Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:9]=[C:8]([CH3:25])[C:4]=1[C:5](O)=[O:6])[CH3:2].C(Cl)(=O)C([Cl:29])=O>COCCOC.CN(C)C=O>[CH2:1]([C:3]1[CH:11]=[C:10]([O:12][CH2:13][C@@H:14]2[CH2:19][N:18]([CH3:20])[C:17]3[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=3[O:15]2)[CH:9]=[C:8]([CH3:25])[C:4]=1[C:5]([Cl:29])=[O:6])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)O
Solvent: CN(C)C=O
Solvent: COCCOC
Product: CCc1cc(OC[C@@H]2CN(C)c3ccccc3O2)cc(C)c1C(=O)Cl
Temperature: 40 °C

Procedure:
Under an argon atmosphere, the compound prepared in Example 18 (79 g) was dissolved in 1,2-dimethoxyethane (500 mL). The reaction mixture was added with anhydrous N,N-dimethylformamide (3 drops) and oxalyl chloride (24 mL), and stirred at 40° C. for an hour. The reaction mixture was concentrated to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[Si:10](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CN=C1>CN(C=O)C>[C:23]([Si:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:9])[CH:4]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(O)ccc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ccc1Cl

Procedure:
4-Chloro-3-methylphenol (33.22 g, 0.233 mol), tert-butyldiphenylsilyl chloride (62.89 g, 0.233 mol), and imidazole (47.59 g, 0.699 mol) in DMF (200 mL) were heated at 70° C. for 18 h. The reaction mixture was partitioned between EtOAc/hexane and H2O, the organic layer separated, washed with H2O, brine, and dried(Na2SO4). Filtration and concentration to dryness gave the title compound which was used without purification.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][N:4]=1)[NH2:2].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(O)C>[N+:9]([C:6]1[CH:7]=[CH:8][C:3]([NH:1][N:2]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: O=Cc1ccccc1
Reactant: NNc1ccc([N+](=O)[O-])cn1
Solvent: CCO
Product: O=[N+]([O-])c1ccc(NN=Cc2ccccc2)nc1
Temperature: 100 °C
Yield: 62 %

Procedure:
In 20 ml of ethanol were dispersed 1.59 g of 2-hydrazino-5-nitropyridine and 1.13 g of benzaldehyde. The dispersion was refluxed at 100° C. for 16.5 hours. The reaction solution was allowed to cool at room temperature. The resulting precipitate was collected by suction filtration, washed with ethanol and air dried, obtaining 1.55 g (yield 62%) of orange yellow fine acicular crystals.
Reaction SMILES: [C:1]([N:5]1[C:9]2[NH:10][C:11](=[O:14])[CH:12]=[CH:13][C:8]=2[C:7]([CH:15]2[CH2:18][CH2:17][CH2:16]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Br:19]Br>CC(O)=O>[Br:19][C:12]1[C:11](=[O:14])[NH:10][C:9]2[N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[N:6]=[C:7]([CH:15]3[CH2:18][CH2:17][CH2:16]3)[C:8]=2[CH:13]=1
Reactant: CC(C)(C)n1nc(C2CCC2)c2ccc(=O)[nH]c21
Reactant: BrBr
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2cc(Br)c(=O)[nH]c21
Reaction time: 0.25 h
Yield: 16.6 %

Procedure:
To a stirring solution of 1-tert-butyl-3-cyclobutyl-1,7-dihydro-pyrazolo[3,4-b]pyridin-6-one (1.0 g, 4.1 mmol) in AcOH (10 mL) was added bromine (236 uL, 4.6 mmol) dropwise. After 15 min, the resulting solid was collected and washed with hexanes. The solution was diluted with EtOAc and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. Purification of the resulting material was accomplished by flash chromatography, using a Biotage® column, eluting with a gradient of 10%, 20% EtOAc/hexanes. The product-containing fractions were collected and concentrated to give the title compound (220 mg, 16% yield) as a tan solid. LRMS m/z (APCl) 322, 324 (M−1); 500 MHz 1H NMR (CDCl3) δ 12.5 (bs, 1H), 8.09 (s, 1H), 3.66 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 2.45-2.34 (m, 4H), 2.15-1.92 (m, 2H), 1.76 (s, 9H).
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:2].[O-]CC.[Na+].C(O)C.Br[CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2>>[CH:1]([NH:3][C:4]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[N:32]=[CH:31][CH:30]=[CH:29]2)([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[O:2]
Reactant: BrCc1cccc2cccnc12
Reactant: CCOC(=O)C(NC=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1cccc2cccnc12)(NC=O)C(=O)OCC
Reaction time: 0.08 h
Yield: 57.8 %

