Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:9]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40].C([O-])(O)=O.[Na+]>C(Cl)Cl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:9]([C:12]2[CH:13]=[N:14][C:15]([NH:18][CH:19]3[CH2:24][CH2:23][N:22]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:21][CH2:20]3)=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCNCC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(NC2CCN(S(C)(=O)=O)CC2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[(4-fluoro-phenyl)-isobutyl-sulfamoyl]-pyridin-2-ylamino}-piperidine-1-carboxylic acid tert-butyl ester (66 mg, 130 μmol) in DCM (8 mL) was added TFA (2 mL) and the reaction was stirred at room temperature for 30 minutes. The reaction was concentrated and purified by SCX column eluting with 2M NH3 in MeOH to give 6-(piperidin-4-ylamino)-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (41 mg, 101 μmol). To a solution of 6-(piperidin-4-ylamino)-pyridine-3-sulfonic acid (4-fluoro-phenyl)-isobutyl-amide (41 mg, 101 μmol) in DCM (5 mL) was added DIPEA (35 μL, 202 μmol) followed by methane sulfonylchloride (1 mL of a 78 μL, 1 mmol solution in 10 mL of DCM) and the reaction stirred at room temperature for 30 minutes. Water and saturated NaHCO3 were then added, extracted, filtered through a phase separator, concentrated and purified by silica gel column chromatography (0-50% EtOAc in cyclohexane) to give the title compound (49 mg). 1H NMR (400 MHz, DMSO): δ 8.03 (d, J=2.52 Hz, 1H), 7.54 (d, J=7.47 Hz, 1H), 7.35 (dd, J=8.95, 2.54 Hz, 1H), 7.17 (t, J=8.01 Hz, 4H), 6.51 (d, J=8.98 Hz, 1H), 3.91 (br s, 1H), 3.51 (d, J=11.88 Hz, 2H), 3.25 (d, J=7.31 Hz, 2H), 2.86 (m, 5H), 1.97 (d, J=12.65 Hz, 2H), 1.44-1.49 (m, 2H), 0.82 (d, J=6.63 Hz, 6H). LCMS (m/z, Method B) ES+ 485.0 [M+1]+.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]([F:15])([F:14])[C:12]#[N:13]>CC(C)([O-])C.[K+]>[C:3]([C:2](=[C:12]([NH2:13])[C:11]([F:15])([F:14])[F:10])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: N#CC(F)(F)F
Reactant: CCOC(=O)CC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCOC(=O)C(C(C)=O)=C(N)C(F)(F)F
Yield: 61.9 %

Procedure:
To a 1 liter, four-necked flask equipped with nitrogen inlet, thermometer, and mechanical stirrer was charged 499.74 g (490 ml, 3.84 mol) of ethyl acetoacetate and 12.9 g (0.115 mol) of potassium-t-butoxide. The resulting mixture was stirred while 391 g (4.04 mol) of trifluoroacetonitrile was added. The reaction mixture was washed with hexane and the resulting solid was dried in vacuo affording 535 g (62%) of the enamine as a yellow solid; mp 63°-65° C.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]([Br:14])=[CH:5][CH:6]1[CH:8]([C:9]([OH:11])=[O:10])[C:7]1([CH3:13])[CH3:12].Br[CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:21][CH:22]=1.N12CCN(CC1)CC2>>[Br:3][C:4]([Br:14])=[CH:5][CH:6]1[CH:8]([C:9]([O:11][CH2:16][C:17]2[CH:18]=[C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:20]=[CH:21][CH:22]=2)=[O:10])[C:7]1([CH3:12])[CH3:13]
Reactant: BrCc1cccc(-c2ccccc2)c1
Reactant: CC1(C)C(C=C(Br)Br)C1C(=O)O
Agent: C1CN2CCN1CC2
Agent: [K+]
Agent: [OH-]
Product: CC1(C)C(C=C(Br)Br)C1C(=O)OCc1cccc(-c2ccccc2)c1

