Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Li].C([Li])(C)(C)C.CN(C)[CH:33]=[O:34]>O.CCOCC>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[CH:11][C:10]=1[CH:33]=[O:34])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(Br)c1
Agent: [Li]C
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1ccc(NC(=O)OC(C)(C)C)c(C=O)c1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
3.3 g (0.01 mol) 2,5-bis-tert.-butyloxycarbonylaminobromobenzene from step A are dissolved in 100 ml of water-free tetrahydrofuran under argon. 17 ml of a 1.6 molar etheric methyl lithium solution (0.03 mol) are gradually added. The reaction mixture is cooled to −20° C., 7 ml of a 1.5 molar tert.-butyl lithium solution (0.01 mol) are gradually added. After the addition has ended the solution is stirred for 30 minutes at the given temperature. Subsequently 1.2 g of dimethyl formamide (0.02 mol) are added and the reaction mixture is stirred for one hour at −20° C. After slowly heating to room temperature the reaction mixture is hydrolyzed with water and then poured into ether, the aqueous phase is extracted with ether and then the organic phase is dried over magnesium sulfate. The solvent is distilled away in a rotary evaporator and the residue is purified on silica gel with a petroleum ether/ethyl acetate solvent (9/1).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[CH2:15][O:16][CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.[CH3:45][Si:46]([CH3:77])([C:71]([CH3:76])([CH3:75])[CH:72]([CH3:74])[CH3:73])[O:47][C:48]1[CH:55]=[C:54]([O:56][CH2:57][CH2:58][C:59]2[N:60]=[C:61]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[O:62][C:63]=2[CH3:64])[CH:53]=[CH:52][C:49]=1[CH:50]=[O:51]>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:18])[C@@H:15]([O:16][CH3:17])[C@@H:50]([C:49]1[CH:52]=[CH:53][C:54]([O:56][CH2:57][CH2:58][C:59]2[N:60]=[C:61]([C:65]3[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=3)[O:62][C:63]=2[CH3:64])=[CH:55][C:48]=1[O:47][Si:46]([CH3:77])([CH3:45])[C:71]([CH3:76])([CH3:75])[CH:72]([CH3:74])[CH3:73])[OH:51])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(C=O)c(O[Si](C)(C)C(C)(C)C(C)C)c1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1O[Si](C)(C)C(C)(C)C(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
1.8 g (7.21 mmol) (S)-4-Benzyl-3-methoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-methoxyacetyl-oxazolidin-2-one see: D. Hunziker, N. Wu, K. Kenoshita, D. E. Cane, C. Khosla, Tetrahedron Lett. 1999, 40, 635-638) were dissolved under an argon atmosphere in 10 ml CH2Cl2 and treated with 1.44 ml (8.42 mmol) Hünig's base. After cooling to −78° C., nBu2BOTf was added slowly (7.21 ml of 1M solution in CH2Cl2) and enolborinate formation allowed to proceed for 0.25 hours at −78° C. and for 1 hour at 0° C. After recooling to −78° C., a solution of 2.8 g (6 mmol) of 2-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde in 10 ml CH2Cl2 was added via dropping funnel during 90 minutes and the mixture kept for 95 minutes at −78° C. and for one hour at 0° C. Pouring onto crashed ice, twofold extraction with AcOEt, washing with brine and water, drying over magnesium sulfate, and evaporation of the solvents, followed by chromatography (silica gel, heptane/AcOEt) left finally 2.905 g (67%) of the title compound as a yellow oil. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: C(C1C=C([CH2+]=NC2C=C[C:15]([O:16]C3C=CN=C(C(NC)=O)C=3)=[CH:14][C:13]=2F)N(C2C=CC=C(CO)C=2)N=1)(C)(C)C.[C:38]([C:42]1[CH:46]=[C:45]([NH:47][C:48]([NH:50][C:51]2[CH:67]=[CH:66][C:54]([O:55][C:56]3[CH:61]=[CH:60][N:59]=[C:58]([C:62]([NH:64][CH3:65])=[O:63])[CH:57]=3)=[CH:53][C:52]=2[F:68])=[O:49])[N:44]([C:69]2[CH:74]=[CH:73][CH:72]=[C:71]([CH2:75][OH:76])[CH:70]=2)[N:43]=1)([CH3:41])([CH3:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+].C(Cl)(=O)CC>O1CCCC1>[C:15]([O:76][CH2:75][C:71]1[CH:72]=[CH:73][CH:74]=[C:69]([N:44]2[C:45]([NH:47][C:48](=[O:49])[NH:50][C:51]3[CH:67]=[CH:66][C:54]([O:55][C:56]4[CH:61]=[CH:60][N:59]=[C:58]([C:62](=[O:63])[NH:64][CH3:65])[CH:57]=4)=[CH:53][C:52]=3[F:68])=[CH:46][C:42]([C:38]([CH3:41])([CH3:39])[CH3:40])=[N:43]2)[CH:70]=1)(=[O:16])[CH2:14][CH3:13]