Procedure:
Diethyl (formylamino)malonate (22.0 g, 0.108 mol) was added to a stirred solution of sodium ethoxide in ethanol (prepared from 2.4 g of sodium and 250 mL of ethanol, 0.10 mol). After 5 min, 8-(bromomethyl)quinoline (22.0 g, 0.10 mol) was added and the solution was stirred for an additional 15 minutes. The solvent was removed under reduced pressure and the product was partitioned between ethyl acetate and water. The ethyl acetate was removed and the residual oil was crystallized from ether to give 19.9 g (58%) of diethyl (formylamino)(8-quinolinylmethyl)propanedioate, mp 120°-122° C. Anal. Calcd. for C18H20N2O5 : C, 62.78; H, 5.85; N, 8.14. Found: C, 62.53; H, 6.03; N, 8.07.
Reaction SMILES: C(O[N:9]=[C:10]([C:12]1[N:13]=[CH:14][N:15]([C@@H:18]2[O:30][C@H:29]([CH2:31][O:32]C(=O)C)[C@@H:24]([O:25]C(=O)C)[C@H:19]2[O:20]C(=O)C)[C:16]=1[NH2:17])[NH2:11])C1C=CC=CC=1.[C:36](=S)=[S:37]>[OH-].[Na+].CO>[CH:14]1[N:15]([C@@H:18]2[O:30][C@H:29]([CH2:31][OH:32])[C@@H:24]([OH:25])[C@H:19]2[OH:20])[C:16]2[C:12](=[C:10]([NH2:11])[NH:9][C:36]([N:17]=2)=[S:37])[N:13]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(N)=NOCc3ccccc3)c2N)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: S=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1[nH]c(=S)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 91 %

Procedure:
0.45 g of 5-amino-1-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)imidazole-4-carboxamide O-benzyl-oxime was dissolved in a mixture of 0.30 g of sodium hydroxide, 5 ml of methanol and 0.5 ml of carbon disulfide, and the resulting mixture was allowed to react in an autoclave at 170° C for 4 hours under autogenous pressure (about 12 - 13 Kg/cm2). The reaction product was worked up in the same manner as described in Example 7 to obtain 0.265 g of 2-thioadenosine having a melting point of 198° C (with decomposition) in a 91% yield.
Reaction SMILES: Br[CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1.[CH3:11][O:12][P:13]([O:16]C)[O:14][CH3:15]>>[CH3:11][O:12][P:13]([CH2:2][C:3]1[S:4][C:5]([N+:8]([O-:10])=[O:9])=[CH:6][CH:7]=1)([O:14][CH3:15])=[O:16]
Reactant: COP(OC)OC
Reactant: O=[N+]([O-])c1ccc(CBr)s1
Product: COP(=O)(Cc1ccc([N+](=O)[O-])s1)OC

Procedure:
2-Bromomethyl-5-nitrothiophene and trimethylphosphite ((CH3O)3 P) were treated in the same manner as in Reference Example 43 to yield 2-dimethoxyphosphorylmethyl-5-nitrothiophene as an oil.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[O:13]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]([CH2:25][CH2:26][NH:27][CH3:28])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>C(Cl)Cl>[O:13]([CH2:20][CH:21]([OH:29])[CH2:22][N:23]([CH2:25][CH2:26][N:27]([C:2]1[N:3]([CH3:12])[C:4](=[O:11])[N:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8])[CH3:28])[CH3:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CNCCN(C)CC(O)COc1ccccc1
Reactant: Cc1c(Cl)n(C)c(=O)n(C)c1=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1c(N(C)CCN(C)CC(O)COc2ccccc2)n(C)c(=O)n(C)c1=O

