Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.C(OC(C(F)(F)F)=O)(C(F)(F)F)=[O:4].[CH2:16]([C:18]1[N:19]=[N+:20]([O-:33])[C:21]2[C:30]([N:31]=1)=[CH:29][C:28]1[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:23]=1[CH:22]=2)[CH3:17].C(O)(C(F)(F)F)=O>C(Cl)Cl.N>[CH2:16]([C:18]1[N:19]=[N+:20]([O-:33])[C:21]2[C:30]([N+:31]=1[O-:4])=[CH:29][C:28]1[CH2:27][N:26]([CH3:32])[CH2:25][CH2:24][C:23]=1[CH:22]=2)[CH3:17]
Reactant: CCc1nc2cc3c(cc2[n+]([O-])n1)CCN(C)C3
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: N
Agent: OO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCc1n[n+]([O-])c2cc3c(cc2[n+]1[O-])CN(C)CC3
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 17.1 %

Procedure:
H2O2 (70%, 2.4 mL, ca. 25 mmol) was added dropwise to a stirred solution of TFAA (3.5 mL, 25 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 10 min, then cooled to 0° C., added to a solution of 1-oxide 260 (590 mg, 2.4 mmol) and TFA (0.96 mL, 12.2 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (80 mL) and extracted with DCM (4×150 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (2-5%) of MeOH/DCM, to give 1,4-dioxide 261 (107 mg, 17%) as a yellow solid: mp 124-128° C.; 1H NMR δ 8.23 (s, 1H, H-10), 8.18 (s, 1H, H-5), 3.83 (s, 2H, H-6), 3.15-3.24 (m, 4H, CH2, H-8), 2.78 (t, J=6.0 Hz, 2H, H-9), 2.51 (s, 3H, NCH3), 1.43 (t, J=7.5 Hz, 3H, CH3); 13C NMR δ 149.3, 145.5, 136.5, 135.3, 129.3, 120.5, 116.3, 58.1, 51.9, 45.8, 29.6, 23.9, 9.3; MS (APCI) m/z 261 (MH+, 100%). Anal. calcd for C13H16N4O2.¼CH2Cl2: C, 56.5; H, 5.9; N, 19.9. Found: C, 56.6; H, 5.9; N, 19.7%.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2C(=C[CH:6]=[C:7]([CH:23]3[CH2:27][CH2:26][CH2:25][CH:24]3C(O)=O)[CH:8]=2)N=1.[CH2:31]([NH2:33])[CH3:32]>>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:31](=[CH:32][CH:6]=[C:7]([C:23]3([C:12]([NH:14][CH2:15][CH3:16])=[O:13])[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:8]=2)[N:33]=1
Reactant: CCN
Reactant: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(C3CCCC3C(=O)O)ccc2n1
Product: CCNC(=O)C1(c2ccc3nc(N)nc(C(=O)N4Cc5ccccc5C4)c3c2)CCCC1

