Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:24])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]1)=[C:8]([CH3:22])[C:7]2=[O:23].C(N(C(C)C)CC)(C)C.Cl[CH2:35][O:36][CH3:37].O>ClCCl>[Br:1][C:2]1[C:3]([O:24][CH2:35][O:36][CH3:37])=[CH:4][CH:5]=[C:6]2[C:11]=1[O:10][C:9]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:21])[CH2:19][CH3:20])[CH2:14][CH2:13]1)=[C:8]([CH3:22])[C:7]2=[O:23]
Reactant: COCCl
Reactant: CCC(=O)N1CCC(c2oc3c(Br)c(O)ccc3c(=O)c2C)CC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCC(=O)N1CCC(c2oc3c(Br)c(OCOC)ccc3c(=O)c2C)CC1
Reaction time: 1 h
Yield: 42.1 %

Procedure:
To a solution of 8-bromo-7-hydroxy-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (3.82 mol) obtained in Example 32 in dichloromethane (25 mL), diisopropylethylamine (1.32 mL, 7.66 mmol) and chloro(methoxy)methane (345 μL, 4.59 mmol) were added under cooling with ice, and the mixture was stirred for 1 hour under cooling with ice and then at room temperature for 2 hours. Water was added to the reaction solution, followed by extraction with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=98/2) to obtain 847 mg of 8-bromo-7-(methoxymethoxy)-3-methyl-2-(1-propanoylpiperidin-4-yl)-4H-chromen-4-one (yield: 51%). Subsequently, 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (181 μL, 0.953 mmol), potassium carbonate (167 mg, 1.21 mmol), and a palladium chloride-dppf complex (40.7 mg) were added to a mixed solution of the obtained compound (104 mg, 0.24 mmol) in N,N-dimethylformamide (2 mL) and water (0.2 mL), and the mixture was stirred at 90° C. for 14 hours under the nitrogen atmosphere. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=50/50→0/100) and then further purified by HPLC to obtain 38 mg of the title compound (yield: 40%) as an oil.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:10][C:11]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]>C(Cl)Cl>[C:13]([C:12]1[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:11]=1[NH:10][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:9])(=[O:14])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C=Nc1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 90.4 %

Procedure:
A solution of 13.1 g (0.11 mole) of phenyl isocyanate and 23.17 g (0.1 mole) of 2-amino-5-chlorobenzophenone in 70 ml of methylene chloride was refluxed for 20 hr, and then evaporated to dryness under reduced pressure. The residue was recrystallized from ethanol to give 31.71 g (90%) of 1-(2-benzoyl-4-chlorophenyl)-3-phenylurea as colorless crystals: mp 145°-147°; 1H nmr (DMSO-d6) δ6.7-8.3 ppm (m, 13H), 9.43 ppm (d, J=7 Hz, 1H, exD2O) and 10.25 ppm (s, 1H, exD2O); 13C nmr (DMSO-d6) δ152.2 ppm (NHCO) and 195.5 ppm (C=O).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH3:9].C1C(=O)[N:14](Br)[C:12](=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.[C-]#N.[Na+]>C(Cl)(Cl)(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH2:9][C:12]#[N:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(F)cccc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#CCc1c(F)cccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A suspension of 2-bromo-6-fluorotoluene (5.00 g, 26.45 mmol), NBS (5.18 g, 29.10 mmol), and VAZO (323 mg, 1.32 mmol) in CCl4 (100 mL) was heated to reflux under vigoroue stirring overnight. The reaction mixture was cooled to room temperature, concentrated and the residue was removed by filtration. The filtrate was concentrated and the residue was re-dissolved in ethanol (90 mL), treated with a solution of NaCN (2.59 g, 52.9 mmol) in water (20 mL) and the combined mixture was heated to reflux for 5 hrs. Ethanol was removed under reduced pressure, the aqueous residue was diluted with water and extracted with AcOEt. The organic layer was successively washed with water and brine, concentrated, adsorbed on silica gel and purified by flash column chromatography (eluents AcOEt/hexanes: 10/90 to 20/80) to afford title compound 329 (3.92 g, 69% yield over 2 steps, slightly contaminated) as a pale yellow sticky solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.62-7.57 (m, 1H), 7.45-7.35 (m, 2H), 4.08 (s, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH:10]=[C:9]([C:12]2C=C[C:15]([O:18][Si](CC(C)C)(C)C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2.CC1(C)CC=C(C2C=CC(C)=CC=2)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:39][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([C:12]2[O:18][CH:15]=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:26]#[C:27][C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:30][CH:29]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(O[Si](C)(C)CC(C)C)cc2)=CCC3(C)C)cc1
Agent: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccco2)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4- methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 250.0 mg (0.52 mmol) of ethyl 4-[(5,6-dihydro-5,5- dimethyl-8-(trifluoromethylsulfonyl)oxy-2- naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 142.4 mg (1.045 mmol) of zinc chloride, 24.1 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2-lithiofuran (prepared by the addition of 53.4 mg (0.52 ml, 0.78 mmol) of n-butyllithium (1.5M solution in hexane) to a cold solution (-78° C.) of 53.4 mg (0.784 mmol) of furan in 1.0 ml of THF). PMR (CDCl3): δ 1.32 (6H, s), 1.41 (3H, t, J=7.1 Hz), 2.35 (2H, d, J=5.0 Hz), 4.39 (2H, q, J=7.1 Hz), 6.41 (1H, t, J=5.0 Hz), 6.50 (2H, s), 7.36 (1H, d, J=8.0 Hz), 7.45 (1H, dd, J=1.7, 8.0 Hz), 7.49 (1H, s), 7.57 (2H, d, J=8.2 Hz), 7.63 (1H, d, J=1.7 Hz), 8.02 (2H, d, J=8.2 Hz).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[S:21][C:22]4[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.Cl>C(Cl)Cl>[N:11]1([C:14]2[N:15]=[CH:16][C:17]([C:20]3[S:21][C:22]4[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:23]=4[N:24]=3)=[CH:18][CH:19]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4ccc(N)cc4s3)cn2)CC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc2nc(-c3ccc(N4CCNCC4)nc3)sc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.4 %

