Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([B:6]2[O:14][C:11]([CH3:13])([CH3:12])[C:8]([CH3:10])([CH3:9])[O:7]2)[CH:3]=[N:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:22][CH2:23][O:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][O:26]1>CN(C=O)C>[O:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH:25]1[O:24][CH2:23][CH2:22][N:2]1[CH:3]=[C:4]([B:6]2[O:7][C:8]([CH3:9])([CH3:10])[C:11]([CH3:13])([CH3:12])[O:14]2)[CH:5]=[N:1]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 4-pyrazole boronic acid pinacol ester (2.0 g, 10.3 mmol) in anhydrous DMF (20 mL) was added cesium carbonate (4.03 g, 12.4 mmol) and the mixture stirred at RT for 10 minutes. 2-(2-Bromoethoxy)tetrahydro-2H-pyran (1.87 mL, 12.4 mmol) was added in two portions and the mixture was heated to 70° C. After heating for 18 hours the mixture was allowed to cool to RT and partitioned between water (100 mL) and EtOAc (100 mL). The aqueous layer was washed with EtOAc (3×20 mL) and the combined organic layers washed with water (3×100 mL) followed by brine, dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-100% EtOAc in cyclohexane) to afford the title compound (2.15 g, 65%). LCMS: RT=3.97 min, [M+Na]+=345
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].O>O1CCCC1>[NH2:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:15])[CH:13]=[CH2:14])=[CH:3][CH:4]=1)(=[O:9])=[O:10]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: C=CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(N)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 100 mL of tetrahydrofuran was dissolved 17 g of p-aminobenzenesulfonamide. This solution was cooled to 0° C. on an ice bath. To this solution was dropwise added 5 g of acryloyl chloride. After completion of the addition, the ice bath was removed and the reaction mixture was warmed to room temperature and stirred for 1 hour. Subsequently, the reaction mixture was heated at 60° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into 1 L of distilled water. Thus, N-(p-aminosulfonylphenyl)acrylamide was obtained as precipitated white particles.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[OH-].[Na+].[Cl:13][CH:14]([CH3:18])[C:15](Cl)=[O:16]>C(Cl)(Cl)Cl>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:15](=[O:16])[CH:14]([Cl:13])[CH3:18])=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CC(Cl)C(=O)Nc1ccc2c(c1)OCO2

Procedure:
To a solution of 3,4-methylenedioxyaniline, (41.1 grams; 0.3 moles) in 270 cc of chloroform containing 90 cc of a 20% solution of sodium hydroxide, there is added 38.1 grams (0.3 moles) of 2-chloropropionyl chloride at about -10° C., while stirring vigorously and keeping the temperature not above -5° C. The mixture is stirred for an additional period of one hour, letting the temperature reach room temperature. The organic phase is then separated, washed with water, neutralized with potassium carbonate and allowed to evaporate at reduced pressure, thus obtaining a solid purplish residue from which the desired product is separated and recrystallized with diisopropyl ether with melting point 116°-117° C.; Rf=0.26 (toluene-AcOEt 9:1) I.R. (nujol) νmax: 3240, 1660, 1540, 1500, 1485, 1445, 1250, 1210, 1040, 930, 815, 790 cm-1 ; chlorine (Schoeninger) calc. % 15.6--Found % 15.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[N:7][CH:8]=1.Br[C:13]1[CH:14]=[C:15]([C:19]2([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([F:28])[CH:26]=3)[C:21]([NH2:29])=[N:20]2)[CH:16]=[CH:17][CH:18]=1>>[F:28][C:25]1[CH:26]=[C:27]2[C:22]([C:21]([NH2:29])=[N:20][C:19]2([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([C:5]3[CH:6]=[N:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:14]=2)[C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:23][CH:24]=1
Reactant: COc1cncc(B(O)O)c1
Reactant: NC1=NC(c2ccncc2)(c2cccc(Br)c2)c2cc(F)ccc21
Product: COc1cncc(-c2cccc(C3(c4ccncc4)N=C(N)c4ccc(F)cc43)c2)c1

