Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:14]([OH:16])=O)[CH:11]=3)[C:4]=2[NH:5][N:6]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1.C(N(C(C)C)CC)(C)C>CN(C=O)C.CCOC(C)=O>[I:1][C:2]1[C:3]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:14]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)=[O:16])[CH:11]=3)[C:4]=2[NH:5][N:6]=1
Reactant: C1COCCN1
Reactant: O=C(O)c1ccc2c(c1)Cc1c(I)n[nH]c1-2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(c1ccc2c(c1)Cc1c(I)n[nH]c1-2)N1CCOCC1
Yield: 47.9 %

Procedure:
A mixture of Example 84A (0.210 g, 0.644 mmol), PyBOP (0.503 g, 0.966 mmol), morpholine (0.084 mL, 0.966 mmol), and diisopropylethylamine (0.39 mL, 2.25 mmol) in DMF (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc and washed with water and NaHCO3. The organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography eluted with EtOAc to give 0.122 g (48%) of the desired product as red solid. MS (DCI/NH3) m/z: 396.0 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 3.46-3.67 (m, 10H) 7.41 (m, 1H) 7.59 (s, brd, 1.5H) 7.67 (d, J=7.46 Hz, 0.5H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH2:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH:12](NNC1C=CC(NC(NC2C=CC=CC=2)=O)=CC=1)=[O:13]>>[N+:1]([C:4]1[CH:5]=[C:6]([NH:10][NH:11][CH:12]=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: O=CNNc1ccc(NC(=O)Nc2ccccc2)cc1
Product: O=CNNc1cccc([N+](=O)[O-])c1

Procedure:
By reacting 3-nitrophenylhydrazine as in the same manner as in (1) above, 430 g of 2-(3-nitrophenyl)-1-formylhydrazine was obtained.
Reaction SMILES: Br[C:2]1[C:3]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4][C:5]2[N:10]([CH2:11][CH3:12])[C:9](=[O:13])[CH2:8][O:7][C:6]=2[N:14]=1.CC1(C)C(C)(C)OB([C:29]2[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:31][CH:30]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[CH2:11]([N:10]1[C:9](=[O:13])[CH2:8][O:7][C:6]2[N:14]=[C:2]([C:29]3[CH:43]=[CH:42][C:32]([CH2:33][NH:34][C:35](=[O:41])[O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[CH:31][CH:30]=3)[C:3]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4][C:5]1=2)[CH3:12]
Reactant: CCN1C(=O)COc2nc(Br)c(-c3ccccc3)cc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CCN1C(=O)COc2nc(-c3ccc(CNC(=O)OC(C)(C)C)cc3)c(-c3ccccc3)cc21
Temperature: 50 °C
Yield: 65.3 %

