Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[O:25])[CH:15]=3)[N:12]=2)[N:7](COCC[Si](C)(C)C)[CH:6]=1)=[O:4]>C(Cl)Cl.CO>[CH3:1][C:2]([CH3:42])([CH3:41])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]([CH2:23][C:24]([N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)=[O:25])[CH:15]=3)[N:12]=2)[NH:7][CH:6]=1)=[O:4]
Reactant: CN1CCN(C(=O)Cn2cc(-c3cnc4c(n3)c(C(=O)C(C)(C)C)cn4COCC[Si](C)(C)C)c3ccccc32)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)Cn2cc(-c3cnc4[nH]cc(C(=O)C(C)(C)C)c4n3)c3ccccc32)CC1
Yield: 67 %

Procedure:
2,2-Dimethyl-1-(2-{1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-indol-3-yl}-5H-pyrrolo[2,3-b]pyrazin-7-yl)-propan-1-one was prepared following the same procedure but using 2,2-dimethyl-1-[2-{1-[2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]-1H-indol-3-yl}-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-propan-1-one as starting material. The product was isolated in 67% yield by SiO2 chromatography (DCM/MeOH 0-10% MeOH).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH:21][NH2:22])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1.[C:23]([O:27][C:28]([N:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([C:40](O)=[O:41])[CH:36]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(N(C(C)C)CC)(C)C.F[B-](F)(F)F.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[NH2:1][C:2]1[C:3]([C:19]([NH:21][NH:22][C:40]([C:35]2[CH:36]=[C:37]3[C:32](=[CH:33][CH:34]=2)[CH2:31][N:30]([C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:29])[CH2:39][CH2:38]3)=[O:41])=[O:20])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([C:17]#[N:18])([CH3:16])[CH3:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C(=O)O)ccc2C1
Reactant: CC(C)(C#N)c1cc(-c2cnc(N)c(C(=O)NN)n2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2cc(C(=O)NNC(=O)c3nc(-c4ccnc(C(C)(C)C#N)c4)cnc3N)ccc2C1

Procedure:
3-amino-6-[2-(1-cyano-1-methyl-ethyl)-4-pyridyl]pyrazine-2-carbohydrazide (49.5 mg, 0.1665 mmol), 2-tert-butoxycarbonyl-3,4-dihydro-1H-isoquinoline-6-carboxylic acid (50.80 mg, 0.1832 mmol), diisopropyl ethyl amine (25.82 mg, 34.80 μL, 0.1998 mmol) and (benzotriazol-1-yloxy-dimethylamino-methylene)-dimethyl-ammonium tetrafluoroborate (58.82 mg, 0.1832 mmol) was stirred at ambient temperature in N,N-dimethyl formamide (495.0 μL) for 1 hour. The reaction mixture was partitioned between water and ethyl acetate. The combined organic extracts were washed with aqueous saturated sodium bicarbonate, then 0.5 N hydrochloric acid, followed by brine. The organic extracts were then dried over MgSO4 and concentrated in vacuo to give the sub-titled product. (92 mg, 99.27%) LC/MS m/z 557.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl[Sn]Cl.O>CC(O)=O.Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(=O)O
Solvent: O
Product: Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 500 mL round bottom flask was suspended 5-Chloro-2-(4-nitro-phenyl)-1H-benzoimidazole (4.23 g, 13.66 mmol) in AcOH (30 mL) at 0° C., and to the suspension was added dropwise SnCl2.H2O (9.4 g, 41.66 mmol), in HCl (15 mL). After the addition, the ice bath was removed and the mixture was allowed to stir at room temperature overnight (16 h). The mixture was poured onto ice, and NaOH (50% aq.) was slowly added to pH 12. Then the mixture was extracted with EtOAc (4×150 mL). The combined organic layers were washed with brine, dried over NaSO4 and filtered, the solvent was evaporated to yield the product as an orange oil. The oil was dissolved in EtOAc and washed with HCl (1.0 N, 100 mL) and the product was isolated as HCl salt (2.13 g, 67%).
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][CH2:6][CH:7]1[CH2:20][C:11]2=[N:12][C:13]3[NH:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=[C:10]2[CH2:9][CH2:8]1)C.[OH-].[Na+]>C1COCC1.O>[NH:14]1[C:13]2[N:12]=[C:11]3[CH2:20][CH:7]([CH2:6][CH2:5][C:4]([OH:21])=[O:3])[CH2:8][CH2:9][C:10]3=[CH:19][C:18]=2[CH2:17][CH2:16][CH2:15]1
Reactant: CCOC(=O)CCC1CCc2cc3c(nc2C1)NCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCC1CCc2cc3c(nc2C1)NCCC3

