Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[S:19][C:20]([C:23]([OH:25])=O)=[CH:21][N:22]=2)[CH2:14][CH2:13]1)=[O:10].Cl.[O:27]([NH2:29])[CH3:28]>>[Cl:1][C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[NH:4][C:3]=1[C:9]([NH:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[S:19][C:20]([C:23]([NH:29][O:27][CH3:28])=[O:25])=[CH:21][N:22]=2)[CH2:16][CH2:17]1)=[O:10]
Reactant: Cc1[nH]c(C(=O)NC2CCN(c3ncc(C(=O)O)s3)CC2)c(Cl)c1Cl
Reactant: CON
Agent: Cl
Product: CONC(=O)c1cnc(N2CCC(NC(=O)c3[nH]c(C)c(Cl)c3Cl)CC2)s1

Procedure:
2-(4-{[(3,4-Dichloro-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-thiazole-5-carboxylic acid (Example 227, 100 mg, 0.25 mmol) was reacted with methoxylamine hydrochloride according to procedure described in Example 8 to afford the title compound (30 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=1[NH:18][C:19](=[O:35])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:30]1[CH:31]=[CH:32][CH:33]=[C:28]([C:24]2[CH:23]=[C:22]([C:21]3[CH2:20][C:19](=[O:35])[NH:18][C:9]4[CH:10]=[C:11]([C:14]([F:17])([F:16])[F:15])[CH:12]=[CH:13][C:8]=4[N:7]=3)[CH:27]=[CH:26][CH:25]=2)[CH:29]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3cccnc3)c2)=Nc2ccc(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from {2-[3-oxo-3-(3-pyridin-3-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M24) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (151 mg).
Reaction SMILES: [H-].[Na+].[C:3]([Si:7]([CH3:33])([CH3:32])[O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([NH2:21])[CH:15]=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[N:13]=1)([CH3:6])([CH3:5])[CH3:4].[C:34]([C:38]1[C:39]([Cl:47])=[C:40]([C:44](Cl)=[O:45])[N:41]([CH3:43])[N:42]=1)([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[C:3]([Si:7]([CH3:33])([CH3:32])[O:8][CH2:9][CH2:10][O:11][C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([NH:21][C:44]([C:40]2[N:41]([CH3:43])[N:42]=[C:38]([C:34]([CH3:36])([CH3:35])[CH3:37])[C:39]=2[Cl:47])=[O:45])[CH:15]=[C:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:30])([F:31])[F:29])[N:13]=1)([CH3:6])([CH3:5])[CH3:4]
Reactant: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCOc1nc(-c2ccccc2C(F)(F)F)cc(N)c1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1nc(C(C)(C)C)c(Cl)c1C(=O)Nc1cc(-c2ccccc2C(F)(F)F)nc(OCCO[Si](C)(C)C(C)(C)C)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 60% sodium hydride in mineral oil (120 mg, 3.00 mmol) in THF (10 mL) at 0° C. was added 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (458 mg, 1.00 mmol, prepared as described in the previous step) slowly. The resulting mixture was warmed to room temperature and then stirred for 1 h under Ar. 5-tert-Butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride (259 mg, 1.10 mmol, prepared as described in Example 1, STEP C) was added and the resulting mixture was stirred for 3 h under Ar. After quenching with saturated aqueous NH4Cl solution (5 mL), the mixture was treated with EtOAc (100 mL) and washed with H2O, brine and dried with Na2SO4. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (0:100-10:90 EtOAc/hexanes) yielded 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3-nitro-6-(2-trifluoromethyl-phenyl)-pyridin-4-yl]-amide as a white solid. 1H-NMR (400 MHz, CD3OD) δ: 10.10 (s, 1H), 8.33 (s, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.62-7.70 (m, 1H), 7.52-7.62 (m, 2H), 4.51-4.61 (m, 2H), 4.11 (s, 3H), 3.94-4.01 (m, 2H), 1.42 (s, 9H), 0.89 (s, 9H), 0.07 (s, 6H). Mass Spectrum (LCMS, ESI pos.) Calculated For C29H37ClF3N5O5Si: 656.2 (M+H), Measured: 656.2.
Reaction SMILES: CS(Cl)(=O)=[O:3].C(N(CC)CC)C.[NH:13]1[CH:17]=[CH:16][C:15]([C:18]([OH:20])=O)=N1.[C:21](O)(=O)[C:22]1C(=CC=[CH:27][CH:28]=1)N>N1C=CC=CC=1>[O:20]1[C:18]2[CH:21]=[CH:22][CH:28]=[CH:27][C:15]=2[CH2:16][C:17](=[O:3])[NH:13]1
Reactant: O=C(O)c1cc[nH]n1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1ccccc1C(=O)O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2ON1

