Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C2C(=CC=C(C(O)=O)C=2)C=[CH:2]1.C1(=O)CCCCC1.[C:20]1([C:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]=1>>[CH:20]1([C:26]2[C:34]3[C:29](=[CH:30][C:31]([C:35]([O:37][CH3:2])=[O:36])=[CH:32][CH:33]=3)[NH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: O=C1CCCCC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1

Procedure:
Condensation of 1H-indole-6-carboxylic acid with cyclohexanone can generate 3-cyclohexenyl-1H-indole-6-carboxylic acid. This indole ester can be subjected to sequential reduction and esterification to provide methyl 3-cyclohexanyl-1H-indole-6-carboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15].NCCCCN.CCCCCC.C([Li])CCC.[F:36]N(S(C1C=CC=CC=1)(=O)=O)S(C1C=CC=CC=1)(=O)=O.[Cl-].[NH4+]>C1COCC1>[F:36][C:5]1[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[NH:11][C:12](=[O:18])[O:13][C:14]([CH3:15])([CH3:17])[CH3:16]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COc1ccc(NC(=O)OC(C)(C)C)c(OC)c1
Agent: NCCCCN
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc(F)c(NC(=O)OC(C)(C)C)c(OC)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.2 %

Procedure:
To a solution of tert-butyl (2,4-dimethoxyphenyl)carbamate (7.09 g) and tetramethylenediamine (12.7 mL) in THF (70 mL) was added 1.6 M n-butyllithium hexane solution (52.5 mL) at −78° C., and the mixture was stirred at the same temperature for 20 min, and then at room temperature for 45 min. To the reaction mixture was added a solution of N-fluoro-N-(phenylsulfonyl)benzenesulfonamide (12.8 g) in THF (30 mL) at −78° C., and the mixture was allowed to warm to room temperature, and stirred overnight. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (2.90 g).
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5](Br)=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)CCC>O1CCCC1>[S:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:2]1[C:10]2[C:6](=[N:7][S:8][N:9]=2)[C:5]([C:19]2[S:18][CH:17]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Brc1ccc(Br)c2nsnc12
Solvent: C1CCOC1
Product: c1csc(-c2ccc(-c3cccs3)c3nsnc23)c1

Procedure:
According to what is described by Kitamura et al. in “Chemistry of Material” (1996), Vol. 8, pages 570-578, for example, 4,7-di-2-thienyl-2,1,3-benzothia-diazole (DTB) can be prepared by reacting 4,7-dibromo-2,1,3-benzothiadiazole and tri-n-butyl(thien-2-yl)stannane, in the presence of tetrahydrofuran, at 66° C., for 3 hours. Bis(triphenylphosphine)palladium-(II)chloride [PdCl2(PPh3)2] is used as catalyst, in a quantity equal to 2 moles per 100 moles of 4,7-dibromo-2,1,3-benzothiadiazole. At the end of the reaction, the solvent is removed by evaporation at reduced pressure and the residue obtained is purified by elution on a silica gel chromatographic column using a mixture of methylene chloride/hexane (1/1 vol/vol) as eluent, obtaining 4,7-di-2-thienyl-2,1,3-benzothiadiazole (DTB) with a yield equal to 82%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][N:10]=[C:9]2[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)([O-])=O.[NH4+].[Cl-]>CCO.O.[Fe]>[F:24][C:21]([F:22])([F:23])[C:17]1[CH:16]=[C:15]([NH:14][C:9]2[C:8]3[C:13](=[C:4]([NH2:1])[CH:5]=[CH:6][CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: O=[N+]([O-])c1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Temperature: 25 °C
Yield: 77.2 %

Procedure:
To a suspension of 8-nitro-N-(3-(trifluoromethyl)phenyl)quinazolin-4-amine (500 mg, 1.49 mmol) and iron powder (834 mg, 14.9 mmol) in EtOH (10 mL) was added a solution of NH4Cl (649 mg, 11.92 mmol) in water (3 mL) and the reaction mixture was heated at reflux for 2 h. Then the reaction mixture was cooled to rt and filtered. The filtrate was concentrated and the concentrate was dissolved in CHCl3. The organic layer was washed with an aq. saturated solution of NaHCO3 and brine. The organic layer was dried, filtered and concentrated to afford 350 mg of the title product. 1H NMR (300 MHz, DMSO d6): δ 9.74 (br s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.64-7.59 (m, 2H), 7.45-7.42 (d, J=7.5 Hz, 1H), 7.37-7.32 (t, J=8.0 Hz, 1H), 7.00-6.98 (d, J=7.8 Hz, 1H), 5.91 (br s, 2H); MS (m/z): 305.27 (M+H)+.
Reaction SMILES: CC(N=NC(C#N)(C)C)(C#N)C.[CH3:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1.C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:29][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]#[N:21])=[N:18][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)nc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)cn1
Temperature: 25 °C
Yield: 43.3 %

