Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([OH:16])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[CH3:23][C:24]([CH3:27])([O-])[CH3:25].[K+].O>ClCCl>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]([O:16][C:24]([CH3:27])([CH3:25])[CH3:23])=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccccc2C(=O)O)cc1
Reactant: CC(C)(C)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.5 %

Procedure:
[Reference: European Patent Application 87-109919.8 example 85a, page 148 line 22]To a solution of 4'-methyl[1,1'-biphenyl]-2-carboxylic acid (25.0 g, 0.118 mol) in dichloromethane (120 mL) at 0° C. was added oxalyl chloride (2.0 M solution in methylene chloride (470 mL, 0.236 mol) over 30 minutes. The solution was warmed to 25° C., stirred for three hours and concentrated in vacuo to remove excess oxalyl chloride. The remaining residue was suspended in diethyl ether (300 mL), cooled to 0° C. and potassium t-butoxide (26.44 g, 0.236 mol) was added over 15 minutes keeping the temperature of the mixture between 15°-25° C. The mixture was allowed to warm to 25° C. and was stirred for one hour, poured into water (200 mL), and extracted with diethyl ether. The ether extract was then washed with aqueous sodium bicarbonate (saturated solution), dried (magnesium sulfate) and concentrated in vacuo to an amber oil. Subsequent distillation (124°-130° C., 0.6 mm Hg) yielded the title compound as a colorless liquid (27.7 g, 92%).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Br[CH2:34][C:35]([NH:37][C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=1)=[O:36]>>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[N:17]([CH2:34][C:35](=[O:36])[NH:37][C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)[C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([O:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:30])([CH3:32])[CH3:31])([CH3:27])[CH3:28])[C:15]=3[N:14]=2)=[O:12])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(OCCO[Si](C)(C)C(C)(C)C)cccc3[nH]2)CC1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Product: CC(C)N1CCC(NC(=O)c2nc3c(OCCO[Si](C)(C)C(C)(C)C)cccc3n2CC(=O)Nc2ccc(Cl)cn2)CC1

Procedure:
4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-1-[(5-chloro-pyridin-2-ylcarbamoyl)-methyl]-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 108 (v) starting from 670.0 mg (1.45 mmol) 4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide and 362.8 mg (1.45 mmol) 2-bromo-N-(5-chloro-pyridin-2-yl)-acetamide. Final purification by flash-chromatography on silica gel using ethyl acetate as eluent gave the title compound as a brown oil.
Reaction SMILES: [CH2:1]([NH:8][S:9]([N:12]1[CH2:16][CH2:15]O[C:13]1=O)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CC[CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:20]C1.C(N(CC)CC)C>C(#N)C>[CH2:1]([NH:8][S:9]([N:12]1[CH2:13][CH2:20][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[NH:26][C:25]2=[O:33])[CH2:15][CH2:16]1)(=[O:10])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OCCN1S(=O)(=O)NCc1ccccc1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=c1[nH]c2ccccc2n1C1CCN(S(=O)(=O)NCc2ccccc2)CC1
Temperature: 80 °C
Yield: 11.3 %

Procedure:
2-Oxo-oxazolidine-3-sulfonic acid benzylamide (0.059 g; 0.23 mmol; 1 equiv) was added to a solution of 1-piperidin-4-yl-1,3-dihydro-benzoimidazol-2-one (0.050 mg; 0.23 mmol) in acetonitrile (2 mL). Triethylamine (32 μL; 0.23 mmol) was added and the reaction mixture was heated at 80° C. for 48 h. The reaction mixture was evaporated under reduced pressure and the crude product was purified by preparative liquid chromatography to provide 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-sulfonic acid benzylamide (0.010 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](F)=[N:12][C:13]([O:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=2[F:29])=[CH:14][C:15]=1[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])=O.[NH2:31][NH2:32]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:10]2[C:11](=[N:12][C:13]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=3[F:29])=[CH:14][C:15]=2[NH:16][CH2:17][C@@H:18]([OH:20])[CH3:19])[NH:32][N:31]=1
Reactant: NN
Reactant: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc(F)c1C(=O)c1ccccc1Cl
Product: C[C@H](O)CNc1cc(Oc2ccc(F)cc2F)nc2[nH]nc(-c3ccccc3Cl)c12

