[O:12])=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: Cc1ccc(C=O)o1
Agent: BrBr
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=O)O)o1
Reaction time: 0.75 h
Yield: 60.6 %

Procedure:
Following the method of Shapiro et al. (Khim. Geterotsikl. Soedin. 1982, 11, 1463), to a stirred solution of 80.3 g (2.00 mol) sodium hydroxide in 330 ml water at 0-5° C. was added dropwise 18 ml (0.35 mol) bromine. 25 ml (0.25 mol) 5-methyl-2-furfural was then added dropwise over 90 minutes and stirring continued for a further 45 minutes at 0-5° C. The reaction mixture was then extracted with ether and the phases separated. The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and the resulting precipitate collected by filtration and dried in vacuo to afford 19.1 g (60%) 5-methyl-2-furoic acid as a beige crystalline solid. 1H NMR δ (CDCl3, 250 MHz): 8.00-6.60 (1H, v. br. s), 7.24 (1H, d, J=3.4 Hz), 6.17 (1H, d, J=3.4 Hz), 2,42 (3H, s).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]([F:17])([F:16])[CH2:14][OH:15].[OH-].[Na+].O>C1(C)C=CC=CC=1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([O:15][CH2:14][C:13]([F:17])([F:16])[F:12])[CH:7]=1
Reactant: OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(F)cc1OCC(F)(F)F
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2,4-difluoronitrobenzene (300.0 g, 1.89 mol) and 2,2,2-trifluoroethanol (245.0 g, 2.45 mol) in toluene (600 mL) was added sodium hydroxide (90.5 g, 2.26 mol) in portions over 30 min to keep the temperature between 30 and 40° C. After the temperature had dropped to 30° C., the reaction mixture was heated to 45-50° C. using an oil bath for additional 16 h. After cooling, water (500 mL) and 2.5 NH2SO4 (200-300 mL, for adjustment of pH to 5) were added and the organic layer was separated. The water layer was extracted with EtOAc (2×300 mL). The combined organic layers were washed with saturated sodium chloride solution (100 mL) and dried over magnesium sulfate. The solvent was evaporated to give a yellow oil, which solidified after 30 min to give a yellowish solid (450.0 g, quantitative). The crude product was used in the next step without purification. 1H NMR (300 MHz, CDCl3/TMS): δ 8.03-7.98 (m, 1H), 6.93-6.82 (m, 2H), 4.49 (q, J=7.7 Hz, 2H). 13C NMR (75 MHz, CDCl3/TMS): δ 165.0 (d, 1JCF=259.6 Hz), 152.3 (d, 3JCF=13.1 Hz), 128.2 (d, 3JCF=11.9 Hz), 122.4 (d, 1JCF=273.4 Hz), 110.1 (d, 2JCF=22.5 Hz), 105.9 (q, 1JCF=242.6 Hz), 104.3 (d, 2JCF=26.1 Hz), 67.6 (q, 1JCF=36.7 Hz).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[N:21]2[CH:22]=[CH:23][C:24]([C:26]([F:29])([F:28])[F:27])=[N:25][C:20]2=[N:19][CH:18]=1)CCC>>[F:28][C:26]([F:27])([F:29])[C:24]1[CH:23]=[CH:22][N:21]2[C:17]([C:2]3[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=3)=[CH:18][N:19]=[C:20]2[N:25]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccc(-c2cnc3nc(C(F)(F)F)ccn23)nc1

Procedure:
2-Bromo-5-trifluoromethylpyridine (1.70 g, 7.5 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (3.8 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from toluene, gave 7-trifluoromethyl-3-(5-trifluoromethylpyridin-2-yl)imidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 10.52 (1H, d, J 7), 8.94-8.97 (1H, m), 8.63 (1H, s), 8.03-8.07 (1H, m), 7.96 (1H, d, J 9), 7.41 (1H, d, J 7); m/z (ES+) 333 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>O1CCOCC1>[CH2:12]([S:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH2:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Nc1cccc(S)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc(SCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
To a stirring suspension of 25 grams (0.20 mole; M.W. 125.19) of 3-aminothiophenol in 200 ml. of 5N NaOH was added dropwise a solution of 34.2 grams of α-bromotoluene (0.20 mole; M.W. 171.04) dissolved in 100 ml. of 1,4-dioxane. The addition required about 30 minutes. The reaction mixture was stirred at room temperature for 2 hours and then extracted with two 500 ml. portions of ethyl ether. The extracts were combined, dried over Na2SO4, and evaporated to yield 41.0 grams of m-benzylthioaniline.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[N+:21]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Product: CCOc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-ethoxy-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example A9) (5.52 g, 15.8 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a yellow solid (3.84 g).
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[NH2:20][CH:21]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]1>>[CH3:27][N:24]1[CH2:25][CH2:26][CH:21]([NH:20][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[N:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:22][CH2:23]1
Reactant: O=C(Nc1nc2cccc(Br)n2n1)c1cccnc1
Reactant: CN1CCC(N)CC1
Product: CN1CCC(Nc2cccc3nc(NC(=O)c4cccnc4)nn23)CC1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)nicotinamide ((B2), 100 mg; 0.31 mmol; 1.0 eq.) and 4-amino-1-methyl-piperidine (1.0 mL) as a white powder (30 mg, 27%). 1H NMR (DMSO-d6) δ 11.25 (brs, 1H), 9.13 (d, J=1.9 Hz, 1H), 8.77 (dd, J=4.7, 1.7 Hz, 1H), 8.32 (dd, J=8.0, 2.0 Hz, 1H), 7.56 (dd, J=8.1, 4.7 Hz, 1H), 7.51 (t, J=8.3 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.46 (d, J=8.3 Hz, 1H), 6.312 (d, J=7.5 Hz, 1H), 3.49 (m, 1H), 2.77 (m, 2H), 2.17 (s, 3H), 2.05 (m, 2H), 1.89 (m, 2H), 1.70 (m, 2H). HPLC, Rt: 1.07 min. (purity 100.0%). LC/MS, M+(ESI): 352.4, M−(ESI): 350.4.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH2:18])[CH:14]=[N:15][CH:16]=1.[CH2:19]([S:21](Cl)(=[O:23])=[O:22])[CH3:20]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:11]1[CH:12]=[C:13]([CH2:17][NH:18][S:21]([CH2:19][CH3:20])(=[O:23])=[O:22])[CH:14]=[N:15][CH:16]=1
Reactant: CCS(=O)(=O)Cl
Reactant: Cn1c(-c2cncc(CN)c2)cc2ccccc21
Product: CCS(=O)(=O)NCc1cncc(-c2cc3ccccc3n2C)c1