Procedure:
In a 15 mL reaction tube was added 6-bromo-1-ethyl-7-phenyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (50 mg, 0.150 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (60.0 mg, 0.180 mmol), and CESIUM CARBONATE (244 mg, 0.750 mmol) in a mixture of 1,4-Dioxane (2814 μl) and water (938 μl) to give a colourless solution. This was degassed by bubbling nitrogen for 15 minutes, followed by the addition of PdCl2(dppf)-CH2Cl2Adduct (24.51 mg, 0.030 mmol) and degassing for a further 5 minutes. The reaction mixture was heated to 50° C. under a nitrogen atmosphere for one hour. LC-MS analysis showed reaction completion. The reaction mixture was allowed to cool to room temperature, diluted with water (5 mL) and extracted into ethyl acetate (3×5 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give an off-white solid. The resulting residue was purified via Biotage (15-85% cyclohexane:EtOAc; 10 g column) to give the title compound (45 mg, 65.3%) as off-white solid. 1H NMR (500 MHz, CDCl3): 7.31-7.27 (6H, m), 7.19-7.18 (2H, d), 7.11-7.10 (2H, d), 4.87 (2H, s), 4.84 (1H, br), 4.27 (2H, s), 4.03-3.98 (2H, q), 1.45 (9H, br), 1.32-1.30 (3H, t).
Reaction SMILES: CN(C)C=O.[Cl:6][C:7]1[C:8](F)=[C:9]([F:33])[CH:10]=[C:11]2[C:16]=1[N:15]([C:17]1[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:28])[CH3:27])[N:18]=1)[CH:14]=[C:13]([C:29]([OH:31])=[O:30])[C:12]2=[O:32].Cl.Cl.[NH2:37][CH:38]1[CH2:41][NH:40][CH2:39]1.CN1CCCC1>C(O)C>[NH2:37][CH:38]1[CH2:41][N:40]([C:8]2[C:7]([Cl:6])=[C:16]3[C:11]([C:12](=[O:32])[C:13]([C:29]([OH:31])=[O:30])=[CH:14][N:15]3[C:17]3[C:22]([F:23])=[CH:21][C:20]([F:24])=[C:19]([NH:25][CH:26]([CH3:27])[CH3:28])[N:18]=3)=[CH:10][C:9]=2[F:33])[CH2:39]1
Reactant: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: NC1CNC1
Agent: CN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)Nc1nc(-n2cc(C(=O)O)c(=O)c3cc(F)c(N4CC(N)C4)c(Cl)c32)c(F)cc1F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
To 160 mg of N,N-dimethylformamide were added 55 mg of 8-chloro-6,7-difluoro-1-(3,5-difluoro-6-isopropylaminopyridine-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid, 35 mg of 3-aminoazetidine dihydrochloride, and 120 mg of N-methylpyrrolidine, and the mixture was stirred at 80° C. for 30 minutes. After adding 0.5 ml of ethanol, the mixture was allowed to cool, and the precipitate was collected by filtration and washed with ethanol and diisopropylether successively to obtain 51 mg of the title compound as a colorless powder.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1.O>[CH:1]1([CH2:7][O:8][C:10]2[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=2)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCC1CCCCC1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(OCC2CCCCC2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
Cyclohexyl methanol (2.0 g, 17.5 mmol), ethyl 3-hydroxybenzoate (2.6 g, 15.8 mmol), tri-n-butyl phosphin (5.3 g, 26 mmol), and ADDP (6.6 g, 26 mmol) were dissolved in dry THF (100 ml) and stirred overnight at 20° C. under N2. Water (100 ml) is added, and the resulting solution is extracted with DCM (3×100 ml). The combined organic layers were washed with water (100 ml), dried (MgSO4) and evaporated. The crude mixture was purified by preparative HPLC to give 1.8 g of the title compound. LC-MS (m/z): 264 (M+2).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:24])=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])([O-:3])=[O:2].[H-].[Na+].[C:27]([C:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[O:33][N:32]=1)([CH3:30])([CH3:29])[CH3:28].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[C:5]([NH:24][C:36]([C:34]2[O:33][N:32]=[C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:35]=2)=[O:37])=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:21])[F:22])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])([O-:3])=[O:2]
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(C(=O)O)on1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(C(F)(F)F)c2[N+](=O)[O-])on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (64.0 mg, 0.182 mmol, prepared as described in STEP D above) in THF (10 mL) was treated with NaH (21.9 mg, 0.547 mmol, 60% dispersion in oil), and the resulting mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (40.1 mg, 0.237 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (20.7 μL, 0.237 mmol) and DMF (2 drops), and the resulting mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4CI (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as an off-white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H16N4O4F6: 503.1 (M+H). Measured: 503.2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[C:14]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[O:21])=[CH:18][CH:17]=1)#[N:15].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:20]([OH:21])[C:19]2[CH:22]=[CH:23][C:16]([C:14]#[N:15])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Br)cc1
Reactant: N#Cc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: N#Cc1ccc(C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
5.00 g (28.57 mmol) of 4-fluorobromobenzene were dissolved in 100 ml tetrahydrofuran at −78° C. Addition of 21.4 ml (34.29 mmol) of a 1.6N solution of n-butyllithium in hexane was followed by stirring for 15 min and then dropwise addition of 4.50 g (34.29 mmol) of 4-cyanobenzaldehyde dissolved in 30 ml of tetrahydrofuran. The mixture was stirred at −78° C. for 1 h, warmed to RT and then stirred for 1 h. The reaction solution was mixed with water and ethyl acetate and the phases were separated. The aqueous phase was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated aqueous sodium chloride solution and dried over sodium sulfate, and the solid was filtered. The solvents were removed in vacuo and the crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). Acetonitrile was removed from the product-containing fractions in a rotary evaporator, and the aqueous residue was extracted with dichloromethane. Removal of the solvent resulted in 2.37 g (36% of theory) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([N:12]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([CH2:28][OH:29])=[CH:24][CH:23]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:30][C:31]1[CH:36]=[C:35](O)[CH:34]=[CH:33][C:32]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]>>[F:30][C:31]1[CH:36]=[C:35]([O:29][CH2:28][C:25]2[CH:24]=[CH:23][C:22]([CH2:21][N:12]([C:9]3[S:10][CH:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:8]=3)[CH2:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:27][CH:26]=2)[CH:34]=[CH:33][C:32]=1[CH2:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41]
Reactant: CCOC(=O)CCc1ccc(O)cc1F
Reactant: OCc1ccc(CN(CCc2ccccn2)c2nc(-c3ccccc3)cs2)cc1
Product: CCOC(=O)CCc1ccc(OCc2ccc(CN(CCc3ccccn3)c3nc(-c4ccccc4)cs3)cc2)cc1F
Yield: 41 %