Procedure:
Coupling of a pyrazolecarboxylic acid of Formula 7 wherein R1 is H with an anthranilic acid of Formula 8 provides the benzoxazinone of Formula 9. In Scheme 9, a benzoxazinone of Formula 9 is prepared directly via sequential addition of methanesulfonyl chloride in the presence of a tertiary amine such as triethylamine or pyridine to a pyrazolecarboxylic acid of Formula 7 wherein R1 is H, followed by the addition of an anthranilic acid of Formula 8, followed by a second addition of tertiary amine and methanesulfonyl chloride.
Reaction SMILES: [OH:1][C:2]1([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[OH:1][C:2]1([C:9]2[N:10]([CH3:14])[CH:11]=[CH:12][N:13]=2)[CH2:7][CH2:6][CH:5]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=3)=[O:21])[CH2:16]2)[CH2:4][CH2:3]1
Reactant: Cn1ccnc1C1(O)CCC(=O)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cn1ccnc1C1(O)CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1

Procedure:
The title compounds were prepared as white solids from reductive amination of 4-hydroxy-4-(1-methyl-1H-imidazol-2-yl)-cyclohexanone, as prepared in the previous step, and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step E of Example 1.
Reaction SMILES: CC(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]([C:21]([NH:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:52])=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]5[CH2:43][CH2:42][N:41](C(OC(C)(C)C)=O)[C@@H:40]([CH3:51])[CH2:39]5)[CH:32]=4)[CH:30]=3)=[O:22])[CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1)=O)(C)C.[H-].[Na+].Br[CH2:56][CH:57]1[CH2:59][CH2:58]1>CN(C=O)C>[CH:59]1([CH2:58][N:23]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([CH2:37][N:38]4[CH2:43][CH2:42][NH:41][C@@H:40]([CH3:51])[CH2:39]4)[CH:32]=3)[C:28]([F:52])=[CH:27][CH:26]=2)[C:21](=[O:22])[C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:16]=2)[CH2:57][CH2:56]1
Reactant: BrCC1CC1
Reactant: C[C@H]1CN(Cc2cccc(-c3cc(CNC(=O)c4cccc(CC5CCN(C(=O)OC(C)(C)C)CC5)c4)ccc3F)c2)CCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CN(Cc2cccc(-c3cc(CN(CC4CC4)C(=O)c4cccc(CC5CCNCC5)c4)ccc3F)c2)CCN1
Yield: 13.9 %

Procedure:
Following the general procedure outlined in Example 66, 1,1-dimethylethyl (2S)-4-[(5′-{[({3-[(1-{[(1,1-dimethylethyl)oxy]carbonyl}-4-piperidinyl)methyl]phenyl}carbonyl)amino]methyl}-2′-fluoro-3-biphenylyl)methyl]-2-methyl-1-piperazinecarboxylate (76.1 mg, 0.106 mmol), NaH (8.29 mg, 0.345 mmol) and (bromomethyl)cyclopropane (0.0155 mL, 0.160 mmol) in DMF (1.0 mL) were reacted to give the desired product (8.4 mg, 13.7%). EI-MS m/z 569(M−H)+.
Reaction SMILES: C([O:5][C:6]([CH:8]1[N:17]([CH3:18])[C:16](=[O:19])[C:15]([OH:20])=[C:14]2[CH:9]1[CH2:10][CH2:11][N:12]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:13]2=[O:21])=[O:7])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:12]2[CH2:11][CH2:10][CH:9]3[C:14](=[C:15]([OH:20])[C:16](=[O:19])[N:17]([CH3:18])[CH:8]3[C:6]([OH:7])=[O:5])[C:13]2=[O:21])=[CH:24][CH:25]=1
Reactant: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1C(=O)O
Reaction time: 1.3 h

