Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:17])[CH2:3][NH:4][CH:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:28][C:27]=2[O:38][CH3:39])[C:22]([Cl:40])=[CH:21][N:20]=1>>[Cl:40][C:22]1[C:23]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[CH:28][C:27]=2[O:38][CH3:39])=[N:24][C:19]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][CH:5]([NH:4][CH2:3][CH:2]([F:17])[F:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:20][CH:21]=1
Reactant: Nc1ccc2c(c1)CCC(NCC(F)F)CC2
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1nc(Nc2ccc3c(c2)CCC(NCC(F)F)CC3)ncc1Cl
Yield: 63 %

Procedure:
In an analogous procedure to Example 651, part c, N*7*-(2,2-Difluoro-ethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine was combined with (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine to yield 5-Chloro-N*2*-[7-(2,2-difluoro-ethylamino)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2-yl]-N*4*-(2-methoxy-4-morpholin-4-yl-phenyl)-pyrimidine-2,4-diamine (72.79 mg, 63% yield) as a white powder. 1H-NMR (CDCl3) δ 8.24 (d, J=8.81 Hz, 1H), 8.00 (s, 1H), 7.58 (s, 1H), 7.34 (s, 1H), 7.24 (m, 2H), 7.03 (d, J=8.16 Hz, 1H), 6.84 (s, 1H), 6.54 (s, 1H), 6.49 (d, J=9.0 Hz, 1H), 5.83 (m, 1H), 3.90 (m, 7H), 3.15 (m, 4H), 3.00 (m, 2H), 2.80 (m, 3H), 2.67 (m, 2H), 2.07 (m, 2H), 1.32 (m, 2H). LC/MS (ESI+)=559 (M+H). MP=181-183° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[Br:12][CH2:13][CH2:14][CH2:15]Br.C([O-])([O-])=O.[K+].[K+]>CCO>[Br:12][CH2:13][CH2:14][CH2:15][O:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ccc(O)cc2[nH]1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1[nH]c2ccc(OCCCBr)cc2[nH]1
Reaction time: 8 h
Yield: 2.7 %

Procedure:
A solution of intermediate 38 (5 g, 33.3 mmol), 1,3-dibromopropane (4 mL, 33.3 mmol) and anhydrous K2CO3 (4.6 g, 33.3 mmol) in EtOH (25 mL) was heated to reflux and stirred overnight. The solvent was removed under vacuum. The residue was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with DCM/MeOH=100:1) to give 5-(3-bromopropoxy)-1H-benzo[d]imidazol-2(3H)-one (intermediate 39) (240 mg, 12%) as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:45])[F:44])[C:39](O)=[N:40][CH:41]=1.C(P(CCCC)CCCC)CCC.C(OC(C)C)(C)C>C1(C)C=CC=CC=1>[Br:35][C:36]1[CH:37]=[C:38]([C:43]([F:46])([F:44])[F:45])[C:39]([O:1][CH2:2][CH2:3][CH:4]2[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]2)=[N:40][CH:41]=1
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ncc(Br)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
tert-Butyl 4-(2-hydroxyethyl)piperidine-1-carboxylate (7.7 g) and 1,1′-(azodicarbonyl)dipiperidine (11.6 g) were added to a mixture of 5-bromo-3-(trifluoromethyl)pyridine-2-ol (7 g) and toluene (124 mL) at room temperature. Tributylphosphine (11.6 mL) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. After diisopropylether was added to the reaction mixture, the mixture was stirred, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex:EtOAc=100:0 to 70:30), whereby tert-butyl 4-(2-{[5-bromo-3-(trifluoromethyl)pyridin-2-yl]oxy}ethyl)piperidine-1-carboxylate (8.93 g) was obtained as a colorless oil.
Reaction SMILES: [C:1]([N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(OCC)=O.[OH-:17].[Na+]>>[C:7]1(=[O:16])[N:6]([CH2:1][C@@H:13]2[CH2:14][CH2:15][CH:8]=[CH:7][O:17]2)[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: [OH-]
Agent: [Na+]
Product: O=C1c2ccccc2C(=O)N1C[C@@H]1CCC=CO1