Procedure:
A solution of 14-3 (0.180 g, 0.62 mmol) and NaOH (1.24 mL of a 1N soln, 1.24 mmol) in THF/H2O (5 mL/5 mL) was stirred at room temperature for 12 h. The solution was concentrated. The residue was triturated with Et2O to give 14-4.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[NH:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=1)CCC.Br[C:25]1[N:30]2[N:31]=[CH:32][N:33]=[C:29]2[C:28]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH2:46][C@@H:45]4[CH2:47][C@H:42]3[CH2:43][N:44]4[CH:48]([CH3:50])[CH3:49])=[CH:37][CH:36]=2)=[N:27][CH:26]=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:48]([N:44]1[CH2:43][C@@H:42]2[CH2:47][C@H:45]1[CH2:46][N:41]2[C:38]1[CH:37]=[CH:36][C:35]([NH:34][C:28]2[C:29]3[N:30]([N:31]=[CH:32][N:33]=3)[C:25]([C:6]3[NH:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=3)=[CH:26][N:27]=2)=[CH:40][CH:39]=1)([CH3:50])[CH3:49]
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)n[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(-c2cnc(Nc3ccc(N4C[C@@H]5C[C@H]4CN5C(C)C)cc3)c3ncnn23)[nH]n1
Yield: 28.7 %

Procedure:
A mixture of ethyl 5-(tributylstannyl)-1H-pyrazole-3-carboxylate (109.0 mg, 0.25 mmol) (Heterocyles, 1992, 813-818), (5-bromo-[1,2,4]triazolo[1,5-a]pyrazin-8-yl)-[4-((1S,4S)-5-isopropyl-2,5-diazabicyclo[2.2.1]hept-2-yl)-phenyl]amine (163.0 mg, 0.38 mmol), and Pd(PPh3)2Cl2 (27.0 mg, 0.04 mmol) in THF (3 mL) is refluxed for 18 hours. After return to room temperature, solvent is removed under reduced pressure. Purification of the residue by silica gel column chromatography eluting with a mixture of DCM/7N NH3 in methanol (97/3) affords the title compound (35.0 mg, 28%).
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([F:12])[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([O:11][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(O)c(F)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)c(F)cc1Br
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A mixture of 4-bromo-2-fluoro-5-nitrophenol (prepared according to WO2004/014361, 10 g, 42.3 mmol) and cesium carbonate (16.42 g, 50.4 mmol) in DMF (80 mL), was stirred at room temperature and treated with benzyl bromide (5.5 g, 46.5 mmol) and the mixture was stirred/sonicated at room temperature for 2 hours (˜30 mins sonication). The DMF was evaporated and water and ethyl acetate were added and the product was extracted into ethyl acetate. The combined extracts were washed with sodium bicarbonate solution, dried (Na2SO4) and concentrated. Trituration of the solid with diethyl ether (3×) and drying gave the title compound (D4), (12.50 g).
Reaction SMILES: [S:1]([Cl:5])(=O)(=[O:3])[OH:2].[S:6]1[CH:10]=[CH:9][N:8]2[CH:11]=[N:12][CH:13]=[C:7]12.O>C(Cl)(Cl)(Cl)Cl>[Cl:5][S:1]([C:13]1[N:12]=[CH:11][N:8]2[CH:9]=[CH:10][S:6][C:7]=12)(=[O:3])=[O:2]
Reactant: c1cn2cncc2s1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Cl)c1ncn2ccsc12

