Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:30]3[CH:31]=[C:32]4[O:37][CH2:36][O:35][C:33]4=[CH:34][C:29]=3[CH2:28][C:27]([CH3:38])=[N:26][N:25]=2)=[CH:20][CH:19]=1.C(O)C>ClCCl>[C:1]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:30]3[CH:31]=[C:32]4[O:37][CH2:36][O:35][C:33]4=[CH:34][C:29]=3[CH2:28][C:27]([CH3:38])=[N:26][N:25]=2)=[CH:20][CH:19]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC1=NN=C(c2ccc(NC(=O)c3ccccc3)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.2 %

Procedure:
1.0 ml (15 mmol) of benzoyl chloride and 2.1 ml (15 mmol) of triethylamine were added to a solution of 4 g (13.6 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine in dichloromethane and the reaction mixture was stirred at 25 ° C. for 24 hours. The solution was extracted with 3×30 ml of water, 3×20 ml of a 4% aqueous sodium hydroxide solution and finally with 2×30 ml of distilled water. The organic layer was dried, evaporated under reduced pressure, then the crystalline residue was treated with 20 ml of hot ethanol to obtain 3.97 g of raw product, m.p. 242°-243° C. This raw product was repeatedly treated with 20 ml of hot ethanol, next day it was filtered at 0°-5° C., washed with 3×3 ml of ethanol and dried at 100° C. to yield 3.85 g (71.3%) of the pure aimed product, m.p. 246°-247° C. (decomp.).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH:3]1C(=C)C(=O)NC2C=CC(OC)=CC=2C1=O.FC1C=CC2NC(=O)CCC(=O)C=2C=1.[CH3:34][C:35]1[CH:36]=[CH:37][C:38]2[C:44](=[O:45])[CH2:43][CH2:42][C:41](=[O:46])[NH:40][C:39]=2[CH:47]=1>>[CH3:1][N:2]([CH:19]=[C:43]1[CH2:42][C:41](=[O:46])[NH:40][C:39]2[CH:47]=[C:35]([CH3:34])[CH:36]=[CH:37][C:38]=2[C:44]1=[O:45])[CH3:3]
Reactant: Cc1ccc2c(c1)NC(=O)CCC2=O
Reactant: C=C1C(=O)Nc2ccc(OC)cc2C(=O)C1N(C)C
Agent: O=C1CCC(=O)c2cc(F)ccc2N1
Product: Cc1ccc2c(c1)NC(=O)CC(=CN(C)C)C2=O

Procedure:
In a manner similar to that described above for 4-dimethylamino-methylene-7-methoxy-3,4-dihydro-1H-benzo[b]azepine-2,5-dione, 7-fluoro-3,4-dihydro-1H-benzo[b]azepine-2,5-dione, 0.64 g of 8-methyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione was converted to v-g (87%): MS m/z=245 (M+H).
Reaction SMILES: [K].[C:2]([O:7][CH2:8][CH2:9][CH2:10][S:11]([OH:14])(=[O:13])=[O:12])(=[O:6])[C:3]([CH3:5])=[CH2:4].[Cl-].[C:16]1([S+:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:2]([O:7][CH2:8][CH2:9][CH2:10][S:11]([O-:14])(=[O:12])=[O:13])(=[O:6])[C:3]([CH3:5])=[CH2:4].[C:29]1([S+:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C=C(C)C(=O)OCCCS(=O)(=O)O
Agent: [Cl-]
Agent: [K]
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 100 g of methylene chloride were added 2.5 g (10 mmol) of a potassium salt of 3-sulfopropyl methacrylate and 23 g (10 mmol) of an aqueous solution of triphenylsulfonium chloride prepared in Synthesis Example 1-1. The mixture was stirred at room temperature for 30 minutes. The organic layer was taken out and washed with water. It was combined with ethanol and concentrated in vacuum while azeotroping off the residual water. There was obtained 3.3 g of triphenylsulfonium 3-methacryloyloxypropanesulfonate. To 3.3 g of triphenylsulfonium 3-methacryloyloxypropanesulfonate were added 100 mg (0.6 mmol) of 28 wt % sodium methoxide in methanol and 15 g of methanol. The mixture was stirred at room temperature for 3 days. Then 70 mg of 35% aqueous hydrochloric acid was added to quench the reaction. The reaction solution was combined with methyl isobutyl ketone and concentrated in vacuum while distilling off the residual water. Diisopropyl ether was added to the residue for recrystallization. The crystals were collected and dried, obtaining the target compound, triphenylsulfonium 3-hydroxypropanesulfonate. White crystals, 2.1 g, yield 52%. The compound, designated PAG intermediate 2, has the following structure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)[CH3:2].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:13](=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[S:9][CH:10]=1)[CH3:2]
Reactant: CCOC(=O)Cc1csc(N)n1
Reactant: CCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCC(=O)Nc1nc(CC(=O)OCC)cs1