Reactant: CNC(=O)c1cc(Oc2ccc(N=[CH2+]c3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Reactant: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3cc(C(C)(C)C)nn3-c3cccc(CO)c3)c(F)c2)ccn1
Agent: CCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCC(=O)OCc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc(C(=O)NC)c3)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a room temperature solution of example 1, (4-{4-[({3-tert-butyl-1-[3-(hydroxymethyl)phenyl]-1H-pyrazol-5-yl}carbamoyl)amino]-3-fluorophenoxy}-N-methylpyridine-2-carboxamide, (0.20 g, 0.38 mmol) and potassium carbonate (0.26 g, 1.88 mmol) in tetrahydrofuran (5 mL) was added dropwise propionyl chloride (0.05 mL, 0.56 mmol). The reaction mixture was allowed to stir at room temperature overnight. The crude material was concentrated and purified via prep-TLC (CH2Cl2:2M NH3 in MeOH, 97:3) to afford 0.09 g (42%) of the desired product as a white powder. MS m/z 589.1 (M+H)+; Retention time (LC-MS): 3.68 min.
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CC(C)=O>[C:10]1([NH:16][C:17]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCC(=N)N
Reactant: O=C=Nc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)Nc1ccccc1

Procedure:
Following a procedure similar to that described in Example 23 but using 6.9 g. sodium in 300 ml. dry acetone, 41.1 g. valeramidine hydrochloride, and 35.7 g. phenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from ethyl alcohol 40.3 g. 1-phenyl-3-(pentanimidoyl)urea hydrochloride; m.p. 155.5°-156°C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4].[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1.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>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:11](=[O:21])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=3[Cl:22])=[CH:16][N:15]=2)=[CH:8][S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1cscc1NC(=O)COc1ccc(Br)cn1
Reactant: OB(O)c1ccccc1Cl
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: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cscc1NC(=O)COc1ccc(-c2ccccc2Cl)cn1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of 4-[2-(5-bromo-pyridin-2-yloxy)-acetylamino]-thiophene-3-carboxylic acid methyl ester (100 mg, 0.269 mmol), 2-chlorophenylboronic acid (50.5 mg) and cesium carbonate (350 mg) in THF (10.5 mL) and degassed water (2.5 mL) was added tetrakis(triphenylphosphine)palladium (8.4 mg) and the reaction mixture was stirred under argon for 2 hours at 80° C. After such time water was added and the precipitate was isolated, washed with water and dried in vacuo to yield 4-{2-[5-(2-chloro-phenyl)-pyridin-2-yloxy]-acetylamino}-thiophene-3-carboxylic acid methyl ester.
Reaction SMILES: Br[C:2]1[C:3]([F:13])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([Cl:12])[N:6]=[CH:5]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18](B(O)O)[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1.C(=O)([O-])[O-].[Ce+3].C(=O)([O-])[O-].C(=O)([O-])[O-].[Ce+3]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:12][C:7]1[N:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:18]3[CH:17]=[C:16]([O:15][CH3:14])[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=3)[C:3]=2[F:13])[N:8]=1
Reactant: Fc1c(Br)ccc2nc(Cl)ncc12
Reactant: COc1cc(OC)cc(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Ce+3]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(-c2ccc3nc(Cl)ncc3c2F)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
A mixture of 6-bromo-2-chloro-5-fluoroquinazoline (1.5 g, 5.74 mmol), 3,5-dimethoxyphenylboronic acid (1.15 g, 6.31 mmol), cerium carbonate (1.87 g, 5.74 mmol) and bis(tri-tert-butylphosphine)palladium (148 mg, 0.29 mmol) in THF (30 mL) and water (3 mL) was degassed with nitrogen for three times and stirred at 80° C. overnight. The mixture was cooled to room temperature and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with water and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=8:1) to get the title product as a white solid (1.3 g, 70%). MS (ES+) C16H12ClFN2O2 requires: 318, found: 319, 321 [M+H]+.