Procedure:
(Preparation by reaction of 2-[2-amino-4-(isoindoline-2-carbonyl)quinazolin-6-yl]cyclopentanecarboxylic acid [“A68”] with ethylamine);
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].C[O-].[Na+].Cl[CH2:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23](=[O:32])[O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:18]([O:33][CH3:34])[CH2:17]1)=[O:15].Cl>CO.C(OCC)(=O)C>[C:3]([CH:2]([CH2:13][C:14]([N:16]1[CH2:21][CH2:20][C@H:19]([NH:22][C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:32])[C@H:18]([O:33][CH3:34])[CH2:17]1)=[O:15])[C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH3:5]
Reactant: COC(=O)CC(C)=O
Reactant: CO[C@@H]1CN(C(=O)CCl)CC[C@@H]1NC(=O)OCc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC)C1)C(C)=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl acetoacetate (510 mg, 4.4 mmol) was dissolved in methanol (15 ml). Sodium methoxide (210 mg, 3.9 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. Further, benzyl cis(±)-[1-(chloroacetyl)-3-methoxypiperidin-4-yl]carbamate obtained in Example (188a) was dissolved in methanol (10 ml). The solution was added to the reaction solution, and the mixture was stirred at 70° C. overnight. The reaction solution was diluted with ethyl acetate, neutralized with 1 N hydrochloric acid, washed with brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the title compound was obtained. The resulting compound was used for the next reaction without purification.
Reaction SMILES: O1CCC[CH2:2]1.C[Mg]Br.[C:9]([CH:12]1[CH2:17][C:16]([CH3:18])=[CH:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10]>C(OCC)C>[CH3:10][C:9]([CH3:2])([CH:12]1[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH2:17]1)[OH:11]
Reactant: C1CCOC1
Reactant: CC(=O)C1CCC=C(C)C1
Agent: C[Mg]Br
Solvent: CCOCC
Product: CC1=CCCC(C(C)(C)O)C1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To 90 ml of dry tetrahydrofuran maintained in an inert atmosphere at -60° C. was added 45.3 ml of a 3.0M solution of methylmagnesium bromide in diethyl ether followed by dropwise addition of 15.6 g of 5-acetyl-1-methylcyclohexene in a solution of 50 ml dry tetrahydrofuran. The reaction mixture was warmed to -20° C. and stirred for two hours. The resulting reaction mixture was poured into 150 ml of chilled, saturated ammonium chloride solution and extracted three times with 300 ml portions of diethyl ether. The combined extracts were washed successively with 300 ml of water and 300 ml of saturated sodium chloride, dried (MgSO4) and concentrated in vacuo to leave 17.1 g of a pale yellow oil. Distillation of the oil gave 10.7 g of the desired product as a colorless oil, b.p. 63°-65° C. (0.65 mm).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[OH:29])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>ClC1C=CC=CC=1Cl>[CH2:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Oc1ccccc1Cc1ccccc1
Solvent: O
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3Cc3ccccc3)c2cc1OC
Temperature: 180 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (230 mg) and 2-benzylphenol (254 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 180° C. overnight. The reaction solution was cooled to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was then removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using ethyl acetate-hexane to give the title compound (40 mg, yield 10%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6](B(O)O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:23]([F:26])([F:25])[F:24])=[N:20][NH:21][CH:22]=1)=[O:17])[CH3:14]>>[CH2:13]([O:15][C:16]([C:18]1[C:19]([C:23]([F:25])([F:26])[F:24])=[N:20][N:21]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)[CH:22]=1)=[O:17])[CH3:14]
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: CCOC(=O)c1c[nH]nc1C(F)(F)F
Product: CCOC(=O)c1cn(-c2ccc3[nH]ccc3c2)nc1C(F)(F)F
Yield: 72.1 %

Procedure:
1H-indol-5-ylboronic acid (1,000 mg, 6.21 mmol) and 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (646 mg, 3.10 mmol) were reacted according to the same procedure as Preparation 1 to give the title compound (723 mg, 72% Yield).
Reaction SMILES: [CH:1]([C:3]1[C:4]([C:27]([F:30])([F:29])[F:28])=[N:5][N:6]([CH2:8][C:9]([NH:11][C:12]2[S:16][C:15]3[CH2:17][CH2:18][CH2:19][CH2:20][C:14]=3[C:13]=2[C:21]([NH:23][CH2:24][CH2:25][OH:26])=[O:22])=[O:10])[CH:7]=1)=O.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[OH:26][CH2:25][CH2:24][NH:23][C:21]([C:13]1[C:14]2[CH2:20][CH2:19][CH2:18][CH2:17][C:15]=2[S:16][C:12]=1[NH:11][C:9](=[O:10])[CH2:8][N:6]1[CH:7]=[C:3]([CH2:1][NH:34][CH2:33][C:32]([F:36])([F:35])[F:31])[C:4]([C:27]([F:29])([F:30])[F:28])=[N:5]1)=[O:22]
Reactant: NCC(F)(F)F
Reactant: O=Cc1cn(CC(=O)Nc2sc3c(c2C(=O)NCCO)CCCC3)nc1C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(Cn1cc(CNCC(F)(F)F)c(C(F)(F)F)n1)Nc1sc2c(c1C(=O)NCCO)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
2-(2-(4-Formyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)acetamido)-N-(2-hydroxyethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carboxamide (30 mg, 0.068 mmol), 2,2,2-trifluoroethylamine (19.8 mg, 0.20 mmol) and DCM (1 mL) were treated with acetic acid (5 drops) and sodium triacetoxyborohydride (58 mg, 0.272 mmol) and the mixture stirred at RT overnight. The sample was concentrated and re-dissolved in dimethylsulfoxide (1 mL), filtered and purified by preparative LCMS followed by additional purification by SCX ion exchange chromatography to yield the title compound (10 mg, 0.02 mmol, 29%).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Si](C)(C)[N:14]1[C:18]2=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:22]=[C:17]2[C:16]([C:30](O)=[O:31])=[CH:15]1)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:1]([NH:8][C:30]([C:16]1[C:17]2[C:18](=[N:19][CH:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)[CH:22]=2)[NH:14][CH:15]=1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)n1cc(C(=O)O)c2cc(-c3cccc(F)c3)cnc21
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)c1c[nH]c2ncc(-c3cccc(F)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.7 %