Procedure:
In a first step, (2-amino-thiazol-4-yl)-acetic acid ethyl ester is coupled to dodecanoyl chloride as described in the method of Example 334 to provide (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester as a crude solid. In a second step, the crude solid of (2-Dodecanoylamino-thiazol-4-yl)-acetic acid ethyl ester was deprotected using LiOH (2-fold excess) in THF/H2O to provide the title compound as a crude solid, which was used directly without further purification or characterization.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])([O-])=O.CC(O)=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(S(F)(F)(F)(F)F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(N)cc(S(F)(F)(F)(F)F)c1
Yield: 92.3 %

Procedure:
3.0 g of methyl 3-nitro-5-pentafluorosulfanylbenzoate were dissolved in 50 ml of MeOH and 5 ml of HOAc and 200 mg of Pd/C (10%) were added. The mixture was hydrogenated under a standard pressure of hydrogen atmosphere for 20 h, then hydrogenation was effected under 6 bar of hydrogen for a further 2 days. The catalyst was filtered off and the solvent removed under reduced pressure to obtain 2.5 g of an amorphous solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:39])[CH:37]=[CH2:38]>CN(C=O)C>[CH2:1]([NH:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([S:17]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:36](=[O:39])[CH:37]=[CH2:38])=[CH:24][CH:25]=2)(=[O:19])=[O:18])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)NCc3ccccc3)CC2)cc1
Reactant: C=CC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)NCc3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 10.1 %

Procedure:
4-(4-Amino-benzenesulfonyl)-piperazine-1-carboxylic acid benzylamide (0.47 g, 1.25 mmol) was dissolved in DMF (10 ml). To this was added diisopropylethylamine (0.33 ml, 1.9 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.12 ml, 1.5 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material was purified by column chromatography (elution: 50% heptane, 50% ethyl acetate to 100% ethyl acetate) to give the title compound (54 mg, 10% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:18]=[CH:17][C:16](Br)=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)=[O:5].[N:20]1([CH2:26][C:27]2[S:31][C:30](B3OC(C)(C)C(C)(C)O3)=[CH:29][CH:28]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>>[NH2:1][C:2]1[N:18]=[CH:17][C:16]([C:30]2[S:31][C:27]([CH2:26][N:20]3[CH2:21][CH2:22][O:23][CH2:24][CH2:25]3)=[CH:28][CH:29]=2)=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([CH3:14])[CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)s2)OC1(C)C
Reactant: Cc1cc(NC(=O)c2cc(Br)cnc2N)cc(C)n1
Product: Cc1cc(NC(=O)c2cc(-c3ccc(CN4CCOCC4)s3)cnc2N)cc(C)n1