Procedure:
A solution of chlorosulfuric acid in 20 ml of carbon tetrachloride was added under ice cooling to a solution of 11.18 g of imidazo[5,1-b]thiazole in 200 ml of carbon tetrachloride. The reaction mixture was heated under reflux for 6 hr. Water was added thereto under ice cooling to terminate the reaction. The mixture was extracted with dichloromethane. The organic layers were combined together. The combined organic layers were washed with a dilute aqueous sodium hydroxide solution and saturated brine in that order and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation. Isopropyl ether was added to the residue. The resultant powder was collected by filtration to give 4.01 g of 7-chlorosulfonylimidazo[5,1-b]thiazole.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH2:13][O:14][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC1CCN(Cc2ccccc2)C1
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: c1ccc(CN2CCC(COC(c3ccccc3)c3ccccc3)C2)cc1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
A mixture of 1-benzylpyrrolidine-3-methanol (1.72 g) (J. Org. Chem., 1961, 26, 1521) and bromodiphenylmethane (4.94 g) in xylene (150 ml) was heated under reflux for 3 hours, allowed to cool to room temperature, diluted with ethyl acetate, washed with 10% aqueous sodium carbonate solution, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica using dichloromethane plus 20% ethyl acetate plus 0-10% methanol as eluant. Appropriate fractions were combined and evaporated to give the title compound (1.57 g) as a pale brown oil which was charcterised by its 1H-NMR spectrum.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([P-:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[K+].F[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][PH:23](=[O:29])[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=1.O>C1COCC1>[C:8]1([P:7]([C:4]2[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:16]2[CH:21]=[CH:20][C:19]([CH2:22][PH:23](=[O:29])[O:24][CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][CH:17]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc([P-]c2ccccc2)cc1
Reactant: CC(C)CO[PH](=O)Cc1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CO[PH](=O)Cc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 20 h
Yield: 98.3 %

Procedure:
200 ml (100 mmol) of potassium diphenylphosphide solution in THF (manufacturer: Aldrich) were added dropwise at -5° C. to a solution of 21.90 g (95 mmol) of isobutyl 4-fluorophenylmethylphosphinate in 150 ml of THF. After stirring for 20 hours at 23° C., the mixture was hydrolyzed by addition of 250 ml of degassed water and stirring for 15 minutes. Extraction with ethyl acetate, drying of the organic phase over Na2SO4, evaporation on a rotary evaporator and drying under reduced pressure gave 37.0 g of isobutyl (4-diphenylphosphinophenyl)methylphosphinate in the form of a yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([NH:8][C:9]2[C:10](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](O)=O)=[CH:6][CH:5]=[N:4]1)[CH3:2].O=P(Cl)(Cl)[Cl:20]>>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:10]([C:11]([Cl:20])=[C:6]2[CH:5]=[N:4]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCn1nccc1Nc1ccccc1C(=O)O
Product: CCn1ncc2c(Cl)c3ccccc3nc21
Temperature: 0 °C
Yield: 68.3 %

Procedure:
A mixture of N-(1-ethylpyrazol-5-yl)anthranilic acid (278 g, 1.2 mol) and POCl3 (550 g, 3.6 mol) was refluxed for 3 hours. The reaction mixture was cooled and then was poured into ice/water (3-4 L). A solid formed which was collected by filtration and washed with water. The filtrate was extracted with CH2Cl2 (1 L) and the CH2Cl2 layer was evaporated to about 50 ml and both this solution and the previously isolated solid were purified by column chromatography on silica gel eluting with CH2Cl2 to afford 190 g (68%) of 1-ethyl-4-chloro-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:3][CH:2]=1.C([O:18]C([NH:21][N:22]=[CH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:26][CH:25]=1)=O)(C)(C)C.N1C=CC=CC=1C1C=CC(C=NN)=CC=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>>[N:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C:27]1[CH:28]=[CH:29][C:24]([CH:23]=[N:22][NH2:21])=[CH:25][CH:26]=1.[N:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:4]1[CH:5]=[CH:6][C:1]([CH:13]=[O:18])=[CH:2][CH:3]=1
Reactant: Cc1ccc(-c2ccccn2)cc1
Reactant: CC(C)(C)OC(=O)NN=Cc1ccc(-c2ccccn2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: NN=Cc1ccc(-c2ccccn2)cc1
Product: O=Cc1ccc(-c2ccccn2)cc1