Procedure:
To a solution of benzylamine (4.4 μL, 40.3 μmol) in dry CH2Cl2 (0.5 mL) was added carboxylic acid 10 (15 mg, 40.5 μmol), WSCHCl (9.32 mg, 44.86 μmol), HOBT (5.5 mg, 40.5 μmol) and i-Pr2NEt (7.1 μL, 40.8 μmol) and the reaction mixture left to stir at r.t. overnight Separation by LCMS (CombiPrep ODS-AM column) using water—acetonitrile as eluent (in gradient) afforded amide 11 (2.33 mg, 17%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 4.70 (d, J=5.5 Hz, 2H), 6.18 (t, J=5.5 Hz, 1H), 7.29-7.44 (m, 8H), 7.80 (s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.66 (d, J=2.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]3)=[C:11]([CH3:23])[CH:10]=2)=[N:6][CH:7]=1.CC([O-])=O.[Na+].[NH2:36][OH:37].Cl>CO>[Cl:1][C:2]1[C:3]([NH:24][C:25]2[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=2)=[N:4][C:5]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH:16]3[CH2:21][CH2:20][C:19](=[N:36][OH:37])[CH2:18][CH2:17]3)=[C:11]([CH3:23])[CH:10]=2)=[N:6][CH:7]=1
Reactant: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=O)CC4)cc3C)ncc2Cl)n[nH]1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Cc1cc(Nc2nc(Nc3cc(C)c(C4CCC(=NO)CC4)cc3C)ncc2Cl)n[nH]1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)cyclohexanone (15 mg, 0.033 mmol) in MeOH (0.5 mL) was added NaOAc (6 mg, 0.073 mmol) and NH2OH HCl (5 mg, 0.073 mmol). The resulting mixture was stirred at 70° C. for 2 h. and then cooled down to room temperature. The mixture was purified directly by preparative RP-HPLC to provide 4-(4-(5-chloro-4-(5-methyl-1H-pyrazol-3-ylamino)pyrimidin-2-ylamino)-2,5-dimethylphenyl)-cyclohexanone oxime; ESMS m/z 440.2 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:23][O:24][NH2:25]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13](=[N:25][O:24][CH3:23])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CON
Reactant: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Agent: Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=NOC
Reaction time: 0.17 h
Yield: 98.2 %

Procedure:
1-Benzyloxycarbonyl-4-ethoxycarbonyl-3-oxopyrrolidine (196.7 g, 600.0 mmol) was dissolved in pyridine (700 ml) and mixed with O-methylhydroxylamine hydrochloride (76.55 g, 916.5 mmol) under ice-cooling, and the mixture was stirred at the same temperature for 10 minutes and then at room temperature for 5 hours. Pyridine was evaporated under a reduced pressure, the residue was mixed with 1 N hydrochloric acid and ethyl acetate and then the mixture was shaken and subjected to separation of layers. The organic layer was washed with saturated brine, and the water layer was further extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and filtered, the solvent was evaporated under a reduced pressure and then the residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=1:1) to obtain 187.5 g (589.1 mmol, 98.2%) of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16](Cl)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:22]1([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)[CH:26]=[CH:25][N:24]=[CH:23]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:33][C:30]3[CH:29]=[CH:28][C:27]([N:22]4[CH:26]=[CH:25][N:24]=[CH:23]4)=[CH:32][CH:31]=3)[N:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(c2ncnc(Oc3ccc(-n4ccnc4)cc3)c2[N+](=O)[O-])CC1
Temperature: 90 °C
Yield: 91.2 %

