Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.F[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=1[CH3:24].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1cc([N+](=O)[O-])ccc1N1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
In the same manner as in Production Example 5-1, but using tert-butyl piperazine-1-carboxylate in place of N-ethylpiperazine used in Production Example 5-1, using 2-fluoro-5-nitrotoluene in place of 2-fluoro-5-nitrobenzyl alcohol, using N,N-diisopropylethylamine in place of potassium carbonate, and using dimethylsulfoxide in place of N-methylpyrrolidone, 4.91 g of crude tert-butyl 4-[2-methyl-4-nitrophenyl]piperazine-1-carboxylate was obtained as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[C:6](=[N:7][C:8](SC)=[N:9][CH:10]=2)[N:5]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[CH:2]=[CH2:3].[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1>>[CH3:23][O:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:8]3[N:7]=[C:6]4[N:5]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=5)[N:4]([CH2:1][C:2]#[CH:3])[C:12](=[O:13])[C:11]4=[CH:10][N:9]=3)=[CH:35][CH:34]=2)[CH2:29][CH2:28]1
Reactant: C=CCn1c(=O)c2cnc(SC)nc2n1-c1cccc(C)n1
Reactant: COCCN1CCN(c2ccc(N)cc2)CC1
Product: C#CCn1c(=O)c2cnc(Nc3ccc(N4CCN(CCOC)CC4)cc3)nc2n1-c1cccc(C)n1

Procedure:
45.3 mg of the entitled compound was obtained as a yellow solid in the same manner as in Example 113-1 to 113-2, for which, however, 2-allyl-1-(6-methylpyridin-2-yl)-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one was used in place of 2-allyl-1-[6-(1-hydroxy-1-methylethyl)-2-pyridinyl]-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one used in Example 113-1, and 4-[4-(2-methoxyethyl)piperazin-1-yl]aniline was used in place of 4-(4-methylpiperazin-1-yl)aniline used in Example 113-2.
Reaction SMILES: [OH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](O)[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[Cl:14][C:6]1[CH:5]=[CH:4][NH:3][C:2](=[O:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1c(O)ccnc1O
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Temperature: 47 °C

Procedure:
A 150 mL flask is charged with 2,4-dihydroxy-3-nitropyridine (Compound XII) (10.0 g, 0.064 mole), and toluene (30 mL). The mixture is stirred at moderate speed and warmed to 47° C. Phosphorus oxychloride (POCl3) (4.4 g, 0.0289 moles) is added over 10 minutes, via a syringe pump, giving an exotherm to 49° C. N,N-diisopropylethylamine (DIPEA) (2.22 g, 0.017 moles) is added over 10 minutes, giving an exotherm to 51° C. Another portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by another portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes. A third portion of POCl3 (4.4 g, 0.0289 moles) is added over 10 minutes, followed by a third portion of DIPEA (2.22 g, 0.017 moles) over 10 minutes, followed by a final portion of POCl3 (4.4 g, 0.0289 moles) over 10 minutes (total POCl3 added is 17.7 g), then by a final portion of DIPEA (2.22 g, 0.017 moles) over 10 min. (total DIPEA added is 8.9 g). The reaction is then stirred at 50° C. for 5 hr until IPC indicates complete consumption of Compound XII. The reaction is allowed to cool to 20° C. over 30 minutes and 50 mL of water is added over 1.5 hr allowing the temperature to rise to 47° C. This mixture is stirred for four hours while cooling to 25° C. The batch is filtered washing twice with 15 mL of water, then twice with 15 mL of toluene. The product is dried to give Compound II.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>>[C:25]([N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])(=[O:27])[CH3:26]
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)n1c(SC(F)(F)C(F)F)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 1.8 g (0.005 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole and 25 ml acetic anhydride was heated at reflux seven hours, then cooled and stirred at room temperature for four days. Most of the acetic anhydride and acetic acid were removed at reduced pressure (~0.5 mm). The white solid residue was chromatographed on silica gel, eluting with toluene, to give 0.8 g of white product, mp 143°-4° (from hexane).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:11][CH:12]=[N:13][CH:14]=1.[Br:21][C:22]1[C:30]2[N:29]=[C:28](Cl)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1.C(N(CC)C(C)C)(C)C>>[Br:21][C:22]1[C:30]2[N:29]=[C:28]([N:18]3[CH2:17][CH2:16][N:15]([C:10]4[C:9]([Cl:8])=[CH:14][N:13]=[CH:12][N:11]=4)[CH2:20][CH2:19]3)[NH:27][C:26]=2[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1
Reactant: FC(F)(F)c1cc(Br)c2nc(Cl)[nH]c2c1
Reactant: Clc1cncnc1N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncncc4Cl)CC3)[nH]c2c1