Procedure:
The amine tartrate (107.0 g, 407 mmol) was added to 4N sodium hydroxide (310 mL) and extracted with ether (3×100 mL). The ether was dried over anhydrous sodium sulfate and evaporated in vacuo. The amine which remained was dissolved in tetrahydrofuran (450 mL). With stirring, N-carboethoxyphthalimide (89.60 g, 409 mmol) was added to the solution. The mixture was refluxed overnight then evaporated in vacuo. The residue was taken up into benzene (660 mL) and water (180 mL). The layers were separated and the organic layer was washed with water (180 mL), 5% sodium hydroxide (180 mL), water (2×180 mL), and saturated brine (180 mL). The organic layer was dried over anhydrous sodium sulfate and evaporated in vacuo leaving the crude product (97.0 g) as a white solid. This was recrystallized from ether-petroleum ether (1:1). Yield 72.64 g (73%), m.p. 87°-88° C.; Anal. Calcd. for C14H13NO3 : C, 69.12 ; H, 5.39; N, 5.76. Found: C, 69.18; H, 5.36; N, 5.66.
Reaction SMILES: [C:1]1([NH2:12])[C:6](F)=[C:5](F)[C:4](F)=[C:3](N)[C:2]=1F.[ClH:13].Cl.N1C2C(=CC=CC=2)C(/C=C/C2C=CC(C(N3CCNCC3)=O)=CC=2)=N1.C(OC(NCC(O)=O)=O)(C)(C)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1.C(OC([NH:89][CH2:90][C:91]([N:93]1[CH2:98][CH2:97][N:96]([C:99](=[O:117])[C:100]2[CH:105]=[CH:104][C:103](/[CH:106]=[CH:107]/[C:108]3C4C(=CC=CC=4)N[N:109]=3)=[CH:102][CH:101]=2)[CH2:95][CH2:94]1)=[O:92])=O)(C)(C)C.Cl.CO>>[ClH:13].[NH2:89][CH2:90][C:91]([N:93]1[CH2:98][CH2:97][N:96]([C:99](=[O:117])[C:100]2[CH:105]=[CH:104][C:103](/[CH:106]=[CH:107]/[C:108]3[C:2]4[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=4)[NH:12][N:109]=3)=[CH:102][CH:101]=2)[CH2:95][CH2:94]1)=[O:92]
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Agent: CC(C)(C)OC(=O)NCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CO
Solvent: O
Product: NCC(=O)N1CCN(C(=O)c2ccc(/C=C/c3n[nH]c4ccccc34)cc2)CC1
Yield: 64 %

Procedure:
In a similar manner to Example 5, (E)-4-(tert-butoxycarbonylamino)acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine was obtained using dihydrochloride of Compound 18 (800 mg, 2.18 mmol), N-(tert-butoxycarbonyl)glycine (314 mg, 1.79 mmol), 1-hydroxybenzotriazole monohydrate (315 mg, 2.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (482 mg, 2.51 mmol) and N-methylmorpholine (0.80 mL, 7.28 mmol). In a similar manner to Example 18, (E)-4-(tert-butoxycarbonylamino)acetyl-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine was treated with 10% hydrogen chloride-methanol solution to obtain Compound 61 (448 mg, 64%).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.Cl>CO>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([N:29]3[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]3)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(N5CCN(C(=O)OC(C)(C)C)CC5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Agent: Cl
Solvent: CO
Product: C[C@@H]1CN2c3c(cc4c(N5CCNCC5)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of tert-butyl 4-[(2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-2′,4′,6′-trioxo-1,1′,2,3′,4,4′,4a,6′-octahydro-2′H,6H-spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5,5′-pyrimidin]-8-yl]piperazine-1-carboxylate (Example 20, 50 mg, 0.08 mmol) and 4N HCl in MeOH (8 mL) was stirred at room temperature for 1 hours. It was concentrated under reduced pressure and the residue was triturated with pet ether to give the title compound as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8](O)=[O:9].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[C:8]([Cl:20])=[O:9]
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1F
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(-c2ccccc2)cc1F
Reaction time: 2 h