Procedure:
Add AIBN (0.25 g, 1.5 mmol) to a slurry of 5-methyl-pyridine-2-carbonitrile (2.5 g, 21.1 mmol) and NBS (3.7 g, 21.1 mmol) in carbon tetrachloride (150 mL) at reflux under a nitrogen atmosphere. Add AIBN (3×0.25 g, 3×1.5 mmol) to the reaction in 0.25 g portions every hour for 3 h. Stir the resulting mixture for one additional hour at reflux. Cool the mixture to room temperature and wash with saturated aqueous NaHCO3 (30 mL). Collect the organic phase, concentrate in vacuo and purify the residue by chromatography on silica gel (330 g) eluting with DCM to obtain the desired intermediate (1.8 g, 44%). MS (ES+) m/z: 199 (M+2)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16](=[O:20])OCC)=[N:5]2.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[N:8]=[C:7]([O:13][CH3:14])[C:6]([NH:15][C:16]([N:31]1[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]1)=[O:20])=[N:5]2
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(Cl)c(Cl)cc2nc1OC
Product: COc1nc2cc(Cl)c(Cl)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 71 %

Procedure:
Ethyl N-(6,7-dichloro-2-methoxyquinoxalin-3-yl)carbamate and 1-(3-methyl phenyl)piperazine were reacted by the same way with the example 176 to obtain the titled compound (yield, 71%). 1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H), 3.18-3.21 (m, 4H), 3.75-3.79 (m, 4H), 4.14 (s, 3H), 6.75-6.78 (m, 4H), 7.32 (br s, 1H), 7.85 (s, 1H), 7.92 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]2=[N:6][C:7]=1[Cl:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)CCCCCCBr
Reactant: O=C1CCc2nc(Br)c(Cl)nc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(Br)c(Cl)nc21

Procedure:
A solution of 2-bromo-3-chloro-7,8-dihydro-5H-pyrido[2,3-b]pyrazin-6-one (Intermediate J) (3.9 g, 14.86 mmol) and ethyl 7-bromoheptanoate (7.05 g, 29.7 mmol) in DMF (75 ml) under nitrogen was treated with potassium carbonate (10.27 g, 74.3 mmol) and the resultant solution was stirred at room temperature for 96 hours. The mixture was diluted with water and extracted with EtOAc (×2). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-60% EtOAc/iso-hexane 0-60% afforded the title compound;
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1>CN(C)C=O>[CH2:16]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C@@H:9]1[CH2:14][N:13]([CH2:30][C:29]2[CH:32]=[CH:33][C:26]([F:25])=[CH:27][CH:28]=2)[C:12](=[O:15])[CH2:11][CH2:10]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
0.8 g (S)-5-dibenzylaminopiperidin-2-one (see 5.1) are placed in 8 ml dimethylformamide, then 200 mg sodium hydride (60% in mineral oil) and 0.4 ml 4-fluorobenzylbromide are added. The reaction mixture is stirred overnight at 70° C. and then combined with ice water. The precipitate is filtered off and washed with water. The product is purified by chromatography (silica gel, petroleum ether/ethyl acetate and ethyl acetate/methanol). 0.5 g product are obtained as an oil. Analytical HPLC-MS (method A): RT=1.21 min.
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>[OH-].[K+].CCO>[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[C:21]2[CH2:20][CH2:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]4[N:10]=[CH:9][NH:8][CH:12]=4)[CH:17]=3)[C:22]2=[O:26])=[CH:30][CH:29]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Br)cc2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 52.4 %