Procedure:
Reaction of 2-amino-5-bromo-N-(2,6-dimethyl-pyridin-4-yl)-nicotinamide with 5-(4-morpholinylmethyl)thiophene-2-boronic acid pinacol ester gives the compound “A26”; HPLC/MS: 1.09 min, [M+H]=424;
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[C:16](Cl)(=[O:18])[CH3:17].O>ClCCl>[Cl:1][C:2]1[C:7]([NH:8][C:16](=[O:18])[CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(=O)Cl
Reactant: Nc1cccnc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cccnc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a solution of 2chloro-3-aminopyridine (51.4 g, 400 mmol) in dichloromethane (800 mL) at 0° C. was added triethylamine (31.0 mL, 440 mmol) followed by acetyl chloride (62.0 mL, 440 mmol). The reaction was allowed to warm to room temperature and was stirred overnight. The reaction mixture was poured into water (800 mL) and the layers were separated. The organic layer was treated with Darco™-G-60 (activated charcoal), heated to reflux, filtered over Celite™ (diatomaceous earth manufactured by Celite Corp., Santa Barbara, Calif.) and concentrated to an oil. The oil was crystallized in diisopropyl ether and the solids were filtered to afford 42.4 g (62% yield) of N-(2-chloro-pyridin-3-yl)-acetamide. M. p.=81-83° C. 1 NMR (400 MHz, CDCl3) δ2.23 (s, 3), 7.21 (dd, 1, J=8.1, 4.7) 7.67 (bs, 1), 8.06 (dd, 1, J=4.7, 1.3), δ8.66 (d, 1, J=7.9). 13C NMR (100 MHz, CDCl3) δ24.93, 123.34, 129.06, 131.89, 143.81, 144.08, 168.79.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[CH:20]=[O:21])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH:13]=[C:12]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[C:16]3[CH2:20][OH:21])[N:11]=[CH:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=Cc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCc1nccn1Cc1cn(-c2ccc(Cl)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-[1-(3,4-dichloro-phenyl)-1H-imidazol-4-ylmethyl]-1H-imidazole-2-carbaldehyde (0.52 g, 1.6 mmol) in MeOH (16 ml) was treated with sodium borohydride (0.12 g, 3.2 mmol). The mixture was stirred at rt for 2 h. Then all volatiles were evaporated and the residue was partitioned (AcOEt/H2O). The organic phase was dried (Na2SO4) and concentrated to approximately 30 ml. The title compound was obtained as a white crystalline material (0.21 g, 41%). Mp. 202-203° C. (AcOEt), MS: m/e=322 (M+).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12](=[O:14])[CH3:13]>>[C:1]1([N:7]2[C:11]([CH:12]([OH:14])[CH3:13])=[CH:10][CH:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC=O
Reactant: c1ccc(-n2cccn2)cc1
Product: CC(O)c1ccnn1-c1ccccc1
Yield: 54 %

Procedure:
This compound was prepared from 1-phenyl-1H-pyrazole and acetaldehyde using the method described in example 100B and isolated as a yellow oil in 54% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:18])([F:17])[F:16].Cl>CO.O>[Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]([F:17])([F:18])[F:16]
Reactant: O=c1c(Cl)c(Oc2ccccc2C(F)(F)F)cnn1C1CCCCO1
Agent: Cl
Solvent: CO
Solvent: O
Product: O=c1[nH]ncc(Oc2ccccc2C(F)(F)F)c1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 101.2 %

Procedure:
A solution of 4-chloro-2-(tetrahydro-pyran-2-yl)-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (4.78 g, 12.78 mmol) in methanol (25.5 mL, 0.5M) was treated with a 6N aqueous hydrochloric acid solution (10.6 mL, 1.2M). The reaction solution was heated to 110° C., where it stirred for 4 h and was then allowed to cool down to 25° C. The reaction was diluted with water (250 mL) and extracted with a 90/10 methylene chloride/methanol solution (3×100 mL). The combined organic layers were dried over sodium sulfate, filtered, and dried in vacuo to afford 4-chloro-5-(2-trifluoromethyl-phenoxy)-2H-pyridazin-3-one (3.76 g, 100%) as a white solid; ES+-HRMS m/e calcd for C11H6N2O2F3Cl [M+H+] 291.0143, found 291.0142. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.41-7.51 (m, 2H), 7.74 (t, J=8.2 Hz, 1H), 7.79 (s, 1H), 7.86 (d, J=7.8 Hz, 1H), 13.59 (br. s., 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:15])[C:10]2([CH3:14])[CH3:13])=[CH:5][CH:4]=1.C1C(=O)N([Br:23])C(=O)C1.O>CC#N>[Br:23][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[O:2][CH3:1])[C:10]([CH3:13])([CH3:14])[C:9](=[O:15])[CH2:8][CH2:7]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1ccc2c(c1)C(C)(C)C(=O)CC2
Solvent: O
Solvent: CC#N
Product: COc1cc2c(cc1Br)CCC(=O)C2(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92 %