Procedure:
4.7 g. 4-Chloro-1,3,5-trimethylpyrimidine-2,6(1H,3H)-dione and 6.0 g. 1-phenoxy-3-(2-methylaminoethyl-N-methylamino)-propan-2-ol (b.p. 138°-142° C./0.01 mm.Hg; obtained from phenyl glycidyl ether and N,N'-dimethylethylenediamine) are stirred for 72 hours at 80° C. in 10 ml. pyridine. The reaction mixture is then dissolved in methylene chloride, washed with water, dried and chromatographed on silica gel using, as elution agent, methylene chloride-methanol (20:1 v/v). By evaporation of the pure fractions, there are obtained 3.0 g. (31% of theory) of the desired product in the form of an almost colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[H-].[Na+].Cl[C:16]1[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:21]1[C:16]([N:9]2[C:10]3[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)=[N:17][CH:18]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:20]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(cnn2-c2ncc(C(F)(F)F)cc2Cl)c1
Reaction time: 0.17 h
Yield: 54 %

Procedure:
To a solution of 5-nitroindazole (1.63 g) in N,N-dimethylformamide (10 ml), 60% sodium hydride (0.5 g) was added, and the resultant mixture was stirred while cooling with ice. After 10 minutes, 2,3-dichloro-5-trifluoromethylpyridine (2.1 g) was added thereto, and the resultant mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give 1-(3-chloro-5-trifluoromethylpyridin-2-yl)-5-nitroindazole (1.8 g)
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:18][C:17]([C:28]#[N:29])=[C:16]([C:30]#[N:31])[N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.[F:39][C:40]([F:55])([F:54])[C:41]1[CH:42]=[C:43]([N:51]=C=O)[CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1>C(Cl)Cl>[F:39][C:40]([F:54])([F:55])[C:41]1[CH:42]=[C:43]([NH:51][C:6]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[C:19]([O:20][CH2:21][C:22]4[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=4)=[N:18][C:17]([C:28]#[N:29])=[C:16]([C:30]#[N:31])[N:15]=3)[CH2:12][CH2:13]2)=[O:5])[CH:44]=[C:45]([C:47]([F:48])([F:50])[F:49])[CH:46]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2OCc2ccncc2)CC1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1nc(OCc2ccncc2)c(N2CCN(C(=O)Nc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)nc1C#N
Reaction time: 2 h

Procedure:
A mixture of 5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (100 mg) and 30% TFA in DCM (11 ml) was stirred for 2 hours. The mixture was concentrated in vacuo to dryness. To the residue was added DCM (5 ml), TEA (0.31 mmol, 51 ul), and 3,5-bis(trifluoromethyl)phenyl isocyanate (0.15 mmol, 26 ul). The resulting mixture was stirred at room temperature for 3 hours. After concentrated in vacuo, the crude product was purified by column on silica using 70% EtOAc/Hexanes to give the product N-[3,5-bis(trifluoromethyl)phenyl]-4-{5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide. 1H NMR (CD3OD) 8.594 (s, 2H), 8.073 (s, 2H), 7.555-7.534 (m, 3H), 5.584 (s, 2H), 4.043-4.029 (m, 4H), 3.739-3.713 (m, 4H) ppm.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].[CH:10]1([CH2:13]O)[CH2:12][CH2:11]1>>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([O:5][CH2:13][CH:10]1[CH2:12][CH2:11]1)=[O:4]
Reactant: CCCCC(C)C(=O)O
Reactant: OCC1CC1
Product: CCCCC(C)C(=O)OCC1CC1

Procedure:
Prepared from 2-methylhexanoic acid and cyclopropanemethanol according to the ester preparation method A described above.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][CH2:10][CH:9]([NH:12][CH3:13])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]>>[N+:14]([C:17]1[CH:25]=[CH:24][C:20]([C:21]([N:12]([CH:9]2[CH2:10][CH2:11][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:8]2)[CH3:13])=[O:22])=[CH:19][CH:18]=1)([O-:16])=[O:15]
Reactant: CNC1CCN(C2CCCCC2)C1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Product: CN(C(=O)c1ccc([N+](=O)[O-])cc1)C1CCN(C2CCCCC2)C1
Reaction time: 2 h