Procedure:
According to the method of Example 32, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.278 g, 0.78 mmol) was reacted with p-bromobenzaldehyde (0.217 g, 1.17 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.173 g (51%) of the title compound as a dark cream-colored powder, mp 176-178° C.: CI-MS m/e 423, 425 (M+ +1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:22]3[C:23]([CH3:27])=[CH:24][CH:25]=[CH:26][C:21]=3[CH3:20])[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Cc1cccc(C)c1N1CCNCC1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2c(C)cccc2C)CC1
Yield: 88 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2,6-dimethylphenyl)piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 88%). 1H NMR (300 MHz, CDCl3): δ 2.04-2.58 (m, 9H), 3.14-3.20 (m, 4H), 3.71-3.76 (m, 3H), 4.07-4.14 (m, 4H), 7.00-7.15 (m, 4H), 7.25-7.76 (m, 3H).
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:12][CH:11]=1.C(=O)(O)[O-].[Na+]>CCO>[C:4]([C:3]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:13][N:12]2[C:2]=1[C:18]1[CH:17]=[CH:16][CH:15]=[CH:14][C:19]=1[N:10]=[CH:11]2)([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCOC(=O)Cc1ncnc2ccccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cn2cnc3ccccc3c2c1C(=O)OCC

Procedure:
A solution of ethyl bromopyruvate (8.0 g, 0.1041 m) and ethyl 4-quinazolylacetate prepared according to the procedure of Elderfield and Serlin, J. Org. Chem. 16, 1669 (1951) (2.32 g, 0.011 m) in dry EtOH (250 ml) was heated at reflux for 24 hr. Sodium bicarbonate was added until effervescence ceased. A solid formed and this was filtered, washed well with H2O, and dried. The crude product (1.8 g) was chromatographed on 150 g of Silicar. The desired product was eluted with 3% EtOAc/benzene. Crystallization from MeOH afforded the desired product as a white solid; m.p. 125°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15]2[N:24](S(C3C=CC=CC=3)(=O)=O)[C:18]3=[N:19][CH:20]=[C:21]([F:23])[CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[F:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:15]2[NH:24][C:18]3=[N:19][CH:20]=[C:21]([F:23])[CH:22]=[C:17]3[CH:16]=2)=[CH:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]=1[F:34]
Reactant: COC(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3n2S(=O)(=O)c2ccccc2)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(=CC(C)C)c2cc3cc(F)cnc3[nH]2)cc1F
Temperature: 25 °C
Reaction time: 40 h
Yield: 37 %

Procedure:
A mixture of 4-[1-(1-benzenesulfonyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl]-2-fluoro-benzoic acid methyl ester (2.50 g, 5 mmol) and tetrabutylammonium fluoride solution in tetrahydrofuran (1 M, 50 mL) was stirred at 25° C. for 40 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (50 mL). The mixture was extracted with ethyl acetate (2×150 mL), washed with a saturated aqueous ammonium chloride solution (3×100 mL), brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-fluoro-4-[1-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-2-yl)-3-methyl-but-1-enyl]-benzoic acid methyl ester (660 mg, 36%) which was used in the next step without further purification: LC/MS m/e calcd for C20H18F2N2O2 [M+H]+ 357.38, observed 356.9.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Cl[C:9]1[N:18]=[C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]3[O:27][CH2:28][O:29][C:23]=3[CH:22]=2)[C:16]2[CH2:15][C:14](Cl)([Cl:30])[CH:13]=[CH:12][C:11]=2[N:10]=1.O>CN(C)C=O>[N:1]1([C:9]2[N:18]=[C:17]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]4[O:27][CH2:28][O:29][C:23]=4[CH:22]=3)[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([Cl:30])[CH:15]=3)[N:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Clc1nc2c(c(NCc3ccc4c(c3)OCO4)n1)CC(Cl)(Cl)C=C2
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2nc(-n3ccnc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Reaction time: 0.17 h
Yield: 65.8 %

Procedure:
103 mg of imidazole was added to a suspension of 66 mg of sodium hydride in 6 ml of dimethylformamide at 0° C. The obtained mixture was stirred for 10 minutes. 500 mg of 2,6-dichloro-4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline was added to the resulting mixture at room temperature. The mixture thus prepared was stirred at 100° C. for 20 minutes, followed by the addition of water. The crystals precipitated were recovered by filtration and washed with water and ethanol/acetone successively to give 325 mg of the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[NH:20][C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Cl:26][C:27]1[CH:35]=[CH:34][C:30]([O:31][CH2:32]Cl)=[CH:29][CH:28]=1>CN(C)C=O>[CH2:7]([N:14]1[C:22]2[C:21](=[O:23])[N:20]([CH2:32][O:31][C:30]3[CH:34]=[CH:35][C:27]([Cl:26])=[CH:28][CH:29]=3)[C:19](=[O:24])[N:18]([CH3:25])[C:17]=2[N:16]=[CH:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCOc1ccc(Cl)cc1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)n(COc2ccc(Cl)cc2)c(=O)c2c1ncn2Cc1ccccc1
Reaction time: 1 h