Procedure:
Crude (S)-(2-Chloro-phenyl)-[6-(2,4-difluoro-phenoxy)-2-fluoro-4-(2-hydroxy-propylamino)-pyridin-3-yl]-methanone (837 mg, 1.92 mmol) was treated with hydrazine using the procedure of step 5 of Example 9 to afford 148 mg of (S)-1-[3-(2-Chloro-phenyl)-6-(2,4-difluoro-phenoxy)-1H-pyrazolo[3,4-b]pyridin-4-ylamino]-propan-2-ol. Mass spec., M+1=432. Mp=237.9-238.5° C.
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)=[N:3]1.O.[NH2:25]N.O.C([O-])(O)=O.[Na+]>Cl.C(O)(=O)C>[CH3:14][O:13][C:10]1[CH:9]=[C:8]2[C:7](=[CH:12][CH:11]=1)[C:4](=[O:5])[NH:3][N:25]=[C:15]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NN
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(C(=O)c2ccccc2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc2c(=O)[nH]nc(-c3ccccc3)c2c1
Temperature: 80 °C
Reaction time: 48 h
Yield: 21.6 %

Procedure:
A suspension of [2-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-5-methoxy-phenyl]-phenyl-methanone (3.4 g, 11 mmoles), prepared as described in example 12, in 3N HCl (45 ml) was refluxed under stirring for 2 days, then added with 36% HCl (10 ml). After 20 hours the mixture was cooled and extracted more times with CHCl3. The organic phases were anhydrified and brought to dryness. The residue was dissolved in acetic acid and treated with hydrazine monohydrate (0.96 g, 19.24 mmoles) in acetic acid (7 ml). The mixture was heated to 80° C. under dry N2 and stirring for 20 hours, then brought to small volume, poured into water, neutralised with NaHCO3 in excess and extracted with CHCl3. The organic phases anhydrified and brought to dryness yielded 0.6 g of the title compound (yield: 37%). m.p.: 230-235° C.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[N:9]([C:17]3[CH:18]=[C:19]([CH:23]=[CH:24][CH:25]=3)[C:20]([OH:22])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:38]([CH2:40][NH2:41])[OH:39]>CN(C=O)C>[OH:39][CH2:38][CH2:40][NH:41][C:20](=[O:22])[C:19]1[CH:23]=[CH:24][CH:25]=[C:17]([N:9]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:16])[C:15]=3[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:8]2)[CH:18]=1
Reactant: NCCO
Reactant: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(C(=O)O)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccccc1)cn2-c1cccc(C(=O)NCCO)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
1.0 g of 3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)benzoic acid (Example 15) is dissolved in 25 ml of warm DMF and the solution is cooled to 0° C. The mixture is treated with 0.54 g of carbonyldiimidazole and stirred at RT for 2 h. 0.19 g of ethanolamine is then added dropwise and the mixture is allowed to warm to RT and is stirred for 3 h. The mixture is then concentrated in an RE. The residue is dissolved in methylene chloride and the solution is crystallized overnight at 0° C. After filtration, the residue is dissolved in methylene chloride and chromatographed on silica gel (methylene chloride/methanol 15:1). The product-containing fractions are concentrated and the residue is taken up in a little methylene chloride and crystallized overnight at 0° C. The crystals formed are filtered off and dried under HV. N-(2-Hydroxyethyl)-3-(5-phenyl-4-aminopyrrolo[2,3-d]pyrimidin-7-yl)-benzamide having a melting point of 194°-198° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:23])=[C:4]([C:19]([F:22])=[CH:20][CH:21]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6].[C:24]1([S:30](Cl)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl.N1C=CC=CC=1>[F:23][C:3]1[C:2]([NH:1][S:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:32])=[O:31])=[CH:21][CH:20]=[C:19]([F:22])[C:4]=1[C:5]([NH:7][C:8]1[CH:9]=[C:10]2[C:16]([O:17][CH3:18])=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:6]
Reactant: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(N)c3F)cc12
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1n[nH]c2ncc(NC(=O)c3c(F)ccc(NS(=O)(=O)c4ccccc4)c3F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
3-Amino-2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (0.005 g, 0.0157 mmol) was taken up as a slurry in CHCl3 (1.0 mL). Three drops of pyridine were added, followed by the addition of benzenesulfonyl chloride (0.00600 mL, 0.0470 mmol). The slurry was stirred overnight at room temperature. The reaction mixture was concentrated and purified by silica gel chromatography to provide 2,6-difluoro-N-(3-methoxy-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(phenylsulfonamido)benzamide (5.7 mg, 79%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 12.59 (s, 1H), 11.01 (s, 1H), 10.39 (br s, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 7.76-7.78 (m, 2H), 7.64-7.68 (m, 1H), 7.57-7.61 (m, 1H), 7.31-7.37 (m, 1H), 7.17-7.21 (m, 1H), 4.01 (s, 3H); m/z (APCI-neg) M−1=458.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([N:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[C:3]=1[C:22]#[N:23].[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27]>>[NH2:23][C:22]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([C:30]([O:32][CH3:33])=[O:31])[N:1]=[C:2]2[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][C:16]([N:19]([CH3:20])[CH3:21])=[CH:15][CH:14]=3)[C:3]=12
Reactant: COC(=O)C#CC(=O)OC
Reactant: CN(C)c1ccc(-c2nn(-c3ccccc3)c(N)c2C#N)cc1
Product: COC(=O)c1nc2c(c(-c3ccc(N(C)C)cc3)nn2-c2ccccc2)c(N)c1C(=O)OC