Procedure:
4-Nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was prepared from 15 g. (0.085 mole) of 1-cyclohexyl-3-methylaminopyrrolidine and 15 g. (0.08 mole) p-nitrobenzoyl chloride. The 4-nitro-N-(1-cyclohexyl-3-pyrrolidinyl)-N-methylbenzamide was converted to the fumarate salt (8.4 g., 24%) by precipitation with fumaric acid from isopropanol-isopropyl ether. The fumarate salt was dissolved in 95% ethanol and hydrogenated at three atmospheres of hydrogen over Raney Nickel for about 2 hours. The mixture was filtered, the filtrate concentrated and the residue partitioned between dilute sodium hydroxide and chloroform. The chloroform layer was dried and concentrated and the residue treated wit hexamic acid in isopropanol-isopropyl ether. Recrystallization from the same solvent gave 5.2 g. (13.5% overall) of the salt melting 196°-199°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1.[C:20]1(=O)[O:25][C:23](=[O:24])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12>CN(C=O)C>[O:24]=[C:23]1[C:22]2[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=2[C:20](=[O:25])[N:1]1[C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:10][S:11]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)(=[O:13])=[O:12])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)s2)cc1
Solvent: CN(C)C=O
Product: O=C(NS(=O)(=O)c1ccc(Cl)s1)c1ccc(N2C(=O)c3ccccc3C2=O)cc1
Temperature: 110 °C
Yield: 55 %

Procedure:
A 22 mg portion (0.070) of (4-aminophenyl)-N-[(5-chloro(2-thienyl))sulfonyl]carboxamide was combined with 15 mg (0.10 mmol) of phthalic anhydride in 140 μL of DMF. After 18 h of heating at 110° C., the mixture was cooled and purified by RP-HPLC, to give 20 mg (55%) of the desired compound. ES-MS (M+H)+=447 (Cl).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.[H-].[Na+].Cl[CH2:24][C:25]#[N:26]>CN(C=O)C>[Cl:1][C:2]1[N:3]([CH2:24][C:25]#[N:26])[C:4](=[O:20])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: N#CCCl
Reactant: COc1ccc(Cn2cnc3nc(Cl)[nH]c(=O)c32)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3nc(Cl)n(CC#N)c(=O)c32)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To 2-chloro-7-(4-methoxybenzyl)-1H-purin-6(7H)-one 7 (5.98 g, 20.62 mmol) in DMF (90 ml) at 0° C. was added NaH (1.072 g, 26.81 mmol). The mixture was stirred at room temperature for 10 minutes, and then stirred at 55° C. for 3 hours. Chloroacetonitrile (1.57 ml, 24.74 mmol) was added to the reaction flask at 0° C. The reaction mixture was stirred over night. Another 0.65 ml (10.31 mmol) of chloroacetonitrile was added into the reaction flask. The mixture was stirred over night. The reaction was quenched with water at 0° C. The mixture was extracted with DCM (3×), washed with water and brine, dried (MgSO4) and concentrated. The crude product was purified by flash chromatography (EtOAc/Hexane) to afford pure product 2-(2-chloro-7-(4-methoxybenzyl)-6-oxo-6,7-dihydro-1H-purin-1-yl)acetonitrile 8. 1H NMR δ 7.878 (s, 1H), 7.269 (d, J=8.8 Hz, 2H), 6.880, (d, J=8.8 Hz, 2H), 5.465 (s, 2H), 5.189 (s, 2H), 3.789 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[NH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[CH2:20][CH2:19]1>>[OH:32][CH:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:24][N:21]2[CH2:20][CH2:19][CH:18]([NH:17][C:11]([C:5]3[NH:6][C:7]4[C:3]([CH:4]=3)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)=[O:13])[CH2:23][CH2:22]2)[CH2:31][CH2:30]1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Reactant: NC1CCN(CCN2CCC(O)CC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCC(O)CC2)CC1)c1cc2c(Br)cccc2[nH]1

