Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][NH:6][N:5]=1)[CH3:2].[CH2:16]([O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Cl)=[CH:26][CH:25]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C)C=O.[H-].[Na+]>O>[CH2:16]([O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:6]2[CH:7]=[C:8]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]([O:3][CH2:1][CH3:2])=[N:5]2)=[CH:30][CH:31]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CCOC(=O)CCc1c[nH]nc1OCC
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To a mixture of ethyl 3-[3-ethoxy-1H-pyrazol-4-yl]propionate (1.50 g), 4-benzyloxybenzyl chloride (1.81 g), and N,N-dimethylformamide (30 ml), sodium hydride (60%, oily, 0.35 g) was added at 0° C., and then the mixture was stirred at room temperature for one hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water, then, with saturated aqueous sodium chloride solution, and dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-(4-benzyloxybenzyl)-3-ethoxy-1H-pyrazol-4-yl]propionate (2.76 g, yield: 96%) was obtained as a colorless oily substance from the faction eluted with ethyl acetate-hexane (1:4, volume ratio).
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=2)[CH3:2].[Br:18][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([C:25]2[O:26][C:27]([CH2:30]Cl)=[N:28][N:29]=2)[CH:24]=1>>[Br:18][C:19]1[CH:24]=[C:23]([C:25]2[O:26][C:27]([CH2:30][N:4]3[C:5]4[C:10](=[C:9]([C:12]([F:15])([F:13])[F:14])[C:8]([C:16]#[N:17])=[CH:7][CH:6]=4)[CH:11]=[C:3]3[CH2:1][CH3:2])=[N:28][N:29]=2)[CH:22]=[N:21][CH:20]=1
Reactant: CCc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Reactant: ClCc1nnc(-c2cncc(Br)c2)o1
Product: CCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1nnc(-c2cncc(Br)c2)o1

Procedure:
Synthesized as described in Example 145B from 2-ethyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 3-bromo-5-[5-(chloromethyl)-1,3,4-oxadiazol-2-yl]pyridine: MS (ESI): m/z 476 (M−1).
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5](=[O:28])[C:6]([F:27])([F:26])[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:17])[OH:8])[CH3:3].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(O)(C)(C)C.C(Cl)Cl>[CH3:3][CH:2]([NH:4][C:5](=[O:28])[C:6]([F:27])([F:26])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH3:25])=[O:17])=[O:8])[CH3:1]
Reactant: COc1ccccc1C(=O)Nc1ccccc1C(O)C(F)(F)C(=O)NC(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: COc1ccccc1C(=O)Nc1ccccc1C(=O)C(F)(F)C(=O)NC(C)C
Temperature: 23 °C
Reaction time: 18 h

Procedure:
To a solution of N-[2-(3-(2-propylamino)-3-oxo-2,2-difluoro-1-hydroxypropyl)phenyl]-2-methoxyphenylcarboxamide of Step 4 (200 mg, 0.51 mmol), CH2Cl2 (5 mL) and tert-butanol (5 mL), was added 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxyl-3(1H)-one (1.5 g, 3.54 mmol) under argon at 23° C. After 18 h, sat. NaHCO3 (10 mL) was added followed by solid Na2S2O3 (1.0 g, 6.3 mmol). After 2 h of vigorous stirring at 23° C., the organic layer was separated, washed with sat. NaHCO3 (2×10 mL), sat. Na2S2O3 (2×10 mL), and brine (1×10 mL) and dried (MgSO4). Upon concentration in vacuo and trituration with ethyl ether, the title compound was afforded (100 mg) as a yellow solid : mp 131.5-132° C. 1H NMR (CDCl3) δ1.27 (d), 4.13 (s,), 4.13-4.20 (m), 6.32 (br d), 7.04 (m), 7.10 (m), 7.19 (m), 7.51 (m) 7.67 (m), 8.11 (m), 8.22 (m), 8.90 (m), 12.01 (br s). MS (EI) 390 (M+), 254, 135. Anal. Calc'd. for C20H20F2N2O4 plus 0.25 mol H2O: C, 60.83; H, 5.23; N, 7.09. Found: C, 60.75; H, 5.00; N, 6.95.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([Mg]Br)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(C1C=CC(Br)=CC=1)(C)(C)C.[Mg].[B:25](OCCCC)([O:31]CCCC)[O:26]CCCC.S(=O)(=O)(O)O>C(OCC)C.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([B:25]([OH:31])[OH:26])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCOB(OCCCC)OCCCC
Reactant: CC(C)(C)c1ccc([Mg]Br)cc1
Agent: CC(C)(C)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: O
Solvent: CCOCC
Product: CC(C)(C)c1ccc(B(O)O)cc1
Temperature: 25 °C