Procedure:
The title compound was prepared as described in Example 78 (Scheme #14, N) using (5-methoxypyridin-3-yl)boronic acid and 1-(3-bromophenyl)-6-fluoro-1-pyridin-4-yl-1H-isoindol-3-amine (Example 82) (16% yield): 1H NMR (CDCl3) δ 8.54 (m, 2 H), 8.36 (d, J=1.77 Hz, 1 H), 8.28 (d, J=2.78 Hz, 1 H), 7.52-7.45 (m, 3 H), 7.42 (m, 1 H), 7.32-7.25 (m, 5 H), 7.18 (m, 1 H), 3.90 (s, 3 H); MS (ESI) m/z 411 [M+1]+.
Reaction SMILES: C([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[CH2:26](N)[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:26]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCCc1ccccc1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Product: O=C(NCCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using phenethylamine instead of benzylamine and obtained in 25% (HPLC: 90%, RT: 6.36 min). 1H NMR (DMSO-d6) 11.96 (br s, 1H), 11.38 (s, 1H), 8.47 (d, J=5.5 Hz, 1H), 8.38 (s, 1H), 8.32 (t, J=5.5 Hz, 1H), 7.75 (d, J=5.1 Hz, 1H), 7.36 (dd, J=3.7, 2.6 Hz, 1H), 7.33-7.18 (m, 5H), 6.46 (dd, J=3.7, 1.8 Hz, 1H), 3.54-3.47 (m, 2H), 2.87 (dd, J=8.1, 7.0 Hz, 2H); MS (m/z) 364 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:25])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12.[OH-].[Na+].C(O)=O>CS(C)=O.O>[NH2:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]2[S:14][C:15]([Br:25])=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[C:3]=12
Reactant: CCOC(=O)c1c(C)nc2sc(Br)c(-c3cccc(OC)c3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(-c2c(Br)sc3nc(C)c(C(=O)O)c(N)c23)c1
Temperature: 150 °C
Yield: 78.5 %

Procedure:
A mixture of ethyl 4-amino-2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridine-5-carboxylate (700 mg, 1.661 mmol) (Description 15) in DMSO (7 mL) and aqueous NaOH (2M) (4.15 mL, 8.31 mmol) was heated at 150° C. for 1 h. The mixture was cooled to RT, diluted with water (20 mL) and acidified with formic acid to pH 6. The mixture was then extracted with ethyl acetate (5×30 mL) and the combined organics washed with brine (2×30 mL), dried and concentrated, to give the title compound (513 mg). LCMS (A) m/z: 393/395 [M+1]+, Rt 1.04 min (acidic).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16](CCC#N)(=[O:18])=[O:17])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C[O-].[Na+:25]>C1COCC1.CO.CCCC(C)C.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([S:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1.[Na+:25]
Reactant: N#CCCS(=O)(=O)c1ccc(/C=C/c2ccc(F)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S([O-])c1ccc(/C=C/c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a mixture of 3-({4-[(E)-2-(4-fluorophenyl)vinyl]phenyl}sulfonyl)propanenitrile (Step 2, 75 g, 0.24 mol) in THF (1 L) and MeOH (500 mL) was added sodium methoxide (13 g, 0.24 mol). The mixture was stirred for 1 h at room temperature then diluted with isohexane and Et2O. The solid was filtered off, triturated with isohexane and dried under vacuum to give sodium 4-[(E)-2-(4-fluorophenyl)vinyl]benzenesulfinate (66 g). δH (500 MHz, d6 DMSO): 7.65 (2H, t, J 6.8), 7.53 (2H, d, J 7.8), 7.45 (2H, d, J 7.7), 7.26-7.18 (4H, m). m/z (ES−) 261 [(M−Na)−].
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:6]([OH:12])[C:5]([N+:13]([O-])=O)=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[NH2:13][C:5]1[C:6]([OH:12])=[C:7]([S:8]([NH2:11])(=[O:10])=[O:9])[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
To a solution of 6-chloro-2-hydroxy-3-nitrobenzenesulfonamide (1.1 g, 4.36 mmol) in ethyl acetate, was added 10% Pd/C (500 mg). The mixture was flushed with argon, and then stirred under a hydrogen atmosphere at balloon pressure for 4 hours at room temperature. The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated to give the desired product (0.9g, 93%). EI-MS (m/z) 221.1, 223.1 (M−).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[C:6]([CH:17]=O)[C:7]3[C:12]([C:13]=2[CH:15]=O)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][NH2:24]>C(O)(=O)C.C(O)C>[CH3:19][N:20]([CH3:25])[CH2:21][CH2:22][NH:23][N:24]=[CH:15][C:13]1[C:14]2[C:5]([C:6]([CH:17]=[N:24][NH:23][CH2:22][CH2:21][N:20]([CH3:25])[CH3:19])=[C:7]3[C:12]=1[CH:11]=[CH:10][CH:9]=[CH:8]3)=[CH:4][CH:3]=[CH:2][CH:1]=2
Reactant: O=Cc1c2ccccc2c(C=O)c2ccccc12
Reactant: CN(C)CCNN
Solvent: CCO
Solvent: CC(=O)O
Product: CN(C)CCNN=Cc1c2ccccc2c(C=NNCCN(C)C)c2ccccc12
Temperature: 45 °C