Procedure:
Using 1.57 mg (5 mmol) of 5-amino-3-(p-dimethylaminophenyl)-1-phenylpyrazole-4-carbonitrile [see Chem. Ber., 99, 3492 (1966)] and 0.85 g (6 mmol) of dimethyl acetylenedicarboxylate, the entitled product having a melting point of 207° to 208° C. was obtained in the same manner as in Example 2-(2).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[C:19]1[S:20][CH:21]=[CH:22][N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[NH:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: Nc1ccc(Nc2ccccc2[N+](=O)[O-])cc1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccccc1Nc1ccc(Nc2nccs2)cc1

Procedure:
2-Nitro-N-(4-aminophenyl)aniline (5.0 g, 21.8 mmol), 2-bromothiazole (3.58 g, 21.8 mmol) and potassium carbonate (3.01 g, 21.8 mmol) was stirred at 150° C. for 24 h. Water (250 ml) was added and the mixture was extracted with ethyl acetate (250 ml).
Reaction SMILES: [C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)[CH2:7][C:8](O)=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12.[OH-].[NH4+:32].O>CN(C)C1C=CN=CC=1.O1CCCC1>[C:1]1(=[O:30])[N:5]([CH:6]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]([CH3:20])[CH3:19])=[C:13]([O:21][CH:22]([CH3:24])[CH3:23])[CH:12]=2)[CH2:7][C:8]([NH2:32])=[O:9])[C:4](=[O:25])[C:3]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:2]12
Reactant: [NH4+]
Reactant: CC(C)Oc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Agent: CN(C)c1ccncc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(C(CC(N)=O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Reaction time: 2 h
Yield: 88.3 %

