Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[CH:4]([O:13]CC)[C:5]1[CH:10]=[CH:9][C:8]([CH:11]=O)=[CH:7][CH:6]=1.[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]([NH2:24])=[C:19]([NH2:25])[CH:18]=1.C1(=O)C=CC(=O)C=C1>C(O)C>[Cl:16][C:17]1[C:22]([Cl:23])=[CH:21][C:20]2[N:24]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([CH:4]=[O:13])=[CH:10][CH:9]=3)[NH:25][C:19]=2[CH:18]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOC(OCC)c1ccc(C=O)cc1
Agent: O=C1C=CC(=O)C=C1
Solvent: CCO
Product: O=Cc1ccc(-c2nc3cc(Cl)c(Cl)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
To a mixture of terephthalaldehyde mono-(diethyl acetal) (2.0 mL, 10 mmol), 4,5-dichloro-1,2-phenylenediamine (1.77 g, 10 mmol) and 1,4-benzoquinone (1.08 g, 10 mmol) in ethanol (50 mL) was heated to reflux for 6 h. The solvent was removed under reduced pressure. To the residue were added tetrahydrofuran (50 mL) and hydrochloric acid (1 mol/L, 10 mL), and the mixture was stirred at room temperature for 2 h. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was triturated with ether to afford 5,6-dichloro-2-(4-formylphenyl)benzimidazole (2.80 g, 97%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[CH2:11][CH2:12][NH2:13].Cl[C:15]1[N:20]=[CH:19][N:18]=[C:17]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[C:24]([CH3:32])[CH:23]=2)[CH:16]=1.[CH:33](N(C(C)C)CC)([CH3:35])[CH3:34]>CCCCO>[CH2:6]([CH:5]1[CH2:10][CH2:1][N:2]([CH2:11][CH2:12][NH:13][C:15]2[CH:16]=[C:17]([NH:21][C:22]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=[C:24]([CH3:32])[CH:23]=3)[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:4]1)[C:7]1[CH:8]=[CH:9][CH:35]=[CH:33][CH:34]=1
Reactant: Cc1cc(Nc2cc(Cl)ncn2)c2ccccc2n1
Reactant: NCCN1CCc2ccccc2C1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2cc(NCCN3CCC(Cc4ccccc4)CC3)ncn2)c2ccccc2n1
Temperature: 100 °C
Yield: 24.5 %

Procedure:
To a solution of diamine 36 (0.05 g, 0.21 mmol) in n-BuOH (2 mL) were sequentially added 108 (0.05 g, 0.18 mmol) and diisopropylethylamine (37 mg, 0.27 mmol). The mixture was heated at 100° C. overnight before the volatiles were removed under reduced pressure. The residue was purified by flash chromatography (SiO2, gradient elution, 3:1 hexanes/ethyl acetate to 7:3 CH2Cl2/MeOH) to yield the desired product (20 mg, 25%) as a yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10]2[CH:11]=[N:12][N:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=3)[C:14]=2[OH:15])=[C:5]([CH3:25])[CH:4]=1)#[N:2].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][C@@H:29]1[CH3:34])[CH3:27]>>[CH2:26]([N:28]1[CH2:33][CH2:32][N:31]([C:20]([C:19]2[CH:23]=[CH:24][C:16]([N:13]3[C:14]([OH:15])=[C:10]([C:6]4[C:5]([CH3:25])=[CH:4][C:3]([C:1]#[N:2])=[C:8]([F:9])[CH:7]=4)[CH:11]=[N:12]3)=[N:17][CH:18]=2)=[O:22])[CH2:30][C@@H:29]1[CH3:34])[CH3:27]
Reactant: Cc1cc(C#N)c(F)cc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: CCN1CCNC[C@@H]1C
Product: CCN1CCN(C(=O)c2ccc(-n3ncc(-c4cc(F)c(C#N)cc4C)c3O)nc2)C[C@@H]1C