Procedure:
A suspension of 4.68 g. of anthracene-9,10-dicarboxaldehyde in 100 ml. of ethanol containing 4.13 g. of [2-(dimethylamino)ethyl]hydrazine [Elslager et al., J. Med. Chem. I, 493 (1964)] containing two drops of acetic acid is stirred and heated under reflux for two hours. The resulting solution is filtered, concentrated, allowed to cool to 45° C., diluted with petroleum ether, then allowed to cool further at 5° C. The desired product separates as an orange solid and is collected by filtration.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:14][CH2:15][S:16][C:17]2[N:18]([CH3:22])[CH:19]=[CH:20][N:21]=2)[CH2:13][CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH3:22][N:18]1[CH:19]=[CH:20][N:21]=[C:17]1[S:16][CH2:15][CH2:14][C:10]1([CH2:9][OH:8])[CH2:13][CH2:12][CH2:11]1
Reactant: Cn1ccnc1SCCC1(CO[Si](C)(C)C(C)(C)C)CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1ccnc1SCCC1(CO)CCC1
Reaction time: 16 h
Yield: 61.4 %

Procedure:
To 1.39 g (4.1 mmol) of 2-({2-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]ethyl}sulfanyl)-1-methyl-1H-imidazole in 10 mL of tetrahydrofuran was added a 1.0 M solution of 4.92 mL (5.33 mmol) of tetrabutylammonium fluoride in tetrahydrofuran and the contents stirred for 16 h. The reaction was concentrated and the residue was poured directly onto a column of silica gel eluting with ethyl acetate:hexane to afford 0.57 g (62%) of (1-{2-[(1-methyl-1H-imidazol-2-yl)sulfanyl]ethyl}cyclobutyl)methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 6.94 (s, 1H), 6.82 (s, 1H), 5.30 (br s, 1H), 3.66 (s, 2H), 3.47 (s, 3H), 2.94 (m, 2H),1.99-1.64 (m, 8H).
Reaction SMILES: S([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)(C1C=CC(C)=CC=1)(=O)=O.[BrH:22].C(O)(=O)C.Br>C1(C)C=CC=CC=1>[BrH:22].[BrH:22].[F:21][C:18]([F:19])([F:20])[CH2:17][N:14]1[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)N2CCN(CC(F)(F)F)CC2)cc1
Agent: Br
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: FC(F)(F)CN1CCNCC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
A suspension of 1-tosyl-4-(2,2,2-trifluoroethyl)piperazine (700 mg, 2.2 mmol) in a 30% HBr/acetic acid solution was stirred at 90° C. for 90 minutes. Toluene was added to the suspension. An orange solid was filtered off and washed with diethyl ether to afford the desired compound (400 mg, 55% yield) as a bis HBr salt.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][NH2:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(N(CC)CC)C>[CH2:16]([O:23][C:24]([NH:26][CH2:27][CH2:28][CH2:29][NH:30][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([Cl:1])[C:11]=1[N+:12]([O-:14])=[O:13])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCNC(=O)OCc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCNc1c([N+](=O)[O-])c(Cl)nc2ccccc12)OCc1ccccc1
Yield: 84.8 %

Procedure:
0.19 g (0.768 mmol) of 2,4-dichloro-3-nitroquinoline and 0.16 g (0.768 mmol) of N-(benzyloxycarbonyl)-1,3-propanediamine was heated at 70° C. in 5 ml of triethylamine for one hour with stirring. After triethylamine was distilled off under reduced pressure, the residue was dissolved in methylene chloride, washed with water, and dried (MgSO4). The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1 (v/v)) to obtain 0.27 g (0.651 mmol) of 4-[3-(benzyloxycarbonylamino)propylamino]-2-chloro-3-nitroquinoline shown below as yellow powder. ##STR29## Its spectroscopic data are as follows: 1H-NMR (CDCl3) δ (ppm) :1.79 (2H, m), 3.35 (4H, m), 5.02 (1H, br), 5.18 (2H, s), 7.15 (1H, br), 7.37 (5H, m), 7.57 (1H, t, J=8.0 Hz), 7.73 (1H, t, J=7.8 Hz), 7.90 (1H, d, J=8.4 Hz), 8.21 (1H, d, J=8.0 Hz).
Reaction SMILES: [Na].[CH3:2][N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH3:12])[C:7]=2[C:6](=[O:13])[NH:5][C:4]1=[O:14].ClCCC[CH2:19][P:20](=[O:23])([CH3:22])[CH3:21]>>[CH3:2][N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH3:12])[C:7]=2[C:6](=[O:13])[N:5]([CH2:19][P:20](=[O:23])([CH3:22])[CH3:21])[C:4]1=[O:14]
Reactant: CP(C)(=O)CCCCCl
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [Na]
Product: Cn1cnc2c1c(=O)n(CP(C)(C)=O)c(=O)n2C