Procedure:
7-Methoxy-1,1-dimethyl-3,4-dihydro-1H-naphthalen-2-one (Compound A2, 2.0 g, 9.791 mmol) was dissolved in CH3CN (40 mL), added with NBS (1.92 g, 1.1 eq.), and the mixture was stirred at room temperature for 2.5 hr. The reaction solution was added to water (40 mL), and the precipitated solid was filtered to obtain the title compound (white powder, 2.55 g, 92%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][NH2:35])[CH2:29][CH2:28]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([NH:35][CH2:34][CH2:33][N:30]3[CH2:31][CH2:32][O:27][CH2:28][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCOCC1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Product: O=S1CCN(c2nc(NCCN3CCOCC3)nc3c(SCc4ccccc4)ncnc23)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine and 2-morpholinoethyl-amine.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[CH:6][N:5]=1.[CH3:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15](Cl)=O.P(Cl)(Cl)(Cl)=O>C(O)C>[CH3:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]1[NH:10][C:9]2[C:4](=[N:5][CH:6]=[N:7][CH:8]=2)[N:3]=1
Reactant: COc1cc(SC)ccc1C(=O)Cl
Reactant: Nc1cncnc1N
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCO
Product: COc1cc(SC)ccc1-c1nc2ncncc2[nH]1

Procedure:
A mixture of 4.1 g of 4,5-diamino-pyrimidine dihydrochloride, 7.1 g of 2-methoxy-4-methylmercapto-benzoylchloride, and 50 ml of phosphorus oxychloride was refluxed for three hours. The reaction mixture was evaporated until one-half of the original volume remained, and then the remaining mixture was poured into water. The precipitate that formed was dissolved in boiling ethanol, precipitated by addition of ether, and purified by chromatography on silicagel (eluate: methylene chloride/ethanol in a volume ratio of 19:1).
Reaction SMILES: [C:1]1([C:7](=O)[C:8](=O)[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:12][CH:13]([C:17]([NH2:19])=[O:18])[C:14]([NH2:16])=[O:15]>>[CH3:9][C:8]1[NH:16][C:14](=[O:15])[C:13]([C:17]([NH2:19])=[O:18])=[N:12][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: NC(=O)C(N)C(N)=O
Product: Cc1[nH]c(=O)c(C(N)=O)nc1-c1ccccc1