Procedure:
A solution of para-tert-butylphenyl magnesium bromide prepared from 52 ml of para-tert-butylphenyl bromide and 8.0 g of the magnesium turnings in 250 ml of diethyl ether was added to 81 ml of tri-n-butyl borate in 250 ml of diethyl ether at −80° C. with stirring under argon. The reaction mixture was allowed to warm to ambient temperature, and was poured into 150 ml of 10% sulfuric acid in water. The organic phase was extracted twice by 100 ml of diethyl ether. The solvent and n-butanol were removed under vacuum. The viscous residue was recrystallized from boiling water. Yield of 4-tert-butylphenyl boronic acid was 10% as white crystals with mp. 202-203° C.
Reaction SMILES: [F:1][CH:2]([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[CH3:26][N:27]([CH3:48])[CH2:28][CH2:29][N:30](CCN(C)C)[S:31]([C:34]1[S:35][C:36]([Cl:42])=[C:37]([N+:39]([O-])=O)[CH:38]=1)(=[O:33])=[O:32]>>[Cl:42][C:36]1[S:35][C:34]([S:31](=[O:33])(=[O:32])[NH:30][CH2:29][CH2:28][N:27]([CH3:48])[CH3:26])=[CH:38][C:37]=1[NH:39][C:12]([C:11]1[CH:10]=[N:9][N:8]2[C:3]([CH:2]([F:25])[F:1])=[CH:4][C:5]([C:15]3[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=3)=[N:6][C:7]=12)=[O:13]
Reactant: CN(C)CCN(CCN(C)C)S(=O)(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: O=C(O)c1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: CN(C)CCNS(=O)(=O)c1cc(NC(=O)c2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c(Cl)s1

Procedure:
The title compound was prepared from 7-difluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C. 1) and 4-amino-5-chloro-thiophene-2-sulfonic acid (2-dimethylamino-ethyl)-amide (example B.14) according to general procedure II.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]4[N:19]([CH2:20][C:21]([F:24])([F:23])[F:22])[N:18]=[CH:17][N:16]=4)[N:14]=[C:7]3[C:6]=2[CH:25]=1.[F:26][C:27]1[C:32](B(O)O)=[CH:31][CH:30]=[CH:29][N:28]=1>>[F:26][C:27]1[C:32]([C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[CH:12]=[C:13]([C:15]5[N:19]([CH2:20][C:21]([F:22])([F:23])[F:24])[N:18]=[CH:17][N:16]=5)[N:14]=[C:7]4[C:6]=3[CH:25]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: FC(F)(F)Cn1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: OB(O)c1cccnc1F
Product: Fc1ncccc1-c1ccc2c(c1)-c1nc(-c3ncnn3CC(F)(F)F)cn1CCO2
Yield: 55 %

