Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([CH2:5][O:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:8](=[O:18])[CH:9]=[C:10]1[C:14](=[O:15])[O:13][C:12](C)(C)[O:11]1)=[O:4]>CO>[CH3:12][O:13][C:14](=[O:15])[C:10]([OH:11])=[CH:9][C:8](=[O:18])[N:7]([O:6][CH2:5][C:3](=[O:4])[N:2]([CH3:27])[CH3:1])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: CN(C)C(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: COC(=O)C(O)=CC(=O)N(Cc1ccc(F)cc1)OCC(=O)N(C)C
Yield: 54 %

Procedure:
N-Dimethylcarbamoylmethoxy-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-acetamide was treated with methanol as described in the preparation of Compound 44-D and gave the title ester as white crystals (54% yield); mp 133–135° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 2.9 (3H, s, NCH3), 2.98 (3H, s, NCH3), 3.91 (3H, s, OCH3), 4.54 (2H, s, CH2), 4.96 (2H, s, CH2), 6.52 (1H, s, CH), 7.06 (2H, m, aromatics), 7.39 (2H, m, aromatics), 13.38 (1H, broad s, OH). Anal. calcd for Cl6H19FN2O6: C, 54.24; H, 5.40; N, 7.90. Found: C, 53.62; H, 5.40; N, 7.79.
Reaction SMILES: CO[C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:35]2[C:36]([CH2:41]CC(F)(F)F)=[N:37]OC=2C)=NC=1>>[CH:36]([NH:37][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)([CH3:41])[CH3:35]
Reactant: COC(=O)c1ccc(OCc2c(N3CCCC3)noc2C)nc1
Reactant: COC(=O)c1ccc(OCc2c(CCC(F)(F)F)noc2C)nc1
Product: Cc1onc(N2CCCC2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 55 %

Procedure:
As described for example 1e, 6-(5-methyl-3-pyrrolidin-1-yl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (100 mg, 0.28 mmol), instead of 6-[5-methyl-3-(3,3,3-trifluoro-propyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester, was converted, to the title compound (30 mg, 55%) which was obtained as a white solid after purification by chromatography (silica, 30 to 60% ethyl acetate in heptane). MS: m/e=345.2 [M+H]+.
Reaction SMILES: [CH:1]([S:4](Cl)(=[O:6])=[O:5])([CH3:3])[CH3:2].CS([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=O)=O>>[CH:1]([S:4]([N:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:24][CH:23]=2)=[O:20])[CH2:14][CH2:13]1)(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Yield: 83 %

Procedure:
Isopropylsulfonyl chloride (70 mg, 0.487 mmol) was reacted with PTU (70 mg, 0.244 mmol) as the same manner as the synthesis of 1-(1-(methylsulfonyl)piperidin-4-yl)-3-(4-(trifluoromethyl)phenyl)urea yielding the final product (80 mg, 0.203 mmol, 83% yield). 1H NMR (d6-DMSO, 300 Mhz): δ 8.78 (s, 1H), 7.57 (s, 4H), 6.38 (d, J=7.5 Hz, 1H), 4.19 (d, J=Hz, 1H), 3.82 (d, J=Hz, 1H), 3.73 (m, 1H), 3.18 (t, J=12.4 Hz, 1H), 2.82 (m, 1H), 2.78 (t, J=Hz, 1H), 1.80 (t, J=9.6, 2H), 1.43 (m, 2H), 0.97 (s, 6H).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].[Br:12][C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>CN(C=O)C>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([CH:2]([C:1]([O:8][CH3:9])=[O:7])[C:3]([O:5][CH3:6])=[O:4])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: COC(=O)CC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C(=O)OC)c1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
Dimethyl malonate (40.34 g, 0.305 mol) in N,N′-dimethylformamide (45 mL) was added dropwise to a stirred suspension of sodium hydride (60% dispersion in mineral oil, 16.2 g, 405 mmol) in N,N′-dimethylformamide (500 mL) at 10° C. The mixture was stirred for 1 hour at room temperature then 4-bromo-1-fluoro-2-nitrobenzene (44.38 g, 202 mmol) in N,N′-dimethylformamide (45 mL) was added dropwise to the reaction mixture. The mixture was stirred 75 minutes at room temperature and then was warmed to 65° C. After 1 hour, the solvent was removed under reduced pressure, the residue was taken up in a mixture of ethyl acetate and water and 2M aqueous hydrochloric acid was added until the mixture became pale yellow in colour. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The crude product was recrystallized from diisopropyl ether to give the title compound (55.0 g, 83%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].CCOCC.Br.[CH3:23][CH:24]1[C:29](=[O:30])[CH2:28][CH2:27][NH:26][CH2:25]1>O>[CH2:1]([O:8][C:9]([N:26]1[CH2:27][CH2:28][C:29](=[O:30])[CH:24]([CH3:23])[CH2:25]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CNCCC1=O
Reactant: O=C(Cl)OCc1ccccc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC1CN(C(=O)OCc2ccccc2)CCC1=O