Procedure:
4-[5-(6-Amino-benzothiazol-2-yl)-pyridin-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (13 mg, 0.032 mmol) was dissolved in DCM (1 mL), followed by addition of TFA (70 μL). The r.m. was thereafter stirred for 4 hrs at r.t. After addition of HCl (1 M; 1 mL), the two layers were separated. The organic layer was extracted with HCl (1M). The combined aqueous layers were made basic (pH 9-10) with NaOH (2 M) and extracted with DCM. The combined organic layers were washed with brine, dried (Na2SO4), filtered and the solvent was evaporated to give the title compound (10 mg) as an opac colored solid. 1H NMR δ 8.70 (d, 1 H) 8.07 (dd, 1 H) 7.67 (d, 1 H) 7.13 (d, 1 H) 6.97 (d, 1 H) 6.81 (dd, 1 H) 5.45 (s, 2 H) 3.53-3.66 (m, 4 H) 2.77-2.92 (m, 4 H); MS m/z (M+H) 311.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH:11]1[O:15][CH2:14][CH2:13][O:12]1
Reactant: BrCC1OCCO1
Reactant: Sc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1SCC1OCCO1
Reaction time: 8 h

Procedure:
To a mixture of 2-bromothiophenol (5 g) and 2-bromomethyl-1,3-dioxolane (2.98 mL) in N,N-dimethylformamide (50 mL) was added potassium carbonate (5.48 g) at room temperature, and the mixture was stirred overnight. The reaction mixture was poured into water, and the mixture was extracted with diethyl ether. The extract washed with water, 1 mol/L sodium hydroxide aqueous solution, water and brine successively, and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to give (2-bromophenylthiomethyl)-1,3-dioxolane (7.25 g). To a mixture of poly phosphoric acid (20 g) and chlorobenzene (40 mL) was added a solution of (2-bromophenylthiomethyl)-1,3-dioxolene (7.25 g) in chlorobenzene (20 mL), and the mixture was refluxed for 8 hours. The reaction mixture was cooled to room temperature and supernatant solution was collected by decantation. Toluene was added to the residue, and the supernatant was collected by decantation after the mixture was stirred. The supernatant was combined and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution washed with a saturated sodium hydrogencarbonate aqueous solution, water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (2.27 g).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:24]([OH:38])[C:25]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([F:27])[F:26])=[O:21])[C:15]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.ClC(Cl)C(O)=O.Cl>CS(C)=O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]([CH2:19][C:20]([NH:22][CH:23]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:24](=[O:38])[C:25]([C:28](=[O:37])[NH:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([F:26])[F:27])=[O:21])[C:15]([C:46]2[CH:51]=[CH:50][CH:49]=[C:48]([Cl:52])[CH:47]=2)=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cn1c(-c2cccc(Cl)c2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(O)C(F)(F)C(=O)NCc1ccccc1
Agent: Cl
Agent: O=C(O)C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=C(Cn1c(-c2cccc(Cl)c2)ncc(NC(=O)OCc2ccccc2)c1=O)NC(Cc1ccccc1)C(=O)C(F)(F)C(=O)NCc1ccccc1
Yield: 76.5 %