Procedure:
C-[5-(1-Methyl-1H-indol-2-yl)-pyridin-3-yl]-methylamine (Example 200b) and ethanesulfonyl chloride are processed according to the method described in Example 186f to give N-[5-(1-methyl-1H-indol-2-yl)-pyridin-3-ylmethyl]-ethanesulfonamide. 1H NMR (400 MHz, MeOD) δ ppm 1.37 (t, J=7.3 Hz, 3H), 3.13 (q, J=7.4 Hz, 2H), 3.82 (s, 3H), 4.43 (s, 2H), 6.70 (s, 1H), 7.01-7.18 (m, 1H), 7.20-7.36 (m, 1H), 7.48 (d, J=8.3 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 8.10 (t, J=2.1 Hz, 1H), 8.61 (d, J=2.0 Hz, 1H), 8.71 (d, J=2.0 Hz, 1H). HRMS (ESI) m/z 330.1288 [(M+H)+ Calcd for C17H20N3O2S: 330.1276].
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N)#[N:2].C1N2CN3CN(C2)CN1C3.O.S(=O)(=O)(O)[OH:23]>C(O)(=O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=[O:23])#[N:2]
Reactant: N#Cc1cccc(CN)c1
Reactant: O=S(=O)(O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 75.3 %

Procedure:
7.9 g of m-cyanobenzylamine, 8.4 g of hexamethylenetetramine, 40 ml of water and 40 ml of acetic acid were mixed and reacted at 104° C. for 2 hours while stirring. The reaction solution was cooled to room temperature and thereto 12 g of concentrated sulfuric acid was added. The solvent was concentrated to dry in an evaporator with a water bath at 70° C. The concentration residue was separated by toluene/water and washed with water. The toluene layer obtained was concentrated until crystals were precipitated. The concentrated toluene solvent was placed in water and after removing toluene by azeotropic distillation, the residue was cooled to room temperature. The crystals precipitated were collected by filtration, washed with water and dried to obtain 5.9 g (yield: 74%) of m-cyanobenzaldehyde. The purity was 99% or more.
Reaction SMILES: Cl[CH2:2][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[CH:9]=2)[N:4]=1.O.[SH:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[NH:26][CH:27]=[N:28]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[N:12]1[C:11](=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:21])[CH:9]=2)[N:4]=[C:3]1[CH2:2][S:23][C:24]1[N:32]=[CH:31][N:30]=[C:29]2[C:25]=1[N:26]=[CH:27][NH:28]2
Reactant: O=c1c2cc(F)ccc2nc(CCl)n1-c1ccccc1Cl
Reactant: Sc1ncnc2nc[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2cc(F)ccc2nc(CSc2ncnc3[nH]cnc23)n1-c1ccccc1Cl
Yield: 64.3 %

Procedure:
Prepared according to Procedure C using Intermediate 2r (118 mg, 0.365 mmol), 6-mercaptopurine monohydrate (68 mg, 0.402 mmol), K2CO3 (56 mg, 0.402 mmol), and DMF (2 mL). The crude product was recrystallized from EtOH to provide 103 mg of an off-white crystalline solid (64%), mp 232.8-233.0° C. (discolors). 1H NMR (DMSO-d6) δ: 13.56 (br s, 1H); 8.48 (s, 1H); 8.44 (s, 1H); 7.81-7.86 (m, 3H); 7.76 (d, J=7.5 Hz, 1H); 7.67 (d, J=7.5 Hz, 1H); 7.40-7.54 (m, 2H); 4.48 (br s, 2H). 13C NMR (DMSO-d6) ppm: 160.8 (d, J=247 Hz), 160.2 (d, J=3.3 Hz), 156.9, 152.3 (d, J=l.9 Hz), 151.5, 149.7, 144.0, 143.6, 134.1, 132.1, 131.7, 131.5, 130.5, 130.4, 130.2, 128.8, 124.0 (d, J=24 Hz), 122.0 (d, J=8.7 Hz), 111.7 (d, J=24 Hz), 32.0. MS (ES): m/z 439.0 (M+). Anal. calcd. for C20H12ClFN6OS.0.2C2H6O.0.1H2O: C, 54.46; H, 3.00; Cl, 7.88; N, 18.68. Found: C, 54.09; H, 2.73; Cl, 7.80; N, 18.77.