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-5-fluoro-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and (S)-1-ethyl-2-methylpiperazine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.95-1.30 (m, 6H) 2.41 (s, 3H) 2.79 (dt, J=12.95, 6.54 Hz, 2H) 2.94-3.10 (m, 2H) 3.13 (d, J=11.37 Hz, 1H) 3.23 (dd, J=13.14, 8.34 Hz, 1H) 3.46 (br. s., 1H) 3.61-4.25 (m, 2H) 7.59 (d, J=7.33 Hz, 1H) 7.91-8.00 (m, 1H) 8.03 (s, 1H) 8.30 (d, J=13.14 Hz, 1H) 8.45-8.57 (m, 2H); ESI-MS m/z [M+H]+ 449.3.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[Cl:10][C:11]1[C:20](Cl)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1>C1COCC1>[Cl:10][C:11]1[C:20]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nc2ccccc2nc1Oc1ccccc1
Reaction time: 72 h

Procedure:
A solution of phenol (564 mg, 6 mmol) in THF (5 ml) was added to a suspension of sodium hydride (60% in mineral oil, 240 mg, 6 mmol) in THF (10 ml). After 10 min 2,3-dichloroquinoxaline (995 mg, 5 mmol) was added. The mixture was stirred for 3 days. The solvent was removed in vacuo, the residue was dissolved in EtOAc, washed with NaOH (1M), dried (Na2SO4) and evaporated in vacuo to give a yellow solid. Recrystallisation from diisopropylether gave the title compound as off-white needles: δH (DMSO d6) 8.01-7.98 (1H, m), 7.77-7.67 (3H, m), 7.53-7.48 (2H, m), 7.37-7.30 (3H, m); m/z (El+, 70V) 257.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.Cl>C(Cl)Cl>[CH3:12][O:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(NS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of methanesulfonyl chloride (15.2 g, 132 mmol) in methylene chloride (50 mL) was added dropwise to a stirring slurry of pyridine (41.8 g, 529 mmol) and methyl-4-aminobenzoate (20.0 g, 132 mmol) in methylene chloride (110 mL) cooled by a dry ice/acetone bath. The reaction mixture was allowed to warm to ambient temperature and was stirred overnight. The reaction mixture was added to 400 mL of 4% aqueous HCl solution and the solid that formed was collected by filtration. The orange solid was recrystallized from methanol to give 28.8 g (91.5%) of an orange-pink solid, mp 147°-150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[C:19]1[N:24]=[C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:22]=[C:21]([N:31]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]2[CH:40]([F:42])[F:41])[N:20]=1>C1COCC1.C(O)(=O)C.O>[F:42][CH:40]([F:41])[C:32]1[N:31]([C:21]2[N:22]=[C:23]([N:25]3[CH2:26][CH2:27][O:28][CH2:29][CH2:30]3)[N:24]=[C:19]([NH:1][C:2]3[CH:7]=[N:6][CH:5]=[CH:4][N:3]=3)[N:20]=2)[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[N:33]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Nc1cnccn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Nc2cnccn2)nc(N2CCOCC2)n1
Reaction time: 0.25 h
Yield: 61.5 %

