Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[Cl:1][CH2:2][C:3]([C:10]1[CH:11]=[CH:12][C:7]([F:6])=[CH:8][CH:9]=1)=[O:4]
Reactant: Fc1ccccc1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCl)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
164 ml. (235.1 g., 2.04 moles) of chloroacetyl chloride is added over a 50 min. period to a mixture of 400 ml. (410 g., 4.22 moles) of fluorobenzene and 300 g. (2.25 moles) of anhydrous aluminum chloride stirred at 75° C. under nitrogen. The reaction mixture is stirred at 80° C. under nitrogen for 1 hour, cooled to 50° C., 500 ml. of fluorobenzene is added, and the reaction mixture is cooled to 0° C. and gradually (over a 30 min. period) siphoned into 1 l. of 6N. hydrochloric acid stirred at 0° C. (The temperature of the aqueous acid is maintained at or below 25° C. throughout the addition.) The quenched, acidified reaction mixture is stirred for 15 min., and the aqueous phase is separated and extracted with 350 ml. of fluorobenzene. The two organic phases are combined and washed twice with 500 ml. portions of 3N. hydrochloric acid and once with 500 ml. of water. The fluorobenzene is distilled at 30 mm. Hg. and 60° C. and, upon cooling, the obtained oily residue solidifies. The crude solid product need not be purified.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH:18]=1)C(=O)OC(C)(C)C>>[F:26][C:25]([F:27])([F:28])[C:24]([NH:23][C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([NH:9][CH3:8])[CH:18]=1)=[O:29]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Product: CNc1cccc(NC(=O)C(F)(F)F)c1
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To trifluoroacetic acid (144 mL) was added tert-butyl methyl{3-[(trifluoroacetyl)amino]phenyl}carbamate (47.8 g, 0.150 mol) at 0° C., and the mixture was stirred for 1 hr. The reaction mixture was concentrated under reduced pressure, ethyl acetate (500 ml) was added to the residue, and the mixture was washed successively with aqueous sodium hydrogen carbonate solution (200 ml) and saturated brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the precipitate was collected by filtration to give the title compound (29.2 g, 89%) as a pale-green powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[C:9](=[O:18])[C:10](=[O:17])[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)C(=O)c2ccccc2)ccn1
Reactant: FC(F)(F)c1ccc(CCBr)cc1
Product: Cc1cc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(=O)c2ccccc2)ccn1