Procedure:
The title substance was prepared from 10.1 g (0.05 mol) of 3,7-dimethylxanthine sodium salt and 4-chlorobutyldimethylphosphine oxide analogously to Example 63.
Reaction SMILES: CC1N=CN([C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:12]=2)C=1.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>>[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:7]2[CH:8]=[C:9]([NH2:17])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=2)[CH2:21][CH2:20]1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: CN1CCC(O)CC1
Product: CN1CCC(Oc2cc(N)cc(C(F)(F)F)c2)CC1

Procedure:
for preparing the compound of examples 43 to 46 may be obtained analogously to a method as described in WO2004005281 for 3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenylamine, but using 1-methyl-piperidin-4-ol. ES-MS: 275.2 [M+H]+; tR=2.41 min
Reaction SMILES: C([O:5][C:6](=[O:27])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.I[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36].[BrH:37].C(O)(=O)C>C(OCC)C>[BrH:37].[CH2:25]([C:22]1[CH:23]=[N:24][C:19]([N:18]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:27])[S:12][CH:13]=2)=[N:20][CH:21]=1)[CH3:26]
Reactant: CCCCCCCCI
Reactant: CCc1cnc(NCCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)nc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(CC)cn1

Procedure:
A compound obtained using 2-[(4-{2-[(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 265-1 and 1-iodooctane as starting materials and by an operation similar to that of Example 326 was dissolved in diethyl ether, and reacted with 30% hydrobromic acid-acetic acid to give the title compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH3:7])=[O:5].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:47]1[C:52](O)=[CH:51][CH:50]=[CH:49][C:48]=1[CH3:54].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[C:48]1([CH3:54])[CH:49]=[CH:50][CH:51]=[C:52]([O:1][CH2:2][C@H:3]([NH:8][C:9]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:4]([O:6][CH3:7])=[O:5])[CH:47]=1
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](COc1cccc(C)c1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a round-bottom flask equipped with a stir bar was added (S)-methyl 3-hydroxy-2-(tritylamino)propanoate (10.0 g, 27.7 mmol), triphenylphosphine (7.98 g, 30.4 mmol) and toluene (100 mL). The solution was stirred at room temperature for 30 min., then to the solution was added m-cresol (3.78 mL, 36.0 mmol) and diisopropylazodicarboxylate (“DIAD”, 5.92 mL, 30.4 mmol). The solution was heated at 80° C. with stirring for 18 h. The solution was cooled to room temperature and concentrated and the resulting residue was subjected to silica gel chromatography (hexanes:EtOAc) to afford (S)-methyl 3-(m-tolyloxy)-2-(tritylamino)propanoate, 8.28 g (66%). 1H-NMR (400 MHz, CDCl3) δ 7.53 (d, J=7.6 Hz, 6H), 7.29-7.23 (m, 5H), 7.21-7.11 (m, 4H), 6.77 (d, J=7.3 Hz, 1H), 6.73-6.64 (m, 2H), 5.30 (s, 2H), 4.25 (dd, J=9.3, 4.9 Hz, 1H), 4.01 (dd, J=9.2, 6.7 Hz, 1H), 3.76-3.68 (m, 1H), 3.22 (s, 3H), 2.88 (d, J=10.5 Hz, 1H), 2.32 (s, 3H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15](OCC)=[O:16].O.Cl>CCOCC>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][OH:16]
Reactant: CCOC(=O)Cc1ccccc1Br
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: OCCc1ccccc1Br
Reaction time: 3 h
Yield: 85.9 %