Procedure:
The present inventors have found that 4-(pyridin-2-yl)benzaldehyde can be produced economically by reacting a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine or a salt thereof, all of which being novel compounds, with hexamethylenetetramine and water, and further that a salt of 2-(4-bromomethylphenyl)pyridine, 2-(4-dibromomethylphenyl)pyridine and a salt thereof can be obtained by reacting a salt of 2-(4-tolyl)pyridine with a brominating agent. In addition, they have found that N-(tert-butoxycarbonyl)-N'-[4-(pyridin-2-yl)phenylmethylidene]hydrazine can be produced more economically and easily by reacting 4-(pyridin-2-yl)benzaldehyde hydrazone with di-tert-butyl dicarbonate, and that 4-(pyridin-2-yl)benzaldehyde hydrazone can be obtained from 4-(pyridin-2-yl)benzaldehyde.
Reaction SMILES: [C:1]1([C:7]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17](OC)=[O:18])=[CH:15][CH:14]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][OH:24].[OH-].[Na+].Cl>C1COCC1.CO>[OH:24][NH:23][C:17](=[O:18])[C:16]1[CH:21]=[CH:22][C:13]([O:12][CH2:11][CH2:10][NH:9][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:8])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)c2ccccc2)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NO)c1ccc(OCCNC(=O)c2ccccc2)cc1
Reaction time: 14 h

Procedure:
To a solution of crude methyl 4-(2-benzenecarbonylamino-ethoxy)benzoate (0.5 mmol) in a 1:1 mixture of THF/methanol (20 ml) was added 50 wt. % aqueous hydroxylamine (3 ml) followed by 1M aqueous NaOH (1 ml) adjusting the pH between 10-11. The reaction mixture was stirred for 14 h, neutralized to pH=7-8 with 6 M aqueous HCl and concentrated in vacuo. The precipitate was collected and purified by HPLC providing the title compound as a white solid. 1H NMR (DMSO-d6): δ 8.69 (t, J=5.8 Hz, 1H), 7.83 (d, J=7.5 Hz, 2H), 7.69 (d, J=9.1 Hz, 2H), 7.46 (m, 3H), 6.99 (d, J=9.1 Hz, 2H), 4.16 (t, J=5.8 Hz, 2H), 3.63 (q, 5.8 Hz, 2H). EM (calc.): 300.1; MS (ESI) m/e: 301.1 (M−1)+, 299.0 (M+1)−.
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[CH3:13][O-:14].[Na+]>CO>[CH3:13][O:14][C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[N:5]=[C:4]([S:11][CH3:12])[N:3]=1
Reactant: C[O-]
Reactant: CSc1nc(Cl)c2c(n1)CCC2
Agent: [Na+]
Solvent: CO
Product: COc1nc(SC)nc2c1CCC2
Reaction time: 2 h