Procedure:
The reaction of 1-(5-chloropyrimidin-4-yl)piperazine trifluoroacetic acid salt (0.414 g, 0.97 mmol, Example 33d), 4-bromo-2-chloro-6-trifluoromethyl-1H-benzoimidazole (0.29 g, 0.97 mmol, Example 9b) and N,N-diisopropylethylamine (0.5 mL, 2.91 mmol, Aldrich) under the conditions of Example 1d gave the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 461 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:4]=1[NH2:5])[CH3:2].[N:13](OC(C)(C)C)=O>C(O)(=O)C.C(OCC)(=O)C>[CH3:2][C:1]1[C:3]2[C:4](=[CH:6][C:7]([N+:10]([O-:12])=[O:11])=[CH:8][CH:9]=2)[NH:5][N:13]=1
Reactant: CC(C)(C)ON=O
Reactant: CCc1ccc([N+](=O)[O-])cc1N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1n[nH]c2cc([N+](=O)[O-])ccc12
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
To a solution of 10 g (0.06 mol) of 2-ethyl-5-nitroaniline (prepared by nitration of 2-ethylaniline: Bergman and Sand, Tetrahedron 1990, 46, 6085-6112) in 300 ml of glacial acetic acid, at room temperature, was added a solution of 8.98 ml (0.06 mol) of tert-butyl nitrite in 40 ml of acetic acid dropwise over 15 min. After the addition was complete the solution was allowed to stir for 30 min. The acetic acid was removed in vacuo to afford an orange solid. The solid was dissolved in approximately 120 ml of ethyl acetate and washed with 3×100 ml sat. aqueous NaHCO3. The organic layer was dried over MgSO4 and the solvent was removed in vacuo to afford 3-methyl-6-nitroindazole as a yellow solid (10.4 g, 98%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1>O1CCCC1>[C:7]([CH:9]=[C:19]1[CH2:22][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:20]1)#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (30.7 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (5.20 mL, 0.0322 mol) in tetrahydrofuran (39.12 mL). The reaction was warmed to room temperature and then cooled to 0° C. again. To the reaction mixture was added a solution of tert-butyl 3-oxoazetidine-1-carboxylate (5.0 g, 0.029 mol) in tetrahydrofuran (7.82 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 70% EtOAc in hexanes, to give the desired product (5.40 g, 95%). LCMS (M+Na) 217.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:16]1[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc2[nH]ccc2c1
Agent: Cl
Solvent: O
Product: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Yield: 71.9 %

Procedure:
Beginning with 4.0 gm (29.6 mMol) 5-fluoro-1H-indole and 9.13 gm (59.0 mMol) 4-piperidone hydrochloride monohydrate, 4.60 gm (72%) of the title compound were recovered as a white solid.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][C:6]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1.NCC1C2[C:29](=[C:30]([OH:35])C=CC=2)CC(C2C=CC=CC=2)C=1.[ClH:42]>C(OC(=O)C)(=O)C>[ClH:42].[NH2:4][CH2:5][C:6]1[C:15]2[C:10](=[C:11]([O:16][C:30](=[O:35])[CH3:29])[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:7]=1
Reactant: NCC1=CC(c2ccccc2)Cc2c(O)cccc21
Agent: Cl
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: CC(=O)Oc1cccc2c1CC(c1ccccc1)C=C2CN