Procedure:
To a solution of the objective compound of step (14) (69 g, 95 mmol) and WSCIHCl (99.87 g, 0.5209 mol) in DMSO (590 mL)-toluene (590 mL) was added dichloroacetic acid (15.6 mL) with drop wise over 20 minutes under ice-cooling. The resulting mixture was stirred under ice-cooling for 2.5 hours, then added to 0.5 M hydrochloric acid (1800 mL) and extracted with ethyl acetate (1800 mL, 2×800 mL). The extract was washed with saturated sodium hydrogencarbonate aqueous solution (800 mL) and saturated brine (800 mL), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (99:1 chloroform-methanol) to give 52.95 g (77%) of 2-[5-benzyloxycarbonylamino-2-(3-chlorophenyl)-1,6-dihydro-6-oxo-1-pyrimidinyl]-N-[1-benzyl-3-[N-(benzyl)carbamoyl]-3,3-difluoro-2-oxopropyl]acetamide as a white solid.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][OH:3].[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][C@@H:26]([NH:28][CH3:29])[CH3:27])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]>>[Cl:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][C:22]=3[O:24][CH2:25][C@@H:26]([N:28]([CH3:29])[C:1](=[O:5])[CH2:2][OH:3])[CH3:27])[N:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[OH:30]
Reactant: CN[C@@H](C)COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12
Reactant: O=C(O)CO
Product: C[C@@H](COc1cccc2ncnc(Nc3ccc(O)c(Cl)c3)c12)N(C)C(=O)CO
Yield: 48 %

Procedure:
The procedure described in Example 3 (preparation of starting materials) was repeated using glycolic acid and 2-chloro-4-[(5-{[(2S)-2-(methylamino)propyl]oxy}quinazolin-4-yl)amino]phenol to give N-[(1S)-2-({4-[(3-chloro-4-hydroxyphenyl)amino]quinazolin-5-yl}oxy)-1-methylethyl]-2-hydroxy-N-methylacetamide in 48% yield; Mass spectrum MH+ 417.3.
Reaction SMILES: C[C:2]1(C)[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12]3[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=3)[C:15]([O:17][CH2:18]C)=[O:16])[C:5]=2[C:4](=[O:23])[O:3]1.C[O-].[Na+]>CO>[OH:7][C:6]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]2[CH:22]=[CH:21][CH:20]=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[C:5]=1[C:4]([O:3][CH3:2])=[O:23]
Reactant: CCOC(=O)c1cccc(-c2cccc3c2C(=O)OC(C)(C)O3)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc(-c2cccc(O)c2C(=O)OC)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 97.5 %

Procedure:
To a solution of 3-(2,2-dimethyl-4-oxo4H-1,3-benzodioxin-5-yl)-benzoic acid, ethyl ester (1.4 g, 4.3 mmol) in methanol (10 mL) was added sodium methoxide (0.5 M in methanol, 25 mL) at 0° C. The solution was stirred at rt for 15 min. The reaction was quenched by addition of 1 N HCl (30 mL) and extracted with EtOAc (3×30 mL). The combined organic extracts were dried over MgSO4 and concentrated to afford 3-hydroxy-[1,1′-biphenyl]-2,3′-dicarboxylic acid, dimethyl ester (1.2 g, 95%) as a yellow solid: 1H NMR (CDCl3) δ3.43 (s, 3H), 3.93 (s, 3H), 6.79 (dd, J=7.5, 0.9 Hz, 1H) 7.04 (dd, J=7.5, 0.9 Hz, 1H), 7.43 (m, 3H), 7.93 (m, 1H), 8.02 (dm, J=7.0 Hz, 1H), 10.8 (s, 1H).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I[CH2:16][CH3:17]>>[CH2:16]([O:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=2)[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)[CH3:17]
Reactant: OC1(c2ccc(I)cc2)CCOCC1
Reactant: CCI
Product: CCOC1(c2ccc(I)cc2)CCOCC1

