Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10](N)=[O:11])=[C:6]([Cl:13])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[CH3:22][CH2:23][OH:24]>>[NH2:1][C:2]1[C:7]([CH2:8][CH2:9][C:10]([O:24][CH2:23][CH3:22])=[O:11])=[C:6]([Cl:13])[N:5]=[C:4](/[CH:14]=[CH:15]/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: NC(=O)CCc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Reactant: CCO
Product: CCOC(=O)CCc1c(N)nc(/C=C/c2ccccc2)nc1Cl
Temperature: 25 °C

Procedure:
3-{4-Amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanamide (0.175 g, 0.58 mmol) was dissolved in EtOH (15 mL) and HCl gas was bubbled through the solution until saturated. The solution was heated at reflux for 2 h, cooled to ambient temperature and concentrated under vacuum. The residue was dissolved in water and extracted with EtOAc (3×). The organic layers were combined, dried over Na2SO4, filtered and concentrated under vacuum to yield ethyl 3-{4-amino-6-chloro-2-[(E)-2-phenylethenyl]-5-pyrimidinyl}propanoate as a white solid. LCMS: m/z 332.2 (MH+). This product was then dissolved in DMF (5 mL), treated with K2CO3 (0.16 g, 1.16 mmol) and heated at 75° C. for 30 minutes. The solution was cooled, diluted with water and extracted with Et2O (3×). The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was then purified by column chromatography (silica gel) to yield an additional 0.11 g of the desired compound as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:18]([OH:20])=O)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:7]=1.[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C@@H:38]([NH2:45])[C:39]3[O:43][N:42]=[C:41]([CH3:44])[N:40]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]>>[Cl:23][C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][C@@H:38]([NH:45][C:18]([C:4]3[CH:5]=[C:6]([C:8]4[CH:9]=[CH:10][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:13]=4)[CH:7]=[C:2]([F:1])[C:3]=3[O:21][CH3:22])=[O:20])[C:39]3[O:43][N:42]=[C:41]([CH3:44])[N:40]=3)=[CH:33][CH:32]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Reactant: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)O
Product: COc1c(F)cc(-c2ccc(C(F)(F)F)cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1

Procedure:
5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide was prepared from 5-Fluoro-4-methoxy-4′-trifluoromethyl-biphenyl-3-carboxylic acid (0.06 g, 0.19 mmol) and 2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine (0.063 g, 0.19 mmol) following general procedure A.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH2:25]>O1CCCC1>[F:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[NH:25][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:2]=1[OH:1]
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: Nc1ccc(F)cc1F
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccc(F)cc2F)c(O)c1

Procedure:
To a solution of 2-hydroxy-4-methoxybenzoic acid (1.68 g, 10 mmole) in tetrahydrofuran (40 mL) was added thionyl chloride (2.5 mL, 35 mmole) and refluxed 3 hr. The mixture was steamed (110° C.) by Dean-Stark. The residue was directly reacted with 2,4-difluorobenzenamine (1 mL, 10 mmole) in THF (40 mL) for 14 hr. The reaction mixture was concentrated and extracted with ethyl acetate, dried over anhydrous magnesium sulfate. Recrystallization of desired products from hot dichloromethane afforded the compound.
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][CH:4]([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:8](=[O:12])[C:9]([CH3:11])=[CH2:10])[CH2:3]1.[O-]Cl.[Na+].C(=O)(O)[O-:26].[Na+]>CN(C=O)C>[F:1][C:2]1([F:21])[CH2:3][CH:4]([CH2:6][C@H:7]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[C:8]([C@@:9]2([CH3:11])[CH2:10][O:26]2)=[O:12])[CH2:5]1
Reactant: O=C([O-])O
Reactant: C=C(C)C(=O)[C@H](CC1CC(F)(F)C1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-]Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CC(F)(F)C1)C(=O)[C@@]1(C)CO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
A solution of (S)-tert-butyl 1-(3,3-difluorocyclobutyl)-4-methyl-3-oxopent-4-en-2-ylcarbamate (0.80 g, 2.6 mmol) in DMF (20 mL) was cooled to 0° C. and 10% aqueous NaClO solution (7.90 mL, 10.6 mmol) was added while keeping the internal temperature below 5° C. The reaction mixture was stirred for 1 h at 0° C. and poured into saturated aqueous sodium bicarbonate (50 mL). The resulting mixture was extracted with EtOAc (50 mL×3). The organic extracts were combined, washed with brine (100 mL×2), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=200:1 to 50:1) to afford tert-butyl ((S)-3-(3,3-difluorocyclobutyl)-1-((R)-2-methyloxiran-2-yl)-1-oxopropan-2-yl)carbamate (510 mg, 62% yield). 1H NMR (300 MHz, CDCl3): δ 5.02 (d, J=8.7 Hz, 1H), 4.25 (m, 1H), 3.23 (d, J=4.5 Hz, 1H), 2.93 (d, J=4.8 Hz, 1H), 2.73 (m, 2H), 2.25 (m, 3H), 1.92 (m, 1H), 1.55 (m, 1H), 1.54 (s, 3H), 1.43 (s, 9H). MS (EI) for C15H23F2NO4, found 358.14 [M+K]+.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:18]([CH:20]([NH2:23])[CH2:21][CH3:22])[CH3:19].C([O-])(=O)C.[K+]>[Cu].O>[CH2:18]([CH:20]([NH:23][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:21][CH3:22])[CH3:19]
Reactant: CCC(N)CC
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Agent: [Cu]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: CCC(CC)Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 180 °C