Procedure:
This compound is synthesized from 4-Bromo-1H-indole-2-carboxylic acid and amine 21 analogously to the method described for 194 (see example 156).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>CO.C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: Oc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Alternately, a solution of 4-aminophenol (1.0 equiv.) (Aldrich) in 2:1 methanol/ethanol was treated with 3-pyridinecarboxaldehyde (1.05 equiv.). The solution was allowed to stir for 1 hour. The reaction was cooled to 0° C. and treated with sodium borohydride (4.2 equiv.) in 5 portions. The cooling bath was removed and stirring continued for 20 hours. The reaction mixture was concentrated in vacuo. The residue was mixed with 1M HCl, warmed, and partitioned between ethyl acetate and 0.1M K2CO3. The pH of the aqueous phase was adjusted to pH=7 (using 1M HCl and 1M K2CO3) and the product extracted 4-6 times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous MgSO4, and concentrated to afford N-(4-hydroxyphenyl)pyridin-3-ylmethylamine. 1H NMR(400 MHz, DMSO-d6): d 4.18(2H, s), 5.65(1H, s), 6.41-6.53(4H, m), 7.29-7.32(1H, m), 7.70-7.72(1H, m), 8.39-8.40(2H, m), 8.53-8.54(1H, m). MS Found 201.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Cl[C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[C:12]([NH:20][C:21]2[CH:25]=[C:24]([CH3:26])[NH:23][N:22]=2)[N:11]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: Fc1ccccc1S
Product: Cc1cc(Nc2cc3ccccc3c(Sc3ccccc3F)n2)n[nH]1

Procedure:
Similar procedure as described in example 305 was used, starting from 2-fluoro-benzenethiol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give [1-(2-fluoro-phenylsulfanyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS: m/e 351 (MH+).
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.CC(C)([O-])C.[K+].[O:13]1[CH2:18][CH2:17][CH2:16][O:15][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:28]([N:41]=2)=[N:29][C:30]([C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH2:34])=[CH:31][CH:32]=3)=[C:21]([F:42])[CH:20]=1>CS(C)=O.C1COCC1>[O:15]1[CH2:16][CH2:17][CH2:18][O:13][CH:14]1[C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[C:28]([N:41]=2)=[N:29][C:30]([C:33]2([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[CH2:2][CH2:34]2)=[CH:31][CH:32]=3)=[C:21]([F:42])[CH:20]=1
Reactant: C=C(c1ccccc1)c1ccc2sc(-c3ccc(C4OCCCO4)cc3F)nc2n1
Reactant: C[S+](C)(C)=O
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1cc(C2OCCCO2)ccc1-c1nc2nc(C3(c4ccccc4)CC3)ccc2s1
Reaction time: 8 h

Procedure:
Trimethylsulfoxonium iodide (0.16 g, 0.72 mmol) and potassium tert-butoxide (0.080 g, 0.72 mmol) were combined in 1.5 mL DMSO to give a clear solution. A slurry of 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylvinyl)thiazolo[4,5-b]pyridine (0.200 g, 0.48 mmol) in 4 mL THF was added dropwise, rinsing with 1 mL THF. The reaction mixture was stirred overnight, and was then quenched with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was treated with DCM and passed through a Redi-Sep® pre-packed silica gel column (12 g) using 0-70% EtOAc/hexane. The product-containing fractions were concentrated to afford 2-(4-(1,3-dioxan-2-yl)-2-fluorophenyl)-5-(1-phenylcyclopropyl)thiazolo[4,5-b]pyridine as a pale yellow solid. MS (ESI) m/z: calculated: 432.1; Observed: 433.1 (M++1).
Reaction SMILES: [CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:27])([CH3:26])[CH3:25])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=O)[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4].Cl.[CH3:29][NH2:30]>>[CH2:1]([C:5]1=[CH:6][N:7]([C:24]([CH3:26])([CH3:25])[CH3:27])[S:8]/[C:9]/1=[N:10]\[C:11]([C:13]1([CH3:23])[CH2:17][CH2:16][CH:15]([C:18]([NH:30][CH3:29])=[O:20])[C:14]1([CH3:22])[CH3:21])=[O:12])[CH2:2][CH2:3][CH3:4]
Reactant: CN
Reactant: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)O)C1(C)C
Agent: Cl
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(C)CCC(C(=O)NC)C1(C)C