Procedure:
In the same manner as in Reference Example 2, tetrahydro-4-(4-iodophenyl)-2H-pyran-4-ol (302 mg) and iodoethane (0.119 ml) were reacted to obtain 4-ethoxy-tetrahydro-4-(4-iodophenyl)-2H-pyran (269 mg).
Reaction SMILES: [C:1]1([N:7]2[CH2:11][CH2:10][C:9](=O)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:9]1[CH2:10][CH2:11][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C1CCN(c2ccccc2)N1
Solvent: Cc1ccccc1
Product: ClC1=NN(c2ccccc2)CC1
Reaction time: 1 h

Procedure:
1-Phenylpyrazolidin-3-one (8.1 g) was suspened in dry toluene (100 ml), followed by addition of phosphoryl chloride (7.0 ml) and the mixture stirred for 1 hour at 85° . When cool the toluene was decanted from the solid and solvent removed in vacuo to give the sub-title compound, (6.9 g), mp 92°-93°.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([O:9][CH2:18][CH3:19])=[O:8])(=[O:3])[CH3:2]
Reactant: CCO
Reactant: CC(=O)c1cccc(C(=O)O)c1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc(C(C)=O)c1
Yield: 98 %

Procedure:
A solution of 3-acetylbenzoic acid (4.00 g, 24.366 mmol) and concentrated sulfuric acid (0.078 mL, 1.462 mmol) in ethanol (100 mL) was stirred at 80° C. for 3 days. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated to give ethyl 3-acetylbenzoate as a brown powder (4.59 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=4[C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[N:9][N:10]=2)[CH:7]=1.[CH3:30][N:31](C=O)C>C(=O)(O)[O-].[Na+].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>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH:16]2[CH2:17][CH2:18][N:13]([C:11]([C:8]3[N:6]4[CH:7]=[C:2]([C:30]#[N:31])[CH:3]=[CH:4][C:5]4=[N:10][N:9]=3)=[O:12])[CH2:14][CH2:15]2)=[C:20]([C:26]([F:29])([F:28])[F:27])[CH:21]=1
Reactant: CN(C)C=O
Reactant: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2ccc(F)cc2C(F)(F)F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc2nnc(C(=O)N3CCC(c4ccc(F)cc4C(F)(F)F)CC3)n2c1
Temperature: 130 °C
Yield: 40.4 %