Procedure:
To a solution of 0.219 g (2.30 mmol) of aminopyrazine in THF (5 mL) at 0° C. was added 1.3 mL of NaHMDS (2 M solution in THF), and the mixture was stirred for 15 min. A solution of 0.238 g (0.65 mmol) of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole in THF (6 mL) was added, and the resulting mixture was stirred for 1 hr at RT. After neutralization with acetic acid, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed sequentially with water and aq. NH3, dried and concentrated. Chromatography on alumina, eluting first with hexanes/EtOAc (1:1) and then with CH2Cl2/EtOAc (1:4) to CH2Cl2/EtOAc (1:1) gave a white powder. Recrystallization from ethanol/CH2Cl2 gave 0.170 g (54% yield) of 4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(2-pyrazinyl)-1,3,5-triazin-2-amine: mp 271-274° C.; 1H NMR (CDCl3) δ9.59 (s, 1H), 8.42-8.33 (m, 3H), 7.92 (d, J=7.4 Hz, 1H), 7.81 (s, 1H), 7.60 (t, JHF=53.5 Hz, 1H), 7.48-7.41 (m, 2H), 3.98 (d, J=4.2 Hz, 4H), 3.85 (d, J=4.2 Hz, 4H); Anal. Calcd. for C19H17F2N9O: C, 53.65; H, 4.1; N, 29.6. Found: C, 53.9; H, 3.8; N, 29.7%.
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:16][C:17](=[O:19])[CH3:18])[CH3:2].[S:22]([O:27]C)([O:25][CH3:26])(=[O:24])=[O:23]>C(OCC)(=O)C>[CH3:26][O:25][S:22]([O-:27])(=[O:24])=[O:23].[C:17]([NH:16][C:8]1[CH:9]=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][N+:3]([CH2:1][CH3:2])([CH2:20][CH3:21])[CH3:26])(=[O:19])[CH3:18]
Reactant: COS(=O)(=O)OC
Reactant: CCN(CC)CCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Solvent: CCOC(C)=O
Product: CC[N+](C)(CC)CCOc1cc([N+](=O)[O-])ccc1NC(C)=O
Product: COS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The quaternization of 59.1 g (0.2 mol) of N-[2-(2-diethylaminoethoxy)-4-nitrophenyl]acetamide dissolved in 700 ml of ethyl acetate was carried but by adding 20.9 ml (0.22 mol) of dimethyl sulphate with stirring for one hour at room temperature.
Reaction SMILES: ClC1C=CC=C([C:8](OO)=[O:9])C=1.[CH3:12][C:13]1[NH:14][C:15](=[O:19])[CH2:16][S:17][CH:18]=1>CO>[CH3:8][O:9][CH:16]1[C:15](=[O:19])[NH:14][C:13]([CH3:12])=[CH:18][S:17]1
Reactant: CC1=CSCC(=O)N1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CO
Product: COC1SC=C(C)NC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.1 %

Procedure:
m-Chloroperbenzoic acid (28.8 g) was added dropwise to a stirred solution of 5-methyl-2H-1,4-thiazin-3(4H)-one (15 g) in methanol (300 ml) under ice-cooling and the mixture was stirred at room temperature for 1 day. After the mixture was evaporated to dryness, the residue was extracted with ethyl acetate, washed with saturated sodium bicarbonate aqueous solution and dried over anhydrous magnesium sulfate. The solvent was evaporated to dryness to give 2-methoxy-5-methyl-2H-1,4-thiazin-3(4H)-one (11.3 g, yield 61%) as pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]([CH2:11]O)[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:35][C:36]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][C:37]=1[C:38](Cl)=[O:39]>C(Cl)Cl.O>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:5]2[CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[N:1]([C:38](=[O:39])[C:37]3[CH:41]=[C:42]([F:45])[CH:43]=[CH:44][C:36]=3[CH3:35])[CH2:11][CH:6]2[C:7]([O:9][CH3:10])=[O:8])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: COC(=O)C(CO)N(Cc1ccccc1N)S(=O)(=O)c1ccc(OC)cc1
Reactant: Cc1ccc(F)cc1C(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2cc(F)ccc2C)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 113 %

Procedure:
To a mixture of 1.5 g (3.80 mmol) of methyl 2-[(2-aminobenzyl)-(4-methoxybenzenesulfonyl)amino]-3-hydroxypropionate and 2.64 ml (18.97 mmol) of triethylamine in 15 ml of CH2Cl2, chilled to 0° C., was added 1.36 g (11.4 mmol) of 2-methyl-5-fluorobenzoyl chloride. The mixture was stirred at room temperature overnight. The solution was then diluted with CH2Cl2 and water and the organic layer separated. The organic layer was washed with 2 N citric acid, brine and dried with Na2SO4. The solvent was removed under vacuum to give 2.2 g of a white foam. Anal. for C26H25FN2O6S: Calc'd: C,60.9; H,4.9; N,5.5; Found: C,60.9; H,5.0; N,5.0; Mass spectrum (ES) 513.4 (M+H).
Reaction SMILES: Cl.[NH:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C.[F:38][CH:39]([F:43])[C:40](O)=[O:41]>C(Cl)(Cl)Cl>[F:38][CH:39]([F:43])[C:40]([N:2]=[C:3]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[CH:6]=[C:5]([CH3:18])[S:4]1)=[O:41]
Reactant: O=C(O)C(F)F
Reactant: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=N)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cn(-c2cccc(C(F)(F)F)c2)c(=NC(=O)C(F)F)s1
Yield: 62.6 %