Procedure:
A solution of 3-phthalimido-3-(3,4-diisopropoxyphenyl)propionic acid (1.0 g, 2.4 mmol), 1,1 carbonyldiimidazole (0.43 g, 2.6 mmol), and 4-dimethylaminopyridine (trace) in tetrahydrofuran (18 mL) was stirred for 1.5 hours at room temperature. To the solution was added ammonium hydroxide (0.24 mL, 3.7 mmol, 28-30%) and stirring was continued for 2 hours. The tetrahydrofuran was removed in vacuo leaving an oil. To the oil was added 2 mL of water and the mixture was stirred at room temperature overnight. The resulting slurry was filtered, the solid was washed with water, air dried, and dried in vacuo (60° C., <1 mm) to afford 0.87 g (88%) of 3-phthalimido-3-(3,4-diisopropoxyphenyl)propionamide as a white solid: mp 153°-154.5° C.; 1H NMR (DMSO-d6) δ 7.92-7.78 (m, 4H), 7.55 (s, 1H), 7.03(s, 1H), 6.93-6.77 (m, 3H), 5.71-5.56 (m, 1H), 4.51-4.33 (m, 2H), 3.25-3.06 (m, 2H), 1.31-1.08 (m, 12H); 13C NMR (DMSO-d6) δ 171.7, 168.3, 148.9, 133.9, 132.1, 131.9, 123.3, 120.9, 117.7, 72.2, 72.1, 51.5, 37.9, 22.2; Anal. Calcd. for C23H26N2O5. Theoretical: C, 67.30; H, 6.38; N, 6.82. Found: C, 67.01; H, 6.35; N, 6.69.
Reaction SMILES: C([O:5][CH2:6][CH:7]([CH2:12][CH3:13])[CH2:8][CH2:9][CH2:10][CH3:11])(=O)C=C.C(=O)([O-])[O-:15].[Cs+].[Cs+]>CCCCCC>[CH3:11][CH2:10][CH2:9][CH2:8][CH:7]([C:6]([OH:5])=[O:15])[CH2:12][CH3:13]
Reactant: O=C([O-])[O-]
Reactant: C=CC(=O)OCC(CC)CCCC
Agent: [Cs+]
Solvent: CCCCCC
Product: CCCCC(CC)C(=O)O
Temperature: 25 °C
Yield: 8029.1 %

Procedure:
A mixture of TMIT (2.37 g, 15 mmol), 2-ethylhexyl acrylate (2.76 g, 15 mmol) and cesium carbonate (0.12 g, 0.38 mmol, 2.5 mole % based on acrylate) was heated in a sand bath at 100–120 ° C. for 2 h, while the progress of the reaction was being followed by IR spectroscopy. The reaction mixture was cooled to room temperature, and to the resulting thick oil was added hexane (40 mL), and the mixture was filtered to remove solid cesium carbonate. Solvent evaporation from the filtrate yielded product as a light-yellow oil (4.4 g, 86%). IR: 3323, 2961, 1733, 1481 cm−1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: FC(F)(F)c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: FC(F)(F)c1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-trifluoromethyl-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH2:1]([NH:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:17][CH2:18][C:19](O)=O>>[Cl:17][CH2:18][C:19]1[N:9]([CH2:1][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]=1
Reactant: O=C(O)CCl
Reactant: Nc1ccccc1NCCc1ccccc1
Product: ClCc1nc2ccccc2n1CCc1ccccc1
Yield: 61.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 191(C), from N1-phenethylbenzene-1,2-diamine (2.57 g, 12.11 mmol) and 2-chloroacetic acid (0.70 g, 18 mmol). The crude residue was purified over silicagel chromatography prepacked 70 g silicagel column, Cyclohexane/AcOEt: from 80/20 to 70/30 as eluent) to afford 2.02 g of 2-(chloromethyl)-1-phenethyl-1H-benzo[d]imidazole (Yield: 61%) as a white crystalline solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([C:11]3[O:15][CH:14]=[N:13][CH:12]=3)[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1.C(OC([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:35]=[N:36][C:37]([NH2:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=O)(C)(C)C>>[CH:16]1([N:8]2[C:6]3[N:7]=[C:2]([NH:40][C:37]4[CH:38]=[CH:39][C:34]([N:31]5[CH2:30][CH2:29][NH:28][CH2:33][CH2:32]5)=[CH:35][N:36]=4)[N:3]=[CH:4][C:5]=3[CH:10]=[C:9]2[C:11]2[O:15][CH:14]=[N:13][CH:12]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Clc1ncc2cc(-c3cnco3)n(C3CCCC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Product: c1ncc(-c2cc3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n2C2CCCC2)o1
Yield: 24.2 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-6-oxazol-5-y-l-7H-pyrrolo[2,3-d]pyrimidine (70 mg, 0.24 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (74 mg, 0.27 mmol), followed by deprotection using General Procedure A to give (7-cyclopentyl-6-oxazol-5-yl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-(5-piperazin-1-yl-pyridin-2-yl)-amine (25 mg, 24%). MS (ESI) m/z 431.2 (M+H)+
Reaction SMILES: [CH2:1]([C:4]1[C:13]2[O:12][C:11]([C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][CH2:9][C:8]=2[C:7]([O:19][CH2:20][CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:6][CH:5]=1)[CH:2]=[CH2:3].C([OH:27])C>[Pd]>[CH3:23][CH:22]([CH3:24])[CH2:21][CH2:20][O:19][C:7]1[C:8]2[C:9](=[O:27])[CH:10]=[C:11]([C:14]3[NH:15][N:16]=[N:17][N:18]=3)[O:12][C:13]=2[C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=1
Reactant: CCO
Reactant: C=CCc1ccc(OCCC(C)C)c2c1OC(c1nnn[nH]1)=CC2
Agent: [Pd]
Product: CCCc1ccc(OCCC(C)C)c2c(=O)cc(-c3nnn[nH]3)oc12