Procedure:
In analogy to the procedure described for the synthesis example 43 (step 2), the title compound N-(2-methyl-pyridin-4-yl)-2-oxo-2-phenyl-N-[2-(4-trifluoromethyl-phenyl)-ethyl]-acetamide (MS m/e: 413.2 [M+H]+) was prepared from N-(2-methyl-pyridin-4-yl)-2-oxo-2-phenyl-acetamide and 1-(2-bromo-ethyl)-4-trifluoromethyl-benzene.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:31]=[CH:30][N:29]=[C:28]([CH3:32])[CH:27]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Reactant: Nc1cc(F)c(F)cc1N
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(F)c(F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from commercially available 4,5-difluoro-1,2-phenylendiamine (400 mg, 2.78 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (864 mg, 2.78 mmol) in xylene (15 ml) under reflux conditions for 1.5 h according to the general procedure M. Obtained as a light brown solid (780 mg, 77%).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].O1CCCC1.C(OC(=O)[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([NH:25][C:26]2[N:34]=[C:33]3[C:29]([N:30]=[CH:31][N:32]3[CH:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[C:28]([NH:40][CH:41]3[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]3)[N:27]=2)[CH2:21][CH2:20]1)(C)(C)C.Cl>O1CCOCC1>[CH3:1][NH:2][S:3]([N:44]1[CH2:45][CH2:46][CH:41]([NH:40][C:28]2[N:27]=[C:26]([NH:25][CH:22]3[CH2:23][CH2:24][CH:19]([NH2:18])[CH2:20][CH2:21]3)[N:34]=[C:33]3[C:29]=2[N:30]=[CH:31][N:32]3[CH:35]2[CH2:39][CH2:38][CH2:37][CH2:36]2)[CH2:42][CH2:43]1)(=[O:5])=[O:4]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(NC3CCNCC3)c3ncn(C4CCCC4)c3n2)CC1
Reactant: CNS(=O)(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CNS(=O)(=O)N1CCC(Nc2nc(NC3CCC(N)CC3)nc3c2ncn3C2CCCC2)CC1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
Treat a stirred, cooled (0° C.) solution of N-methyl sulfamoyl chloride (0.2 mmol) and anhydrous tetrahydrofuran (275 mL) with a solution of trans-{4-[9-cyclopentyl-6-(piperidin-4-ylamino)-9H-purin-2-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (9a, 0.2 mmol) triethylamine (9a 0.2 mmol) and tetrahydrofuran (4 mL) overnight at room temperature. Warm to 55° C., cool to room temperature and add 1.0 ml of 4N HCl in dioxane. Allow to stand for 3 hours, concentrate and dissolve the residue in DCM using a small amount of methanol as co-solvent if necessary. Purify the product by chromatography on a 2 g silica gel SPE cartridge pre-equilibrated with heptane. Elute the column in three fractions; first fraction 5 ml DCM; fractions 2 and 3 with 10-15 ml of DCM/methanol (4:1). Concentrate the desired fractions, dissolve the residue in ethanol and adjust to pH 2.0 with 10% HCl. Concentrate to dryness to give 4-[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purin-6-ylamino]-piperidine-1-sulfonic acid methylamide. Using N,N-dimethyl sulfamoyl chloride under similar conditions provides the corresponding trans-4-[2-(4-amino-cyclohexylamino)-9-cyclopentyl-9H-purin-6-ylamino]-piperidine-1-sulfonic acid dimethylamide. The corresponding 9-isopropyl and 9-cyclopent-2-enyl compound I sulfonic acid amides are prepared in a similar manner from 9b and 9c.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([N+:14]([O-:16])=[O:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:20])=[O:7]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)cc([N+](=O)[O-])c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound (F) was prepared as described in the procedure of compound (C). The 3,4-dimethoxy-5-nitrobenzoyl chloride was prepared by the reaction of 3,4-dimethoxy-5-nitrobenzoic acid (585 mg, 2.57 mmol) with oxalyl chloride (0.36 mL, 4.1 mmol) in dichloromethane using N,N-dimethylformamide as a catalyst. The resulting mixture was stirred at room temperature for 1 h, the volatile liquids were removed and the resulting acid chloride was used without further purification.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21]([C@@H:25](O)[CH3:26])[CH:22]=[CH:23][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:18][C:19]1[CH:20]=[C:21]([C@H:25]([O:17][C:14]2[CH:13]=[CH:12][C:11]([CH:4]([O:3][CH2:1][CH3:2])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:16][CH:15]=2)[CH3:26])[CH:22]=[CH:23][CH:24]=1
Reactant: C[C@H](O)c1cccc(Cl)c1
Reactant: CCOC(=O)CC(OCC)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(OCC)c1ccc(O[C@H](C)c2cccc(Cl)c2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Ethyl 3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.420 mmol) produced in Example 1 (1C) and (1S)-1-(3-chlorophenyl)ethanol (99 mg, 0.630 mmol) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours. After the reaction solution was cooled to room temperature, the solvent was distilled off under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 95:5 (v/v)), whereby the objective title compound was obtained as a yellow oily substance (142 mg, yield: 90%).
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Na+].[Na+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]=[O:24])[N:18]=1>C1(C)C=CC=CC=1.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>[CH:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=1)=[O:24]
Reactant: OB(O)c1ccccc1
Reactant: O=Cc1cccc(Br)n1
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: [Na+]
Solvent: Cc1ccccc1
Product: O=Cc1cccc(-c2ccccc2)n1
Temperature: 70 °C

Procedure:
Phenylboronic acid (1.46 g, 12 mmol) and Na2CO3 (2.65 g, 25 mmol) were dissolved in 60 mL of degassed 4:1 H2O/MeOH. This solution was added via cannula to a solution of 1.86 g (10 mmol) of 2-bromo-6-formylpyridine and 116 mg (0.10 mmol) of Pd(PPh3)4 in 50 mL of degassed toluene. The biphasic mixture was vigorously stirred and heated at 70° C. under N2 for 4 h. On cooling to RT, the organic phase was separated and the aqueous phase was washed with 3×25 mL of Et2O. The combined organic extracts were washed with 3×25 mL of H2O and 20 mL of brine and dried over Na2SO4. After removing the volatiles in vacuo, the resultant brown oil was chromatographed on silica with hexanes/CH2Cl2. Clean fractions were combined and the volatiles were removed to provide 2-formyl-6-phenylpyridine as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[NH:5][C:6](=[O:27])[N:7]([CH:26]=1)[C@@H:8]1[O:25][C@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+].[N-]=[N+]=[N-].[Li+]>CN(C)C=O>[N:29]([CH2:13][C@H:12]1[O:25][C@@H:8]([N:7]2[CH:26]=[C:3]([CH2:1][CH3:2])[C:4](=[O:28])[NH:5][C:6]2=[O:27])[CH2:9][C@@H:10]1[OH:11])=[N+:30]=[N-:31]
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 85 °C
Yield: 90.2 %