Procedure:
A mixture of 2-imino-3-(3-trifluoromethylphenyl)-5-methylthiazoline hydrochloride (0.42 g), triethylamine (2.2 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.8 g) and difluoroacetic acid (0.75 g) in chloroform (10 ml) was refluxed for 8 hours. The residue was Washed with aqueous hydrochloric acid and aqueous potassium carbonate and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the residue was subjected to column chromatography to give 2-difluoroacetylimino-3-(3-trifluoromethylphenyl)-5-methylthiazoline (Compound No. 63) (0.3 g). m.p., 117.9° C.
Reaction SMILES: [O:1]1[C:5]([NH:6][C:7](=[O:14])OCC(Cl)(Cl)Cl)=[CH:4][CH:3]=[N:2]1.[C:15]1([C:21]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[S:23][N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[O:1]1[C:5]([NH:6][C:7]([N:29]2[CH2:30][CH2:31][N:26]([C:24]3[S:23][N:22]=[C:21]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:25]=3)[CH2:27][CH2:28]2)=[O:14])=[CH:4][CH:3]=[N:2]1
Reactant: O=C(Nc1ccno1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccno1)N1CCN(c2nc(-c3ccccc3)ns2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl isoxazol-5-ylcarbamate (200 mg, 0.771 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (190 mg, 0.771 mmol), diisopropylethylamine (0.134 ml, 0.771 mmol) and dimethylsulfoxide (7 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of tetrahydrofuran, ethyl acetate and hexane to obtain the desired product (61.5 mg, 22.4%) as a solid.
Reaction SMILES: ON1C2N=CC=CC=2N=N1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26](O)=[O:27])[CH:24]=2)[CH:19]=[CH:18]1.O>CN(C=O)C>[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:27])[CH:24]=2)[CH:19]=[CH:18]1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Reactant: C1COCCN1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(c1ccc2cc[nH]c2c1)N1CCOCC1
Reaction time: 16 h

Procedure:
1-Hydroxy-7-azabenzotriazole (0.844 g, 6.21 mmol, 0.05 eq), EDCxHCl (26.09 g, 136.64 mmol, 1.1 eq) and morpholine (12.9 g, 149.06 mmol, 1.2 eq) were added to a stirred solution of 1H-indole-6-carboxylic acid (20.0 g, 124.22 mmol, 1.0 eq) in DMF (150 mL). Stirring was continued for 16 h at room temperature and water (200 mL) was then poured into the reaction mixture. The mixture was extracted with dichloromethane (2×150 mL) and the combined organic layers were washed with brine (100 mL), dried over anhydrous sodium sulphate and evaporated. White solid. Yield: 16.0 g (56% of theory).
Reaction SMILES: CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1.C([O:19][C:20](=O)/[CH:21]=[CH:22]/[C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1)C.CO>C1COCC1>[N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1/[CH:22]=[CH:21]/[CH2:20][OH:19]
Reactant: CCOC(=O)/C=C/c1ccc2ccccc2n1
Agent: CC(C)C[AlH]CC(C)C
Solvent: CO
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC/C=C/c1ccc2ccccc2n1
Reaction time: 3 h
Yield: 55 %