Procedure:
The product from Example 96 and methylamine hydrochloride (Aldrich) were processed using the method described in Example 99 to afford the title compound. 1H NMR (DMSO-d6) δ ppm 0.47 (s, 3H), 0.90 (t, J=7.3 Hz, 3H), 1.19 (s, 3H), 1.22 (s, 3H), 1.26-1.33 (m, 2H), 1.36-1.45 (m, 1H), 1.57 (s, 9H), 1.57-1.68 (m, 3H), 1.95-2.07 (m, 1H), 2.57 (d, J=4.7 Hz, 3H), 2.60-2.67 (m, 3H), 2.72-2.83 (m, 1H), 4.78 (q, J=4.5 Hz, 1H), 8.49 (s, 1H). MS (ESI+) m/z 408 (M+H)+. Anal. calcd. for C22H37N3O2S: C, 64.83; H, 9.15; N, 10.31. Found: C, 64.55; H, 9.02; N, 10.29.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].N[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[C:20]1([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccccc4)c3c2s1
Yield: 67 %

Procedure:
Prepared from VII and aniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 67%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 3395, 3057, 2228, 1731, 1644, 1608, 1577, 1491, 1459, 1378, 1352, 1301, 1255, 1214, 1147, 1128, 1106, 1071, 967, 896, 827; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=9.0 Hz), 8.11 (s, 1H), 7.78 (d, 1H, J=9.0 Hz), 7.40 (t, 2H, J=7.5 Hz), 7.20 (m, 2H), 7.11 (t, 1H, J=7.5 Hz); HRMS calcd for C16H10N5S (M+H+): 304.0657, found 304.0657.
Reaction SMILES: [CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH2:6].[CH3:19][C:20]([CH3:22])=O>[Pt]=O.C(O)C>[CH3:1][N:2]([CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:3][CH2:4][CH2:5][NH:6][CH:20]([CH3:22])[CH3:19]
Reactant: COc1ccc(CCN(C)CCCN)cc1OC
Reactant: CC(C)=O
Agent: O=[Pt]
Solvent: CCO
Product: COc1ccc(CCN(C)CCCNC(C)C)cc1OC
Yield: 100 %

Procedure:
3.87 g of N-methyl-N-(2-(3,4-dimethoxyphenyl)ethyl)-1,3-propanediamine and 15 ml of acetone were dissolved into 50 ml of ethanol. To this was added 0.1 g of platinum oxide and then hydrogenetion was made at room temperature and under pressure of 3 kg/cm2. At the end of 3 hours catalyst was concentrated after filtering and 4.52 of marked compound was obtained as yellow oily matter (yield: 100%).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[N+:13]1([O-:22])[C:14]([C:19]([OH:21])=O)=[CH:15][CH:16]=[CH:17][CH:18]=1.[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1>CN(C)C=O>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[NH:23][C:19]([C:14]1[N+:13]([O-:22])=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:21]
Reactant: O=C(O)c1cccc[n+]1[O-]
Reactant: Nc1ccccn1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccn1)c1cccc[n+]1[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 0.1 %

Procedure:
1,1'-Carbonyldiimidazole (4.254 g, 26.2 mol) was added to a solution of picolinic acid N-oxide (3.318g, 23.9 mol) in dry dimethylformamide (50 ml). After 4 hours, 2-aminopyridine (2.466 g, 26.2 mol) was added. After 1 hour, the solution was warmed to 100° for 80 minutes and cooled to room temperature. After 18 hours the solution was subjected to evaporation in vacuo to give an oil which slowly crystallised. The solid was recrystallised from EtOH to give the title compound (3.775 g) as needles, m.p. 140°-5°.