Procedure:
A solution of 1.0 parts of 5-[8-allyl-5-(3-methyl-n-butoxy)-4H-1-benzopyran-2-yl]tetrazole in 19 parts of ethanol was hydrogenated overnight at room temperature and pressure using 0.02 parts of 5% palladium on charcoal as catalyst. The reaction mixture was filtered and the solvent removed by evaporation. Cystallisation of the residue from ethanol gave 0.52 parts of 5-[5-(3-methyl-n-butoxy)-8-n-propyl-4-oxo-4H-1-benzopyran-2-yl]tetrazole, m.p. 202°-204° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[S:9][C:10]([C:14]#[C:15][Si](C)(C)C)=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[S:9][C:10]([C:14]#[CH:15])=[C:11]([CH3:13])[N:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1sc(NC(=O)OC(C)(C)C)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To the above prepared (4-methyl-5-trimethylsilanylethynyl-thiazol-2-yl)-carbamic acid tert-butyl ester (0.592 g, 1.907 mmol), dissolved in 10 mL of MeOH, was added K2CO3 (0.395 g, 1.5 eq.)) and the mixture was stirred for 2 h at ambient temperature. Pouring onto crashed ice/NH4Cl, twofold extraction with ethyl acetate, washing with water and brine, drying over sodium sulfate, and evaporation to dryness, followed by flash chromatography (SiO2, hexane/ethyl acetate=4/1), produced 0.391 g of the title compound as light brown foam.
Reaction SMILES: Cl.[CH:2]([NH:5][C:6]1([C:10]([NH2:12])=[O:11])[CH2:9][NH:8][CH2:7]1)([CH3:4])[CH3:3].Cl[C:14]1[N:19]2[N:20]=[C:21]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])[C:22]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[C:18]2[N:17]=[C:16]([CH3:37])[N:15]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:21]1[C:22]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[C:18]2[N:17]=[C:16]([CH3:37])[N:15]=[C:14]([N:8]3[CH2:9][C:6]([NH:5][CH:2]([CH3:4])[CH3:3])([C:10]([NH2:12])=[O:11])[CH2:7]3)[N:19]2[N:20]=1
Reactant: CC(C)NC1(C(N)=O)CNC1
Reactant: Cc1nc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(N2CC(NC(C)C)(C(N)=O)C2)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reaction time: 1.5 h