Procedure:
A solution of (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone (90 mg, 0.19 mmol) in DMF (2.2 mL) zinc cyanide (45 mg, 0.38 mmol) was sparged with Ar for 15 min. To the solution was added Pd(PPh3)4 (22 mg, 0.019 mmol) and the vessel was sealed and heated to 130° C. microwaves for 30 min. The mixture was diluted with saturated sodium bicarbonate solution (10 mL) and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with saturated brine solution (30 mL) and concentrated to dryness under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) followed by HPLC (Phenomenex Luna C18 (2), 250.0×50.0 mm, 15 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA) and was washed with saturated sodium bicarbonate solution (3×30 mL) then freeze dried to provide 3-(4-(4-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-[1,2,4]triazolo[4,3-a]pyridine-6-carbonitrile as a white solid (32 mg, 40%): mp 158-162° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.53 (s, 1H), 8.14 (dd, J=9.0, 0.9 Hz, 1H), 7.82 (dd, J=9.6, 1.5 Hz, 1H), 7.77-7.67 (m, 1H), 7.61-7.47 (m, 2H), 5.19-5.04 (m, 1H), 4.80-4.67 (m, 1H), 3.46-3.14 (m, 2H, overlaps with H2O), 3.12-2.94 (m, 1H), 2.02-1.70 (m, 4H); ESI MS m/z 418 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].CN.Cl.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.CN(C)C=O>[C:29]([O:28][C:26]([CH2:25][NH:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5])=[O:27])([CH3:32])([CH3:31])[CH3:30]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1ccccc1C(=O)c1ccccc1
Agent: CN
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CNc1ccccc1C(=O)c1ccccc1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
A mixture of 2-aminobenzophenone (20.00 g, 0.101 mol), potassium iodide (8.42 g, 0.0507 mol), potassium carbonate (21.02 g, 0.152 mol), N,N-dimethylformamide (30 ml) and t-butyl bromoacetate (29.67 g, 0.152 mol) was stirred at room temperature, and allowed to react at 80° C. for 5.5 hr. The mixture was cooled to give slurry, to which 40% aqueous methylamine solution (11.81 g, 0.152mol) was added to decompose excess t-butyl bromoacetate. To the mixture were added ethyl acetate (60 ml) and 6.4% hydrochloric acid (147 g, 0.259 mol) for partition. The ethyl acetate layer was washed once with 2.1% sodium hydrogencarbonate (41 g, 0.010 mol) and condensed under reduced pressure to remove the solvent. The residue was crystallized from n-hexane (70 ml) to yield 2-[N-(tert-butoxycarbonylmethyl)amino]benzophenone (27.41 g, yield 86.8%) as a yellow crystal. (Reference value, mp: 88° C. (DSC).) 1H-NMR 200 MHz (CDCl3) δ: 1.50 (s, 9 H), 3.96 (d, J=5.3,2 H), 6.55-6.65 (m, 2H), 7.33-7.66 (m, 7H)), 8.90 (t, J=5.3,1 H) ##STR12##
Reaction SMILES: CN(C)CCCN=C=NCC.[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:26])([F:25])[F:24])[C:14]=1[C:29]([OH:31])=O.ON1C2C=CC=CC=2N=N1.Cl.[NH:43]([CH2:45][C:46]([O:48][CH3:49])=[O:47])[CH3:44].C(N(CC)CC)C>CN(C=O)C.O>[Br:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:27][CH3:28])[C:19]=2[C:23]([F:25])([F:24])[F:26])[C:14]=1[C:29]([N:43]([CH3:44])[CH2:45][C:46]([O:48][CH3:49])=[O:47])=[O:31]
Reactant: COc1ccc2c(C(=O)O)c(Br)ccc2c1C(F)(F)F
Reactant: CNCC(=O)OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CN(C)C(=O)c1c(Br)ccc2c(C(F)(F)F)c(OC)ccc12
Reaction time: 0.33 h
Yield: 75 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (7.91 g, 1.2 eq) was added to a stirred solution of 2-bromo-6-methoxy-5-trifluoromethyl-1-naphthoic acid, prepared by the process of Example 14, Step 2 (12.00 g, 34.4 mmol) and 1-hydroxybenzotriazole (6.97 g, 1.5 eq) in anhydrous DMF (105 mL) at room temperature under a dry nitrogen atmosphere. Dissolution occurred after 20 minutes. After 1 hour, a suspension of methyl sarcosinate hydrochloride (9.56 g, 2.0 eq) in anhydrous DMF (60 mL) was added to the reaction mixture followed by triethylamine (15.8 mL, 3.3 eq). After 21/2 hours, more triethylamine (4.8 mL, 1.0 eq) was added. The reaction was diluted with water (1.6 L) after 181/2 hours. The aqueous phase was extracted with ether (4×250 mL). The extracts were combined and washed with 0.5N sodium hydroxide solution (1×200 mL) and saturated aqueous sodium chloride (1×200 mL). The ether phase was dried with magnesium sulfate and the ether was removed. The crude product was flash chromatographed (3:2 to 2:3 petroleum ether:ethyl acetate eluent gradient, silica) then reflash chromatographed (99:1 to 9:1 methylene chloride:acetonitrile eluent gradient, silica) to provide the product as a white foam (11.16 g, 75%).
Reaction SMILES: C(N(CC)CC)C.C(#N)C.[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][NH:30][CH2:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[CH:27]=[CH:28][C:14]1=2)[CH3:12].[C:39]1([S:45](Cl)(=[O:47])=[O:46])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O>[CH2:11]([N:13]1[C:19](=[O:20])[C:18]([CH3:22])([CH3:21])[C:17](=[O:23])[N:16]([CH3:24])[C:15]2[CH:25]=[C:26]([CH2:29][N:30]([CH2:31][CH2:32][C:33]3[CH:34]=[N:35][CH:36]=[CH:37][CH:38]=3)[S:45]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:47])=[O:46])[CH:27]=[CH:28][C:14]1=2)[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CNCCc3cccnc3)ccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCc3cccnc3)S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine(0.15 ml) was added to a acetonitrile solution (6 ml) of 1-ethyl-3,3,5-trimethyl-7-[(2-pyridin-3-yl-ethylamino)methyl]-1,5-dihydrobenzo[b][1,4]diazepine-2,4-dione(0.35 g). The mixture was cooled with ice. Benzenesulphonyl chloride(0.13 ml) was added, and the mixture was stirred at room temperature overnight. The reaction liquid was condensed under reduced pressure. Water was added to the residue, followed by extraction by ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by NH silica gel column chromatography (hexane: ethyl acetate=30:70). The purified product was condensed under reduced pressure, and the residue was recrystallized from the ethyl acetate-ether mixture to give the title compound(0.1 g) as a white powder.