Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][C:23]([CH3:26])=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[CH3:26][C:23]1[CH:22]=[N:21][C:20]([NH:1][CH2:2][CH:3]2[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])[CH2:5][CH2:4]2)=[N:25][CH:24]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Cc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(NCC2CCN(C(=O)OCc3ccccc3)CC2)nc1
Temperature: 150 °C

Procedure:
A stirred mixture of benzyl 4-(aminomethyl)-piperidine-1-carboxylate (EXAMPLE 13, STEP 1) (20.0 g, 0.081 mol), 2-chloro-5-methylpyrimidine (10.4 g, 0.081 mol) and cesium carbonate (52.5 g, 0.161 mol) in DMF (200 mL) was heated at 150° C. for 6 h. The reaction mixture was cooled to rt, diluted with ethyl acetate (700 mL), washed with aqueous saturated NaHCO3 (200 mL), water (5×200 mL), and brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was chromatographed on silica gel 60 (1 kg), eluting with 50–100% ethyl acetate in hexane to give the title compound. M.S. (M+1): 341.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:21])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=2)=[CH:7][C:6]=1[C:22]1[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=1.Br[CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32].C(N(CC)CC)C>CN(C=O)C>[CH3:20][O:19][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=1)[C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:29][CH2:30][C:31]([F:34])([F:33])[F:32])=[C:6]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:7]=1)=[O:21]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: FC(F)(F)CCBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2ccc(OCCNCCC(F)(F)F)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 2.3 %

Procedure:
A mixture of N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (14.5 mg, 81.9 μmol), 3-bromo-1,1,1-trifluoropropane (30 mg, 81.9 μmol) and triethylamine (34.2 μL, 246 μmol) in DMF was heated to 150° C. for 1 hour under microwave irradiation in a heavy-walled sealed tube. The crude product was purified by PLC. The proper fractions were collected and lyophilized to afford the title compound as a brown solid in 2.3% yield. LCMS m/z (%)=463 (M+H, 100). 1H NMR (400 MHz, MeOH-d4) δ 2.6 (m, 2H) 3.2 (dd, J=15.4, 7.8 Hz, 2H) 3.5 (m, 2H) 3.8 (s, 3H) 3.9 (s, 3H) 4.4 (m, 2H) 6.4 (d, J=2.0 Hz, 1H) 7.2 (dd, J=8.6, 3.5 Hz, 1H) 7.3 (d, J=9.1 Hz, 1H) 7.4 (t, J=8.1 Hz, 1H) 7.5 (m, 2H) 7.6 (d, J=2.0 Hz, 1H) 7.7 (d, J=2.5 Hz, 1H) 7.9 (dd, J=9.1, 2.5 Hz, 1H).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C1(P(C2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=C(C3C4C(=CC=CC=4)C=CC=3)C3C(C=2)=CC=CC=3)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:57][O:58][C:59]([C:61]1[CH:66]=[CH:65][C:64](Br)=[C:63]([O:68][CH2:69][CH:70]2[CH2:72][CH2:71]2)[N:62]=1)=[O:60]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:57][O:58][C:59]([C:61]1[CH:66]=[CH:65][C:64]([NH:4][CH:1]2[CH2:3][CH2:2]2)=[C:63]([O:68][CH2:69][CH:70]2[CH2:72][CH2:71]2)[N:62]=1)=[O:60]
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(NC2CC2)c(OCC2CC2)n1
Temperature: 110 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Cyclopropanamine (CAS 765-30-0, 158 mg, 2.8 mmol), bis(diphenylphosphino)-1,1′-binaphthalene (CAS 98327-87-8, 115 mg, 0.19 mmol), tris(dibenzylideneacetone)dipalladium (CAS 51364-51-3, 84 mg, 0.093 mmol) and cesium carbonate (CAS 534-17-8, 1.8 g, 6.6 mmol) were added to solution of 5-bromo-6-(cyclopropylmethoxy)-pyridine-2-carboxylic acid methyl ester (Example 114 a, 530 mg, 1.85 mmol) in toluene (20 mL) under a nitrogen atmosphere. The reaction mixture was stirred overnight at 110° C. and concentrated in vacuo. The residue was dissolved in water and extracted with ethyl acetate (30 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N HCl, the resulting precipitate was collected by filtration, dried in vacuo and purified by column chromatography (silica gel, 50 g, 50% ethyl acetate in petroleum ether) to yield the title compound (400 mg, 82%) as a yellow solid; MS (EI): m/e=263.1 [M+H]+.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].C(O[CH:9]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])[CH:10]1[CH2:12][C:11]1([F:14])[F:13])(=O)C.[CH3:23][S:24]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[C:32]2[C:36]=1[NH:35][CH:34]=[CH:33]2)(=[O:26])=[O:25].C(=O)(O)[O-].[Na+]>ClCCCl.C(OCC)(=O)C>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[CH:9]([CH:10]1[CH2:12][C:11]1([F:13])[F:14])[C:33]1[C:32]2[C:36](=[C:28]([CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[CH:29]=[CH:30][CH:31]=2)[NH:35][CH:34]=1
Reactant: CC(=O)OC(c1ccc(Cl)cc1Cl)C1CC1(F)F
Reactant: CS(=O)(=O)Cc1cccc2cc[nH]c12
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [In+3]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: CS(=O)(=O)Cc1cccc2c(C(c3ccc(Cl)cc3Cl)C3CC3(F)F)c[nH]c12