Procedure:
A Parr stainless steel high pressure reactor was charged with 1-chloroanthraquinone (24.3 g), 1-ethylpropylamine (17.5 g), potassium acetate.(14.0 g), activated copper metal (0.7 g), and water (0.05 g). The reaction vessel was sealed and heated to a temperature of 180° C. in an oil bath and maintained at that temperature for 12 hours. The oil bath was removed and the vessel was allowed to return to ambient conditions. The solid was extracted with methylene chloride and the insoluble materials removed by filtration. The solvent was removed and the solid recrystallized from hot methanol. The material was chromatographed on a silica gel column using toluene as the eluent.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][NH:20]3)=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:23])[CH3:2].[Cl:25][C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([Cl:25])[CH:27]=3)(=[O:34])=[O:33])=[CH:16][CH:15]=2)=[O:13])=[CH:7][C:6]=1[F:23])[CH3:2]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)NCC3)cc1F
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cccc(Cl)c2)CC3)cc1F

Procedure:
4-{[1-(3-Chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid, m/z (ES+): 475.18 (M+H+.), was prepared in analogy to example 1, steps 1 to 5. Step 2 was performed using 4-amino-2-fluorobenzoic acid ethyl ester and yielded 2-fluoro-4-[(1H-indole-6-carbonyl)-amino]-benzoic acid ethyl ester. This was reduced to 4-[(2,3-dihydro-1H-indole-6-carbonyl)-amino]-2-fluoro-benzoic acid ethyl ester in step 3. Step 4 was performed using 3-chloro-benzenesulfonyl chloride, yielding 4-{[1-(3-chloro-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-2-fluoro-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Cl[C:7]1[C:12]([NH2:13])=[C:11]([Cl:14])[N:10]=[CH:9][N:8]=1>C(N(CC)CC)C>[NH2:13][C:12]1[C:7]([CH2:1][NH2:2])=[N:8][CH:9]=[N:10][C:11]=1[Cl:14]
Reactant: CN
Reactant: Nc1c(Cl)ncnc1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: NCc1ncnc(Cl)c1N
Temperature: 80 °C

Procedure:
To 1 mL of methylamine, cooled at −80° C. in a steel vial, ethanol (13 mL) and triethylamine (1.3 mL) were added. Commercially available 4,6-dichloro-pyrimidin-5-yl-amine (3.0 mmol) was added to the solution and the reaction mixture heated at 80° C. for 3 hours. The solvent was removed in vacuo, and the resulting compound, (5-amino-6-chloropyrimidin-4-yl)methylamine, was obtained after silica gel chromatography and/or crystallization.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12](O)=[O:13]>>[F:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[CH3:18])[C:12]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:13]
Reactant: O=C1CNCCN1
Reactant: Cc1ccc(C(=O)O)cc1F
Product: Cc1ccc(C(=O)N2CCNC(=O)C2)cc1F