Procedure:
Following the procedure for 203, 10-bromo-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine was reacted with 2-fluoropyridin-3-ylboronic acid to give 10-(2-fluoropyridin-3-yl)-2-(1-(2,2,2-trifluoroethyl)-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (0.108 g, 55%), 1H NMR (400 MHz, DMSO) δ 8.71 (t, J=2.0, 1H), 8.57-7.83 (m, 4H), 7.80-7.39 (m, 2H), 7.22 (d, J=8.5, 1H), 5.88 (q, J=8.8, 2H), 4.79-4.38 (m, 4H). MS (ESI(+)): m/z 431.1 (M+H), which was hydrolyzed with HCl to give 218 (0.072 g, 72%). 1H NMR (400 MHz, DMSO) δ 11.85 (s, 1H), 8.78 (d, J=2.3, 1H), 8.09 (d, J=2.8, 2H), 7.69 (ddd, J=8.9, 7.7, 2.2, 2H), 7.36 (t, J=23.8, 1H), 7.08 (d, J=8.6, 1H), 6.30 (t, J=6.7, 1H), 5.91 (q, J=8.8, 2H), 4.56 (dd, J=13.5, 5.5, 4H). MS (ESI(+)): m/z 429.1 (M+H)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH2:29])=[O:28]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[C:26]([C:27]([NH2:29])=[O:28])=[CH:30][CH:31]=[CH:32][CH:33]=3)=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: NC(=O)c1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: NC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-bromobenzamide. MS (ESI): mass calcd. for C17H13FN4O, 308.11; m/z found, 309.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 8.01 (s, 1H), 7.86 (m, 1H), 7.75 (s, 1H), 7.55-7.26 (m, 7H), 6.70 (s, 2H).
Reaction SMILES: COC1C=CC(C[S:10][CH:11]2[CH2:15][S:14](=[O:17])(=[O:16])[CH:13]([CH2:18][OH:19])[CH2:12]2)=CC=1.C1(OC)C=CC=CC=1.C(O)(=O)C>C(OCC)(=O)C.CCCCCC>[SH:10][CH:11]1[CH2:15][S:14](=[O:17])(=[O:16])[CH:13]([CH2:18][OH:19])[CH2:12]1
Reactant: COc1ccc(CSC2CC(CO)S(=O)(=O)C2)cc1
Solvent: CCOC(C)=O
Solvent: COc1ccccc1
Solvent: CC(=O)O
Product: O=S1(=O)CC(S)CC1CO
Yield: 86.9 %

Procedure:
The title compound is prepared by the procedure of Example 202 using 0.615 g of product from Example 177, 1.04 g of mercuric trifluoroacetate, 0.440 g of anisole and 31 ml of 80% acetic acid to give, after chromatography (Silica gel: 10-100% ethyl acetate/hexane), 0.322 g of the desired product.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([OH:17])=[O:16])[N:8]=1.O.[CH3:22]O>>[CH3:6][C:7]1[O:11][N:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=2)[C:15]([O:17][CH3:22])=[O:16])[N:8]=1
Reactant: CO
Reactant: Cc1nc(-c2cccc(C(=O)O)c2)no1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)c1cccc(-c2noc(C)n2)c1