Procedure:
[1,1'-Biphenyl]-3-ylmethyl 3-(2,2-dibromoethenyl)-2,2-dimethycyclopropanecarboxylate was prepared by the method described in Example 1B above using potassium hydroxide (0.66 g, 0.12 mole), 3-(2,2-dibromoethenyl)-2,2-dimethylcyclopropanecarboxylic acid (5.3 g, 0.12 mole), which may be prepared according to the method of Elliott, et al., U.S. Pat. No. 4,024,163, 3-bromomethylbiphenyl (2.7 g, 0.12 mole), and 0.1 g of 1,4-diazabicyclo[2.2.2]octane.
Reaction SMILES: [Na].[CH3:2][N:3]1[S:7](=[O:9])(=[O:8])[NH:6][C:5](=[O:10])[CH:4]1[CH2:11][CH2:12][CH3:13].[F:14][C:15]1[N:20]=[C:19]([F:21])[C:18]([F:22])=[C:17](F)[C:16]=1[F:24].C1OCCOCCOCCOCCOC1>C(#N)C.CN(C=O)C>[F:21][C:19]1[C:18]([F:22])=[C:17]([N:6]2[C:5](=[O:10])[CH:4]([CH2:11][CH2:12][CH3:13])[N:3]([CH3:2])[S:7]2(=[O:9])=[O:8])[C:16]([F:24])=[C:15]([F:14])[N:20]=1
Reactant: CCCC1C(=O)NS(=O)(=O)N1C
Reactant: Fc1nc(F)c(F)c(F)c1F
Agent: C1COCCOCCOCCOCCO1
Agent: [Na]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCCC1C(=O)N(c2c(F)c(F)nc(F)c2F)S(=O)(=O)N1C
Yield: 22 %

Procedure:
To a mixture of the sodium salt of 5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.2 mmol, prepared by treatment with sodium methoxide) suspended in 30 ml of acetonitrile was added pentafluoropyridine (0.57 ml, 5.2 mmol) and 1.14 g (5.17 mmol) of 15-Crown-5 and DMF (25 ml), and the resulting mixture was refluxed for 20 hours. The mixture was cooled, concentrated in vacuo, and the residue diluted with water, extracted with methylene chloride, and the organic layer was washed with water and brine. The organic layer was concentrated in vacuo and a crude product was purified by flash chromatography to afford 0.39 g (22%) of 2-(2,3,5,6-tetrafluoro-4-pyridyl)-5-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: R1 =propyl; R2 =H; R3 =CH3).
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.C=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CCCC)CCCC)CCC>C1(=O)CCCCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccccc1C(=O)Cl
Reactant: C=Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCCCN(CCCC)CCCC
Solvent: O=C1CCCCC1
Product: Cc1ccccc1C=Cc1ccccc1
Yield: 55.6 %

Procedure:
The procedure described in Example 1 is followed, except that 15.5 g (0.1 mol) of o-toluic acid chloride, 13 g (0.125 mol) of styrene, 23.2 g (0.125 mol) of tri-n-butylamine and 0.225 g (0.001 mol) of palladium acetate are used. After a reaction time of 4 hours at 120° C., in 100 ml of cyclohexanone as the solvent, 10.8 g (0.0556 mol) of 2-methylstilbene, corresponding to a yield of 55.6% of theory, are obtained; melting point 92°-93° C.
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[C:27]([O:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)([CH3:30])([CH3:29])[CH3:28]>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:36](=[O:37])[C:35]3[CH:34]=[CH:33][C:32]([O:31][C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:40][CH:39]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: CC(C)(C)Oc1ccc(C(=O)O)cc1
Agent: Cl
Product: CC(C)(C)Oc1ccc(C(=O)N[C@H]2CC[C@H](CCN3CCCCC3c3coc4cccc-4c3)CC2)cc1

Procedure:
The title compound, white solid (82 mg, 65%), MS (ISP) m/z=503.3 [(M+H)+], mp 186° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-tert-butoxy-benzoic acid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][O:48]C3CCCCO3)[CH:45]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O.C([O-])(O)=O.[Na+]>CO>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C@H:17]([O:24][C:25]3[CH:26]=[CH:27][C:28]4[N:29]([C:31]([N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][C@@H:35]5[CH3:40])=[N:32][N:33]=4)[CH:30]=3)[CH2:16][CH2:15]2)=[O:12])[N:7]([C:41]2[CH:42]=[N:43][N:44]([CH2:46][CH2:47][OH:48])[CH:45]=2)[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cnn(CCO)c4)c4ccccc43)cn12
Temperature: 55 °C
Yield: 75.1 %