Procedure:
To a mechanically stirred mixture of benzylchloroformate (33.1 mL, 232 mmol, 105 mol %), sodium bicarbonate (37.2 g, 442 mmol, 200 mol %), ether (250 mL), and water (250 mL) is added 3-methyl-4-piperidone hydrobromide salt (42.9 g, 221 mmol) in portions over 10 min. The resultant mixture is stirred for 2 h and the organic phase separated. The aqueous phase is extracted with ether (2×150 mL) and the combined organics dried (MgSO4), filtered, and concentrated to an oily residue. This residue crystallized on standing at 23° C. and was recrystallized from hexanes/ethyl acetate to give N-benzyloxycarbonyl-3-methyl-4-piperidone as a solid: 51.2 g; 93%; mp 33°-35° C.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:6](=[O:12])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[H][H]>C(O)C.[Pd]>[CH3:1][C@H:2]1[N:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6](=[O:12])[C@@H:5]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18])[CH2:4][C@H:3]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: [H][H]
Reactant: C=C(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C
Agent: [Pd]
Solvent: CCO
Product: CC(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C

Procedure:
To a solution of tert-butyl [(3S,5S,6R)-6-methyl-1-(2-methylprop-2-en-1-yl)-2-oxo-5-phenylpiperidin-3-yl]carbamate (0.129 g, 0.364 mmol) in ethanol (15 mL) was added 10 wt. % palladium on carbon (39 mg, 0.036 mmol) and the mixture was stirred under a balloon of hydrogen at 23° C. for 1 h. The catalyst was removed by filtration through Celite® and washed thoroughly with ethanol and ethyl acetate. Concentration of the organics afforded the title compound which was used as is. MS: m/z=361.2 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C(Cl)Cl>[C:25]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1ccccc1N1CCc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1N1CCc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stirred mixture, under N2, of 24.6 g of 1-(2-aminophenyl)indoline hydrochloride in 225 ml of dry CH2Cl2 is treated with 20.2 g of triethylamine over 10 minutes. The mixture is cooled to 0°-5° C., and kept at that temperature while a solution of 14.1 g of benzoyl chloride and 25 ml of CH2Cl2 is added dropwise over 1.0 hour. After stirring at room temperature overnight, H2O was added and the layers are separated. The organic phase is washed further with H2O, 3 N--HCl, 3 N--NaOH, again with H2O, and dried. The solvent is removed to leave an oil which crystallizes on standing to yield 1-(2-benzamidophenyl)indoline, m.p. 73°-76° C.
Reaction SMILES: CCN(CC)CC.[CH2:8]([O:10][C:11](=[O:36])[CH2:12][CH2:13][NH:14][C:15]([C:17]1[N:22]=[CH:21][C:20]([C:23]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:24]=2[C:25](O)=[O:26])=[CH:19][CH:18]=1)=[O:16])[CH3:9].[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH2:50])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1.CCN=C=NCCCN(C)C>C(Cl)Cl>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:44]2[CH:49]=[CH:48][C:47]([NH:50][C:25]([C:24]3[CH:28]=[CH:29][C:30]([C:32]([F:34])([F:35])[F:33])=[CH:31][C:23]=3[C:20]3[CH:19]=[CH:18][C:17]([C:15]([NH:14][CH2:13][CH2:12][C:11]([O:10][CH2:8][CH3:9])=[O:36])=[O:16])=[N:22][CH:21]=3)=[O:26])=[CH:46][CH:45]=2)=[C:40]([CH3:51])[CH:39]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)O)cn1
Reactant: Cc1cc(Cl)ccc1-c1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3C)cc2)cn1
Temperature: 25 °C