Procedure:
A mixture of 1-(6-chloro-5-nitro-pyrimidin-4-yl)-piperidine-4-carboxylic acid ethyl ester (63 mg, 0.2 mmol), 4-imidazol-1-yl-phenol (42 mg, 0.26 mmol) and potassium carbonate (36 mg, 0.26 mmol, 1 equivalent) in anhydrous DMF (1 ml) was heated to 90° C. overnight. The resulting residue was purified by Flash Chromatography (hexanes:ethyl acetate=1:1) to give 1-[6-(4-Imidazol-1-yl-phenoxy)-5-nitro-pyrimidin-4-yl]-piperidine-4-carboxylic acid ethyl ester [A1] as a yellow solid (80 mg, 92%). 1H NMR (CDCl3, 400 MHz)δ 1.28 (t, 3H), 1.80-1.96 (m, 2H), 2.00-2.08 (m, 2H), 2.65-2.75 (m, 1H), 3.22 (t, 2H), 3.96-4.03 (m, 2H), 4.15 (q, 2H), 7.38-7.42 (m, 2H), 7.46 (t, 1H), 7.55-7.59 (m, 3H), 8.17 (s, 1H), 8.90-8.92 (m, 1H). Exact mass calculated for C21H22N6O5 438.17, found 439.2 (MH+).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([OH:11])=[C:4]([CH3:12])[CH:3]=1>CO.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[CH:3][C:4]([CH3:12])=[C:5]([OH:11])[CH:6]=1
Reactant: Cc1cc(F)c([N+](=O)[O-])cc1O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(F)c(N)cc1O
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A mixture of 4-fluoro-2-methyl-5-nitro-phenol (1.4 g, 8.2 mmol) and 10% Pd/C (0.3 g, 20%/w) in MeOH (80 mL) was stirred under H2 (30 psi) for 2 h. The Pd/C was removed by filtration and the filtrate was concentrated to give 5-amino-4-fluoro-2-methyl-phenol (0.68 g, 62% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 6.62 (d, J=12.0 Hz, 1H), 6.21 (d, J=8.1 Hz, 1H), 4.69 (s, 2H), 1.93 (s, 3H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH:6]1[CH2:10][CH:9]([OH:11])[CH2:8][NH:7]1)=[O:5].[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([N:22]=[C:23]=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]>>[Cl:12][C:13]1[C:20]([CH3:21])=[C:19]([NH:22][C:23]([N:7]2[CH2:8][C@H:9]([OH:11])[CH2:10][C@H:6]2[C:4]([O:3][CH3:2])=[O:5])=[O:24])[CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: COC(=O)C1CC(O)CN1
Reactant: Cc1c(N=C=O)ccc(C#N)c1Cl
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)Nc1ccc(C#N)c(Cl)c1C

Procedure:
The title compound was prepared from compound 56A (300 mg, 1.65 mmol) and isocyanate 23E (312 mg, 1.62 mmol) by procedures analogous to that described for Example 55A to afford a white foam (375.6 mg, 69%). HPLC: 1.68 min (retention time) (Conditions: YMC S-5 C-18 (4.6×250 mm), eluting with 0-100% B, 4 min gradient. (A=90% H2O—10% CH3CN—0.1% TFA and B=10% H2O—90% CH3CN—0.1% TFA); Flow rate at 4 mL/min. UV detection at 220 nm. Chiral HPLC: retention time=12.92 min (98.9%); Conditions: AD (4.6×250 mm); Eluted with 20% isopropanol in heptane for 30 min at 1 mL/min. MS (ES) m/z 338 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:27]=1.CCCCCC>CC(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C@@:7]([CH2:16][NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([C:12]([F:15])([F:14])[F:13])[C:6]=2[CH:27]=1
Reactant: O=C1Nc2ccc(Cl)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CC(C)O
Solvent: CCCCCC
Product: O=C1Nc2ccc(Cl)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
N-{[6-chloro-2-oxo-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}-4-fluorobenzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:2-propanol=4:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][OH:9])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][O:9][CH2:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(CBr)OCc1ccccc1
Reactant: OCc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(COCc1cncc(Br)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
(5-Bromo-pyridin-3-yl)-methanol (25.0 g, 0.13 mol) is added to a solution of NaH (6.45 g, 0.27 mol) in THF (500 ml) at 0° C. and stirred at room temperature for 30 min. Benzyl bromoacetate (34.4 g, 0.15 mol) is added to this solution at 0° C. and stirred at room temperature overnight. The mixture is quenched with water and diluted with DCM. The organic layer is dried over Na2SO4 and concentrated in vacuo. The product is chromatographed on silica gel to give (5-bromo-pyridin-3-ylmethoxy)-acetic acid benzyl ester (10 g).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=2)[C:9]#[N:10])=[N:2]1.[F:14][CH:15]([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.N1C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:14][CH:15]([F:26])[O:16][C:17]1[CH:22]=[CH:21][C:20]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=3)[C:9]#[N:10])=[N:2]2)=[CH:19][CH:18]=1
Reactant: OB(O)c1ccc(OC(F)F)cc1
Reactant: N#Cc1cccc(-c2cc[nH]n2)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: N#Cc1cccc(-c2ccn(-c3ccc(OC(F)F)cc3)n2)c1
Temperature: 35 °C
Yield: 27.2 %