Procedure:
In analogy to the procedure described in example 75a-c, 1-phenyl-1,2-propanedione and 2-aminomalonamide were heated in an aqueous solution to give 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide. Then, the 5-methyl-3-oxo-6-phenyl-3,4-dihydro-pyrazine-2-carboxylic acid amide was treated with triethylamine and phosphorus pentachloride in phosphorus oxychloride at reflux to give 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile. The 3-chloro-5-methyl-6-phenyl-pyrazine-2-carbonitrile was finally treated with 1-(4-fluorophenyl)piperazine and N-ethyldiiso-propyl-amine in N,N-dimethylformamide at room temperature to yield the 4-(4-fluoro-phenyl)-6′-methyl-5′-phenyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl-3′-carbonitrile as yellow solid; m.p. 117-120° C.; MS: 374 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33]([NH2:35])=[O:34]>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][C:31]3[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=3[C:33](=[O:34])[NH2:35])[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH3:29])[CH:15]=1)(=[O:25])[O:22][CH2:23][CH3:24])[CH3:21]
Reactant: NC(=O)c1ccccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccccc3C(N)=O)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and the commercially available 2-aminobenzamide. 1H NMR (400 MHz, DMSO-d6) δ 1.19 (t, J=7.07 Hz, 6H), 3.25 (d, J=21.50 Hz, 2H), 3.76 (s, 3H), 3.93-4.03 (m, 4H), 6.85 (dt, J=8.08, 2.15 Hz, 1H), 7.02 (s, 1H), 7.06 (t, J=7.83 Hz, 1H), 7.38 (t, J=8.21 Hz, 1H), 7.52 (d, J=8.34 Hz, 1H), 7.75 (dd, J=7.96, 1.39 Hz, 1H), 7.77 (br. s., 1H), 8.27 (br. s., 1H), 8.36 (s, 1H), 8.47 (br. s., 1H), 8.80 (s, 1H), 11.82 (s, 1H). MS (ES+): m/z 406.04 (100) [MH+]. HPLC: tR=4.01 min (ZQ3, polar—5 min).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2Cl)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:15]=[N:16][N:17]([CH3:20])[C:18]=2[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1Cl
Reactant: NCc1ccncc1
Product: Cn1ncc(C(=O)Nc2ccc(C(C)(C)C)cc2)c1NCc1ccncc1
Temperature: 160 °C

Procedure:
5-Chloro-1-methyl-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide (530 mg, 1.80 mmol) and powered 40% KF/Alumina (1.04 g, effective 6.0 mmol of KF) were combined and treated with IpOH (6 mL). 4-(Aminomethyl)pyridine (3.9 g, 36 mmol) was added. The headspace of the reaction vessel was purged with argon and the reaction vessel was sealed. The reaction was then heated to 160° C. overnight with stirring. The reaction was cooled to RT and filtered under vacuum, washing the collected solid with fresh IpOH. The filtrate was concentrated under reduced pressure and the recovered material was eluted through a 17×2.5 cm column of silica gel with a 14:7:7:1 and 7:7:7:1 Hexane:MtBE:CH2Cl2:MeOH step gradient giving 1-methyl-5-[(pyridin-4-ylmethyl)-amino]-1H-pyrazole-4-carboxylic acid (4-tert-butyl-phenyl)-amide as a white foamy solid. MS: 364 (M+1). Calc'd. for C21H25N5 O—363.46.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9]CC)=[O:8])[CH2:3][CH2:2]1.[F:12][C:13]([F:55])([F:54])[C:14]1[CH:15]=[C:16]([CH:47]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:49]=1)[CH2:17][N:18]([C@H:31]1[CH2:35][C@@H:34]([CH2:36][O:37][CH3:38])[N:33]([C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41](Cl)[N:40]=2)[CH2:32]1)[C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:21][N:20]=1.[OH-].[Na+].Cl>C(O)(C)C>[F:52][C:50]([F:51])([F:53])[C:48]1[CH:47]=[C:16]([CH:15]=[C:14]([C:13]([F:12])([F:55])[F:54])[CH:49]=1)[CH2:17][N:18]([C:19]1[N:20]=[CH:21][C:22]([C:25]2[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=2)=[CH:23][N:24]=1)[C@@H:31]1[CH2:32][N:33]([C:39]2[C:44]([Cl:45])=[CH:43][N:42]=[C:41]([N:1]3[CH2:2][CH2:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][CH2:6]3)[N:40]=2)[C@H:34]([CH2:36][O:37][CH3:38])[CH2:35]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(Cl)ncc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: COC[C@@H]1C[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(-c3cnn(C)c3)cn2)CN1c1nc(N2CCC(C(=O)O)CC2)ncc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 284.6 %