Procedure:
18.05 g (90 mmol) of 4-chloro-2-methylthio-6,7-dihydro-5H-cyclopentapyrimidine were dissolved in 200 ml of methanol. At 45° C., 16.7 g of sodium methoxide (as 30% strength solution in methanol) were added dropwise, and the mixture was stirred for 2 hours. The solution was evaporated, taken up in ethyl acetate and acidified with dilute hydrochloric acid, and the ethyl acetate extract was evaporated. 15.5 g of an oil remained.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[O:16]=[C:17]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=1>C1COCC1.O>[OH:4][C:3]1[CH2:5][C:17]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C:1](=[O:6])[CH:2]=1
Reactant: CC(=O)Nc1ccc(CCC(=O)c2ccccc2)cc1
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CCC2(c3ccccc3)CC(O)=CC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Methyl acetoacetate (4.5 mL, 41.7 mmol) was added dropwise to a slurry of 60% sodium hydride (1.75 g, 43.7 mmol) in THF (135 mL) at 0° C. After stirring 15 minutes, n-butyllithium (21 mL of 2.1 M, 44.1 mmol) was added and the reaction stirred an additional 15 minutes at 0° C. N-[4-(3-Oxo-3-phenyl-propyl)-phenyl]-acetamide, prepared in Example Y (5.3 g, 19.8 mmol) in THF (15 mL) was added in one portion and the reaction allowed to warm to room temperature over 4 hours. H2O was added and the reaction allowed to stir overnight. The mixture was extracted with Et2O and the aqueous layer acidified with 1N HCl. The precipitate was filtered, then washed with EtOAc to give the title compound, m.p. 155-160° C. 1H NMR (DMSO-d6) δ 2.0 (s, 3 H), 2.17 (m, 2 H), 2.50 (m, 2 H), 3.02 (dd, 2 H), 4.88 (s, 1 H), 6.99 (d, 2 H), 7.25-7.50 (m, 7 H), 9.81 (s, 1 H), 11.50 (s, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH2:38][C:39](Cl)=[O:40])[CH:35]=[CH:36][CH:37]=1>ClCCl>[Cl:12][C:10]1[C:9]([C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH3:22])[CH:17]=[CH:16]3)=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([NH:1][C:39](=[O:40])[CH2:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([O:31][CH3:30])[CH:33]=2)[CH:11]=1
Reactant: COc1cccc(CC(=O)Cl)c1
Reactant: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(-c2ccc3c(ccn3C)c2)c(Cl)cc1NC(=O)Cc1cccc(OC)c1
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To a suspension of methyl 2-amino-4-chloro-5-(1-methyl-1H-indol-5-yl)benzoate (Intermediate 45) (150 mg, 0.427 mmol) in dichloromethane (20 mL) at 0° C. was added triethylamine (0.131 mL, 0.940 mmol) and [3-(methyloxy)phenyl]acetyl chloride (Acros Organics, 79 mg, 0.427 mmol) was added dropwise. The reaction mixture was stirred from 0° C. to RT for 1 h before being quenched with 1N HCl. The organic layer was separated and washed successively with sat. NaHCO3 and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by chromatography using a cyclohexane to cyclohexane/EtOAc 80:20 as eluant. The appropriate fractions were combined and concentrated in vacuo to give the title compound methyl 4-chloro-5-(1-methyl-1H-indol-5-yl)-2-({[3-(methyloxy)phenyl]acetyl}amino)benzoate (150 mg, 0.324 mmol, 76% yield) as a white amorphous solid. LCMS: (M+H)+=463; Rt=4.23 min.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)(C)(C)C.C(OC(=O)N[C@@H]1CCN([C:27]2[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][N:28]=2)C1)(C)(C)C.FC(F)(F)C1C(N2CC[C@@H](N)C2)=NC=CC=1>>[F:34][C:33]([F:36])([F:35])[C:32]1[CH:31]=[CH:30][C:29]([N:11]2[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]2)=[N:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: N[C@@H]1CCN(c2ncccc2C(F)(F)F)C1
Product: NC1CCN(c2ccc(C(F)(F)F)cn2)CC1