Procedure:
Under an atmosphere of nitrogen a 1M solution of DIBAL-H in toluene (82 ml, 82 mmol) was added dropwise at −70° C. over 20 min. to a stirred solution of (E)-3-quinolin-2-yl-acrylic acid ethyl ester (12.5 g, 55 mmol) in dry THF (400 ml) and the mixture stirred for 3 h. Methanol (100 ml) was added, and the mixture was concentrated in vacuo. The residue was dissolved in 1N HCl (500 mL) and ethyl acetate (100 mL). The aqueous phase was separated and added 1 N NaOH to pH 8. The product was extracted with dichloromethane. The combined organic phases were washed with water, dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in ethyl acetate, treated with activated charcoal, filtered, and concentrated in vacuo yielding 5.6 g (56%) of (E)-3-quinolin-2-yl-prop-2-en-1-ol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH2:15]1[O:25][C:18]2([CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]2)[O:17][CH2:16]1.[NH4+].[Cl-]>C1COCC1>[CH3:13][C:11]1([CH3:14])[CH2:10][O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([C:21]3([OH:24])[CH2:22][CH2:23][C:18]4([O:25][CH2:15][CH2:16][O:17]4)[CH2:19][CH2:20]3)=[CH:3][CH:4]=2)=[N:12]1
Reactant: CC1(C)COC(c2ccc(Br)cc2)=N1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)COC(c2ccc(C3(O)CCC4(CC3)OCCO4)cc2)=N1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 8 g of 2-(4-bromophenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole (31.5 mmol) in 15 ml of anhydrous THF is poured dropwise onto 956 mg of Mg (39.3 mmol) in such a way as to maintain the mixture at the reflux temperature and the mixture is refluxed for 2.5 hours. The mixture is cooled to room temperature and a solution of 5.41 g of 1,4-cyclohexandione monoethyleneacetal (34.65 mmol) in 20 ml of anhydrous THF is added to it dropwise. The mixture is stirred at room temperature for 1.5 hours and then at reflux temperature for 1 hour. The mixture is poured into 500 ml of a 10% NH4Cl solution and extracted with ethyl acetate. The organic phase is dried and, after filtration, the solvent is evaporated off under reduced pressure. The residue is crystallized in ethyl acetate. The product of the title is obtained in the form of a white solid.
Reaction SMILES: [Br-].C1([PH+](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Li]CCCC.[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[CH2:35]1C[O:38][CH2:37][CH2:36]1>>[Cl:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[CH:35][CH2:36][CH2:37][OH:38])=[CH:29][CH:28]=1
Reactant: C1CCOC1
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: c1ccc([PH+](c2ccccc2)c2ccccc2)cc1
Product: OCCC=Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-((2-methoxy)-2-propoxy)propyl)triphenyl phosphonium bromide (4.42 g, 10 mmoles) in THF (100 mL) was added n-BuLi (6 mL of 1.6M) at -78°. The reaction mixture was stirred at -78° for 30 min. 4-Chlorobenzaldehyde (1.4 g, 10 mM) was added and the reaction was warmed to RT. The reaction mixture was quenched with buffer and extracted with ethyl acetate. After evaporation of the ethyl acetate, the crude residue was dissolved in 25 mL THF and 5 mL of AcOH plus 5 mL H2O was added. The mixture was stirred for 2 hours at RT and evaporated. The residue was extracted with ethyl acetate, and the ethyl acetate evaporated. Flash chromatography of the residue using 25% ethyl acetate/hexane afforded the title compound as a mixture of cis and trans isomers.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][C:7](=[O:15])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:5]2=[O:21].[NH:22]1[CH:26]=[N:25][CH:24]=[N:23]1>>[N+:12]([C:11]1[CH:10]=[C:9]2[C:4]([C:5](=[O:21])[N:6]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:7](=[O:15])[NH:8]2)=[CH:3][C:2]=1[N:22]1[CH:26]=[N:25][CH:24]=[N:23]1)([O-:14])=[O:13]
Reactant: c1nc[nH]n1
Reactant: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc2c1=O
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cncn3)cc2c1=O
Yield: 83 %