Procedure:
A solution of 5-(tert-butyloxycarbonyl)-2-(4-fluorobenzyl)-8-hydroxy-6-methyl-2,3,4,4a,5,6-hexahydro-2,6-naphthyridine-1,7-dione, Diastereomer 1 from Example 4, (0.015 g, 0.037 mmol) in 50% TFA in CH2Cl2 (2.4 mL) was stirred at room temperature. After 1.3 hours, TFA acid (0.5 mL) was added to the reaction mixture. After 48 hours, the reaction mixture was concentrated under vacuum to give the title compound. ES MS M+1=349.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8].[SH:19][C:20]1[O:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:21]1[C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=[C:20]1[S:19][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][C:10]1[C:11]([S:17][CH3:18])=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:8]
Reactant: Sc1nc2ccccc2o1
Reactant: CSc1nc(C)ccc1NC(=O)CCCCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1nc(C)ccc1NC(=O)CCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 77.8 %

Procedure:
Triethylamine (475 mg, 4.7 mmol) was added to a chloroform (10 ml) solution of this aminopyridine (601 mg, 3.9 mmol), and 6-bromohexanoyl chloride (944 mg, 4.29 mmol) was then slowly added thereto dropwise while being cooled with ice, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with water, and extracted with methylene chloride. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 50 g, eluent—hexane:ethyl acetate=10:1→5:1) to obtain 773 mg (yield 59%) of 6-bromo-N-(6-methyl-2-methylthio-3-pyridyl)hexanamide as a colorless crystal (melting point: 98 to 99° C.). To a DMF (2 ml) solution of this amide (133 mg, 0.4 mmol) and 2-mercaptobenzoxazole (67 mg, 0.44 mmol) were added 18-crown-6 (11 mg, 0.04 mmol) and potassium carbonate (67 mg, 0.44 mmol), and the mixture was stirred at 80° C. for 90 minutes. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 20 g, eluent-hexane:acetone=5:1→5:3) to obtain 125 mg (yield 78%) of the desired compound as a colorless needle crystal.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1.[BrH:23].N([O-])=O.[Na+].[C:28]([O:32][CH3:33])(=[O:31])[CH:29]=[CH2:30]>O.CC(C)=O>[CH3:33][O:32][C:28](=[O:31])[CH:29]([Br:23])[CH2:30][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:14][C:15]=2[CH3:16])=[N:6][CH:7]=1
Reactant: Br
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)cn1
Reactant: C=CC(=O)OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C(Br)Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)nc1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a mixture of 5-amino-2-[2-(5-methyl-2-phenyl-4-oxazolyl) ethoxy]pyridine (4.5 g), aqueous HBr (47%, 7.1 ml) and acetone (70 ml) was added an aqueous solution of sodium nitrite (NaNO2) (1.17 g) in water (5 ml) dropwise at a temperature of under 10° C. After stirring at 10° C. for 30 minutes, the temperature was increased to 30° C., and methyl acrylate (8.3 ml) was added. Then, cuprous oxide (Cu2O) (0.1 g) was added little by little, and the mixture was vigorously stirred. The reaction mixture was further stirred at 40° to 45° C. for 1 more hour and then concentrated under reduced pressure. After alkalinization with concentrated aqueous ammonia, the residue was extracted with ethyl acetate. After the ethyl acetate layer was washed with water and dried (MgSO4), the solvent was distilled off under reduced pressure. The residual oily substance was subjected to silica gel chromatography. From the fraction eluted with ethyl acetate-hexane (2:1, v/v), 2-bromo-3-[2-[2-(5-methyl-2-phenyl-4-oxazolyl]ethoxy]-5-pyridyl]propionic acid methyl ester (4.7 g, 68%) was obtained. NMR (δ ppm in CDCl3): 2.34 (3H, s), 2.98 (2H, t, J=6.7 Hz), 3.16 (1H, dd, J=7.0 & 14.5 Hz), 3.37 (1H, dd, J=8.0 & 14.5 Hz), 3.74 (3H, s), 4.31 (1H, dd, J=8.0 & 7.0 Hz), 4.55 (2H, t, J=6.7 Hz), 6.67 (1H, d, J=8.6 Hz), 7.35-7.50 (4H, m), 7.90-8.05 (3H, m)
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16](=O)[CH2:17][C:18](=O)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].[NH2:27][NH2:28]>CC(O)=O>[C:1]([NH:5][C:6]1[C:7]([CH3:26])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:28][N:27]=[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1cccc2nc(C)c(NC(C)(C)C)nc12
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(NC(C)(C)C)nc23)[nH]n1
Temperature: 85 °C
Yield: 75.9 %