Procedure:
Combine 3-fluorobiphenyl-4-carboxylic acid 10.46 g (0.048 mol), 432 mL of methylene chloride, 7 drops of dimethylformamide, and 5.44 mL (0.062 mol, 1.3 equiv) of oxalyl chloride. After 2 h, evaporate the solvent to afford 3-fluorobiphenyl-4-carbonyl chloride as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH2:8][CH2:9][C:10](=[O:16])[NH:11]2.[CH2:17]([CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1>[CH2:17]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C:10](=[O:16])[NH:11]3)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C1CCc2c(cccc2OCCCCl)N1
Solvent: Cc1ccccc1
Product: O=C1CCc2c(cccc2OCCCN2CCC(Cc3ccccc3)CC2)N1
Yield: 76 %

Procedure:
4.8 Grams of 5-(3-chloropropoxy)-3,4-dihydrocarbostyril and 4.2 g of 4-benzylpiperidine were mixed with 40 ml of toluene and the mixture was heated under refluxing condition for 24 hours. After cooling of the reaction mixture, the precipitates thus formed were obtained by filtration and washed with water, then recrystallized from ethanol to obtain 6.3 g (yield: 76%) of 5-[3-(4-benzyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril as in the form of colorless needle-like crystals. Melting point: 143°-145° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[C:14](O)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.O1CCCC1.O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][OH:15])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)O
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CO
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a solution of (S)-Piperidine-1,2-dicarboxylic acid 1-tert-butyl ester (5 g, 21.8 mmol) in anhydrous THF (32 mL) at 0-5° C. was added borane-tetrahydrofuran complex (1M solution in THF) (3.6 g, 41.84 mmol) over a period of 15 min. The mixture was stirred at 0-5° C. for 2 h and then at rt for 2 h. The mixture was added over a period of 10 min to cold water (75 mL) and extracted with EtOAc (300 mL). The aqueous layer was re-extracted with EtOAc (2×150 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated to obtain the title product as a colorless oil (4.72 g).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8]N(CC)CC)=[CH:6][C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:16])[CH3:15])=[CH:4][C:3]=1[N:22]1[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]2=[N:23]1.[OH:31][C:32]1[CH:45]=[C:44]([O:46][CH3:47])[CH:43]=[CH:42][C:33]=1[C:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:35]>>[N:23]1[N:22]([C:3]2[CH:4]=[C:5]([C:14]([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:15])[CH3:16])[CH:6]=[C:7]([CH2:8][C:45]3[C:44]([O:46][CH3:47])=[CH:43][CH:42]=[C:33]([C:34](=[O:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:32]=3[OH:31])[C:2]=2[OH:1])[N:26]=[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=12
Reactant: CCN(CC)Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O
Reactant: COc1ccc(C(=O)c2ccccc2)c(O)c1
Product: COc1ccc(C(=O)c2ccccc2)c(O)c1Cc1cc(C(C)(C)CC(C)(C)C)cc(-n2nc3ccccc3n2)c1O

Procedure:
Following the general procedure of Example 5 using the Mannich intermediate of Example 2 and 2-hydroxy-4-methoxybenzophenone, the title compound is obtained as a yellow crystalline solid melting at 137°-139° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13].[OH-].[Na+]>Cl.C1COCC1.[Cl-].[Cl-].[Ti+2]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH2:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cc1cc([N+](=O)[O-])ccc1F
Agent: [Ti+2]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Cc1cc(N)ccc1F
Reaction time: 16 h
Yield: 116.9 %

Procedure:
A solution of titanous chloride (about 15%) in about 10% hydrochloric acid (MERCK (MDA) INCL SCHUCHARDT, 71.5 mL) was added to a stirred solution of 1-fluoro-2-[(methylsulfonyl)methyl]-4-nitrobenzene (1.61 g) in THF (80 mL) at room temperature and stirred for 16 hours. By adding 1N sodium hydroxide solution the pH value of the reaction mixture was raised to 10 before it was extracted with ethyl acetate (2×). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated to give the crude title compound (1.64 g) which crystallized from diethylether/Ethyl acetate (1.16 g).
Reaction SMILES: C(=[N:14][CH:15]([CH:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)[CH3:19])[C:16]#[N:17])(C1C=CC=CC=1)C1C=CC=CC=1.Cl>O1CCOCC1>[NH2:14][CH:15]([CH:18]([C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)[CH3:19])[C:16]#[N:17]
Reactant: CC(c1cccc2ncccc12)C(C#N)N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(c1cccc2ncccc12)C(N)C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.6 %