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCC[CH2:2]1.[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([OH:18])=[O:17].C(O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][Br:24])=[CH:21][CH:20]=1)([O:18][CH2:1][CH3:2])=[O:17]
Reactant: O=C(O)c1ccc(CBr)cc1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CBr)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 16.09 g (78 mmol) of 1,3-dicyclohexylcarbodiimide (Aldrich) in 100 ml methylene chloride was added a suspension of 15.4 g (71 mmol) of 4-carboxybenzyl bromide in 100 ml methylene chloride and then 4.9 g (106.5 mmol) of absolute ethanol and 0.81 g (7.1 mmol) of 4-dimethylaminopyridine. A further 50 ml of methylene chloride was added to the reaction mixture and mixture heated at reflux for 2 hours. The mixture was allowed to cool to room temperature and the resultant white precipitate removed by filtration. The filtrate was washed with water, dried (MgSO4) and then concentrated in-vacuo to give the title compound as a colorless oil which crystallized on standing. PMR (CDCl3); δ 1.39 (3H, t, J~7.2 Hz), 4.38 (2H, q, J~7.2 Hz), 4.50 (2H, s), 7.45 (2H, d, J~7.7 Hz), 8.03 (2H, d, J~7.7 Hz).
Reaction SMILES: [CH:1]1([C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)O)[CH2:3][CH2:2]1.[ClH:18]>CC(O)C.CCOCC>[Cl:18][CH2:3][CH2:2][CH:1]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Reactant: Cl
Solvent: CC(C)O
Solvent: CCOCC
Product: ClCCC=C(c1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 93 %

Procedure:
Cyclopropyldiphenylmethanol (500 mg, 2.23 mmol) was dissolved in 1M HCl in i-PrOH (4.0 mL). The reaction mixture was then heated at 60° C. for 1 h. The reaction was cooled 20° C. and diluted with Et2O (100 mL). The organic solution was successively washed with H2O, NaHCO3 saturated aqueous solution and brine. It was then dried over MgSO4, filtered, concentrated in vacuo and chromatographed on a silica gel column by elution with Hexanes to give 4-Chloro-1,1-diphenyl-1-butene (506 mg, 93%) as a colorless oil. 1H NMR (CDCl3, 300 MHz) δ2.59 (q, 2H, J=6.9 Hz), 3.58 (t, 2H, J=6.9 Hz), 6.12 (t, 1H, J=7.3 Hz), 7.16-7.42 (m, 10H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([NH:25][CH2:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29](=[O:45])[N:30]([CH:37]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][C:38]1=[O:44])[C:31]2=[O:36])=[O:7]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
3,4-Dichlorobenzoic acid (0.30 g, 1.6 mmol) was dissolved in 10 mL DMF and CDI (0.30 g, 1.9 mmol) was added. The mixture was stirred at 40° C. for 1 hour, and then 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol) and triethylamine (0.31 g, 3.1 mmol) were added. After an additional 90 minutes stirring at 40° C., the mixture was cooled. The solvent was evaporated, and the residue was dissolved in 60 mL CH2Cl2, and this solution was washed with water (2×60 mL), dried (MgSO4), and evaporated. The residue was chromatographed using a methylene chloride-methanol gradient, eluting 0.49 g of the product with 98:2 methylene chloride-methanol, in 70% yield: mp 161-163° C.; 1H NMR (DMSO-d6) δ 2.06-2.09 (m, 1H), 2.51-2.58 (m, 2H), 2.84-2.91 (m, 1H), 4.94 (d, J=5.7 Hz, 2H), 5.17 (dd, J=12.6 Hz, d=5.3 Hz, 1H), 7.74-7.95 (m, 5H), 8.17 (d, J=1.9 Hz, 1H), 9.33 (t, J=5.7 Hz, 1H), 11.10 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.5, 48.9, 122.0, 127.2, 127.7, 129.3, 130.8, 131.3, 131.6, 133.3, 134.3, 134.9, 138.8, 164.4, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C21H15Cl2N3O5: C, 54.80; H, 3.28; N, 9.13. Found: C, 54.85; H, 3.36; N, 8.95.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1>[CH2:11]([NH:18][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccnc1NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Grams 47.4 of 2-chloro-3-nitropyridine are refluxed for 2 hours in 600 ml toluene with 33 ml benzylamine and 31.8 g sodium carbonate. The reaction mixture is cooled to room temperature and 200 ml water are added thereto. The phases are separated, the organic phase evaporated to small volume, diluted with 400 ml isopropyl ether and kept under stirring for 30 minutes while cooling with water. It is filtered, washed with isopropyl ether, evaporated to dryness to give 46 g 2-benzylamino-3-nitropyridine melting at 81°-82° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([O:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)Oc1ncccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)Oc1ncccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