Procedure:
A suspension of 1-aminomethyl-5-hydroxy-3-phenyl-3,4-dihydronaphthalene formic acid salt, the product of Example 2, in acetic anhydride saturated with anhydrous hydrogen chloride is stirred at ambient temperature for 48 h. A solid is collected by filtration and washed with diethyl ether. Crystallization of the crude material is achieved by dissolving the powder in hot ethanol, adding water, filtering the solution hot and allowing it to cool. Filtration and drying of the solid collected affords 1-aminomethyl-5-acetoxy-3-phenyl-3,4dihydronaphthalene hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([SH:11])[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14].[OH-].[Na+].Cl.[CH3:18][C:19]1[C:20]([CH2:26]Cl)=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25]>CO.O>[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([S:11][CH2:26][C:20]3[C:19]([CH3:18])=[C:24]([CH3:25])[CH:23]=[CH:22][N:21]=3)[NH:7][C:6]=2[CH:5]=[C:4]([CH3:12])[C:3]=1[O:13][CH3:14]
Reactant: COc1c(C)cc2[nH]c(S)nc2c1C
Reactant: Cc1ccnc(CCl)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1c(C)cc2[nH]c(SCc3nccc(C)c3C)nc2c1C
Reaction time: 3 h
Yield: 67.2 %

Procedure:
To 4,6-dimethyl-5-methoxy-2-mercapto-1H-benzimidazole (1.04 g, 0.0050 mol) in methanol (50 ml) were added (in the following order) NaOH (0.2 g, 0.0050 mol) dissolved in water (2 ml) and 3,4-dimethyl-2-chloromethylpyridine hydrochloride (0.96 g, 0.0050 mol). The mixture was heated until reflux. NaOH (0.2 g, 0.0050 mol) dissolved in water (2 ml) was added dropwise and then the reflux was continued for 3 hours. The mixture was poured on ice-water (200 ml). Filtration and recrystallization from CH3CN gave the desired product (1.1 g, 67%). NMR data for the final product is given below.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1.[F:33][C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[F:33][C:34]1[CH:39]=[C:38]([C:15]2[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@H:21]([OH:30])[CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)=[CH:17][CH:16]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: O[C@H](CCc1cccnc1)COc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2cccc(F)c2)cc1
Temperature: 110 °C

Procedure:
Prepared according to the method described in Example 33a) from toluene (5 ml), ethanol (3 ml), aqueous sodium carbonate (2 M, 1 ml), (2R)-1-(4-bromophenoxy)-4-(3-pyridyl)-2-butanol (0.25 g), ethanol (1 ml), 3-fluorobenzeneboronic acid (0.16 g) and tetrakis(triphenylphosphine)palladium(0) (60 mg) with heating at 110° C. for 4 hours. The residue obtained after work up was purified by column chromatography over silica eluting with ethyl acetate to give the title compound after trituration with diethyl ether:hexane (1:1) as a white solid (0.13 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[Cl:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH:14]=[C:10]([Cl:9])[N:11]=[CH:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Clc1c[nH]cn1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(-n2cnc(Cl)c2)ncn1
Yield: 54.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine (1.8 g, 12 mmol), 4-chloro-1H-imidazole (1.23 g, 12.00 mmol), and cesium carbonate (3.91 g, 12.00 mmol) was stirred in DMF (8 mL) at room temperature for 18 h. The reaction was diluted into water and extracted with EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 120 g silica gel cartridge with 0 to 40% ethyl acetate in hexane to yield 4-chloro-6-(4-chloro-1H-imidazol-1-yl)pyrimidine (1.41 g, 54.6% yield). The positive identification of the 4-chloroimidazole regioisomer was accomplished by its NMR NOE properties. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.86 (1H, d, J=0.76 Hz), 8.33 (1H, d, J=1.51 Hz), 7.54 (1H, d, J=1.76 Hz), 7.30 (1H, d, J=0.76 Hz). LCMS: RT=0.81 min, MH+=215.1
Reaction SMILES: [N:1]1[N:2]([CH2:6][C:7]([OH:9])=O)[N:3]=[CH:4][CH:5]=1.[F:10][C:11]1[CH:41]=[CH:40][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([C@@H:25]3[CH2:29][C@@H:28]([CH2:30][C:31]4[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=4[F:39])[CH2:27][NH:26]3)=[O:24])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1>>[N:3]1[N:2]([CH2:6][C:7]([N:26]2[CH2:27][C@H:28]([CH2:30][C:31]3[C:36]([F:37])=[CH:35][C:34]([F:38])=[CH:33][C:32]=3[F:39])[CH2:29][C@H:25]2[C:23]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([F:10])=[CH:41][CH:40]=3)=[CH:21][CH:20]=2)=[O:24])=[O:9])[N:1]=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1
Reactant: O=C(O)Cn1nccn1
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2c(F)cc(F)cc2F)CN1C(=O)Cn1nccn1