Procedure:
2-(Benzhydrylidene-amino)-3-quinolin-5-yl-butyronitrile (8.36 g, 22.3 mmol) in dioxane (90 mL) was hydrolyzed with 1M HCl (90 mL) and the solution was stirred at rt for 16 h. The dioxane was removed under vacuum and the mixture was made basic with 2 M NaOH. The aqueous solution was extracted with chloroform:isopropanol (3:1). The organic extracts were pooled, dried over MgSO4, filtered and evaporated to leave an oil. The oily residue was purified by chromatography on SiO2, eluting with ethyl acetate and 5% methanol:ethyl acetate to give 2-amino-3-quinolin-5-yl-butyronitrile (Intermediate-E2) as a yellow solid 3.61 g (77%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH:6]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH:20]C(=O)C4C=CC=CC=4)=[S:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[CH2:3][CH:4]=[C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]([NH2:20])=[S:19])[CH:15]=3)[NH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CC=C(c2c[nH]c3ccc(NC(=S)NC(=O)c4ccccc4)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CC=C(c2c[nH]c3ccc(NC(N)=S)cc23)CC1
Yield: 79.1 %

Procedure:
A solution of compound 63 (1.12 g, 2.868 mmol) in THF (20 mL) was treated with 2 N NaOH (3.1 mL, 6.309 mmol) at room temperature and the resulting solution was refluxed for 5 h. The reaction was brought to room temperature, solvent was evaporated. The crude was diluted with water (20 mL) and ethyl acetate (20 mL). The precipitated solid was filtered, washed with water (10 mL), EtOAc (10 mL) and ether (2×10 mL) and dried under vacuum to obtain compound 65 (0.65 g, 79%). mp 209-211° C.; 1H NMR (DMSO-d6) δ 2.27 (s, 3H), 2.50-2.56 (m, 4H), 3.00-3.08 (m, 2H), 6.05 (s, 1H), 6.98 (d, 1H, J=8.4 Hz), 7.32-7.40 (m, 3H), 7.67 (s, 1H), 9.51 (s, 1H), 11.15 (s, 1H); ESI-MS m/z (%):: 287 (M+, 71), 249 (46), 244 (100).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[S:9][CH2:10][CH2:11][C:12]([OH:14])=O>S(=O)(=O)(O)O>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]2[C:4]=1[C:12](=[O:14])[CH2:11][CH2:10][S:9]2
Reactant: Cc1ccc(C)c(SCCC(=O)O)c1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C)c2c1SCCC2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −10° C., 100 g (0.48 mol) of 3-[(2,5-dimethylphenyl)thio]propanoic acid were dissolved in 2200 ml of conc. sulfuric acid. The reaction solution was stirred at room temperature for 1 h and then poured onto crushed ice. The aqueous solution was extracted with a diethyl ether/hexane mixture (1:9) (6×500 ml). The combined organic phases were dried over MgSO4 and concentrated completely using a rotary evaporator.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([NH:13][CH2:14][CH2:15][N:16]2[CH:21]=[C:20]([CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:35])=[O:12])[CH:6]=1)(=O)C.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:23]1([CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:20]2[CH:19]=[CH:18][C:17](=[O:35])[N:16]([CH2:15][CH2:14][NH:13][C:11](=[O:12])[C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([OH:4])[CH:6]=3)[CH:21]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(=O)Oc1cccc(C(=O)NCCn2cc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: O=C(NCCn1cc(C(c2ccccc2)c2ccccc2)ccc1=O)c1cccc(O)c1
Reaction time: 0.25 h
Yield: 99.9 %

Procedure:
To a solution of 3-[({2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}amino)carbonyl]phenyl acetate (77.0 mg) in MeOH (2.3 mL) was added portionwise K2CO3 (68.4 mg) at ambient temperature and the mixture was stirred at the same temperature for 15 minutes. The resulting mixture was diluted with water (5.0 mL) and the aqueous solution was extracted with EtOAc (10.0 mL). The organic layer was washed successively with 1M HCl aqueous solution, saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo to give N-{2-[5-(diphenylmethyl)-2-oxo-1(2H)-pyridinyl]ethyl}-3-hydroxybenzamide (70 mg) as a off-white amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:14]([F:17])([F:16])[F:15])=[N:4][N:5]([CH2:8][C:9]([O:11]CC)=[O:10])[C:6]=1[CH3:7].O[Li].O.Cl>C1COCC1.O>[Cl:1][C:2]1[C:3]([C:14]([F:16])([F:15])[F:17])=[N:4][N:5]([CH2:8][C:9]([OH:11])=[O:10])[C:6]=1[CH3:7]
Reactant: CCOC(=O)Cn1nc(C(F)(F)F)c(Cl)c1C
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Temperature: 60 °C
Reaction time: 5 h
Yield: 89.2 %