A mixture of 0.34 g of 3-acetoxy-2-{1-(methoxycarbonyl)ethoxy}pyridine, 0.11 g of potassium carbonate and 2 ml methanol was stirred for 1 hour at room temperature. The reaction solution was poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 190 mg of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14]SCCC(OCC)=O)=[O:5])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:28]>ClCCl>[CH2:1]([O:3][C:4]([CH2:6][CH2:7][S:8][C:9]1[S:13][N:12]=[N:11][C:10]=1[CH2:14][OH:28])=[O:5])[CH3:2]
Reactant: CCOC(=O)CCSCc1nnsc1SCCC(=O)OCC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)CCSc1snnc1CO
Reaction time: 0.5 h

Procedure:
To a solution of 5-[(2-ethoxycarbonylethyl)thio]-4-[(2-ethoxycarbonylethy l)thiomethyl]-1,2,3-thiadiazole (1.0 g, 3.0 mmol) in dichloromethane (40 mL) was added m-chloroperoxybenzoic acid in several portions at 0° C. until the starting material was disappeared. The mixture was then sequentially washed with saturated aqueous sodium thiosulfate, cold aqueous 1% sodium hydroxide and brine, and was concentrated to dryness. The oxidized product was treated with trifluoroacetic anhydride (2 mL) for 30 min at room temperature. After removal of trifluoroacetic anhydride under the reduced pressure, the mixture was stirred in ethyl acetate/1% sodium hydroxide (30 ml/30 mL) for 30 min. The ethyl acetate layer was concentrated to a volume of 5 mL and methanol (10 mL) was added. Excess sodium borohydride (200 mg) was added in portions at 0° C. while stirring. After 30 min, the reaction was quenched with diluted hydrochloric acid. The mixture was extracted with ethyl acetate and concentrated. The residue was purified by silica gel chromatography (1% methanol/dichloromethane) to provide 225 mg of 5-[(2-ethoxycarbonylethyl)thio]-4-hydroxymethyl-1,2,3-th iadiazole. 1H NMR (CDCl3) δ1.27 (t, 3H, J=8), 2.71 (t, 2H, J=7), 3.27 (t, 2H, J=7), 4.16 (q, 2H, J=8), 5.03 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.Cl.Cl.[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C(Cl)Cl>[F:29][C:30]1[CH:31]=[CH:32][C:33]([N:36]2[CH2:41][CH2:40][N:39]([C:8](=[O:10])[CH2:7][C@H:5]3[O:6][C:2]([CH3:1])([CH3:12])[O:3][C:4]3=[O:11])[CH2:38][CH2:37]2)=[CH:34][CH:35]=1
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Reactant: Fc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC1(C)OC(=O)[C@@H](CC(=O)N2CCN(c3ccc(F)cc3)CC2)O1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 76.1 %

Procedure:
To a solution of [(4R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]acetic acid (3.48 g; 20.0 mmol; 1.0 eq.), TEA (6.07 g; 60.0 mmol; 3.0 eq.) in DCM (60 mL) was added HOBt (2.97 g; 22.0 mmol; 1.1 eq.) and the mixture was chilled to 0° C. EDC (4.6 g; 24.0 mmol; 1.2 eq.) was then added and the resulting reaction mixture was stirred for 15 min at 0° C. 1-(4-fluorophenyl)piperazine dihydrochloride (5.57 g; 22.0 mmol; 1.1 eq.) was added and the resulting reaction mixture was stirred at RT over night. Purification by flash chromatography (AcOEt/c-Hex: 50/50) gave the title compound as a colorless oil (5.12 g, 76%). M+(ESI): 337.2. HPLC (Condition A): Rt: 2.5 min (HPLC purity: 97.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([O:27]C)=O)=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+:30].N>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C:25]([NH2:30])=[O:27])=[CH:20][CH:19]=3)[C:11]3[CH2:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)Cc1ccc(Cc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 100 °C
Reaction time: 40 h
Yield: 70.9 %

Procedure:
A 20-mL vial was charged with methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetate (98 mg, 0.25 mmol, 1.0 eq.) and ammonium chloride (40 mg, 0.75 mmol, 3.0 eq.). Methanol (3 mL) was added to the mixture followed by NH3 (7.1 mL, 7N in methanol, 50 mmol, 200 eq.). The vial was sealed and the resulting mixture was stirred at 100° C. for 40 hr. The crude reaction solution was adsorbed onto silica, then purified by chromatography on silica gel using dichloromethane/methanol (0 to 10%) as eluent, to give 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetamide (67 mg, 71% yield) as a white solid. MW=377.87. 1H NMR (DMSO-d6, 500 MHz) δ 8.36-8.31 (m, 2H), 7.57-7.51 (m, 2H), 7.40 (br s, 1H), 7.25 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.08 (s, 2H), 3.31 (s, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.90 (t, J=7.5 Hz, 3H), 2.07 (quintet, J=7.5 Hz, 2H).