Procedure:
To a 25-mL round-bottomed flask was added EtOH (4 mL) and sodium ethoxyde (1.01 g of 21% in EtOH, 3.11 mmol). The reaction mixture was cooled to −10° C. and added ethyl oxalate (0.21 mL, 1.55 mmol, Sigma-Aldrich) and 1-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)ethanone (606a) (0.4 g, 1.55 mmol) slowly. The reaction mixture was warmed to RT and stirred at RT for 18 h. The reaction mixture was diluted with water (10 mL) and partially concentrated under vacuum. The reaction mixture was diluted with HCl (1 N, 5 mL) and extracted with EtOAc (15 mL). The organic extract was washed with brine (10 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 10% to 30% EtOAc in hexanes to give ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate as an orange oil (135 mg, 24% yield). m/z (ESI, +ve) 358.1 (M+H)+. To a 15-mL glass tube was added ethyl 4-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-2,4-dioxobutanoate (135 mg, 0.38 mmol), hydrazine (12 μL, 0.38 mmol), and AcOH (2 mL). The tube was sealed and heated at 85° C. for 1 h. The reaction mixture was cooled to RT and the solvent was removed under vacuum. The mixture was diluted with EtOAc (10 mL) and NaOH (1 N, 5 mL). The organic extract was washed with water (5 mL), dried over Na2SO4, and concentrated. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (12 g), eluting with a gradient of 30% to 40% EtOAc in hexanes to give ethyl 5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrazole-3-carboxylate (467a) (102 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 7.82-7.97 (m, 1H), 7.74 (d, J=7.82 Hz, 1H), 7.51-7.60 (m, 1H), 7.40 (t, J=8.90 Hz, 1H), 6.00-6.07 (m, 1H), 4.31 (q, J=7.11 Hz, 2H), 2.56 (s, 3H), 1.53 (s, 9H), 1.33 (t, J=7.14 Hz, 3H). m/z (ESI, +ve) 354.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([NH:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:36][CH3:37].O>CN(C)C=O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([N:26]([CH2:36][CH3:37])[C:27](=[O:32])[C:28]([F:30])([F:29])[F:31])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCI
Reactant: CCC(NC(=O)C(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)N(CC)C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 31 %

Procedure:
To a solution of N-{1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propyl}-2,2,2-trifluoroacetamide (400 mg, 0.79 mmol) in N,N-dimethylformamide (5.0 mL) was added sodium hydride (60% dispersion in mineral oil, 38 mg, 0.95 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Iodoethane (0.095 mL, 1.19 mmol) was added to the reaction mixture at 0° C. The mixture was stirred at 60° C. for 16 hr. Water was added to the reaction mixture at room temperature and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture to give the title compound (131 mg, 0.245 mmol, 31%) as a pale yellow amorphous.
Reaction SMILES: CS(O[CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)(=O)=O.[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOCC>[N:18]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)=[N+:19]=[N-:20]
Reactant: COc1ccc2c(c1)CCC(OS(C)(=O)=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc2c(c1)CCC(N=[N+]=[N-])C2

Procedure:
8.0 g (31 mmol) of 2-methanesulfonyloxy-6-methoxytetralin and 2.6 g (40 mmol) of sodium azide were heated for 3 hours at 90° C. in 100 ml of DMF. After the mixture had been cooled, it was diluted with ether, washed with water and saturated NaCl solution, dried and concentrated in vacuo. This gave 6 g (95% of theory) of a colorless oil which was further reacted directly.
Reaction SMILES: O=[C:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:13]1([C:19]2[N:20]=[C:21](NC)[S:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH3-][C:27]#[N:28].[Na+]>CO>[C:7]1([CH2:6][CH:2]([NH:28][CH2:27][C:21]2[S:22][CH:23]=[C:19]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:20]=2)[C:3]([OH:5])=[O:4])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [BH3-]C#N
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: CNc1nc(-c2ccccc2)cs1
Agent: [Na+]
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)NCc1nc(-c2ccccc2)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.1 %