Procedure:
To a solution of Intermediate 187a (377 mg, 0.51 mmol) in MeOH (5 mL) was added pyridinium p-toluenesulfonate (257 mg, 1.02 mmol) and the reaction mixture was heated at 55° C. for 3 h. The resultant mixture was poured into water and a saturated aqueous solution of NaHCO3 was added. The aqueous phase was extracted with EtOAc (×3) and the combined organic layers were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by FCC on silica, using a gradient of 3-10% MeOH in DCM, to give the title compound (250 mg, 75%). LCMS (Method 1): Rt 3.09 min, m/z 653 [MH+].
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[C:11]=[S:12])=[CH:6][N:5]=1)[CH3:2].[CH3:15][NH:16][NH2:17]>C(O)C>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[S:12])[N:16]([CH3:15])[NH2:17])=[CH:6][N:5]=1)[CH3:14]
Reactant: CCN(CC)c1ccc(N=C=S)cn1
Reactant: CNN
Solvent: CCO
Product: CCN(CC)c1ccc(NC(=S)N(C)N)cn1

Procedure:
Following procedures similar to those employed in Step A of Example 2, the reaction of 3.5 g (0.017 mole) of (2-diethylaminopyridin-5-yl) isothiocyanate with 0.86 (0.019 mole) of methylhydrazine in 150 ml of ethanol yielded 2.5 g of 4-(2-diethylaminopyridin-5-yl)-2-methyl-3-thiosemicarbazide as a solid, mp 147°-149° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:40]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:10][N:9]=1.[OH-].[Na+:48]>C(O)C>[Na+:48].[F:46][C:2]([F:1])([F:45])[C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([C:41]([F:42])([F:43])[F:44])[CH:40]=1)[CH2:6][N:7]([CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O-:20])=[O:19])=[CH:12][N:13]=1
Reactant: O=C(O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2ccccc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2ccccc2)nc1

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-2-ylmethyl}-amino]-pyrimidin-5-yloxy}-butyrate (185 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→19:1) to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (160 mg). The resulting 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid (160 mg) is dissolved in ethanol (1 ml) and thereto is added 1N-aqueous sodium hydroxide solution (245 μl) and concentrated under reduced pressure to give 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyric acid sodium salt (158 mg). MS (m/z): 656 [M−Na]−
Reaction SMILES: [N:1]([CH2:4][CH2:5][N:6]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[C:9]([C:19]2[CH:20]=[CH:21][C:22]3[N:23]([C:25]([CH:28]([CH3:30])[CH3:29])=[N:26][N:27]=3)[N:24]=2)[CH:8]=[N:7]1)=[N+]=[N-]>CCO.[Pt](=O)=O>[F:18][C:12]1[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=1[C:10]1[N:6]([CH2:5][CH2:4][NH2:1])[N:7]=[CH:8][C:9]=1[C:19]1[CH:20]=[CH:21][C:22]2[N:23]([C:25]([CH:28]([CH3:30])[CH3:29])=[N:26][N:27]=2)[N:24]=1
Reactant: CC(C)c1nnc2ccc(-c3cnn(CCN=[N+]=[N-])c3-c3ccc(F)cc3F)nn12
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)c1nnc2ccc(-c3cnn(CCN)c3-c3ccc(F)cc3F)nn12
Reaction time: 16 h
Yield: 98 %

Procedure:
The 6-(1-(2-azidoethyl)-5-(2,4-difluorophenyl)-1H-pyrazol-4-yl)-3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazine (0.485 g, 1.19 mmol; prepared using General Procedure L.1 from 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (Preparation #K.1) with hydroxylethylhydrazine, General Procedure W with methanesulfonyl chloride, General Procedure X.1 with sodium azide) was dissolved in EtOH (20 mL) then platinum (IV) oxide (0.090 g, 0.40 mmol) was added. The mixture was hydrogenated at atmospheric pressure and ambient temperature for about 16 h then filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give the title compound (0.447 g, 98%): LC/MS (Table 1, Method a) Rt=1.66 min; MS m/z: 384.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]3[CH:26]=[CH:25][C:16]([O:17][CH:18]([CH3:24])[C:19]([O:21]CC)=[O:20])=[CH:15][CH:14]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[OH-].[K+].Cl>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([NH:12][C:13]3[CH:14]=[CH:15][C:16]([O:17][CH:18]([CH3:24])[C:19]([OH:21])=[O:20])=[CH:25][CH:26]=3)[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Oc1ccc(Nc2cnc3cc(Cl)ccc3c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(Oc1ccc(Nc2cnc3cc(Cl)ccc3c2)cc1)C(=O)O
Reaction time: 24 h
Yield: 58.5 %