Procedure:
1.64 g (7.39 mmol) of indium(III) chloride were added to 2.00 g (6.78 mmol) of the compound from Example 193A and 1.29 g (6.16 mmol) of the compound from Example 86A in 20 ml of 1,2-dichloroethane under argon and reflux, and the mixture was heated under reflux for 1.5 h. This was followed by addition of ethyl acetate and saturated aqueous sodium bicarbonate solution, separation of the phases, drying of the organic phase and concentration. The residue was purified by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 2/1 and 1/1) and by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 28.0 mg (1% of theory) of diastereomer 1 and 28.0 mg (1% of theory) of diastereomer 2 of the title compound.
Reaction SMILES: [CH3:1][N:2](C)C=O.Cl[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([CH3:17])[N:8]=1>[C-]#N.[Zn+2].[C-]#N.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.O>[CH3:17][C:9]1[N:8]=[C:7]([C:1]#[N:2])[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=1
Reactant: Cc1cc(C(F)(F)F)cc(Cl)n1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: Cc1cc(C(F)(F)F)cc(C#N)n1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To 10 ml of N,N-dimethylformamide were added 1 g of 2-chloro-6-methyl-4-trifluoromethylpyridine, 1.2 g of zinc cyanide and 0.24 g of tetrakistriphenylphosphinepalladium, and the mixture was stirred at 90° C. for 10 hours. After allowing to cool, the reaction solution was poured into water, and the resultant solution was extracted with diethyl ether three times, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.8 g of 6-methyl-4-trifluoromethylpyridine-2-carbonitrile.
Reaction SMILES: BrC1C=C(C(F)(C(F)(F)F)C(F)(F)F)C=C(Br)C=1[NH2:4].[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)[CH:24]=[N:23][CH:22]=[N:21]1.[OH-].[Na+]>N1C=CC=CC=1.O.O1CCCC1>[N:20]1([C:25]2[CH:33]=[CH:32][C:28]([C:29]([NH2:4])=[O:30])=[CH:27][CH:26]=2)[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: Nc1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Reactant: O=C(Cl)c1ccc(-n2cncn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc(-n2cncn2)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
2,6-Dibromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)aniline (0.45 g) was dissolved in pyridine (5 ml). To the solution, the crude product of 4-(1H-1,2,4-triazol-1-yl)benzoyl chloride (0.45 g) was added and the mixture was refluxed under heating for 1.5 hours. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with 2N hydrochloric acid and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a residue, which were then dissolved in tetrahydrofuran (20 ml), added with a 2N sodium hydroxide solution (5 ml) and stirred under heating at 50° C. for 2 hours. After cooling to room temperature, the reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phases were combined, washed with water and dried over magnesium sulfate. After filtering off the drying agent, the solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain N-[2,6-d]bromo-4-(1,1,1,2,3,3,3-heptafluoropropan-2-yl)phenyl]-4-(1H-1,2,4-triazol-1-yl)benzamide (0.18 g, yield 28%).
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[N:12]=[C:11]([NH:13][C:14]([NH:16][C:17]3[C:26]4[C:21](=[C:22]([F:27])[CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[O:15])[CH:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.CN(C=O)C.[H][H]>[Pd].CO.CC(O)=O>[F:27][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:21]=1[N:20]=[CH:19][CH:18]=[C:17]2[NH:16][C:14]([NH:13][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[N:12]=1)=[O:15]
Reactant: [H][H]
Reactant: O=C(Nc1cccc(C2=CCOCC2)n1)Nc1ccnc2c(F)cccc12
Agent: [Pd]
Solvent: CO
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C(Nc1cccc(C2CCOCC2)n1)Nc1ccnc2c(F)cccc12
Yield: 98.8 %