Procedure:
2.59 g (19.0 mmol) of potassium carbonate were added at 60° C. to a suspension of 3.0 g (12.0 mmol) of 7-benzyl-3-methylxanthine (prepared according to Example 1a) in 50 ml of dimethylformamide and the mixture was stirred at this temperature for one hour. 2.69 g (15.0 mmol) of 4-chlorophenoxymethyl chloride were then added dropwise and the mixture was stirred at 80° C. for 8 hours. The crude mixture was then filtered, the filtrate was concentrated under reduced pressure, the residue was taken up in dichloromethane, and the solution was washed once with 1 N sodium hydroxide solution and twice with water. The organic phases were dried using magnesium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography on a silica gel column, dichloromethane/methanol (19.8/0.2) Yield: 4.15 g (87% of theory); melting point: 96° C.
Reaction SMILES: C([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#N.BrC1C=C[N:26]2[CH:29]=[N:30]C=C2C=1>>[CH:3]1[N:26]=[CH:29][N:30]2[CH:4]=[CH:5][C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]3)=[CH:7][C:8]=12
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Reactant: Brc1ccn2cncc2c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccn3cncc3c2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.1, except 7-bromoimidazo[1,5-a]pyridine (compound 39.3) was used in place of 4-bromobenzonitrile.
Reaction SMILES: CCCCCC.C1(C)C=CC=CC=1.C([N:17]([C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C=C.[OH-].[Na+]>ClC(Cl)C(P(C1C=CC=CC=1)C1C=CC=CC=1)(P(C1C=CC=CC=1)C1C=CC=CC=1)C.[Ni].C(OCC)C>[C:24]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: C=CCN(C(=O)c1ccccc1)c1ccccc1
Agent: [Ni]
Agent: CC(C(Cl)Cl)(P(c1ccccc1)c1ccccc1)P(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
Trimetyl alminum (0.98M n-hexane solution, 1.3 ml, 1.3 mmol) was added to an anhydrous toluene solution (2 ml) of N-allyl-N-benzoyl aniline (100 mg, 422 mmol) and nickel dichloro bis (diphenyl phosphino) propane (9 mg, 17 mmol) under ice cooling, and the mixture was refluxed for 7 hours. After the reaction, diethyl ether (3 ml) and a 0.5N solution (1.3 ml) of sodium hydroxide were added under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction solution was dried over anhydrous magnesium sulfate, cerite was added thereto, the mixture was filtered, and the solvent was distilled away from the filtrate in vacuo. The resulting residue was subjected to silica gel chromatography (elution solution: diethyl ether/n-hexane=1/5, v/v) to N-benzoyl aniline (61 mg, yield 73%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][C:8]#[C:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([CH:23]=[CH:24][C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[O:21][CH:22]=3)=[N:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1>C(OCC)(=O)C.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:11]=[N:12][C:13]([O:16][CH2:17][C:18]3[N:19]=[C:20]([CH:23]=[CH:24][C:25]4[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:32])[F:33])=[CH:29][CH:30]=4)[O:21][CH:22]=3)=[N:14][CH:15]=2)[CH:5]=[CH:4][N:3]=[N:2]1
Reactant: FC(F)(F)c1ccc(C=Cc2nc(COc3ncc(C#CCCn4ccnn4)cn3)co2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: FC(F)(F)c1ccc(C=Cc2nc(COc3ncc(CCCCn4ccnn4)cn3)co2)cc1

Procedure:
5-(4-[1,2,3]Triazol-1-yl-but-1-ynyl)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine (0.047 g, 0.1 mmol) is dissolved in ethyl acetate (3 ml) and hydrogenated for 1 h at r.t. in the presence of palladium on charcoal (10%, 20 mg). After filtration and concentration in vacuo the crude product is purified by flash column chromatography (ethyl acetate/hexanes 1:3->ethyl acetate (100%)) yielding 5-(4-[1,2,3]-triazol-1-yl-butyl)-2-{2-[2-(4-trifluoromethyl-phenyl)-vinyl]-oxazol-4-ylmethoxy}-pyrimidine as a white solid. Yield 35 mg (74%)
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])=[CH:11][CH:12]=1)C.[BH4-].[Li+].O>C1COCC1>[F:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCc1ccc(-c2ccccc2F)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(-c2ccccc2F)nc1

