Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:43][CH2:44][CH:45]([OH:52])[CH2:46][N:47]([CH2:50][CH3:51])[CH2:48][CH3:49]>CN(C=O)C>[CH2:48]([N:47]([CH2:50][CH3:51])[CH2:46][CH:45]([OH:52])[CH2:44][NH:43][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13])[CH3:49]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CCN(CC)CC(O)CN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CC(O)CNC(=O)c1c(C)[nH]c2c1CCCC2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80.9 %

Procedure:
A mixture of 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol), HOBt 0.16 g (1.2 mmol), EDCI 0.24 g (1.2 mmol) and triethylamine 0.2 g (2.0 mmol) in 10 ml DMF was stirred at room temperature for 20 min, then 1-amino-3-(diethylamino)propan-2-ol 0.31 g (2.1 mmol) was added. After stirred at room temperature for 24 hours, the mixture was poured into the ice water and extracted with CH2Cl2. The organic layer separated was washed with water and saturated sodium chloride solution, then dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column, eluted with CH2Cl2/MeOH (3:1), to give 0.26 g (81%) of the titled compound as a white solid.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH3:5].C(N(CC)CC)C.Cl.[F:14][C:15]([F:49])([F:48])[C:16]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:19]=[C:18]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[CH:39]=[C:40]([S:44](Cl)(=[O:46])=[O:45])[CH:41]=[CH:42][CH:43]=3)[CH:33]=2)[N:17]=1>C1COCC1>[CH3:1][N:2]([CH2:3][CH2:4][CH3:5])[S:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([C:34]2[CH:33]=[C:32]([C:18]3[N:17]=[C:16]([C:15]([F:14])([F:48])[F:49])[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:29])[F:30])=[CH:24][CH:23]=4)[N:19]=3)[CH:37]=[CH:36][N:35]=2)[CH:39]=1)(=[O:45])=[O:46]
Reactant: CCCNC
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCN(C)S(=O)(=O)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 81 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of N-methylpropylamine (0.23 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.47 g, 86%). MS (ISP) 580.6 [(M+H)+]; mp 144° C.
Reaction SMILES: [F:1][C:2]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12]C)=[CH:8][CH:7]=1)=[O:5].Br>C(O)(=O)C>[F:1][C:2]1[C:17]([F:18])=[C:16]([F:19])[C:15]([F:20])=[C:14]([F:21])[C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: COc1ccc(C(=O)c2c(F)c(F)c(F)c(F)c2F)cc1
Agent: Br
Solvent: CC(=O)O
Product: O=C(c1ccc(O)cc1)c1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A round bottom flask provided with a condenser was supplied with 6.0 g of 2,3,4,5,6-pentafluoro-4′-methoxybenzophenone, 40 ml of glacial acetic acid, and 30 ml of an aqueous 48% hydrogen bromide solution. The resultant mixture was refluxed overnight and then cooled to a room temperature. The product was extracted from diethyl ether, dried with magnesium sulfate, filtered, and separated by distillation. It was recrystallized from toluene, to afford as white crystals 3.7 g (yield 78.8%) of 2,3,4,5,6-pentafluoro-4′-hydroxybenzophenone (hereinafter referred to as “HPBP”). The melting point of the product was 142° to 143° C. The NMR chemical shift of the crystals is shown in Table 1.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:8]([CH3:19])=[CH:7]2.C([Sn](CCCC)(CCCC)[C:25]([O:27]CC)=[CH2:26])CCC>C1(C)C=CC=CC=1.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>[CH3:19][C:8]1[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:11]2[C:6]([CH:7]=1)=[CH:5][CH:4]=[CH:3][C:2]=2[C:25](=[O:27])[CH3:26]
Reactant: Cc1cc2cccc(Br)c2nc1Oc1ccccc1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(=O)c1cccc2cc(C)c(Oc3ccccc3)nc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 73.1 %