Procedure:
A solution of ethyl 2-{4-[N-(7-chloroquinolin-3-yl)amino]phenoxy}propionate (370 mg) and potassium hydroxide (200 mg) in methanol (10 ml) was warmed and stirred for 24 hours. The solution was poured into dilute hydrochloric acid (50 ml of 0.5M) and extracted with ethyl acetate (2×50 ml). The organic layer was dried over magnesium sulphate, filtered and evaporated to give 2-{4-[N-(7-chloroquinolin-3-yl)amino]phenoxy}propionic acid (200 mg) as a brown solid, mp 150° C.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].Cl[CH2:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>CN(C)C=O>[C:19]1([NH:18][C:16]([CH2:15][N:4]2[C:5](=[O:6])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[S:1]2(=[O:2])=[O:3])=[O:17])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: O=C(CCl)Nc1ccccc1
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2S1(=O)=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.9 %

Procedure:
A solution of 22.6g (0.11 mole) of sodium saccharin and 16.7g (0.1 mole) of N-chloroacetylaniline in 150ml of dimethylformamide is heated on a steam bath for one hour, allowed to stir at room temperature for 16 hrs. and poured into ice-water. The resulting precipitate is collected and dissolved in dichloromethane. This solution is dried over magnesium sulfate, and the solvent is evaporated. The residue is recrystallized from methanol to give 19.9g of product, mp. 180°-182° C. EXAMPLE 2 ##STR5##
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:24][CH2:23][C:21]3=[O:22])[CH2:16][CH2:15]2)=[O:13])=[CH:10][CH:9]=1.[F:33][C:34]([F:45])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:36].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:45][C:34]([F:33])([F:44])[C:35]([NH:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]2[CH:32]=[CH:31][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[CH2:24][CH2:23][C:21]4=[O:22])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH2:40][CH2:39]1)=[O:36]
Reactant: O=C(c1ccc(OCCCCCBr)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reactant: O=C(NC1CCNCC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCCCCCN2CCC(NC(=O)C(F)(F)F)CC2)cc1)N1CCC(N2C(=O)CCc3ccccc32)CC1
Reaction time: 8 h
Yield: 81.2 %

Procedure:
1-{1-[4-(5-Bromopentyloxy)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (2 g) and 4-trifluoroacetylaminopiperidine (2 g) are dissolved in dimethylformamide (40 ml), and thereto is added potassium carbonate (2 g) and the mixture is stirred overnight. The reaction mixture is poured into water, and the mixture is extracted with toluene/ethyl acetate (1:1), dried over magnesium sulfate, and purified by silica gel column chromatography (eluent; dichloromethane:methanol=50:1) to give 1-[1-{4-[5-(4-trifluoroacetylamino-1-piperidinyl)pentyloxy]benzoyl}-4-piperidinyl]-3,4-dihydrocarbostyril (2 g) as colorless oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:21]1[S:25][C:24]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[C:29]#[N:30])=[N:23][CH:22]=1)CCC>>[CH3:15][C:13]1[CH:12]=[CH:11][N:10]=[C:9]([NH:8][C:6]2[N:7]=[C:2]([C:21]3[S:25][C:24]([C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[N:23][CH:22]=3)[CH:3]=[CH:4][CH:5]=2)[N:14]=1
Reactant: Cc1ccnc(Nc2cccc(Br)n2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc(-c2cccc(C#N)c2)s1
Product: Cc1ccnc(Nc2cccc(-c3cnc(-c4cccc(C#N)c4)s3)n2)n1