Procedure:
The title compound was synthesized in the same manner as in Example 8 from (4-{[(4-phenyl-1,3-thiazol-2-yl)(2-pyridin-2-ylethyl)amino]methyl}phenyl)methanol and ethyl 3-(2-fluoro-4-hydroxyphenyl)propanoate by Mitsunobu reaction (yield 41%). Yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:18]1[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]2[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=2[F:37])=[O:25])=[N:22][CH:23]=1)[CH:3]1[C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][C:6]=2[CH2:5][CH2:4]1)[N:13]=[C:12]([CH3:16])[NH:11][C:10]3=[O:17].F[C:39](F)(F)[C:40](OC1C(F)=C(F)C(F)=C(F)C=1F)=O>>[CH3:16][C:12]1[NH:11][C:10](=[O:17])[C:9]2[C:14](=[CH:15][C:6]3[CH2:5][CH2:4][CH:3]([N:2]([C:18]4[CH:19]=[CH:20][C:21]([C:24]([O:26][C:27]5[C:32]([F:33])=[C:31]([F:34])[C:30]([F:35])=[C:29]([F:36])[C:28]=5[F:37])=[O:25])=[N:22][CH:23]=4)[CH2:1][C:39]#[CH:40])[C:7]=3[CH:8]=2)[N:13]=1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: Cc1nc2cc3c(cc2c(=O)[nH]1)C(N(C)c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)nc1)CC3
Product: C#CCN(c1ccc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)nc1)C1CCc2cc3nc(C)[nH]c(=O)c3cc21

Procedure:
Using an analogous procedure to that described in section (5) of Example 6, 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)]pyridine-2-carboxylic acid was reacted with pentafluorophenyl trifluoroacetate to give pentafluorophenyl 5-[N-((6RS)-2-methyl-4-oxo-3,4,7,8-tetrahydro-6H-cyclopenta[g]quinazolin-6-yl)-N-(prop-2-ynyl)amino]-pyridine-2-carboxylate as a foam.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.N1C=CN=C1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[Si:27]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of 2.42 g (10 mmol) thymidine in 15 ml DMF was added 1.7 g (25 mmol) imidazole and 1.6 g (10.6 mmol) tert-butyldimethyl silyl chloride. The solution was stirred at room temperature for 3 hours. DMF was then removed in vacuo and the residue was dissolved in 150 ml of ethyl acetate. The solution was washed with water and the organic layer was dried over MgSO4. After removing the solvent, the solid was recrystallized with ethyl acetate/pentane to obtain 2.5 g pure 5′-O-(tert-butyldimethylsilyl) thymidine 1 (70% yield).: m.p. 193-194° C.; 1H NMR (500 MHz, CDCl3) δ 9.0 (s, 1H, NH), 7.50 (s, 1H, H-6), 6.36 (dd, J=5.8, 8.1 Hz, 1H, H-1′), 4.44 (m, 1H, H-3′), 4.03 (m, 1H, H-4′), 3.85 (m, 2H, H-5′), 2.66 (d, J=3.8 Hz, 1H, OH), 2.35 (m, 1H, H-2′), 2.07 (m, 1H, H-2′), 1.89 (s, 3H, C═CMe), 0.89 (s, 9H, CMe3), 0.09 (s, 6H, SiMe2); 13C NMR (125 MHz, CDCl3) δ 163.8 (C-4), 150.4 (C-2), 135.4 (C-6), 110.9 (C-5), 87.2 (C-4′), 85.0 (C-1′), 72.6 (C-3′), 63.6 (C-5′), 41.1 (C-2′), 25.9 (SiCMe3), 18.3 (SiCMe3), 12.5 (C═CMe), −5.4 (SiMe2), −5.5 (SiMe2).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14](O)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[C:12]([CH:14]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([CH:20]([CH3:22])[CH3:21])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(N)cc1
Reactant: COc1ccc(-n2cc(C(O)CC(C)C)c(C(C)C)n2)cc1
Product: COc1ccc(-n2cc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C(C)C)n2)cc1
Yield: 3 %