Procedure:
To a solution of 2-Oxo-3-phenyl-propionic acid (1.6 mmol, 264 mg) and (4-Phenyl-thiazol-2-yl)-methylamine (1.0 mmol, 190 mg) in MeOH (4 mL), is added NaBH3CN (2.0 mmol, 1N in THF). The pH was then adjusted at 6 with 1M HClaq. The mixture was stirred at room temperature for 3 days. The product was purified by HPLC to give the pure product (210 mg, 62%).
Reaction SMILES: C(OC(C)C)(C)C.[CH3:8][C:9]1[N:10]([CH2:44][O:45][CH3:46])[C:11]([CH3:43])=[C:12]([C:32]([O:34]COC(=O)C(C)(C)C)=[O:33])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:14]=1[C:15]([O:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[O:16]>O>[CH3:43][C:11]1[N:10]([CH2:44][O:45][CH3:46])[C:9]([CH3:8])=[C:14]([C:15]([O:17][CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])=[O:16])[CH:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:12]=1[C:32]([OH:34])=[O:33]
Reactant: COCN1C(C)=C(C(=O)OCOC(=O)C(C)(C)C)C(c2ccccc2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: CC(C)OC(C)C
Solvent: O
Product: COCN1C(C)=C(C(=O)O)C(c2ccccc2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.1 %

Procedure:
To 20 ml of isopropyl ether saturated with water were added 545 mg of bis(pivaloyloxymethyl) 1,4-dihydro-2,6-dimethyl-1-methoxymethyl-4-phenyl-3,5-pyridinedicarboxylate obtained in Example 10 and 100 mg of Lipase B, and the system was stirred at 25 ° C. for 5 hours. Any insoluble matter was removed by filtration and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate/hexane=1/1) to obtain 328 mg (yield: 76%) of (+)-1,4-dihydro-2,6-dimethyl -1-methoxymethyl-4-phenyl-5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid as a colorless crystal.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][NH2:21].C(N(CC)CC)C>C(O)C>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:21]([CH2:20][C:19]2[CH:22]=[CH:23][CH:24]=[C:17]([O:16][CH3:15])[CH:18]=2)[CH:10]=1
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Reactant: COc1cccc(CN)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cccc(Cn2cc(Cl)cc(C(N)=O)c2=N)c1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.5 g) in ethanol (5 ml) was added a solution (3 ml) of 3-methoxybenzylamine (410 μl) and triethylamine (450 μl) in ethanol at 0° C., and the mixture was stirred at room temperature for 24 hr. The reaction solvent was evaporated under reduced pressure, and the residue was purified by preparative HPLC. 4N Hydrochloric acid-ethyl acetate solution (1 ml) was added to the obtained yellow oil at room temperature, and the precipitated crystals were filtered and recrystallized to give the title compound (110 mg).
Reaction SMILES: Br[CH2:2][C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[Br:14][C:15]1[CH:26]=[CH:25][C:18]([CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=1>CN(C=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[CH2:2][C:3]([F:6])([F:5])[F:4])=[CH:25][CH:26]=1
Reactant: COCCNCc1ccc(Br)cc1
Reactant: FC(F)(F)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCN(Cc1ccc(Br)cc1)CC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-1,1,1-trifluoroethane (0.74 ml) and triethylamine (1.13 ml) in DMF (30 ml) was added (4-bromobenzyl)-(2-methoxyethyl)amine (2.05 g). The resulting mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and water, the organic layer was dried and evaporated to an oil, which was purified by column chromatography eluting with a gradient of ethyl acetate (60 to 100%) in isohexane to give (4-bromobenzyl)-(2-methoxyethyl)-(2,2,2-trifluoroethyl) amine (1.84 g). 1H NMR (DMSO-D6) δ 2.1 (bs, 2H), 2.6 (t, 2H), 3.2 (s, 3H), 3.4 (t, 2H), 3.65 (d, 2H), 7.25 (d, 2H), 7.45 (d, 2H). c) (4-Bromobenzyl)-(2-methoxyethyl)amine 2-Methoxyethylamine (16 ml) was added to a solution of 4-bromobenzaldehyde (17.2 g) in THF (150 ml). Glacial acetic acid (5.32 ml) and MgSO4 (0.5 g) were added and the mixture was stirred for 45 min. Sodium triacetoxyborohydride (29.7 g) was added and the resulting mixture was stirred for 4 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was dried and concentrated to an oil, which was purified by column chromatography, eluting with a gradient of ethyl acetate (10 to 100%) in isohexane, then eluting with methanol/DCM (10:90) to give (4-bromobenzyl)-(2-methoxyethyl)amine (13.0 g) as a yellow oil. MS (ES) 244 (M+H)+. 1H NMR (DMSO-D6) δ 2.05 (bs, 1H), 2.6 (t, 2H), 3.38 (t, 2H), 3.2 (s, 3H), 3.62 (s, 2H), 7.25 (d, 2H), 7.45 (d, 2H).