Procedure:
A solution of 8-bromo-3-methyl-2-phenoxyquinoline (505.5 mg, 1.609 mmol), tributyl(1-ethoxyvinyl)stannane (Synthonix, Inc., Wake Forest, N.C.; 0.598 mL, 1.770 mmol), and Pd(PPh3)4 (93 mg, 0.080 mmol) in toluene (8.0 mL) was sparged with argon and then stirred under N2 at 100° C. for 16 h. The mixture was cooled to 25° C. and concentrated onto silica gel. Chromatographic purification (silica gel, 0-20% EtOAc/hexanes) furnished 1-(3-methyl-2-phenoxyquinolin-8-yl)ethanone (326.0 mg, 1.176 mmol, 73% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ ppm 7.95 (1H, s), 7.90 (1H, dd, J=7.2, 1.4 Hz), 7.82 (1H, dd, J=8.0, 1.2 Hz), 7.37-7.47 (3H, m), 7.23-7.25 (1H, m), 7.19 (2H, d, J=8.1 Hz), 2.55 (3H, d, J=0.6 Hz), 2.28 (3H, s). m/z (EST, +ve) 278.1 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:11][CH2:12][OH:13])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:14](Cl)(=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>>[CH3:1][N:2]([CH2:11][CH2:12][O:13][C:14](=[O:30])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[C:3](=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: CN(CCO)C(=O)c1ccccc1
Product: CCCCCCCCCCCCCCCC(=O)OCCN(C)C(=O)c1ccccc1

Procedure:
N-methyl-N-(2-palmitoyloxyethyl)benzamide was prepared by the procedure of example 1 from 18 gms. (0.1 mole) of N-methyl-N-(2-hydroxyethyl)benzamide and 26 gms. (0.1 mole) of palmitoyl chloride. The structure of the final product was characterized on the basis of IR and NMR spectral analyses as described in example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[NH2:10].[OH-].[K+].[C:13](=S)=[S:14].C>O.C(O)C>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]2[N:1]=[C:13]([SH:14])[NH:10][C:3]=2[CH:4]=1
Reactant: S=C=S
Reactant: Nc1cc(F)c(Cl)cc1N
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Fc1cc2nc(S)[nH]c2cc1Cl
Reaction time: 4 h
Yield: 575.7 %

Procedure:
The procedure of Van Allan and Deacon, Org. Synth. Coll. Vol. IV, 569, was adapted. A mixture of 1,2-diamino-4-chloro-5-fluorobenzene (528 mg, 3.29 mmol, Aldrich), potassium hydroxide (202 mg, 0.36 mmol), carbon disulfide (280 mg, 0.36 mmol), 95% ethanol (3 mL) and water (0.45 mL) was heated under reflux for 3 h. Activated charcoal (120 mg) was then added cautiously, and after the mixture has been heated at the refluxing temperature for 10 min the activated charcoal was removed by filtration. The filtrate was heated to 60°-70° C., warm water (3 mL) was added, and then acetic acid (0.25 mL) in water (0.5 mL) was added with good stirring for 4 h. The mixture was placed in a refrigerator overnight to give a mixture of brown and white crystals. The brown crystals were removed by washing with chloroform (5 mL). Recrystallization from hot EtOH/H2O gave pure title compound (420 mg, 63.5%, purity >99.57% by HPLC) as a white cubic crystals; top: 294°-6° C. (sub. from 250° C.). IR (KBr, cm-1): 3443, 3131, 3075, 1618, 1506, 1487, 1462. 1H NMR (DMSO-d6): δ 7.169 (d, J=9 Hz, 1H); 7.245 (d, J=6.6 Hz, 1H); 12.758 (s, 2H). HRMS: calcd for C7H4ClFN2S (M+) m/z: 201.9766, Found: 201.9779.
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([CH2:17][NH:18][C:19](=[O:34])[O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2)=[O:4].CO.COCCOC.Cl>[OH-].[Na+]>[C:3]([CH2:5][O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH2:9][CH2:10][CH:11]([CH2:17][NH:18][C:19](=[O:34])[O:20][CH:21]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:12]2)([OH:4])=[O:2]
Reactant: COC(=O)COc1cccc2c1CCC(CNC(=O)OC(c1ccccc1)c1ccccc1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Solvent: CO
Product: O=C(O)COc1cccc2c1CCC(CNC(=O)OC(c1ccccc1)c1ccccc1)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
A solution of benzhydryl N-[[1,2,3,4-tetrahydro-5-(methoxycarbonyimethoxy)-2-naphthyl]methyl]carbamate (60 mg) in a mixture of 1N sodium hydroxide aqueous solution (0.20 ml), methanol (1 ml), and 1,2-dimethoxyethane (1 ml) was stirred at room temperature for 30 minutes, neutralized with 1N hvdrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was powdered from diisopropyl ether to afford benzhydryl N-[[1,2,3,4-tetrahydro-5-(carboxymethoxy)-2-naphthyl]methyl]carbamate (51 mg) as a colorless powder.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[Cl:19]C1C=C([N+]([O-])=O)C=CN=1>>[Cl:19][C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: Nc1ccc(Cc2ccnc(C(F)(F)F)c2)cc1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Product: Nc1ccc(Cc2ccnc(Cl)c2)cc1