Procedure:
Under argon, 400 mg (1.46 mmol) of 3-(6-(2-fluorophenyl)pyridin-3-yl)propionic acid ethyl ester and 63.8 mg (2.93 mmol) of lithium borohydride were stirred in 20 ml of THF at 40° C. for 3 h. After cooling, the mixture was cautiously hydrolyzed with water, the precipitate was filtered off with suction, and water and methylene chloride were added to the filtrate. The organic phase was separated, washed with water and concentrated. Yield: 241 mg (71%).
Reaction SMILES: [F:1][C:2]([F:15])([CH3:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8]([CH:11]=O)=[N:9][CH:10]=1.[CH3:16][C:17]([S@:20]([NH2:22])=[O:21])([CH3:19])[CH3:18]>>[F:1][C:2]([F:15])([CH3:14])[CH2:3][O:4][C:5]1[C:6]([CH3:13])=[CH:7][C:8](/[CH:11]=[N:22]/[S@@:20]([C:17]([CH3:19])([CH3:18])[CH3:16])=[O:21])=[N:9][CH:10]=1
Reactant: Cc1cc(C=O)ncc1OCC(C)(F)F
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(/C=N/[S@](=O)C(C)(C)C)ncc1OCC(C)(F)F
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (1.10 g, pale yellow solid) from 5-(2,2-difluoropropoxy)-4-methylpicolinaldehyde (1.01 g, 4.68 mmol, Step-5) and (R)-2-methylpropane-2-sulfinamide (851 mg, 7.02 mmol) in a similar manner to Step-6 of Amine-49.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:40])[NH:10][C:11]1([C@H:14]([NH:18][C:19]2[CH:24]=[N:23][C:22]([C:25]#[N:26])=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[N:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[CH:29]=3)[N:20]=2)[CH:15]2[CH2:17][CH2:16]2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=[O:42].[K+].[K+]>CO.OO>[CH2:1]([O:8][C:9](=[O:40])[NH:10][C:11]1([C@H:14]([NH:18][C:19]2[CH:24]=[N:23][C:22]([C:25](=[O:42])[NH2:26])=[C:21]([NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([C:34]4[N:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[CH:29]=3)[N:20]=2)[CH:15]2[CH2:17][CH2:16]2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Nc1cccc(-c2ncccn2)c1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: NC(=O)c1ncc(N[C@H](C2CC2)C2(NC(=O)OCc3ccccc3)CC2)nc1Nc1cccc(-c2ncccn2)c1

Procedure:
To a mixture of (R)-benzyl-1-((5-cyano-6-(3-(pyrimidin-2-yl)phenylamino)pyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate in methanol (2 ml) was added K2CO3 (excess) and H2O2 (50%, a few drops). After completion, it was concentrated to give (R)-benzyl-1-((5-carbamoyl-6-(3-(pyrimidin-2-yl)phenylamino)pyrazin-2-ylamino)(cyclopropyl)methyl)cyclopropylcarbamate.
Reaction SMILES: NN.[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:26][O:27][N:28]3C(=O)C4C(=CC=CC=4)C3=O)[N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1>C(O)C>[NH2:3][C:4]1[C:13]2[N:14]=[C:15]([CH2:26][O:27][NH2:28])[N:16]([CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[C:12]=2[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=1
Reactant: CC(C)C(=O)NCCCn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3cccnc3c21
Agent: NN
Solvent: CCO
Product: CC(C)C(=O)NCCCn1c(CON)nc2c(N)nc3cccnc3c21
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Anhydrous hydrazine (0.160 mL, 5.22 mmol) was added to a suspension of N-[3-(4-amino-2-{[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]methyl}-1H-imidazo[4,5-c]-[1,5]naphthyridin-1-yl)propyl]-2-methylpropanamide (0.848 g, 1.74 mmol) in ethanol (10 mL). The mixture was allowed to stir at room temperature for 2.5 hours, then was concentrated under reduced pressure to yield crude N-(3-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}propyl)-2-methylpropanamide as a yellow solid, all of which was used in the next step.