Procedure:
To a mixture of 3-isopropylaminoazetidine-3-carboxylic acid amide hydrochloride salt (I-3A-1c; 72 mg, 0.361 mmol) and 4-chloro-7-(2-chlorophenyl)-8-(4-chlorophenyl)-2-methylpyrazolo[1,5-a][1,3,5]triazine (I-2A-1b; 102 mg, 0.261 mmol) in methylene chloride (1.3 ml) was added diisopropylethylamine (0.16 ml, 0.91 mmol), dropwise. After stirring for 90 minutes, the reaction was extracted from saturated aqueous NaHCO3 with methylene chloride. The combined extracts were dried (MgSO4), concentrated, in vacuo, and then purified on a Biotage™ Flash 12M column using 0-5% methanol in methylene chloride as eluant. The resultant solid was triturated from methanol and then dried, in vacuo, to afford 3A-1 (104 mg, 78%) as a colorless solid: +ESI MS (M+1) 510.1; 1H NMR (400 MHz, CD2Cl2) δ 7.47-7.34 (m, 6H), 7.21 (d, J=8.7 Hz, 2H), 6.96 (br s, 1H), 5.42 (br s, 1H), 5.22 (br m, 1H), 4.73 (br m, 2H), 4.18 (br m, 1H), 3.11 (septuplet, J=6.2 Hz, 1H), 2.48 (s, 3H), 1.06 (d, J=6.2 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH:18]=[O:19])=[CH:7]2.[CH2:20]([Li])[CH3:21]>>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH:18]([OH:19])[CH2:20][CH3:21])=[CH:7]2
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3)nc12
Reactant: [Li]CC
Product: CCC(O)c1cc2cccc(C)c2nc1-c1ccccc1

Procedure:
The title compound was prepared in a similar manner to Intermediate 55, using 8-methyl-2-phenylquinoline-3-carboxaldehyde and ethyllithium (0.5N solution in ether, 4.6 mL, 2.3 mmol) and was obtained as a white solid (85 mg, 33%) after purification by column chromatography (SiO2, 10-50% EtOAc in heptane). δH (CDCl3) 8.35 (s, 1H), 7.66-7.72 (m, 1H), 7.40-7.62 (m, 7H), 4.96-5.04 (m, 1H), 2.80 (s, 3H), 1.97 (d, J 3.8 Hz, 1H), 1.60-1.70 (m, 2H), 0.84 (t, J 7.3 Hz, 3H). LCMS (ES+) 278 (M+H)+, RT 3.91 minutes (Method 3).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:5].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:23]=[C:24]([F:29])[C:25](F)=[N:26][CH:27]=1>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:25]2[C:24]([F:29])=[CH:23][C:22]([Cl:21])=[CH:27][N:26]=2)=[CH:9][CH:8]=1)[CH3:5]
Reactant: Fc1cc(Cl)cnc1F
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 0 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 21.6 g (0.11 mol) of 2-(4-hydroxyphenoxy)-propionic acid methyl ester, 15.2 g (0.11 mol) of potassium carbonate, 1.45 g (0.0055 mol) of 18-Crown-6 ether and 100 ml of acetonitrile is added dropwise a solution of 14.95 g (0.10 mol) of 5-chloro-2,3-difluoropyridine in 30 ml of acetonitrile and the mixture is heated at a temperature of 50° to 60° C. during 40 hours. The mixture is then poured into ice/water. The organic material is extracted with ethyl acetate, washed with a saturated salt solution, dried over magnesium sulfate, filtered and evaporated. The oily residue is purified by chromatography over a silica gel column with a hexane/ethyl acetate 3:1 solvent. After evaporation of the solvent one obtain 20.4 g of the above ester (63% of the theory) is obtained in crystalline form. The melting point is 63°-64° C.
Reaction SMILES: CC1[N:7]=[CH:6]C(COP(O)(O)=O)=C(C=O)C=1O.C(O[CH2:21][CH2:22][C@@H:23]([C:25]([OH:27])=[O:26])[NH2:24])(=O)C>OP([O-])([O-])=O.[K+].[K+]>[C:6]([CH2:21][CH2:22][CH:23]([NH2:24])[C:25]([OH:27])=[O:26])#[N:7]
Reactant: CC(=O)OCC[C@H](N)C(=O)O
Reactant: Cc1ncc(COP(=O)(O)O)c(C=O)c1O
Agent: O=P([O-])([O-])O
Agent: [K+]
Product: N#CCCC(N)C(=O)O

Procedure:
Then, 250 μl 200 mM K2HPO4, 10 μl 10 mM pyridoxal phosphate (PLP), 110 μl 25 mM O-acetyl-L-homoserine (OAHS) dissolved in 100 mM K2HPO4, and γ-cyano-α-aminobutyric acid synthase (GCAs) obtained in Example 5 were added to this trapped H11 CN, and the mixture was subjected to enzymatic reaction at 65° C. for 10 minutes.