Procedure:
A solution of (1-(6-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yl)-3-(8-fluoroquinolin-4-yl)urea (21 mg, 0.058 mmol) and 12.3 mg of palladium on charcoal in 20 mL of methanol together with 1 mL of DMF and 1 drop of AcOH was stirred under 1 atm of hydrogen for 18 h. Filtration and evaporation to dryness afforded 21 mg (99%) of the desired title product.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)[CH2:6][C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[N:9]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[N:8]=1)C.[OH-].[Li+].C1COCC1.CO>O>[Cl:19][C:14]1[CH:13]=[C:12]([C:10]2[N:9]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[N:8]=[C:7]([CH2:6][C:5]([CH3:35])([C:28]3[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=3)[C:4]([OH:36])=[O:3])[CH:11]=2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CCOC(=O)C(C)(Cc1cc(-c2ccc(Cl)c(Cl)c2)n(-c2ccc(OC)cc2)n1)c1cccc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1ccc(-n2nc(CC(C)(C(=O)O)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Yield: 89.4 %

Procedure:
The title compound was prepared by Method 2 from 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionic acid ethyl ester (0.11 g, 0.21 mmol), lithium hydroxide (88 mg, 2.1 mmol), THF (2.3 mL), MeOH (0.87 mL) and water (0.87 mL) giving 93 mg (90%) of 3-[5-(3,4-dichloro-phenyl)-1-(4-methoxy-phenyl)-1H-pyrazol-3-yl]-2-methyl-2-m-tolyl-propionic acid. HPLC: Rt=3.42 (Method B). MS (ES+): mass calculated for C27H24Cl2N2O3, 494.12; m/z found 495.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.50 (s, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.26-7.19 (m, 3H), 7.16 (d, J=9.0 Hz, 2H), 7.08 (d, J=7.1 Hz, 1H), 7.03 (dd, J=2.0 Hz, 8.4 Hz, 1H), 6.97 (d, J=9.0 Hz, 2H), 6.20 (s, 1H), 3.78 (s, 3H), 3.37 (d, J=14.0 Hz, 1H), 3.14 (d, J=14.0 Hz, 1H), 2.31 (s, 3H), 1.46 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](OS(C(F)(F)F)(=O)=O)=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][C:4]=2[N+:16]([O-:18])=[O:17])=[CH:22][CH:21]=1
Reactant: Cc1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: Fc1ccc(S)cc1
Product: Cc1ccc(Sc2ccc(F)cc2)c([N+](=O)[O-])c1

Procedure:
The product from Example 4a (5.00 g, 17.53 mmol) was reacted with 4-fluorothiophenol (2.24 g, 17.53 mmol) in place of thiophenol following the procedure from Example 1e for 18 h giving the crude title compound which was purified by silica gel column chromatography eluting with 5% EtOAc hexane providing a solid (3.39 g, 74%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([OH:13])=O)[O:8][N:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[F:22])[NH2:18].P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:10]=[C:9]([C:11]([NH:18][C:17]2[CH:19]=[CH:20][C:21]([F:22])=[C:15]([Cl:14])[CH:16]=2)=[O:13])[O:8][N:7]=1
Reactant: O=C(O)c1cc(OCCCBr)no1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: O=C(Nc1ccc(F)c(Cl)c1)c1cc(OCCCBr)no1
Temperature: 0 °C
Yield: 387.4 %