Procedure:
The title compound was prepared according to the procedure described in Step-1 of Intermediate F using piperazin-2-one and 3-fluoro-4-methylbenzoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([OH:13])=O)[S:8][C:6]=2[N:7]=1.[CH3:20][C:21]1([CH3:31])[NH:26][CH2:25][CH2:24][N:23]([CH:27]2[CH2:30][O:29][CH2:28]2)[CH2:22]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[N:10]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][N:23]([CH:27]4[CH2:30][O:29][CH2:28]4)[CH2:22][C:21]3([CH3:31])[CH3:20])=[O:13])[S:8][C:6]=2[N:7]=1
Reactant: O=C(O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: CC1(C)CN(C2COC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(C2COC2)CCN1C(=O)c1nc2c(N3CCOCC3)nc(Cl)nc2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carboxylic acid (100 mg, 0.33 mmol), 3,3-dimethyl-1-oxetan-3-ylpiperazine (62 mg, 0.36 mmol), HATU (278 mg, 0.37 mmol) and DIPEA (65 μL, 0.37 mmol) in DCM (3 mL) was allowed to stir at r.t. for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 0-2%) affording the title compound as a yellow solid. LCMS (method H): RT 2.67 min, [M+H]+ 453.3
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([P:16]([CH3:19])([CH3:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[C:30]([CH:32]=[CH:33][CH:34]=2)[NH2:31])[CH2:24][CH2:23]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:18][P:16]([CH3:19])([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:31][C:30]4[CH:32]=[CH:33][CH:34]=[C:28]([N:25]5[CH2:24][CH2:23][N:22]([CH3:21])[CH2:27][CH2:26]5)[CH:29]=4)[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)=[O:17]
Reactant: CP(C)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: CN1CCN(c2cccc(N)c2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1CCN(c2cccc(Nc3nc4c(-c5ccc(P(C)(C)=O)cc5)cccn4n3)c2)CC1

Procedure:
198 c) {8-[4-(Dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine was prepared from 2-chloro-8-[4-(dimethyl-phosphinoyl)-phenyl]-[1,2,4]triazolo[1,5-a]pyridine (100.0 mg, 0.3271 mmol) and 3-(4-methylpiperazin-1-yl)aniline (70.0 mg, 0.366 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (28.0 mg, 0.0512 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a tan solid (0.097 g, 64%). MP=243-246° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.46 (d, J=6.2 Hz, 1H), 8.15 (d, J=8.0 Hz, 2H), 7.92-7.84 (m, 2H), 7.63-7.50 (m, 1H), 7.34 (s, 1H), 7.23 (t, J=8.2 Hz, 1H), 7.02-6.96 (m, 2H), 6.84 (s, 1H), 6.59 (d, J=7.8 Hz, 1H), 3.30-3.25 (m, 4H), 2.63-2.58 (m, 4H), 2.37 (s, 3H), 1.80 (s, 3H), 1.77 (s, 3H). MS=461 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([C:21](O)=[O:22])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH3:27])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.C([N:38](CC)CC)C.N>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[C:20]([C:21](=[O:22])[NH2:38])=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([CH3:27])[CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)CC
Reactant: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(=O)O)cc1[N+](=O)[O-]
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c(C(N)=O)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 97 %

Procedure:
To a solution of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-5-carboxy-2-methylnitrobenzene (4.8 g) in dichloromethane (100 ml) were added isobutyl chloroformate (1.7 ml) and triethylamine (1.8 ml) in an ice bath and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added 28% aqueous ammonia (0.8 ml) and the resulting mixture was stirred for 2 hours. The reaction mixture was concentrated in vacuo. The residue was purified by chromatography on a silica gel column using dichloromethane/methanol=19/1 as an eluant to give the desired compound (4.7 g, yield 97%) as a white solid.
Reaction SMILES: [O:1]=[S:2]1(=[O:39])[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[N:18](COCC[Si](C)(C)C)[CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[C:10]([N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)[CH:9]=2)[CH2:4][CH2:3]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[O:39]=[S:2]1(=[O:1])[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]([C:17]3[NH:18][CH:19]=[C:20]([C:22]#[N:23])[N:21]=3)=[O:16])=[C:10]([N:32]3[CH2:37][CH2:36][CH:35]([CH3:38])[CH2:34][CH2:33]3)[CH:9]=2)[CH2:6][CH2:7]1
Reactant: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCN(c2cc(C3CCS(=O)(=O)CC3)ccc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-yl)-2-(4-methyl-piperidin-1-yl)-phenyl]-amide (as prepared in the previous step, 19.0 mg, 0.0330 mmol) in 1 mL of 2:1 TFA/DCM was stirred at RT for 4 h. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10-20% EtOAc/DCM) gave 13.2 mg (90%) of the title compound as a white solid: 1H-NMR (CDCl3; 400 MHz): δ 12.00 (s, 1H), 10.29 (s, 1H), 8.33 (d, 1H, J=8.3 Hz), 7.76 (d, 1H, J=2.3 Hz), 7.12 (dd, 1H, J=8.3, 1.7 Hz), 7.06 (d, 1H, J=1.7 Hz), 3.14-3.22 (m, 4H), 3.01 (d, 2H, J=12.0 Hz), 2.68-2.83 (m, 3H), 2.38-2.53 (m, 2H), 2.23 (d, 2H, J=14.5 Hz), 1.50-1.85 (m, 5H), 1.09 (d, 3H, J=5.8 Hz). Mass spectrum (ESI, m/z): Calcd. for C22H27N5O3S, 442.2 (M+H), found 442.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].[NH2:32][CH2:33][CH2:34][CH2:35][N:36]1[CH2:40][CH2:39][CH2:38][C:37]1=[O:41]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:32][CH2:33][CH2:34][CH2:35][N:36]3[CH2:40][CH2:39][CH2:38][C:37]3=[O:41])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NCCCN1CCCC1=O
Product: Cc1cc(F)ccc1-c1nc(NCCCN2CCCC2=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 85.1 %