Procedure:
To a stirred suspension of 106.0 g of lithium aluminum hydride in 3.7 l of anhydrous ether, is added, dropwise, a solution of 780.0 g of ethyl o-bromophenylacetate in 3.1 l of anhydrous ether. The reaction mixture is stirred for about three hours and then heated under reflux for about five hours. The mixture is cooled, then treated dropwise with 800 ml of water, and 1.5 l of 10% aqueous hydrochloric acid. The ether solution is washed, dried, concentrated, and the residue is distilled to give 554.0 g of o-bromophenethyl alcohol, bp. about 130°-132° (8mm), nD20 1,5760.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:11][C:12](N)=[O:13]>>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[N:11][C:12]([OH:13])=[N:1]2)=[CH:6][CH:7]=1
Reactant: NC(N)=O
Reactant: Nc1cc(Cl)ccc1C=O
Product: Oc1ncc2ccc(Cl)cc2n1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
In a 500 mL round bottom flask, the uniform mixture of 2-amino-4-chlorobenzaldehyde (16 g, 103.2 2 mmol) and urea (123.8 g, 2063 mmol) was heated at 170° C. with vigorous stirring for 2 h. On completion of reaction, the reaction mixture was cooled to rt and diluted with ice-cold water. The solid that formed was collected by filtration and washed with ice-cold water. The solid was dried under reduced pressure to give crude 7-chloroquinazolin-2-ol as a yellow solid. Yield: 19 g. LCMS (ESI, m/z): 181 (M+1)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:15]1([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]2[S:22][C:23]([C:7]([C:6]3[CH:10]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[C:11]([F:14])([F:13])[F:12])=[O:9])=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(O)c1cc(Br)ccc1C(F)(F)F
Reactant: c1ccc(-c2cccs2)cc1
Product: O=C(c1ccc(-c2ccccc2)s1)c1cc(Br)ccc1C(F)(F)F

Procedure:
To a solution of the above methyl 5-bromo-2-iodobenzoate (4.65 g) in N-methyl-2-pyrrolydinone (20 ml) were added copper (I) bromide (235 mg) and methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (2.6 ml), and the mixture was stirred under heating at 120° C. for 1.5 hours. The reaction mixture was cooled, and added thereto were 10% aqueous hydrochloric acid solution and ethyl acetate. Insoluble materials were filtered off, and an organic layer of the filtrate was washed with water for 4 times, and subsequently washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexan:ethyl acetate=80:1) to give methyl 5-bromo-2-trifluoromethylbenzoate (3.55 g) as colorless oil. (3) The above methyl 5-bromo-2-trifluoromethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2-trifluoromethylbenzoic acid as pale brown crystals. ESI-Mass m/Z 267/269 (M−H). (4) The above 5-bromo-2-trifluoromethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5-(1) to give 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone as pale yellow crystals. APCI-Mass m/Z 411/413 (M+H). (5) To a mixed solution of the above 5-bromo-2-trifluoromethylphenyl 5-phenyl-2-thienyl ketone (670 mg) in methanol (20 ml)-tetrahydrofuran (10 ml) was added sodium borohydride (62 mg), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in chloroform (10 ml)acetonitrile (20 ml). Thereto was added triethylsilane (0.78 ml), and the mixture was cooled to 0° C. Thereto was added dropwise boron trifluoride•diethyl ether complex (0.52 ml). The mixture was stirred at room temperature for 45 minutes, and added thereto was a saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane) to give the desired 5-bromo-1-(5-phenyl-2-thienylmethyl)-2-trifluoromethylbenzene (565 mg) as colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C:5](=[O:15])/[C:4](=[CH:16]/[C:17]2[N:18]=[CH:19][N:20]([C@H:22]3[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]3)[CH:21]=2)/[CH2:3]1>C(O)C.[C].[Pd]>[CH3:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C:5](=[O:15])[CH:4]([CH2:16][C:17]2[N:18]=[CH:19][N:20]([C@H:22]3[CH2:23][CH2:24][C@H:25]([CH3:28])[CH2:26][CH2:27]3)[CH:21]=2)[CH2:3]1
Reactant: C[C@H]1C/C(=C\c2cn([C@H]3CC[C@H](C)CC3)cn2)C(=O)N(C(=O)OC(C)(C)C)C1
Agent: [Pd]
Solvent: CCO
Product: C[C@H]1CC(Cc2cn([C@H]3CC[C@H](C)CC3)cn2)C(=O)N(C(=O)OC(C)(C)C)C1
Reaction time: 13 h

Procedure:
The compound (830 mg) obtained in Step 2 of this Example was dissolved in ethanol (25 mL). To the solution, 10% palladium-carbon catalyst (hydrated, 207 mg) was added, and the mixture was stirred for 13 hours under a hydrogen atmosphere. The catalyst was filtered off, and the solvent in the filtrate was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=1/1-ethyl acetate) to obtain the title compound (788 mg).