Procedure:
By following essentially the same procedure in preparative example 019 and starting with N-(6-bromopyridin-2-yl)-4-methylpyrimidin-2-amine (215 mg 0.81 mmol) and 3-(5-(tributylstannyl)thiazol-2-yl)benzonitrile (656 mg, 1.38 mmol), the 3-(5-(6-(4-methylpyrimidin-2-ylamino)pyridin-2-yl)thiazol-2-yl)benzonitrile was obtained and purified by dry flash chromatography over SiO2 eluting with DCM/MeOH (5%)/NEt3 (0.5%), by precipitation in DCM/MeOH and by trituration with Et2O (119 mg, 39%). 1H NMR (300 MHz, DMSO-d6) δ 9.60 (br s, 1H), 8.62 (s, 1H), 8.43 (d, J=5.0 Hz, 1H), 8.38 (d, J=2.3 Hz, 1H), 8.31-8.23 (m, 2H), 8.01-7.95 (m, 1H), 7.86 (t, J=8.0 Hz, 1H), 7.75 (t, J=7.9 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 6.89 (d, J=5.0 Hz, 1H), 2.42 (s, 3H). (APCI+) m/z 371 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1>C(Cl)Cl.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[CH:12]1)[NH2:8]
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(F)c1
Agent: [Pd]
Solvent: ClCCl
Product: Nc1ccc(-n2cccc2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To a solution of 1-(2-fluoro-4-nitrophenyl)-1H-pyrrole (2.00 g, 9.70 mmol) in CH2Cl2 (35 mL) was added catalyst Pd/C (0.20 g). The reaction mixture was stirred at rt under H2 for 5 h, and filtered. The filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/CH2Cl2 (V/V)=3:1) to give the title compound as a white solid (1.30 g, 76%).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]1[C:15]([O:17]CC)=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>CO.O1CCCC1>[CH2:1]([N:8]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[C:9]1[C:15]([OH:17])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(C#N)ccn1Cc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccn(Cc2ccccc2)c1C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A solution of ethyl 1-benzyl-3-cyano-1H-pyrrole-2-carboxylate (8.7 g, 34.1 mmol) in Methanol (40 mL) and Tetrahydrofuran (THF) (40 mL) was treated with 2M LiOH (40 mL, 80 mmol) and then stirred at 50° C. for 1 hour. The mixture was adjusted to pH<2 by adding HCl (1M) and then concentrated to afford 1-benzyl-3-cyano-1H-pyrrole-2-carboxylic acid as a white solid (7.3 g, 32.4 mmol, 95% yield) which was used in the next step without any further purification. 1H NMR (400 MHz, DMSO-d6) ppm 7.54 (d, J=6.4 Hz, 1H), 7.45-7.27 (m, 4H), 7.12 (d, J=7.2 Hz, 1H), 6.76-6.69 (d, J=7.2 Hz, 1H), 5.64 (s, 2H); LCMS (m/z) ES+=227 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:35])([F:34])[CH2:26][C@@H:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH2:28])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[N+:36]([C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1)([O-:38])=[O:37]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:20]([NH:22][CH2:23][CH2:24][C:25]([F:34])([F:35])[CH2:26][C@@H:27]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[NH:28][S:45]([C:42]1[CH:41]=[CH:40][C:39]([N+:36]([O-:38])=[O:37])=[CH:44][CH:43]=1)(=[O:46])=[O:47])=[O:21])[CH:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)[C@@H](N)CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H](CC(F)(F)CCNC(=O)[C@@H](NC(=O)OC)C(c1ccccc1)c1ccccc1)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a solution of the material from Step 8 (210 mg, 0.427 mmol) in pyridine (2 mL) at room temperature were added 4-nitrobenzenesulfonyl chloride (142 mg, 0.641 mmol) and DMAP (10.44 mg, 0.085 mmol). The reaction mixture was stirred at 85° C. overnight, concentrated in vacuo, and the residue was purified by column chromatography on silica gel using ethyl acetate-hexanes (0:100 to 90:10) followed by 10% MeOH/DCM to afford 150 mg of the title compound as a yellow foam. LCMS (M+1)=677.
Reaction SMILES: [S:1](Cl)([CH3:4])(=[O:3])=[O:2].[CH2:6]([CH:8]1[CH:12]([C:13]2[N:17]3[C:18]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:19]=4[N:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH2:11][C:10](=[O:33])[CH2:9]1)[CH3:7]>C(Cl)Cl>[CH3:4][S:1]([O:33][CH:10]1[CH2:11][CH:12]([C:13]2[N:17]3[C:18]4[CH:24]=[CH:23][N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:19]=4[N:20]=[CH:21][C:16]3=[N:15][N:14]=2)[CH:8]([CH2:6][CH3:7])[CH2:9]1)(=[O:3])=[O:2]
Reactant: CCC1CC(=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCC1CC(OS(C)(=O)=O)CC1c1nnc2cnc3c(ccn3COCC[Si](C)(C)C)n12
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
Mesyl chloride (0.067 mL, 0.866 mmol) was added dropwise to a solution of 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.316 g, 0.787 mmol, Example #35 Step H) and TEA (0.219 mL, 1.57 mmol) in DCM (8 mL), and the reaction mixture was stirred at rt overnight. The solvent was removed under reduced pressure and the residue purified by silica gel column chromatography (0 to 60% EtOAc in DCM) to yield 3-ethyl-4-(6-((2-(trimethylsilyl)ethoxy)methyl)-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl methanesulfonate (0.29 g, 77%) as a white amorphous solid: LC/MS (Table 1, Method a) Rt=2.53 min; MS m/z 480 (M+H)+.