Procedure:
A mixture of 5-ethyl-5'-O-tosyl-2'-deoxyuridine (550 mg, 1.34 mmole) and sodium azide (480 mg, 7.4 mmole) or lithium azide (400 mg) in dry dimethylformamide (10 ml) is heated at 85° C. for 2 hr. Tlc indicates all the starting material has reacted. The solvent is evaporated in vacuo to dryness, and the remaining material is triturated with ice-cold water, filtered to collect the product, and dried over P2O5 to give a white solid (340 mg, 90%), m.p. 174°-177° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[N:12][CH2:13][C:14](=S)[NH:15][C:9]=2[CH:8]=[C:7]([Br:24])[CH:6]=1)(=[O:4])=[O:3].[OH:25][CH2:26][C:27]([NH:29][NH2:30])=O>C(O)CCC>[CH3:1][S:2]([C:5]1[C:10]2[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)=[N:12][CH2:13][C:14]3[N:15]([C:27]([CH2:26][OH:25])=[N:29][N:30]=3)[C:9]=2[CH:8]=[C:7]([Br:24])[CH:6]=1)(=[O:4])=[O:3]
Reactant: NNC(=O)CO
Reactant: CS(=O)(=O)c1cc(Br)cc2c1C(c1cccc(F)c1)=NCC(=S)N2
Solvent: CCCCO
Product: CS(=O)(=O)c1cc(Br)cc2c1C(c1cccc(F)c1)=NCc1nnc(CO)n1-2

Procedure:
In the manner given in Example 11, a solution of 1,3-dihydro-6-(methylsulfonyl)-8-bromo-5-(m-fluorophenyl)-2H-1,4-benzodiazepine-2-thione and hydroxyacetic acid hydrazide in n-butyl alcohol was refluxed to give 7-(methylsulfonyl)-9-bromo-1-(hydroxymethyl)-6-(m-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC)(OC)(OC)[CH3:21]>C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH3:20][C:21]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Reactant: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Product: CCOC(=O)CCn1c(C)nc2cnc3ccccc3c21
Yield: 85.5 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (15.0 g, 57.8 mmol) was treated with trimethyl orthoacetate (10.3 mL, 81.0 mmol) and pyridinium p-toluenesulfonate (0.200 g) according to the method described in Part A of Example 10 to provide 14.0 g of ethyl 3-(2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate as a brown solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[C:12]1([N:18]=[C:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([NH:18][C:19](=[O:20])[NH:1][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)c1ccc(N)nc1
Product: COC(=O)c1ccc(NC(=O)Nc2ccccc2)nc1
Temperature: 100 °C
Yield: 104 %

Procedure:
To a solution of methyl 6-aminonicotinate (500 mg, 3.29 mmol) in N,N-diemthylformamide (5 mL) was added phenyl isocyanate (358 μL, 3.29 mmol). The mixture was heated to 100° C. for 2 hours and was then concentrated under vacuum to give the title compound (928 mg).
Reaction SMILES: O[CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.CCN(S(F)(F)[F:29])CC>C(Cl)Cl>[F:29][CH:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C(O)c2ccc(C(F)(F)F)cc2)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(C(F)c2ccc(C(F)(F)F)cc2)cc1
Reaction time: 0.5 h

Procedure:
To a solution of 63c (0.97 mmol, 300 mg) in CH2Cl2 was added DAST (1.015 mmol, 0.133 mL) dropwise at −78° C. under N2. The reaction was kept at −78° C. for 30 min and then quenched with aqueous NaHCO3 solution at low temperature. Additional CH2Cl2 was added to the reaction and the organic solution was concentrated. The crude material was purified flash column chromatography (silica gel, 10% EtOAc/hexanes) to give 63d.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH:6]([C:10](=[O:12])[CH3:11])[C:7](=[O:9])[CH3:8].[Na].[C:15](Cl)(=[O:17])[CH3:16]>C(OCC)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]([C:15](=[O:17])[CH3:16])([C:7](=[O:9])[CH3:8])[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)Cl
Reactant: COC(=O)CCC(C(C)=O)C(C)=O
Agent: [Na]
Solvent: CCOCC
Product: COC(=O)CCC(C(C)=O)(C(C)=O)C(C)=O
Reaction time: 6 h