Procedure:
7.83 ml (147 mmol) of concentrated sulfuric acid are added to a suspension of 30.0 g (147 mmol) of 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoic acid in 150 ml of methanol, and the mixture is heated at the boil for 18 hours. The reaction mixture is cooled in an ice bath, water is added, the mixture is filtered off with suction and washed well with water: methyl 3-(5-methyl-1,2,4-oxadiazol-3-yl)benzoate as colourless crystals; m.p. 81° C., ESI 219 (M+H), HPLC: Rt.=2.65 min (method A).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:38])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21](=[O:38])[CH2:22][C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CC(=O)N1CCNCC1)NC(CCCc1ccccc1)CCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-3-oxopropionic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (37) (2.05 g; 3.93 mmol) is dissolved in methylene chloride (30 mL) at ambient temperature. Trifluoroacetic acid (15 mL) is added in a slow stream, and the solution is stirred for 1 hour at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product as an oil. ESMS: MH+ 422.2
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[N:14]=[CH:13][C:12]4[N:18]([CH3:35])[C:19](=[N:32][C:33]#[N:34])[N:20]([C:21]5[CH:26]=[CH:25][C:24]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])=[CH:23][CH:22]=5)[C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:36]([F:39])([F:38])[F:37].[CH3:40]C(C)([O-])C.[K+].CI>C1COCC1>[C:30]([C:27]([C:24]1[CH:23]=[CH:22][C:21]([N:20]2[C:11]3[C:10]4[CH:9]=[C:8]([C:5]5[CH:6]=[N:7][C:2]([NH:1][CH3:40])=[C:3]([C:36]([F:38])([F:37])[F:39])[CH:4]=5)[CH:17]=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:18]([CH3:35])[C:19]2=[N:32][C:33]#[N:34])=[CH:26][CH:25]=1)([CH3:28])[CH3:29])#[N:31]
Reactant: CC(C)(C)[O-]
Reactant: Cn1c(=NC#N)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(-c4cnc(N)c(C(F)(F)F)c4)ccc3ncc21
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2ccc(C(C)(C)C#N)cc2)c(=NC#N)n4C)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To the stirred solution of Example 6 (0.014 mmol) in dry THF was added potassium-t-butoxide (0.157 mmol) at 0° C. Reaction mixture was stirred further for 15 minutes, followed by addition of methyl iodide (0.125 mmol). Reaction mixture was warmed to RT and stirred overnight. Solvent was removed and diluted with EtOAc. Organic layer was washed with water, dried over anhydrous Na2SO4 and solvent was removed. Crude product was further purified (silica gel column, MeOH/CHCl3 as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 9.19 (s, 1H), 8.16-8.11 (m, 2H), 8.00-7.91 (m, 1H), 7.89 (s, 3H), 7.76 (brs, 1H), 6.87 (d, J=1.8 Hz, 1H), 6.79 (q, J=4.5 Hz, 1H), 3.92 (s, 3H), 2.89 (d, J=4.2 Hz, 3H), 1.82 (s, 6H); MS (m/z): 541(M+1)+.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1>[C:1]([CH:5]1[CH2:10][CH2:9][C:8]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C1CCC(=O)CC1
Reactant: C1CCNC1
Solvent: Cc1ccccc1
Product: CC(C)(C)C1CC=C(N2CCCC2)CC1

Procedure:
A 50 mL round-bottomed flask containing 4-tert-butylcyclohexanone (6.01 gm) in anhydrous toluene (20 mL) was fitted with a Dean-Stark trap containing 3A molecular sieves, reflux condenser and a heating mantle. Pyrrolidine (6.00 mL) was added, and the solution heated to reflux for 18 hr. The solvent was evaporated and the crude product was used directly for the next reaction.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[CH:29][C:25]=1[C:26](O)=[O:27].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][C:35](=[O:40])[C:36]([CH3:38])([CH3:37])[CH3:39])=[CH:29][C:25]=1[C:26]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:21])[F:22])[CH:4]=1)=[O:27]
Reactant: Nc1cccc2c(Nc3cccc(C(F)(F)F)c3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)c1
Yield: 27.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (Intermediate-7, 50 mg, 0.164 mmol), 2-chloro-5-(pivalamidomethyl)benzoic acid (Intermediate-5, 88 mg, 0.326 mmol), oxalyl chloride (59 mg, 0.47 mmol), DMF (1 drop) and DIPEA (63 mg, 0.49 mmol) in CH2Cl2 (2 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.24 (s, 1H), 10.16 (s, 1H), 8.83 (d, J=6.6 Hz, 1H), 8.69 (s, 1H), 8.33 (m, 2H), 8.23 (m, 2H), 7.75-7.55 (m, 4H), 7.50 (d, J=6.9 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 4.31 (d, J=5.4 Hz, 2H), 1.13 (s, 9H); MS [M+H]+: 556.23.
Reaction SMILES: [CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].S(Cl)([Cl:19])=O>>[CH:1]([SiH:4]([CH:14]([CH3:16])[CH3:15])[C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:19])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)[SiH](c1ccc(C(=O)O)cc1)C(C)C
Product: CC(C)[SiH](c1ccc(C(=O)Cl)cc1)C(C)C