Procedure:
Proceeding as in Example 1, but substituting 2-(2H-1,2,3-triazol-2-yl)acetic acid and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 169, (2S,4R)-1-(2-(2H-1,2,3-triazol-2-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(2,4,6-trifluorobenzyl)pyrrolidine-2-carboxamide. Major isomer: 1H-NMR (400 MHz, CDCl3): δ 9.12 (s, 1H), 7.72 (s, 2H), 7.43-7.38 (m, 2H), 7.03-6.86 (m, 6H), 6.72-6.64 (m, 2H), 5.12 (s, 2H), 4.82 (d, 1H), 3.63-3.57 (m, 1H), 3.22 (t, 1H), 2.92-2.74 (m, 3H), 2.59 (dd, 1H), 1.78-1.69 (m, 1H). MS (EI) for C28H23F4N5O3 found 554 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15][C:16](=[O:20])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:15][C:16]([N:31]2[CH2:30][CH2:29][N:28]([C:25]3[CH:24]=[CH:23][C:22]([Cl:21])=[CH:27][CH:26]=3)[CH2:33][CH2:32]2)=[O:20])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(OC)cc2nc1OC
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: COc1ccc2nc(NC(=O)N3CCN(c4ccc(Cl)cc4)CC3)c(OC)nc2c1
Yield: 93 %

Procedure:
Ethyl N-(3,6-dimethoxyquinoxalin-2-yl)carbamate and 1-(4-chlorophenyl)piperazine were reacted by the same way with the example 148 to obtain the titled compound (yield, 93%). 1H NMR (300 MHz, CDCl3): δ 3.23 (s, 4H), 3.75 (s, 4H), 3.90 (s, 3H), 4.13 (s, 3H), 6.85 (d, J=9.0 Hz, 2H), 7.14 (s, 2H), 7.20-7.25 (m, 3H), 7.71-7.74 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(N(CC)CC)C>CC1CCCO1>[CH3:8][C:6]1[C:5]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:3]=[C:2]([N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[N:7]=1
Reactant: C1CCNCC1
Reactant: COC(=O)Cc1c(C)nc(Cl)nc1-c1ccc(C)cc1
Solvent: CCN(CC)CC
Solvent: CC1CCCO1
Product: COC(=O)Cc1c(C)nc(N2CCCCC2)nc1-c1ccc(C)cc1
Yield: 53.7 %