Procedure:
Neat Et3N (0.28 mL, 2.0 mmol) was added to a DCM mixture (3 mL) of 2-(6-((3-ethoxy-3-oxopropyl)carbamoyl)pyridin-3-yl)-4-(trifluoromethyl)benzoic acid (˜40% pure) (616 mg, 0.6 mmol), 4′-chloro-2′-methyl-[1,1′-biphenyl]-4-amine (109 mg, 0.5 mmol), and EDCI (383 mg, 2.0 mmol) and the resulting mixture was stirred at room temperature. After 3 h the resulting mixture was directly purified via column chromatography to yield the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8](CC1C=CC(OC)=CC=1)[C:7](=[O:21])[N:6]([CH3:22])[C:5]2([CH2:27][NH:28][C:29](=[O:37])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:23]([F:26])([F:25])[F:24].[N+]([O-])([O-])=O.[NH4+].[Ce].C(Cl)(Cl)Cl>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:21])[N:6]([CH3:22])[C:5]2([CH2:27][NH:28][C:29](=[O:37])[C:30]1[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=1)[C:23]([F:25])([F:26])[F:24]
Reactant: COc1ccc(CN2C(=O)N(C)C(CNC(=O)c3ccc(F)cc3)(C(F)(F)F)c3cc(Br)ccc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC#N
Product: CN1C(=O)Nc2ccc(Br)cc2C1(CNC(=O)c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-{[6-bromo-1-(4-methoxybenzyl)-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}4-fluorobenzamide (9.6 mg, 0.017 mmol) was dissolved in acetonitrile (1.0 mL) and water (0.25 mL), and cerium ammonium nitrate (27.2 mg, 0.050 mmol) was added to the reaction solution under ice-cooling. After the reaction solution was stirred at room temperature for 4 hours, chloroform and water were added thereto and the solution was stirred at room temperature. The organic layer was separated and washed with saturated brine and then dried over magnesium sulfate. After the drying agent was removed by filtration, the solvent was evaporated under reduced pressure. The residue was purified by thin-layer chromatography (chloroform/methanol=1/4), whereby the objective N-{[6-bromo-3-methyl-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydroquinazolin-4-yl]methyl}4-fluorobenzamide (4.0 mg, 53%) was obtained as a white solid.
Reaction SMILES: [I-].[F:2][C:3]([F:30])([F:29])[C:4]([NH:6][C@H:7]([CH3:28])[CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:5].C([Li])CCC.[CH2:36]([O:43][CH2:44][CH:45]=O)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:36]([O:43][CH2:44][CH:45]=[CH:8][C@H:7]([NH:6][C:4](=[O:5])[C:3]([F:30])([F:29])[F:2])[CH3:28])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=CCOCc1ccccc1
Reactant: C[C@H](C[P+](c1ccccc1)(c1ccccc1)c1ccccc1)NC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [I-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](C=CCOCc1ccccc1)NC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 52.4 %

Procedure:
(2R)-(2-trifluoroacetamidopropyl)triphenylphosphonium iodide (8.3 g) synthesized according to J. Med. Chem. 2007, 50, 5627-5643 was dissolved in anhydrous tetrahydrofuran and cooled to −78° C. n-butyllithium (1.6 M n-hexane solution, 18.7 mL) was slowly added dropwise. After the dropwise addition, the mixture was stirred at room temperature for 20 minutes. Subsequently, the mixture was cooled to −78° C., and an anhydrous tetrahydrofuran (10 mL) solution of 2-benzyloxyacetaldehyde (2.35 g) was added. The mixture was gradually returned to room temperature and stirred at room temperature for 12 hours. After the completion of reaction, a saturated aqueous solution of ammonium chloride was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain the compound of interest as a pale yellow oil (2.30 g, 52.6%).
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4][CH:5]=[CH:6][CH2:7][NH:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1>CN(C)C=O>[CH3:1][C:2]([CH3:11])([CH3:10])[C:3]#[C:4]/[CH:5]=[CH:6]/[CH2:7][N:8]([CH2:19][C:20]1[CH:21]=[C:22]([C:26](=[O:28])[CH3:27])[CH:23]=[CH:24][CH:25]=1)[CH3:9]
Reactant: CNCC=CC#CC(C)(C)C
Reactant: CC(=O)c1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(CN(C)C/C=C/C#CC(C)(C)C)c1
Yield: 88.4 %