Procedure:
A solution of 3-(3-bromopropoxy)isoxazole-5-carboxylic acid (130 mg, 0.054 mmol) and 3-chloro-4-fluoroaniline (78 mg, 0.054 mmol) in pyridine (2.0 mL) was stirred at room temperature until totally dissolved. The solution was cooled to −30° C. (acetonitrile/ice) and phosphoryl chloride (240 μL, 2.6 mmol) was added dropwise. The mixture was stirred for 1 h in the ice bath. The mixture was diluted with toluene before evaporation in vacuo. The crude was purified by reverse phase chromatography to give the desired product (79 mg, 39%). MF=C13H12BrClFN2O3; LCMS calculated for C13H12BrClFN2O3 (M+H)+: m/z=377.
Reaction SMILES: [Cl-:1].[Ca+2].[Cl-].[BH4-].[Na+].C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][NH:16]2)[CH:10]=1.Cl>C(O)C>[ClH:1].[OH:7][CH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]([N:15]2[C:19](=[O:20])[C:18]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)=[CH:17][NH:16]2)[CH:10]=1
Reactant: [Cl-]
Reactant: COC(=O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CCO
Product: O=c1c(-c2cccnc2)c[nH]n1-c1cc(CO)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
197 mg (1.77 mmol) calcium chloride and 319 mg (8.44 mmol) sodium borohydride are initially introduced into 26 ml ethanol, 50 mg (169 μmol) of the compound from Example 42 are added in portions at 0° C. and the mixture is stirred overnight at RT. The reaction mixture is adjusted to a slightly acid pH by addition of 1 M hydrochloric acid and concentrated and the residue is purified by means of preparative HPLC(RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3]1.[CH2:22]([CH2:29][C:30](=O)[C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:14]([O:13][C:11]([CH2:10][N:7]1[C:6]2[CH:18]=[CH:19][CH:20]=[CH:21][C:5]=2[S:4][CH2:3][CH:2]([NH:1][CH:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:29][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:8]1=[O:9])=[O:12])([CH3:16])([CH3:17])[CH3:15]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(N)CSc2ccccc21
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Product: CCOC(=O)C(CCc1ccccc1)NC1CSc2ccccc2N(CC(=O)OC(C)(C)C)C1=O

Procedure:
The compound obtained in Example 7 was reacted with ethyl benzylpyruvate in the same manner as described in Example 9. Thus, there was obtained 5-t-butoxycarbonylmethyl-3-(1-ethoxycarbonyl-3-phenylpropylamino)-2,3-dihydro-1,5-benzothiazepin-4(5H)-one in the form of an oily material.
Reaction SMILES: C[C:2]1[CH:3]=[C:4]([C:8]2C=[CH:12][C:11](C(O)=O)=[CH:10][CH:9]=2)C=[CH:6][CH:7]=1.[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1.O>C1C=CC=CC=1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([O:24][CH2:6][CH2:7][CH2:2][CH2:3][CH2:4][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:23])=[CH:20][CH:19]=1
Reactant: Cc1cccc(-c2ccc(C(=O)O)cc2)c1
Reactant: O=C(O)c1ccc(Br)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCOC(=O)c1ccc(Br)cc1