Procedure:
Using 1-[1-(4-methoxyphenyl)-3-(1-methylethyl)-1H-pyrazol-4-yl]-3-methylbutan-1-ol (0.57 g) synthesized above and ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (0.45 g) synthesized in Example 1(2) and in the same manner as in Example 1(7), the title object compound (28.0 mg, 3%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:24]1[CH2:28][CH2:27][CH2:26][NH:25]1)[C@@H:4]([CH3:23])[C:5]([NH:7][C@H:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([NH:46][C:47]([CH3:72])([C:49]([NH:51][C@H:52]([C:56]([N:58]([C@@H:60]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:61]([O:66][CH3:67])[CH2:62][C:63](O)=[O:64])[CH3:59])=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:48])=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.C(OCC)(=O)C>[CH:29]1[C:41]2[CH:40]([CH2:42][O:43][C:44]([NH:46][C:47]([CH3:72])([C:49]([NH:51][C@H:52]([C:56]([N:58]([C@@H:60]([C@@H:68]([CH3:71])[CH2:69][CH3:70])[C@H:61]([O:66][CH3:67])[CH2:62][C:63]([N:25]3[CH2:26][CH2:27][CH2:28][C@H:24]3[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:23])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:6])=[O:64])[CH3:59])=[O:57])[CH:53]([CH3:55])[CH3:54])=[O:50])[CH3:48])=[O:45])[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:33]=2[CH:32]=[CH:31][CH:30]=1
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 21 h
Yield: 63.1 %

Procedure:
To a stirring solution of #121 (0.55 g, 1.0 mmol, 1.0 eq.) in 10 mL of dichloromethane and 1 mL of DMF, #32 (0.62 g, 1.0 mmol, 1.0 eq.) was added followed by HATU (0.42 g, 1.1 mmol, 1.1 eq.) and Hunig's base (0.72 mL, 4.1 mmol, 4.0 eq.). The reaction was allowed to stir at room temperature for approximately 21 hours. Reaction was reduced down, diluted with ethyl acetate, and then washed with 0.5 N HCl and brine. Organic layer was dried over sodium sulfate, filtered, and concentrated to a smaller volume before being concentrated down onto silica. Silica chromatography was then performed (Gradient: 0%-40% acetone in heptane) producing #122 (0.62 g, 62%) as a white solid. LC-MS (Protocol Q): m/z 982.3 [M+H+] retention time=2.44 minutes.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[C:4]([F:10])[C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH3:20])=[CH:17][CH:18]=2)[CH2:13][C:12]1=[O:21].C([OH:24])C>O>[CH3:20][C:16]1[CH:17]=[CH:18][C:19]([NH:11][C:3]2[C:4]([F:10])=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=2[F:1])=[C:14]([CH2:13][C:12]([OH:21])=[O:24])[CH:15]=1
Reactant: CCO
Reactant: Cc1ccc2c(c1)CC(=O)N2c1c(F)cc(F)c(F)c1F
Solvent: O
Product: Cc1ccc(Nc2c(F)cc(F)c(F)c2F)c(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
The suspension of 350 mg of N-(2′,3′,4′,6′-tetrafluorophenyl)-5-methyloxindole in 20 ml of ethanol and 5 ml of water is degassed by passing through nitrogen for 1.5 h. Then 260 mg of 30% aqueous sodium hydroxide is added and the mixture is heated to reflux for 6.5 hours. Most of the ethanol is then removed by distillation the mixture is cooled to room temperature followed by the slow addition of 1N hydrochloric acid (1.05 g) to reach a pH of about 3. The precipitate is then filtered, washed with ethanol/water (1:1) and dried in vacuo at room temperature affording the title product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[CH:11]([O:15][CH2:16][CH3:17])[C:12]([OH:14])=O.Cl.[NH2:19][CH2:20][C:21]1[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][C:22]=1[OH:29]>>[C:25]([C:24]1[CH:27]=[CH:28][C:21]([CH2:20][NH:19][C:12](=[O:14])[CH:11]([C:3]2[C:4]([F:10])=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:15][CH2:16][CH3:17])=[C:22]([OH:29])[CH:23]=1)#[N:26]
Reactant: CCOC(C(=O)O)c1c(F)cc(OC)cc1F
Reactant: N#Cc1ccc(CN)c(O)c1
Agent: Cl
Product: CCOC(C(=O)NCc1ccc(C#N)cc1O)c1c(F)cc(OC)cc1F