Procedure:
The title compound was prepared from D7 and 2-chloro-5-ifluoromethylpyridine using the procedure outlined for Descriptions D1 and D2.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:3][CH2:2]1.Cl[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[N:17]1[CH:18]=[CH:19][CH:20]=[N:21][C:16]=1[N:1]1[CH2:2][CH2:3][CH:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][CH2:6]1
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1CCN(c2ncccn2)CC1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of tert-butyl piperidin-4-ylcarbamate (2.00 g, 9.99 mmol), 2-chloropyrimidine (3.43 g, 30.0 mmol), and K2CO3 (6.90 g, 49.9 mmol) in 1,4-dioxane (57 mL) was refluxed for 2 days. After cooled to room temperature, the mixture was filtered and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue was purified by column chromatography (Hexane:EtOAC=3:1) to give tert-butyl 1-(pyrimidine-2-yl)piperidin-4-ylcarbamate (2.78 g, quant.) as a white solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 1.23-1.44 (2H, m), 1.45 (9H, s), 1.95-2.08 (2H, m), 2.99-3.10 (2H, m), 3.72 (1H, brs), 4.39-4.53 (1H, m), 4.59-4.69 (2H, m), 6.47 (1H, t, J=4.8 Hz), 8.29 (2H, d, J=4.8 Hz). m/z=278.87 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH:20]3[CH2:25][CH2:24][CH:23]([C:26](O)=[O:27])[CH2:22][CH2:21]3)[N:14]=2)[CH:5]=1)(=[O:3])[NH2:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[CH3:65][N:66]([CH:68]1[CH2:73][CH2:72][NH:71][CH2:70][CH2:69]1)[CH3:67]>C1COCC1>[CH3:65][N:66]([CH3:67])[CH:68]1[CH2:73][CH2:72][N:71]([C:26]([CH:23]2[CH2:24][CH2:25][CH:20]([NH:19][C:15]3[N:14]=[C:13]([N:6]4[C:7]5[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=5)[C:4]([C:1]([NH2:2])=[O:3])=[CH:5]4)[CH:18]=[CH:17][N:16]=3)[CH2:21][CH2:22]2)=[O:27])[CH2:70][CH2:69]1
Reactant: NC(=O)c1cn(-c2ccnc(NC3CCC(C(=O)O)CC3)n2)c2ccccc12
Reactant: CN(C)C1CCNCC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(C)C1CCN(C(=O)C2CCC(Nc3nccc(-n4cc(C(N)=O)c5ccccc54)n3)CC2)CC1
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a suspension of 4-[4-(3-carbamoyl-indol-1-yl)-pyrimidin-2-ylamino]-cyclo-hexanecarboxylic acid (150 mg, 0.395 mmol) in THF was added BOP, followed by Hünig's base (103 μL, 0.593 mmol), the mixture stirred for 10 min, and 4-(N,N-dimethylamino)-piperidine (76 mg, 0.593 mmol) was added and stirred for 6 days at RT. The resulting white solid was filtered off, washed with dry THF (20 mL) and DCM (30 mL), and air-dried overnight. The product was purified by prep-TLC using 5% MeOH/DCM+NH4OH, and dried under vacuum to provide 1-{2-[4-(4-dimethylamino-piperidine-1-carbonyl)-cyclohexylamino]-pyrimidin-4-yl}-1H-indole-3-carboxylic acid amide (78 mg, 40.3% yield) as a yellow solid (Compound 295).
Reaction SMILES: [C:1]([CH:4]([C:11](=[O:13])[CH3:12])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])(=O)[CH3:2].Cl.[NH2:15]O.CC([O-])=O.[Na+].C(O)(=O)C>C(O)C>[CH3:2][C:1]1[C:4]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:11]([CH3:12])[O:13][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CC(C(C)=O)C(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)Cc1c(C)noc1C
Yield: 3.4 %

Procedure:
A mixture of ethyl 3-acetyl-4-oxopentanoate (37.24 g, 0.2 mol), hydroxylamine hydrochloride (14.6 g, 0.21 mol), NaOAc (17.23 g, 0.21 mol) and ethanol (500 mL) was refluxed for 4 hours. The reaction mixture was filtered, the filtrate was concentrated in vacuo and the residue was heated in acetic acid (12.61 g, 0.21 mol) and toluene (300 mL) for 6 to 6.5 hours with the removal of water. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford a tan oil which crystallized on cooling. The product was collected by filtration and washed with ether to afford 1.26 g of ethyl 3,5-dimethyl-4-isoxazolylacetate, m.p. 180-182° C. Additional product was obtained by concentration of the ether filtrate and distillation of the residue at 69-81.5° C. and 0.05 mm Hg to afford a total of 31.18 g (85%).