Procedure:
Preparation of 3′-methyl-4-biphenylcarboxylic acid with OXO-C10 alcohols (NGP-87): Decyl 4-bromobenzoate was Prepared from the Condensation of 4-bromobenzoic acid and OXO-C10 alcohols by Refluxing in Benzene with Water Removal via a Dean-Stark Trap
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(Cl)Cl>[CH:2]([C@H:3]1[CH2:19][N:7]2[CH2:8][CH2:9][N:10]([C:12]3[N:17]=[CH:16][C:15]([F:18])=[CH:14][N:13]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1)=[O:1]
Reactant: OC[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: O=C[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 3.75 g (14.1 mmol) of (7R,9aS)-7-hydroxymethyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 5), 2.48 g (21.2 mmol) of N-methylmorpholine-N-oxide, 5.0 g of 4 Å molecular sieves, 0.495 g (1.41 mmol) of tetrapropylammonium perruthenate, and 375 mL of methylene chloride was stirred at ambient temperature for 2 h. The reaction was quenched with saturated sodium thiosulfate and filtered through Celite. The filtrate was washed with brine, dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 chloroform:methanol gave 2.27 g (61%) of (7R,9aS)-7-formyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:34][O:33][C@H:32]5[C@@H:27]([O:28]C(C6C=CC=CC=6)[O:30][CH2:31]5)[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:12]=[C:11]3[N:13]=[C:14]([O:24][C@H:25]4[CH2:34][O:33][C@H:32]([CH2:31][OH:30])[C@@H:27]([OH:28])[CH2:26]4)[N:15]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:21])[CH3:22])[C:10]3=[CH:9][C:8]=2[Cl:41])=[CH:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(O[C@H]2CO[C@H](CO)[C@@H](O)C2)nc2nc(-c3ccc(-c4ccccc4)cc3)c(Cl)cc21
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 5-([1,1′-biphenyl]-4-yl)-6-chloro-2-(((4aR,7R,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl)oxy)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazo[4,5-b]pyridine (476 mg, 0.710 mmol) under nitrogen in anhydrous DCM (6.0 mL) was added 4A molecular sieves (1.6 g). The mixture was cooled to 0° C., then triethylsilane (0.85 mL, 619 mg, 5.33 mmol) and TFA (0.41 mL, 607 mg, 5.33 mmol) were added. The mixture was stirred at 0° C. for 1.5 hours, and then allowed to stir 1 hour at room temperature. The mixture was then cooled to 0° C. and a saturated aqueous solution of potassium carbonate (30 mL) was added dropwise over 3 minutes. After stirring at room temperature for an additional 5 minutes, the mixture was filtered, diluted with saturated aqueous sodium bicarbonate (30 mL), and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with brine (60 mL), dried over sodium sulfate, and concentrated under reduced pressure. The resultant residue was chromatographed using a Biotage™ 25 g silica gel cartridge eluted with 0-100% EtOAc in 1:1 Hexane/DCM over 25 column volumes with a 15 column volume hold at 100% EtOAc. The product fractions were combined and concentrated under reduced pressure to give the desired product as a white solid. LC-MS: calculated for C30H36ClN3O5Si 581.21, observed m/e: 582.31 (M+H)+ (Rt 2.66/4 min).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:6][C:5]2([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]2)[CH2:4]1.[C:18](=O)([O:30]C1C=CC([N+]([O-])=O)=CC=1)[O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26](=[O:29])[NH:27][CH3:28])[CH:22]=1.C(N(CC)C(C)C)(C)C>>[CH3:28][NH:27][C:26]([C:23]1[CH:22]=[C:21]([CH2:20][O:19][C:18]([NH:1][CH2:2][CH:3]2[CH2:4][C:5]3([CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]3)[CH2:6]2)=[O:30])[O:25][N:24]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(CN)C2)C1
Reactant: CNC(=O)c1cc(COC(=O)Oc2ccc([N+](=O)[O-])cc2)on1
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(COC(=O)NCC2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)on1

Procedure:
The process is performed according to the procedure described in Example 1, step 1.1. Starting with 0.22 g (0.92 mmol) of tert-butyl 2-aminomethyl-6-azaspiro[3.4]octane-6-carboxylate (isomer 2a), described in Example 8 (step 8.2.), 0.294 g (0.92 mmol) of 3-(methylcarbamoyl)isoxazol-5-ylmethyl 4-nitrophenyl carbonate, obtained in step 4.1., 0.236 g (1.83 mmol) of N,N-diisopropylethylamine and 0.011 g (0.09 mmol) of N,N-dimethylaminopyridine, and after purification by chromatography on silica gel, eluting with a 98/2 mixture of dichloromethane and methanol, 0.310 g of pure product is thus obtained in the form of an amorphous solid.
Reaction SMILES: CS(C)=O.[C-:5]#[N:6].[Na+].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([CH:19]=1)[C:14](Cl)=[N:15][O:16][CH3:17]>C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:13]([C:14](=[N:15][O:16][CH3:17])[C:5]#[N:6])[CH:19]=1
Reactant: [C-]#N
Reactant: CON=C(Cl)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CON=C(C#N)c1cc(Cl)ccc1OCc1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 91.5 %

Procedure:
Dimethyl sulfoxide (3 ml) and 95% sodium cyanide (0.31 g, 6 mmol) were added to 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminobenzyl chloride (1.03 g, 3 mmol), and the mixture was stirred at 100° C. for 4 hours. After completion of the reaction, ethyl acetate (150 ml) was added, and the mixture was washed with saturated brine (100 ml) twice. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 5-chloro-2-(4-chlorobenzyloxy)-α-methoxyiminophenylacetonitrile (0.92 g, 91.5%) as crystals.