Procedure:
A solution of 3-(1H-pyrazol-3-yl)-benzonitrile (400 mg, 2.36 mmol) and 4-difluoromethoxybenzeneboronic acid (1.02 g, 5.44 mmol) in dimethylformamide (20 mL) is treated with copper (II) acetate (472 mg), pyridine (0.36 mL), and powdered, activated 4 Å molecular sieves (1 g). The resulting mixture is heated to 35° C. for 3 h, cooled and partially evaporated. The residue is partitioned between 1 M aq. HCl and ethyl acetate (200 mL each), and the extract is washed with brine (100 mL), dried over MgSO4, filtered and evaporated. The residue is separated by column chromatography (silica gel, 1:1 CH2Cl2-hexane) to afford 3-[1-(4-difluoromethoxy-phenyl)-1H-pyrazol-3-yl]-benzonitrile (200 mg, 23%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11](NCC#N)=[O:12])=[CH:4][CH:3]=1.BrC(CC(C)C)[C:29](OC)=[O:30]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[O:9][CH:10]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:11]([O:30][CH3:29])=[O:12])=[CH:4][CH:3]=1
Reactant: CC(C)CC(OC(c1ccncc1)c1ccc(Br)cc1)C(=O)NCC#N
Reactant: COC(=O)C(Br)CC(C)C
Product: COC(=O)C(CC(C)C)OC(c1ccncc1)c1ccc(Br)cc1

Procedure:
Using the same protocol as described in example 23, step 2, (4-bromophenyl)(pyridin-4-yl)methanol from step 1 (594 mg, 2.20 mmol) was added to methyl 2-bromo-4-methylpentanoate (377 μL, 2.31 mmol). The crude residue was chromatographed on silica gel using 50% ethyl acetate in hexanes to afford the title compound.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:14][C:15]1[CH:22]=[CH:21][C:18](C=O)=[CH:17][CH:16]=1>>[C:1]1([S:7](/[CH:10]=[CH:11]/[C:18]2[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: O=C(O)CS(=O)(=O)c1ccccc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)c1ccccc1
Yield: 78 %

Procedure:
A solution of phenyl sulfonylacetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 78-80% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34](O)=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:9][CH:8]=1.Cl.Cl.C[O:45][C:46](=[O:64])[C@@H:47]([NH2:63])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[C:56]=2[CH3:62])=[CH:51][CH:50]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:39]=[CH:40][CH:41]=1)[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C@H:13]2[CH2:38][O:37][C:16]3=[CH:17][C:18]4[CH2:19][C@@H:20]([C:34]([NH:63][C@@H:47]([CH2:48][C:49]5[CH:54]=[CH:53][C:52]([C:55]6[CH:60]=[CH:59][N:58]=[C:57]([CH3:61])[C:56]=6[CH3:62])=[CH:51][CH:50]=5)[C:46]([OH:45])=[O:64])=[O:35])[N:21]([C@H:25]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH2:26][CH3:27])[CH2:22][C:23]=4[CH:24]=[C:15]3[O:14]2)=[CH:11][CH:12]=1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCc2cccc(Cl)c2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCc2cccc(Cl)c2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with 3-chloro-benzyl bromide according to General Procedure J and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg). The title compound (18 mg) was prepared from (3S,8S)-3-[4-(3-chloro-benzyloxy)-phenyl]-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (20 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 823.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1I.[C-:17]#[N:18].[Na+]>CN(C=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8]([CH2:11][C:12]([F:15])([F:14])[F:13])=[CH:9][N:10]=[C:4]2[C:3]=1[C:17]#[N:18]
Reactant: FC(F)(F)Cc1cnc2c(I)c(Cl)ccn12
Reactant: [C-]#N
Agent: [Cu]I
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)ccn2c(CC(F)(F)F)cnc12
Reaction time: 2 h

Procedure:
A 2.0-5.0 mL microwave vial was charged with 7-chloro-8-iodo-3-(2,2,2-trifluoroethyl)imidazo[1,2-a]pyridine (50 mg, 0.139 mmol) and dissolved in DMF (1387 μl). To that stirring solution was added sodium cyanide (7.14 mg, 0.146 mmol) followed by copper(I) iodide (39.6 mg, 0.208 mmol). The vial was sealed and degassed using ultra pure argon and sonication for 2 min. The vial was then placed in a reaction block preheated to 120° C. After 2 hours, LCMS showed ˜7.5:1 (product:starting material). The mixture was diluted with EtOAc and sat'd sodium bicarbonate and the contents of the flask were transferred into a separatory funnel where the aqueous was extracted twice with EtOAc and discarded. The combined organics were washed with brine, dried with magnesium sulfate, and concentrated under reduced pressure. The crude was taken on into a coupling reaction without any further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (d, J=7.3 Hz, 1H), 7.78 (s, 1H), 7.43 (d, J=7.5 Hz, 1H), 4.30 (q, J=11.0 Hz, 2H).