Procedure:
To a solution of methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)acetate (3 g; 10.32 mmol) in 2-methyltetrahydrofuran (20 ml) was added piperidine (4.09 mL; 41.3 mmol) and triethylamine (5.72 mL; 41.3 mmol). The reaction was heated under reflux for 5 h and the reaction mixture was partitioned between ethyl acetate and a saturated solution of sodium hydrogen carbonate. The phases were separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulphate, filtered and concentrated under reduced pressure. Purification by flash-chromatography on silica gel using a gradient of ethyl acetate (2-20%) in heptane furnished 1.88 g (48%) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[C:19]([O:23][C:24]([N:26]1[CH2:36][CH2:35][C:29]2([O:34][CH2:33][CH2:32][NH:31][CH2:30]2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH2:28][C:29]2([O:34][CH2:33][CH2:32][N:31]([CH2:11][C:9]3[S:10][C:5]4[C:4]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)=[N:3][C:2]([Cl:1])=[N:7][C:6]=4[CH:8]=3)[CH2:30]2)[CH2:35][CH2:36]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (100 mg, 0.352 mmol) in dichloroethane (10 mL) were added 1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester (110 mg, 0.376 mmol) and sodium triacetoxyborohydride (113 mg, 0.533 mmol) and the resulting solution stirred at RT for 3 h. The reaction was quenched with water and loaded onto an Isolute® SCX-2 cartridge, washed with MeOH then eluted with 2 M NH3 in MeOH. The resulting residue was then purified by column chromatography to give the title compound as a white solid (98 mg, 53%) [M+H]+ 524.3
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:38]=[CH:37][C:22]([CH2:23][N:24]6[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(O)(C(F)(F)F)=O>ClCCl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]4[C:13](=[N:14][CH:15]=[C:16]([C:19]5[CH:38]=[CH:37][C:22]([CH2:23][N:24]6[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]6)=[CH:21][CH:20]=5)[CH:17]=4)[NH:12][CH:11]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(-c3cnc4[nH]cc(-c5ccc6[nH]ccc6c5)c4c3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc2cc(-c3c[nH]c4ncc(-c5ccc(CN6CCNCC6)cc5)cc34)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
tert-butyl 4-(4-(3-(1H-indol-5-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)benzyl)piperazine-1-carboxylate (63 mg) was suspended in dichloromethane (2 mL) and treated with TFA (2 mL). The resulting mixture was stirred for 90 minutes at room temperature, after which the solvent was removed in vacuo. The residue was dissolved in EtOAc and washed with 10% sodium hydroxide solution, water, and brine. The organic layer was dried over MgSO4, and the solvent was removed in vacuo. MPLC silica gel chromatography (0-20% MeOH in dichloromethane) provided an analytical sample (10 mg, 408 M+H) of the title compound.
Reaction SMILES: C(N(CC)CC)C.Cl[C:9]1[N:14]=[C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:12]=[C:11](Cl)[N:10]=1>O1CCCC1.[C].[Pd]>[N:10]1[CH:11]=[CH:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:14][CH:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc(Cl)n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccncn1
Reaction time: 6 h
Yield: 86605.9 %

Procedure:
Triethylamine (48.03 g, 0.475 mmol) was added to a solution of ethyl 2,6-dichloropyrimidine-4-carboxylate (intermediate 4, 38.60 g, 0.175 mmol) in tetrahydrofuran (700 ml). The solution was added with Palladium-carbon(5%), and stirred under a hydrogen atmosphere for 6 hours. The solid in the reaction system was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give ethyl pyrimidine-4-carboxylate (intermediate 5, 23.06 g, 87%).
Reaction SMILES: C(N(CC)CC)C.[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14])([O-:10])=[O:9].[C:20]1([CH:26]2[NH:31][C:30](=[O:32])[CH2:29][C:28](=O)[CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[N+:8]([C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13]([C:28]1[CH2:27][CH:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:31][C:30](=[O:32])[CH:29]=1)=[O:14])([O-:10])=[O:9]
Reactant: O=C1CC(=O)NC(c2ccccc2)C1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C=C(C(=O)c2ccccc2[N+](=O)[O-])CC(c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 56.4 %

Procedure:
Triethylamine (3.4 ml) was added at 0°-5° C. to a stirred solution of 2-nitrobenzoyl chloride (4.9 g) and 6-phenylpiperidine-2,4-dione (5 g) in dry dichloromethane (100 ml) and the mixture stirred at ambient temperature for 3.5 hours. The solution was washed successively with 2N hydrochloric acid (25 ml), water (2×25 ml), 5% w/v aqueous sodium carbonate solution (25 ml) and water (3×25 ), dried over magnesium sulphate and evaporated under reduced pressure to give a pale yellow solid which was recrystallised from a mixture of ethyl acetate and hexane (4:1; 20 ml) to give 5,6-dihydro-4-(2-nitrobenzoyl)-6-phenylpyridin-2(1H)-one (4.8 g), mp 139°-141° C., as a light yellow crystalline solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[C:11]([Cl:18])=[CH:10][C:9]=1[NH:19][C:20](=[O:36])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:18][C:11]1[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]2[N:7]=[C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=4)[CH:24]=3)[CH2:21][C:20](=[O:36])[NH:19][C:9]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)c(Cl)cc1NC(=O)CC(=O)c1cccc(-c2ccccn2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(c2cccc(-c3ccccn3)c2)=Nc2cc(C(F)(F)F)c(Cl)cc2N1

Procedure:
The title compound was prepared from {4-chloro-2-[3-oxo-3-(3-pyridin-2-yl-phenyl)-propionylamino]-5-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M98) (0.27 g, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (120 mg, 57%).