Procedure:
N-(6-Fluoro-7-nitro-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-methanesulfonamide (20 mg, 0.0628 mmol) is reacted with 1H-[1,2,4]triazole according to the GPB affording 19 mg (83%) of a yellowish powder. Rt=2.87 min.
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13].C[O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)=O>C(O)(=O)C>[CH2:16]([O:15][C:12](=[O:14])[CH2:13][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)=[O:19])[CH3:17]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cccc(C)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cccc(C)n1
Temperature: 92 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
Stir a mixture of sodium ethoxide (90 g, 1.32 mol, 2 eq), toluene (0.5 L, 5 vol), and ethyl acetate (0.2 L, 1.98 mol, 3 eq) in a 2 L flask equipped with reflux condenser, mechanical stirrer, and nitrogen inlet. After 1 h, add 6-methyl-pyridine-2-carboxylic acid methyl ester (Cheung, Y, Tetrahedron Lett. 1979, 40, 3809-10; 100 g, 0.66 mol). Heat the mixture at reflux (92° C.) for 20 h. Cool the mixture to room temperature and acidify with glacial acetic acid to pH 6. Wash the resulting gel with water (0.5 L). Separate the layers and extract the aqueous layer with toluene (1×0.5 L) Dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield the subtitled product (154 g) as a dark oil in 86% purity by HPLC analysis. MS ES+ m/e 208 (M+1).
Reaction SMILES: Cl.[C:2]1([N:8]2[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[N:11][N:10]=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O>[C:2]1([N:8]2[C:12]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[N:11][N:10]=[N:9]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCCCc1nnnn1-c1ccccc1
Agent: Cl
Solvent: O
Product: O=C(O)CCCCc1nnnn1-c1ccccc1
Yield: 93.2 %

Procedure:
20 % aqueous Hydrochloric acid (100 ml) is added to methyl 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valerate (9.3 g) and the mixture is refluxed for 4 hours. After cooling, water is added and the mixture is extracted with chloroform. The chloroform solution is extracted with aqueous saturated sodium bicarbonate solution. The aqueous layer is acidified with concentrated hydrochloric acid and again extracted with chloroform. The latter chloroform extract is washed with aqueous saturated sodium chloride solution and dried over magnesium sulfate. Chloroform is distilled off to give 5-(1-phenyl-1,2,3,4-tetrazol-5-yl)valeric acid (8.2 g), pale yellow liquid.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[CH3:7][Si:8](Cl)([CH3:10])[CH3:9]>C[Si](N[Si](C)(C)C)(C)C>[Si:8]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][Si:8]([CH3:10])([CH3:9])[CH3:7])([CH3:10])([CH3:9])[CH3:7]
Reactant: OCCCCO
Reactant: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: C[Si](C)(C)OCCCCO[Si](C)(C)C
Temperature: 50 °C

Procedure:
1,4-Butanediol (54 g, 0.60 mol) was placed in a 500 mL 3-necked RB flask and treated with 0.3 mL trimethylsilyl chloride. A portion of HMDS (ca. 20 mL) was added, and an exothermic reaction took place as the mixture became homogeneous. The remainder of the HMDS (120 mL, 0.66 mol total) was added at a controlled rate (ca. 3-5 mL/min), maintaining the reaction temperature at ca. 50° C. Heating was continued at 100° C. (3 h), and 150° C. (1.5 h). GC analysis (method 1) revealed excess HMDS and one product. Distillation provided 127.8 g of colorless oil, bp 97°-99° C./15 mm. 1H NMR (CDCl3): 3.75-3.50 (m, 4H), 1.75-1.50 (m, 4H), 0.16 (s, 18H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>S(=O)(=O)(O)O.O>[C:17]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1)(=[O:19])[CH3:18]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Temperature: 80 °C
Yield: 99.7 %

Procedure:
50 Grams (234 mmol) of 4′-hydroxybiphenyl-4-carboxylic acid and 238 g (2.34 mol) of acetic anhydride were placed in a reactor, and while these stirred, 0.1 g of concentrated sulfuric acid was added. The mixture was stirred until heat generation ceased, and the mixture was further heated at 80° C. for 4 hours with stirring and then gradually cooled to room temperature. While the reaction mixture was cooled in an ice bath, 500 g of water was gradually added, and the mixture was stirred at room temperature for 3 hours to quench unreacted acetic anhydride. A precipitated white solid was recovered by filtration, washed with water to remove acetic acid, and dried with a vacuum drier to give 59.8 g of an end compound (yield 99%).