Procedure:
92.5 g of 4-acetyl-5-oxohexanoic acid methyl ester was reacted with 11.5 g of metallic sodium in 200 ml of diethyl ether. After the dissolving of sodium was finished, 39.25 g of acetyl chloride was dropped in, and the resulting boiling mixture was stirred for 6 hours. Then, the reaction mixture was filtered, washed with aqueous potassium hydroxide and water, following by evaporation of solvent. The final vacuum distillation yielded the subject compound as a yellowish liquid having a purity of above 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([NH2:17])=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH:18]1([O:23][C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH:27]=O)[CH2:22][CH2:21][CH2:20][CH2:19]1.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[C:16]([NH:17][CH2:27][C:26]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([O:23][CH:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)[CH:25]=4)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cccc2nc(-c3cccc(Cl)c3)oc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cccc3nc(-c4cccc(Cl)c4)oc23)cc1OC1CCCC1
Yield: 59.8 %

Procedure:
By employing a procedure similar to that in Example 33 and using 2-(3-chlorophenyl)-7-aminobenzoxazole (1.00 g, 0.0041 mol), 3-cyclopentyloxy-4-methoxybenzaldehyde (1.08 g, 0.0049 mol), sodium cyanoborohydride (0.41 g, 0.0065 mol) and 35 ml of methanol, a white, crystalline solid was isolated. This crude product (1.4 g) was recrystallized from 200 ml of methanol to yield the title compound (1.1 g), mp 133-134° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH2:20]>>[F:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][C:23]=1[F:24])[CH2:19][NH:20][C:2]1[C:11]2[C:6](=[C:7]([S:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:14])[CH:3]=1
Reactant: CSc1cccc2c(Cl)cc(C)nc12
Reactant: NCc1ccc(F)c(F)c1
Product: CSc1cccc2c(NCc3ccc(F)c(F)c3)cc(C)nc12

Procedure:
Preparation was made using a similar procedure as described in example 1, method 1.3. Starting materials were 4-chloro-2-methyl-8-methylsulfanylquinoline and 3,4-difluorobenzylamine.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:27]=[CH:26][C:17]([C:18]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.Cl[C:31]1[C:36]([CH3:37])=[N:35][CH:34]=[CH:33][N:32]=1.C(N(CC)CC)C>C(O)CO>[CH3:37][C:36]1[C:31]([N:23]2[CH2:24][CH2:25][N:20]([C:18](=[O:19])[C:17]3[CH:26]=[CH:27][C:14]([NH:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([C:2]([F:1])([F:28])[F:29])=[CH:4][CH:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)[CH2:21][CH2:22]2)=[N:32][CH:33]=[CH:34][N:35]=1
Reactant: Cc1nccnc1Cl
Reactant: O=C(c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1)N1CCNCC1
Solvent: OCCO
Solvent: CCN(CC)CC
Product: Cc1nccnc1N1CCN(C(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1

Procedure:
In the manner given in Example 6, a mixture of 4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine, 2-chloro-3-methylpyrazine and triethylamine is heated in ethylene glycol at 75° to 95° C. to give 1-(3-methylpyrazin-2-yl)-4-[4-[[7-(trifluoromethyl)-4-quinolinyl]amino]benzoyl]piperazine.
Reaction SMILES: Cl.[CH3:2][S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C@@H:12]2[CH2:16][NH:15][C@H:14]([C:17]3[NH:18][C:19]([C:22]4[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:24][CH:23]=4)=[CH:20][N:21]=3)[CH2:13]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4].[CH3:33][C:34]([O:37][C:38]([NH:40][C:41](=[N:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[NH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47](O)=[O:48])=[CH:45][CH:44]=1)=[O:39])([CH3:36])[CH3:35]>>[CH3:59][C:56]([O:55][C:53]([NH:52][C:41](=[N:40][C:38]([O:37][C:34]([CH3:36])([CH3:35])[CH3:33])=[O:39])[NH:42][C:43]1[CH:51]=[CH:50][C:46]([C:47]([N:15]2[CH2:16][C@H:12]([CH:9]3[CH2:8][CH2:7][N:6]([S:3]([CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]3)[CH2:13][C@@H:14]2[C:17]2[NH:18][C:19]([C:22]3[CH:23]=[CH:24][C:25]([NH:28][C:29](=[O:32])[O:30][CH3:31])=[CH:26][CH:27]=3)=[CH:20][N:21]=2)=[O:48])=[CH:45][CH:44]=1)=[O:54])([CH3:57])[CH3:58]
Reactant: COC(=O)Nc1ccc(-c2cnc([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)[nH]2)cc1
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)Nc1ccc(C(=O)O)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2cnc([C@H]3C[C@@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)c3ccc(NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)[nH]2)cc1