Procedure:
A 5 ml test tube for microwave reactor is charged with ethyl piperidine 4-carboxylate (202 mg, 1.28 mmol), (3,5-bis-trifluoromethyl-benzyl)-[(3S,5S)-1-(2,5-dichloro-pyrimidin-4-yl)-5-methoxymethyl-pyrrolidin-3-yl]-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amine (170 mg, 0.26 mmol) and isopropanol (1.5 ml). Then, the test tube is set into microwave reactor at 95 degree for 2 hours. After cooling to rt, reaction mixture is transferred into a 25 ml round-bottom flask and solvent is removed under reduced pressure. Then, into the flask is added 1N NaOH (1.28 ml, 1.28 mmol). The mixture is stirred for 1 hour, and pH is adjusted to 6-7 using 1.5 N HCl. The resulted solution is extracted with EtOAc and the organic layer is dried over MgSO4. The solvent is removed under reduced pressure, and the obtained residue is purified with reverse phase column to give 1-[4-((2S,4S)-4-{(3,5-bis-trifluoromethyl-benzyl)-[5-(1-methyl-1H-pyrazol-4-yl)-pyrimidin-2-yl]-amino}-2-methoxymethyl-pyrrolidin-1-yl)-5-chloro-pyrimidin-2-yl]-piperidine-4-carboxylic acid (78 mg, 0.74 mmol, 58% for 2 steps).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C:4](=[O:17])[CH2:5][N:6]1C(=O)C2C(=CC=CC=2)C1=O.[ClH:19]>C(O)(=O)C.O>[ClH:19].[NH2:6][CH2:5][C:4](=[O:17])[CH2:3][CH:2]([CH3:18])[CH3:1]
Reactant: CC(C)CC(=O)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)CC(=O)CN
Temperature: 25 °C
Yield: 81 %

Procedure:
Slurry 2-(4-methyl-2-oxo-pentyl)-isoindole-1,3-dione (2.8 g, 11.4 mmol) in concentrated HCl (18 mL), glacial acetic acid (16 mL) and water (13 mL). Stir the mixture at reflux for 16 h. Cool to room temperature and pour the solution onto ice (25 mL). Filter off the solids, wash the filtrate with cold water (20 mL) and concentrate in vacuo to a solid. Recrystallize the solid in ethanol (15 mL) and diethyl ether (50 mL). Decant off the solvent and dry the white paste under reduced pressure to obtain the desired intermediate as a white solid (1.4 g, 81%).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[NH:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH3:18].[K].[CH3:21]C(C)([O-])C.CI>CN(C=O)C>[O:19]=[S:2]1(=[O:1])[N:7]([CH3:21])[CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]=1[CH3:18]
Reactant: COC(=O)c1ccc(N2CCCNS2(=O)=O)c(C)c1
Reactant: CC(C)(C)[O-]
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCCN(C)S2(=O)=O)c(C)c1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
400 mg (1.41 mmol) methyl 4-(1,1-dioxo-[1,2,6]-thiadiazinan-2-yl)-3-methyl-benzoate dissolved in 4 ml DMF at 40° C. are combined with 240 mg (2.14 mmol) potassium-tert.-butoxide and 96 μl (1.54 mmol) methyl iodide and stirred for 5 hours at 40° C. The reaction solution is evaporated down i. vac., combined with water and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated down i. vac.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:8](Br)Br)=[N:4][CH:5]=[CH:6][CH:7]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:14]>N1CCOCC1.CCOC(C)=O>[Br:1][C:2]1[C:3]([CH:8]=[O:14])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: Brc1cccnc1C(Br)Br
Solvent: C1COCCN1
Solvent: CCOC(C)=O
Product: O=Cc1ncccc1Br
Temperature: 60 °C

Procedure:
A suspension of 3-bromo-2-dibromomethyl-pyridine (10.0 g, 30.32 mmole) in morpholine (30.0 mL) was heated to 60° C. for 1 h. The reaction mixture was cooled to rt and diluted with EtOAc (200 mL). The pH was adjusted to 4.0 by adding citric acid (40.0 g). The reaction mixture was then extracted with EtOAc (3×200 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography using silica (100-200 mesh) using 3% EtOAc in hexane as eluent to give 3-bromo-pyridine-2-carbaldehyde. 1H-NMR (400 MHz, CDCl3): δ 10.23 (s, 1H), 8.74-8.76 (d, 1H), 8.02-8.04 (d, 1H), 7.26-7.38 (t, 1H).