Procedure:
4-diisopropylsilanyl benzoic acid (1) (6.7 g, 28.4 mmol) and thionyl chloride (3.2 mL, 42.6 mmol) were mixed together and heated to reflux for 2 hours. a desired compound was then purified and identified by distillation under a reduced pressure (1 mmHg, 102-104° C.) (5.6 g, 77%). Its NMR data are as follows:
Reaction SMILES: [C:1]([N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH2:33]([NH:40][CH2:25][C:21]1[N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=[CH:23][N:22]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: O=Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(CNCc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Yield: 76.8 %

Procedure:
N-tritylimidazole-2-carboxaldehyde (338 mg, 1 mmol, prepared according to K. L. Kirk; J.Org.Chem., 1978, 43, 4381) was dissolved in dry toluene (7 mL) and anhydrous magnesium sulfate (602 mg, 5 mmol) added with stirring under nitrogen. Benzylamine (131 μL, 1.2 mmol) was added and the solution stirred for 3.5 hr. The solids were filtered under nitrogen and the reaction concentrated. The residue is redissolved in 1,2-dichloroethane (25 mL) and cooled to 0° C. Sodium triacetoxyborohydride (1.06 g, 5 mmol) was added slowly. The solution was allowed to warm to room temperature over 2.5 hours. The reaction mixture was added to water/ethyl acetate and the layers separated. The aqueous layer was extracted with two portions of ethyl acetate and the combined organic layers washed with sat. bicarbonate, water, and brine. The solution was concentrated to an oil and purified by flash chromatography on silica gel (99:1 EtOAc/EtOH with 0.1% triethylamine) to afford 330 mg (77%) of product as an oil which solidified on standing. LRMS (ES): 430.4 [M+H]+, 243.2; 1HNMR (600.1328 MHz, DMSO-d6): 7.37 (m, 11H), 7.04 (m, 9 H), 6.92 (d, 1H), 6.64 (d, 1H), 3.34 (s, 2H), 2.77 (2H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH2:24][OH:25])=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:8])([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)=O.N1C=CC=CC=1>CS(C)=O.CN(C)C>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:9][C:10]1[C:11]2[C:16]([C:17]([CH:24]=[O:25])=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(Cc1c2ccccc2c(CO)c2ccccc12)C(=O)OC(C)(C)C
Agent: CN(C)C
Agent: O=S(=O)=O
Solvent: c1ccncc1
Solvent: CS(C)=O
Product: CN(Cc1c2ccccc2c(C=O)c2ccccc12)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.5 %

Procedure:
Compound 3 (2.30 g, 6.55 mmol) was dissolved in the mixture of dry DMSO (20 mL) and trimethylamine (20 mL). To the solution thus prepared was added the solution of pyridine sulfur trioxide (7.30 g, 45.9 mmol) dissolved in dry DMSO (20 mL) over a period of 30 min. The reaction mixture was stirred at room temperature under nitrogen for 30 min, and then poured into ice-water (300 mL), extracted with ethyl acetate (3×100 mL), dried over MgSO4. Solvent evaporation gave a yellow solid (2.30 g, 100%), without further purification. 1H NMR (CDCl3) δ 11.51 (s, 1H), 8.90 (d, J=8.5 Hz, 2H), 8.51 (d, J=8.5 Hz, 2H), 7.70-7.61 (m, 4H), 5.56 (s, 2H), 2.48 (s, 3H), 1.56 (s, 9H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6].[C:11]([O-:14])(=[S:13])[CH3:12].[K+].O>CN(C)C=O>[C:11]([S:13][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH:9]=[CH2:10])=[O:6])(=[O:14])[CH3:12]
Reactant: CC([O-])=S
Reactant: C=CCOC(=O)CCCBr
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)CCCSC(C)=O
Yield: 96.7 %