Procedure:
N-(6,6-dimethyl-2-hepten-4-ynyl)methylamine (trans:cis=about 3:1) (1.06 g; 7.04 mmol) and potassium carbonate (1.95 g; 14.1 mmol) were added to N,N-dimethylformamide (20 ml). While the mixture was stirred in an ice bath, 3′-bromomethylacetophenone (1.31 g; 6.15 mmol) in N,N-dimethylformamide (15 ml) was added dropwise. After completion of addition, the mixture was removed from the ice bath, and stirred for 15 minutes at room temperature. Reaction was stopped by pouring the mixture into ice+saturated aqueous sodium bicarbonate solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with saturated aqueous sodium bicarbonate solution and with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform), to thereby yield 1.54 g of the target compound (yield: 88.4%).
Reaction SMILES: C[O:2][C:3](=[O:39])[C@H:4]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([C:31]2[C:36]([Cl:37])=[CH:35][CH:34]=[CH:33][C:32]=2[Cl:38])=[O:30])=[CH:24][CH:23]=1)[NH:5][C:6]([C:8]1([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:9]1)=[S:7].[OH-].[Na+]>C(O)C.O.C(OCC)C>[Cl:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([Cl:37])[C:31]=1[C:29]([NH:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][C@@H:4]([C:3]([OH:39])=[O:2])[NH:5][C:6]([C:8]2([CH2:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[S:7])=[CH:23][CH:24]=1)=[O:30]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=S)C1(CCCCS(C)(=O)=O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)CCCCC1(C(=S)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Temperature: 52.5 °C
Reaction time: 22 h
Yield: 70.2 %

Procedure:
To a solution of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine methyl ester (25.86 mmol, 15.87 g) in ethanol (75 mL) was added aqueous 1.0N sodium hydroxide (60 mL) at 50° C. The mixture was heated to 50-55° C. and the resulting clear light brown solution was stirred for 22 h at which time TLC analysis of the mixture indicated the absence of starting material. The mixture was diluted with water and allowed to cool to room temperature and was filtered to remove a small amount of solids. The filtrate was concentrated and the residual aqueous solution was washed with diethyl ether (2×75 mL). The basic aqueous layer was acidified with 3.0N HCl to form a cloudy suspension and was extracted with ethyl acetate (3×100 mL). The combined ethyl acetate extracts were washed with brine (200 mL) then the dried (MgSO4) solution was filtered and evaporated to dryness. The residue was taken up in dichloromethane and diluted with diethyl ether:hexane (1:1) to obtain a solid which was collected by filtration. Trituration of the solid with hot ethyl acetate (˜100 mL) resulted in a suspension that was then diluted with diethyl ether (˜50 mL) and the solid was collected by filtration. The above Trituration was repeated to afford 10.89 g (70%) of 4-[[(2,6-dichlorophenyl)carbonyl]amino]-N-[[1-[4-(methylsulfonyl)butyl]cyclopentyl]thioxomethyl]-L-phenylalanine as a colorless solid. HR MS: Obs. mass, 599.1193. Calcd. mass, 599.1208 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)([C:8]([O:10]C)=[O:9])[CH2:4][O:3]1.C1COCC1.[OH-].[Na+:26]>CO>[CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)([C:8]([O-:10])=[O:9])[CH2:4][O:3]1.[Na+:26]
Reactant: COC(=O)C1(c2ccc(C)cn2)COC(C)(C)OC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C2(C(=O)[O-])COC(C)(C)OC2)nc1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
To a mixture of 1.17 g of methyl 2,2-dimethyl-5-(5-methylpyridin-2-yl)-1,3-dioxane-5-carboxylate, 14 ml of THF, and 14 ml of methanol was added 4.7 ml of a 1 M aqueous sodium hydroxide solution, followed by stirring at 50° C. for 20 hours. The reaction mixture was left to be cooled to room temperature and the solvent was then evaporated under reduced pressure to obtain 1.19 g of sodium 2,2-dimethyl-5-(5-methylpyridin-2-yl)-1,3-dioxane-5-carboxylate.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14](N(OC)C)=[O:15])[N:11]([CH3:20])[C:10]=2[CH:21]=1>C1COCC1>[Br:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14](=[O:15])[CH2:1][CH3:2])[N:11]([CH3:20])[C:10]=2[CH:21]=1
Reactant: CON(C)C(=O)c1nc2ccc(Br)cc2n1C
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(=O)c1nc2ccc(Br)cc2n1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethylmagnesium bromide (1 M in THF, 11.0 ml) was added to a solution of 6-bromo-N-methoxy-N,1-dimethyl-1H-benzo[d]imidazole-2-carboxamide (1.09 g) in THF (15 ml) at 0° C. The mixture was stirred at 0° C. under N2 atmosphere for 2 h. The mixture was quenched with saturated NH4Cl solution, and extracted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (hexane/EtOAc) to give the title compound (0.86 g) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Si:7]([O:24][CH2:25][C@@H:26]1[CH2:28][C@H:27]1[C:29](OCC)=[O:30])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[OH-].[Na+]>C1COCC1>[Si:7]([O:24][CH2:25][C@@H:26]1[CH2:28][C@H:27]1[CH2:29][OH:30])([C:20]([CH3:23])([CH3:22])[CH3:21])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](OC[C@@H]1C[C@H]1CO)(c1ccccc1)c1ccccc1
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a suspension of LAH (0.92 g, 24.24 mmol) in THF (100 mL) was added a solution of ethyl trans-2-((tert-butyldiphenylsilyloxy)methyl)cyclopropanecarboxylate (21.4 g, 55.94 mmol) in THF (20 mL) at 0° C., and the mixture was stirred for 2 hr. To the reaction mixture were added successively water (0.92 mL), 15% aqueous sodium hydroxide solution (0.92 mL) and water (2.76 mL). The precipitate was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 1→30% ethyl acetate/hexane) to give trans-(2-((tert-butyldiphenylsilyloxy)methyl)cyclopropyl)methanol (14.16 g, 41.66 mmol, 74%) as a colorless oil.
Reaction SMILES: CO[N:3]=[C:4]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1>C(O)(C(F)(F)F)=O.[Pd]>[F:18][C:14]1[CH:13]=[C:12]([CH:4]([NH2:3])[CH2:5][C:6]2[CH:7]=[CH:8][N:9]=[CH:10][CH:11]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CON=C(Cc1ccncc1)c1cccc(F)c1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1ccncc1)c1cccc(F)c1