Procedure:
Following the general procedure outlined in Example 225, the product of Example 48 (100 mg, 0.22 mmol) and N-(3′-aminopropyl)-2-pyrrolidinone (96 mg, 0.67 mmol) were reacted to give the crude material. Purification by flash chromatography eluting with EtOAc/hexane/triethylamine (70/30/2, v/v/v), followed by recrystallization from ethanol and hexane, gave the desired product 95 mg (85%). LC-MS: 508.2 (MH+, m/z), 2.02 (Rt, min).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:23])=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(Cc2cccc(OC)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3cccc(OC)c3)CC2)cc1

Procedure:
4-(4-Methoxy-benzenesulfonyl)1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-Methoxy-benzenesulfonyl)-1-(3-methoxy-benzyl)-piperidine-4-carboxylic acid ethyl ester (2.4 g, 5.36 mmol) dissolve in methanol (30 mL), 10 N sodium hydroxide (10 mL), tetrahydrohydrofuran (20 mL). The resulting reaction mixture was worked up as outlined in example 83. Yield 710 mg (32%). white solid mp 199° C., MS: 419.9 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.Br[CH2:23][C:24]1[CH:25]=[C:26]([C:41]([F:44])([F:43])[F:42])[CH:27]=[C:28]2[C:32]=1[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[N:30]=[CH:29]2.[H-].[Na+]>CN(C)C=O>[C:16]1([C:3]2([CH2:2][O:1][CH2:23][C:24]3[CH:25]=[C:26]([C:41]([F:44])([F:42])[F:43])[CH:27]=[C:28]4[C:32]=3[N:31]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[N:30]=[CH:29]4)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Reactant: C[Si](C)(C)CCOCn1ncc2cc(C(F)(F)F)cc(CBr)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cnn(COCC[Si](C)(C)C)c23)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (0.669 g, 2.3 mmol) and 7-(bromomethyl)-5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole (0.94 g, 2.3 mmol) in dimethylformamide (7 mL) at 0° C. was added sodium hydride (60% in mineral oil, 0.119 g, 3.0 mmol). The resulting solution was stirred at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12% EtOAc/Hex) gave 1.13 g (79%) as an oil. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.98 (s, 1H), 7.41 (d, J=0.9 Hz, 1H), 7.10-7.28 (m, 5H), 5.37 (s, 2H), 4.73 (s, 2H), 3.69 (bs, 2H), 3.45 (s, 2H), 3.39 (m, 2H), 3.01 (m, 2H), 2.13 (m, 2H), 1.77 (m, 2H), 1.41 (s, 9H), 0.77 (m, 2H), −0.11 (s, 9H); 13C-NMR (CDCl3, 126 MHz) δ 155.0 142.7, 139.3, 134.7, 128.4, 127.1, 126.4, 125.6, 124.8, 124.6 (q, J=273 Hz), 123.5 (q, J=32 Hz), 122.1, 119.2, 79.4, 79.2, 79.0, 70.6, 66.1, 41.5, 40.3 (br), 32.2, 28.5, 17.8, −1.4. Mass spec.: 620.15 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Br.Br.Br[CH2:24][C:25]1[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:24][C:25]3[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncc(CBr)c(N)n1
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: Br
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ncc(CN2CCN(c3cccc(Cl)c3)CC2)c(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.7 %