Procedure:
To a solution of ethyl 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetate (7.5 g, 27.7 mmol) in THF (100 mL) and water (50 mL) was added LiOH.H2O (2.33 g, 55.4 mmol). The mixture was stirred at 60° C. for 5 hours. After cooling to room temperature, the mixture was acidified with 1 N HCl (80 mL) and extracted with 1:2 IPA/CHCl3 (2×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to give the desired compound (6 g, 24.7 mmol, 89%). 1H NMR (400 MHz, DMSO-d6) δ 4.98 (s, 2H), 2.21 (s, 3H); MS: (ES) m/z calculated for C7H6ClF3N2O2 [M+H]+ 243.0, found 243.0.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>>[F:17][C:18]([F:28])([F:29])[C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:24])=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(C(F)(F)F)cc3)c2)CC1
Yield: 98.4 %

Procedure:
Beginning with 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and 4-(trifluoromethyl)benzoyl chloride (102 μl, 0.687 mmol), 88.0 mg (98%) of the title compound were recovered.
Reaction SMILES: Br[C:2]([F:16])([F:15])[C:3](F)([F:13])[O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.O>[Zn].C(#N)C>[F:13][C:3]([O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1)=[C:2]([F:16])[F:15]
Reactant: O=Cc1ccc(OC(F)(F)C(F)(F)Br)cc1
Agent: [Zn]
Solvent: CC#N
Solvent: O
Product: O=Cc1ccc(OC(F)=C(F)F)cc1
Temperature: 79 °C
Yield: 63.3 %

Procedure:
Acetonitrile (300 ml) and granular zinc (30.0 g) are combined in a 1 liter round bottomed flask and stirred at 75° C. under nitrogen as 4-(2-bromotetrafluoroethoxy)benzaldehyde (111.39 g, 0.37 mole) is added slowly by dropping addition funnel. The resulting mixture is stirred and heated at 79° C. for 12 hours. After filtration to remove zinc salts and unreacted zinc, the acetonitrile is removed under vacuum on a rotary evaporator. The resulting oily residue is flash distilled on a rotary evaporator under high vacuum (26.6 Pa) to provide 47.33 g (0.234 mole) of a water white oil in 63.3 percent yield.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:12]=[C:13]([NH:17]C(=O)OC(C)(C)C)[CH:14]=[CH:15][CH:16]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=1)[C:5](=[O:25])[N:6]2[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1cccc(-n2c(=O)n(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(6-amino-7-(4-chlorophenyl)-8-oxo-7H-purin-9(8H)-yl)phenylcarbamate (12) (234 mg, 0.52 mmol) in DCM (8 mL) was added TFA (2 mL) dropwise. The reaction mixture was stirred at rt for 1 h before concentrated. The residue was purified by column chromatography (silica gel, 0 to 5% methanol in methylene chloride (0.3% Et3N)) to give 6-amino-9-(3-aminophenyl)-7-(4-chlorophenyl)-7H-purin-8(9H)-one as a brown solid (13) (180 mg, 98.9%). LC-MS (ESI): m/z (M/M+2) 353/355.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([OH:12])=[CH:4][CH:3]=1.CS([C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5]([O:12][C:17]2[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=2)=[CH:4][CH:3]=1
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Reactant: COC(=O)c1nc(N)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(N)ccc1Oc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
A DMF suspension (50 ml) of 3.0 g (17.8 mmol) of methyl 6-amino-3-hydroxypicolinate, 3.9 g (17.8 mmol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine and 1.23 g (8.9 mmol) of potassium carbonate in a 100 ml round bottomed flask, was stirred at 80° C. for 4 hours. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was washed with water, dried, concentrated and purified by silica gel chromatography (n-hexane/AcOEt=1/1+0.1 MeOH) to obtain 4.43 g (yield: 81.3%) of the desired product.