Procedure:
A mixture of 1-(3-fluorophenyl)-2-(pyridin-4-yl)ethanone O-methyl oxime, (19) (1.86 g) in TFA (20 mL) was reduced by the action of 10% Pd/C (186 mg) under H2 at 50 psi for 12 h at rt. The mixture was filtered through Celite and freed of solvent under reduced pressure. The residue was basified using 6N KOH. The aqueous layer was extracted with EtOAc (3×, 500 mL). The pooled organic layer was dried over magnesium sulfate. The mixture was filtered. The solvents were removed under vacuum gave 1-(3-fluorophenyl)-2-(pyridin-4-yl)ethanamine, (20): as a solid (1.6 g, 97% yield).
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>CC(O)C>[CH2:12]([NH:19][C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCc1ccccc1
Reactant: Clc1ncnc2cccnc12
Agent: Cl
Solvent: CC(C)O
Product: c1ccc(CNc2ncnc3cccnc23)cc1
Temperature: 50 °C

Procedure:
A solution of freshly prepared 4-chloropyrido[3,2-d]pyrimidine (0.10 g, 0.60 mmol) (prepared as described in the previous experimental) and benzylamine (0.13 mL, 1.20 mmol) in propan-2-ol (15 mL) containing a trace of conc. HCl is warmed at 50° C. for 30 min, and then concentrated to dryness. The residue is partitioned between water and EtOAc, and the organic layer worked up and chromatographed on silica gel. EtOAc elutes foreruns, while MeOH/EtOAc (1:9) elutes 4-(benzylamino)pyrido[3,2-d]pyrimidine (0.11 g, 77%). 1H NMR (CDCl3) δ 8.67 (1H, s), 6.50 (1H, dd, J=4.3, 1.5 Hz), 8.10 (1H, dd, J=8.5, 1.5 Hz), 7.63 (1H, dd, J=8.8, 4.3 Hz), 7.55 (1H, brs), 7.41-7.29 (5H, m), 4.86 (2H, d, J=5.9 Hz).