Procedure:
A solution of 13.5 g (0.050 mol) of 1-(3-chloro-phenyl)-piperazine in 500 ml of tetrahydrofuran was treated with 35 ml (0.25 mol) of triethylamine and 18.2 g (0.050 mol) of 5-bromomethyl-pyrimidine-2,4-diamine dihydrobromide and the mixture was stirred at room temperature under argon for 16 hours. The suspension obtained was suction filtered and the filtrate was completely freed from the solvents. The residue was chromatographed over silica gel with acetonitrile/methanol 1:1 as the eluent and digested in diethyl ether. 10 g (63%) of 5-[4-(3-chloro-phenyl)-piperazin-1-ylmethyl]-pyrimidine-2,4-diamine were obtained as beige crystals; m.p. 222°-226°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[C:13]([CH2:14][C:15]([NH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[CH:21]=2)=O)=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1.P(Cl)(Cl)(Cl)=O>>[CH3:1][O:2][C:3](=[O:28])[CH2:4][C:5]1[C:13]([CH2:14][C:15]2[C:25]3[C:20](=[CH:21][C:22]([O:26][CH3:27])=[CH:23][CH:24]=3)[CH2:19][CH2:18][N:17]=2)=[CH:12][C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=1
Reactant: COC(=O)Cc1cc2c(cc1CC(=O)NCCc1cccc(OC)c1)OCO2
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)Cc1cc2c(cc1CC1=NCCc3cc(OC)ccc31)OCO2

Procedure:
The title compound was prepared as described in Example 7 using 6-[2-[[2-(3-methoxyphenyl)ethyl]amino]-2-oxoethyl]-1,3-benzodioxole-5-acetic acid methyl ester (VIIIb) (7.71 g, 0.02 mole) and phosphorus oxychloride (7.66 g, 0.05 mole). The crystalline product that was obtained was recrystallized from acetonitrile. The product was amounted to 1.4 g (15%), and melted at 182°-184° dec.
Reaction SMILES: [2H][C:2]1[C:7]([2H])=[C:6]([NH2:9])[C:5]([NH2:10])=[C:4]([2H])[C:3]=1[2H].[Br:13][CH2:14][C:15](=O)[C:16](O)=[O:17]>O1CCCC1>[Br:13][CH2:14][C:15]1[C:16](=[O:17])[NH:10][C:5]2[C:6]([N:9]=1)=[CH:7][CH:2]=[CH:3][CH:4]=2
Reactant: O=C(O)C(=O)CBr
Reactant: [2H]c1c([2H])c([2H])c(N)c(N)c1[2H]
Solvent: C1CCOC1
Product: O=c1[nH]c2ccccc2nc1CBr
Temperature: 25 °C
Reaction time: 1 h

Procedure:
O-phenylenediamine (1.0 g., 0.0092 mol.) was dissolved in tetrahydrofuran (50 ml.) and 3-bromopyruvic acid (1.7 g., 0.0102 mol.) added. The reaction mixture was stirred at room temperature for one hour, during which time the product precipitated as a yellow solid. The product was collected by filtration and crystallized from methylene chloride. (0.91 g., m.p. 221°-223° (dec.) 41%)
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=1.[Br:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH:19]=[O:20].C1C=C[NH+]=CC=1.C1C=C[NH+]=CC=1.[O-][Cr](O[Cr]([O-])(=O)=O)(=O)=O>>[Br:15][C:16]1[CH:17]=[C:18]([C:19]([C:3]2[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH3:12])=[C:5]([O:13][CH3:14])[CH:4]=2)=[O:20])[CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc(Br)cc(OC)c1OC
Reactant: O=Cc1cccc(Br)c1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Mg]
Agent: c1cc[nH+]cc1
Product: COc1cc(C(=O)c2cccc(Br)c2)cc(OC)c1OC

Procedure:
First, magnesium was added to 1-bromo-3,4,5-trimethoxybenzene as a starting material, as shown in Reaction 6, and then 3-bromobenzaldehyde was added thereto to obtain a compound. Thus obtained compound was oxidized using PDC to obtain a Compound 21 derivative [(3-bromophenyl)(3,4,5-trimethoxyphenyl)methanone]. Thus obtained compound and thiophen-3-boronic acid were subjected to the Suzuki reaction, in the same manner as in the synthesis of Compound 457, to obtain Compound 568.