Reaction SMILES: C(N)(=O)CCC(N)=O.[C:9]1([NH:15][C:16](=[O:21])[CH2:17][C:18](O)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.NC1C=CC=CC=1.ClCC(=O)C[C:33]([O:35]C)=[O:34].[OH-].[Li+]>>[C:9]1([NH:15][C:16](=[O:21])[CH2:17][CH2:18][C:33]([OH:35])=[O:34])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1
Reactant: COC(=O)CC(=O)CCl
Agent: NC(=O)CCC(N)=O
Agent: [Li+]
Agent: [OH-]
Solvent: Nc1ccccc1
Product: O=C(O)CCC(=O)Nc1ccccc1

Procedure:
The synthesis of the succinamide analogs 29, 30, 31, 32, and 33 are described in Schemes 12, 13, and 14. N-Phenyl-succinamic acid was prepared via a two step reaction sequence analogous to the preparation of the N-phenyl-malonamic acid: 1) reaction of aniline with methyl 4-chloro-3-oxobutyrate followed by 2) treatment with lithium hydroxide. Coupling of N-phenyl-succinamic acid with 1-(2-methylamino-(S)-2-phenyl-ethyl)-pyrrolidin-(S)-3-ol, 1-(3-methyl-(S)-2-methylamino-butyl)-pyrrolidin-(S)-3-ol or 1-piperidin-(S)-2-ylmethyl-pyrrolidin-(S)-3-ol afforded 29, 30 and 31, respectively.
Reaction SMILES: [NH2:1]/[C:2](=[N:14]\[OH:15])/[CH2:3][N:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]1.[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=O.O>N1C=CC=CC=1>[F:16][C:17]([F:27])([F:28])[C:18]1[CH:19]=[C:20]([C:21]2[O:15][N:14]=[C:2]([CH2:3][N:4]3[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[N:5]3)[N:1]=2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1cnn(C/C(N)=N/O)c1
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)c1cnn(Cc2noc(-c3cccc(C(F)(F)F)c3)n2)c1
Temperature: 115 °C
Yield: 22.4 %

Procedure:
A solution of the compound (2.2 g) obtained in Example 114a in pyridine (40 mL) was cooled in an ice bath and 3-(trifluoromethyl)benzoyl chloride (4.16 g) was added. The reaction mixture was heated to 110-120° C. overnight, cooled to room temperature, and poured into water. The mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed successively with 1N aqueous hydrochloric acid solution, and saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-petroleum ether) to give the title compound (0.85 g) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[CH:13][N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][CH:25]=[N:26]2)=[CH:21][CH:20]=1.[H-].[Na+]>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[CH:13][N:14]=[C:15]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][CH:25]=[N:26]4)=[CH:21][CH:20]=3)[CH:16]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc2cccnc2c1
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)ncn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(-c2cc(Oc3ccc4cccnc4c3)ncn2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 100-mL, round-bottomed flask containing 4-(4-tert-butyl-phenyl)-6-chloro-pyrimidine, (Example 1(a)), (0.15 g, 0.61 mmol) and 7-hydroxyquinoline (0.12 g, 0.85 mmol, Acros) in DMF (4 mL), was added NaH (34 mg, 0.85 mmol, 60% in mineral oil, Aldrich) at room temperature. The solution was then stirred at room temperature for 4 h. After the solvent was removed in vacuum, the residue was taken up in EtOAc (10 mL), and the organic layers were washed with water (8 mL), dried over Na2SO4, filtered, and concentrated in vacuum. Silica gel chromatography (3:1 hexanes/EtOAc) gave the title compound as a white solid. Mp: 133–135° C. MS (ESI, pos. ion) m/z: 356 (M+1). Anal. Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82. Found: C, 77.43; H, 5.99; N, 11.74.