Procedure:
(RS)-(2,6-Difluoro-4-methoxy-phenyl)-ethoxy-acetic acid (example 101.3) was coupled with 4-aminomethyl-3-hydroxy-benzonitrile hydrochloride (example 110.2) according to general procedure B to give (RS)-N-(4-cyano-2-hydroxy-benzyl)-2-(2,6-difluoro-4-methoxy-phenyl)-2-ethoxy-acetamide. Colorless foam. MS 375.4 ([M−H]−)
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([F:17])[C:12]([N+:14]([O-])=O)=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]>[Pd].C(O)C>[CH2:1]([N:3]1[C:9]2[CH:10]=[C:11]([F:17])[C:12]([NH2:14])=[CH:13][C:8]=2[O:7][CH2:6][CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCCOc2cc([N+](=O)[O-])c(F)cc21
Agent: [Pd]
Solvent: CCO
Product: CCN1CCCOc2cc(N)c(F)cc21

Procedure:
9-Ethyl-2-fluoro-3-nitro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocycloheptene (515 mg, 2.14 mmol) and 10% Palladium on Carbon (50% Wet) (0.25 g) in Ethanol (30 mL) were shaken under an atmosphere of Hydrogen (40 psi) for 4 h. The mixture was filtered through Celite, washing with ethanol, and conc. in vacuo to afford 9-Ethyl-2-fluoro-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-3-ylamine as a green film (0.375 g, 84%). 1H-NMR (CDCl3): 6.60 (d, 1H, J=12.8 Hz), 6.44 (d, 1H, J=9.2 Hz), 3.99 (m, 2H), 3.42 (s, 1H), 3.09 (m, 4H), 1.96 (m, 2H), 1.56 (m, 2H), 1.17 (t, 3H, J=7.0 Hz).
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][CH:16]([CH3:20])[CH2:17][CH:18]=[O:19]>>[CH3:3][C@H:2]([C@@H:18]([OH:19])[CH2:17][CH:16]([CH3:20])[CH3:15])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CC(C)CC=O
Product: CC(C)C[C@H](O)[C@@H](C)C(=O)n1c(=O)oc2ccccc21

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolinone with 3-methylbutanal. 1H-NMR (CDCl3, 400 MHz): δ 8.06 (m, 1H); 7.25 (m, 3H); 4.17 (m, 1H); 3.91 (dq, 1H, J=3,7); 2.52 (br s, 1H); 1.82 (m, 1H); 1.56 (ddd, 1H, J=5,9,13); 1.31 (d, 3H, J=7); 1.25 (ddd, 1H, J=4,6,13); 0.95 (d, 3H, J=7); 0.94 (d, 3H, J=7).
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([OH:10])=[O:9]
Reactant: CC(C)=CCBr
Reactant: CCOC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCOc1ccccc1C(=O)O

Procedure:
The reaction of ethyl salicylate and 3,3-dimethylallyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 2-(3-Methyl-but-2-enyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.50 (s, —CO2H); 7.55 (m, 1 arom. H); 7.41 (m, 1 arom. H); 7.07 (m, 1 arom. H); 6.92 (m, 1 arom. H); 5.36 (m, CH═C(CH3)2); 4.54 (d-like, CH2CH═C(CH3)2); 1.72, 1.68 (2s, CH═C(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.42 (C═O); 157.06; 136.97; 132.70; 130.44; 121.91; 119.99; 119.82; 113.79; 65.23; 25.42; 18.03.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]#[N:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1.O>[CH2:28]([N:10]1[C:9]([CH2:8][NH:7][C:6](=[O:32])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:25]3[N:33]=[N:34][NH:35][N:26]=3)[CH:16]=2)[C:11]1=[O:27])[CH:29]([CH3:30])[CH3:31]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(C#N)ccc2c1=O
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccccc2)c2cc(-c3nn[nH]n3)ccc2c1=O
Temperature: 90 °C
Reaction time: 24 h
Yield: 37.9 %

Procedure:
To a solution (30 mL) of tert-butyl(6-cyano-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methylcarbamate (0.86 g, 2.0 mmol) in toluene were added sodium azide (0.16 g, 2.5 mmol) and triethylamine hydrochloride (0.28 g, 2.5 mmol) and the mixture was stirred at 90° C. for 24 h. The reaction mixture was poured into water (100 mL), acidified with 1N hydrochloric acid and extracted twice with ethyl acetate (50 mL). The extracts were combined and washed with saturated brine (15 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was recrystallized from tetrahydrofuran-diisopropyl ether (1:5) to give tert-butyl [2-isobutyl-1-oxo-4-phenyl-6-(2H-tetrazol-5-yl)-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.36 g, 37%) as colorless crystals.