Procedure:
Allyl 4-bromobutyrate (19.7 g) was treated with potassium thioacetate (10.9 g) in dimethyl formamide (100 ml) at 20° C. for 2 hours. Water (500 ml) was added and the mixture extracted with diethyl ether. The ethereal solution was washed with dilute aq. HCl, brine, dried (MgSO4) and evaporated to give the title compound as an oil (18.6 g, 97%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:22]1CCOC[CH2:23]1>ClC(OC(Cl)(Cl)Cl)=O>[N:1]([C:2]1[CH:3]=[C:4]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:21])[C:17]([F:20])([F:18])[F:19])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])=[C:23]=[O:22]
Reactant: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N
Reactant: C1COCCO1
Agent: O=C(Cl)OC(Cl)(Cl)Cl
Product: COc1ccc(C2CCCN(C(=O)C(F)(F)F)C2)cc1N=C=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
6.04 g of 3-(3-amino-4-methoxyphenyl)-1-trifluoroacetyl piperidine in 120 ml of dioxane and 2.9 ml of trichloromethyl chloroformate were mixed together and stirred for 4 hours at 80° C. Then, the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed on silica and eluted with a mixture of cyclohexane and ethyl acetate (7-3) to obtain 6.4 g of crude product which was used as is for the following step.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](OCC)=[O:18])=[CH:16][C:11]=2[N:10]=[CH:9]1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH3:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([CH2:17][OH:18])=[CH:16][C:11]=2[N:10]=[CH:9]1
Reactant: CCOC(=O)c1ccc2c(c1)ncn2C
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cn1cnc2cc(CO)ccc21
Reaction time: 1 h
Yield: 54.9 %

Procedure:
Under an argon gas flow, lithium aluminum hydride (9.70 g, 256 mmol) was suspended in tetrahydrofuran (100 ml); and under an ice cooling, a solution (100 ml) of ethyl 1-methyl-1H-benzimidazole-5-carboxylate (26.1 g, 128 mmol) prepared in the Step 1-1-4 in tetrahydrofuran was slowly added thereto. The mixture was stirred under an ice cooling for one hour. Under an ice cooling, a saturated sodium bicarbonate solution was slowly added to the mixture. The precipitate was removed by filtration, and the residue was concentrated. The concentrate was dissolved in chloroform, and the solution was washed with a saturated sodium bicarbonate solution and then concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=10:1 to 5:1) to give the title compound (11.4 g, 55%) as a light-red powder.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[CH3:24])[CH2:13][CH2:12]2)=[O:10])=[C:4]([F:25])[CH:3]=1.[O:26]1[CH2:30][CH2:29][NH:28][C:27]1=[O:31].C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:24][C:18]1[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:14]1[CH2:15][CH2:16][N:11]([C:9]([C:5]2[C:6]([F:8])=[CH:7][C:2]([N:28]3[CH2:29][CH2:30][O:26][C:27]3=[O:31])=[CH:3][C:4]=2[F:25])=[O:10])[CH2:12][CH2:13]1
Reactant: O=C1NCCO1
Reactant: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(N4CCOC4=O)cc3F)CC2)c(C)c1
Yield: 14.2 %

Procedure:
To a mixture of (4-bromo-2,6-difluorophenyl)[4-(2,4-dimethylphenyl)piperazin-1-yl]methanone (819 mg) described in Preparation Example 1, oxazolidin-2-one (174 mg), potassium carbonate (553 mg) and copper (I) iodide (76 mg) were added toluene (2 mL) and N,N′-dimethylethylenediamine (100 μL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (118 mg).