Procedure:
The compound prepared in Example 66 was treated with the compound prepared in Example 10 following the procedure described in Example 8 to give the title compound as a light brown solid.
Reaction SMILES: N1C=CN=C1.[Si:6](Cl)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[OH:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22].S(=O)(=O)(O)O>CN(C)C=O.CCOCC>[Si:6]([O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH2:21][OH:22])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: OC[C@@H]1CCC[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=S(=O)(O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CCC[C@H]1CO
Temperature: 24 °C
Reaction time: 22 h
Yield: 39.9 %

Procedure:
17.1 g of imidazole and 18.9 g of tert-butyldimethylsilyl chloride are added to a solution of 16 g of trans-1,2-dihydroxymethyl-cyclopentane in 146 ml of dimethylformamide at 0° C. and stirred for 22 hours at 24° C. It is diluted with 1.6 l of ether, shaken twice with 80 ml of 10% sulfuric acid each, washed neutral with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. The residue is chromatographed on silica gel. With hexane/ethyl acetate (9+1), 12 g of trans-1-(tert-butyldimethylsilyloxymethyl)-2-hydroxymethyl-cyclopentane is obtained as colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:10]([O-:12])=[O:11])=[N:5]C(C)=[CH:7][CH:8]=1.[O-][Mn](=O)(=O)=O.[K+].CC[O:21][C:22]([CH3:24])=[O:23]>O.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:24]([C:22]([OH:21])=[O:23])=[N:5][C:4]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1ccc(C)nc1[N+](=O)[O-]
Reactant: CCOC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(C(=O)O)nc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-methoxy-6-methyl-2-nitropyridine (7 g, 0.041 mol) in water (140.0 mL) was added KMnO4 (32.88 g, 0.208 mol, S.d. fine chemicals, India) at 80° C. The reaction mixture was stirred for 16 h at 100° C. After completion of the reaction (monitored by TLC, 50% EtOAc in hexane), the reaction mixture was filtered and the solids were washed with water. The filtrate was acidified and extracted with EtOAc (500 mL×2). The organic layers were then dried over sodium sulfate and concentrated under reduced pressure to afford the title compound as an off white solid. 1H-NMR (400 MHz, DMSO-d6): δ 13.6 (br. s., 1H), 8.39 (d, J=8.8 Hz, 1H), 8.09 (d, J=8.8 Hz, 1H), 4.06 (s, 3H). MS (ESI, positive ion) m/z: 199 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31][C:32]([OH:34])=[O:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O=S(Cl)Cl.[CH3:39]O>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:31][C:32]([O:34][CH3:39])=[O:33])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH:28]=[CH:27][C:26](=[O:29])[N:25]([CH3:30])[CH:24]=4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(=O)O)(c2ccc(F)cc2)OC1=O
Solvent: O=S(Cl)Cl
Product: COC(=O)C[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(=O)n(C)c3)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.5 %

Procedure:
To a solution of 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetic acid (290 mg, 0.625 mol) in MeOH (20 mL) was added SOCl2 (2 mL) at 0° C., and the reaction mixture was stirred at rt for 2 h. The reaction mixture was concentrated to give the residue, which was purified by preparative TLC to give methyl 2-((S)-6-(4-fluorophenyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-2-oxo-1,3-oxazinan-6-yl)acetate (130 mg, 43.5%). 1H NMR (CDCl3): δ=1.52 (d, 3H), 2.36-2.55 (m, 3H), 2.67-2.71 (m, 2H), 2.90-3.04 (m, 3H), 3.68 (s, 3H), 3.71 (s, 3H), 5.66 (m, 2H), 6.66 (d, 1H), 6.90 (d, 2H), 7.03 (t, 2H), 7.13-7.15 (d, 2H), 7.23-7.29 (m, 2H), 7.42 (m, 1H), 7.56 (m, 1H).