Procedure:
4-(2-Chloro-pyridin-4-ylmethyl)-phenylamine was prepared by a method analogous to that described for 4-(2-trifluoromethyl-pyridin-4-ylmethyl)-phenylamine (Intermediate 2P), starting from ethyl (4-nitrophenyl) acetate and 2-chloro-4-nitro-pyridine. 1H NMR (CHCl3-d) δ 8.23 (dd, J=5.1, 0.5 Hz, 1H), 7.11 (m, 1H), 7.01 (m, 1H), 6.95 (m, 2H), 6.65 (m, 2H), 3.83 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([CH3:9])[CH:3]=1.[C:10](Cl)(Cl)=[S:11].O.C([O-])(=O)C>C(=O)(O)[O-].[Na+].O1CCCC1>[Cl:1][C:2]1[N:7]=[N:6][C:5]([N:8]=[C:10]=[S:11])=[C:4]([CH3:9])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Cc1cc(Cl)nnc1N
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Cl)nnc1N=C=S
Reaction time: 1 h
Yield: 8.2 %

Procedure:
To a solution of 6-chloro-4-methylpyridazin-3-amine (2.86 g, 20.0 mmol) in aqueous sodium bicarbonate (10 mL) and tetrahydrofuran (40 mL) was added thiophosgene (1.69 mL, 22.0 mmol) dropwise at 0° C. After stirring for 1 hr, water and ethyl, acetate were added to the mixture and the insoluble materials were filtered off. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (304 mg, 1.64 mmol, 8%) as a pale yellow solid.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][N:5]=[C:6]=[S:7].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][NH:5][C:6](=[S:7])[NH:11][NH2:12]
Reactant: COC(CN=C=S)OC
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(CNC(=S)NN)OC
Reaction time: 12 h
Yield: 70.4 %

Procedure:
2,2-Dimethoxyethyl isothiocyanate (37.7 g) is added in the course of 1 hour to a solution of hydrazine hydrate (14.35 g) in ethanol (40 cc), whilst stirring at a temperature of between 5 and 9° C. After 12 hours at 4° C., the mixture is concentrated to dryness at 20° C. under reduced pressure (20 mm Hg; 2.7 kPa). The yellow syrup obtained crystallises after seeding. The solid is dissolved in hot methanol (50 cc) and the solution is filtered and diluted with diethyl ether (200 cc). After about ten hours at 4° C., the mixture is filtered and 4-(2,2-dimethoxyethyl)-thiosemicarbazide (32.3 g) is obtained in the form of a white solid.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4]Cl.[CH:6]1([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH:6]1([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:4][CH:2]3[CH2:1][O:3]3)=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: Oc1ccc(C2CCCCC2)cc1
Reactant: ClC[C@H]1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: c1cc(C2CCCCC2)ccc1OCC1CO1

Procedure:
To a mixture of R-epichlorohydrin (9.8 g, 106 mmol) and 4-cyclohexylphenol (3.73 g, 21.2 mmol) in acetonitrile (40 ml) was added cesium carbonate (6.9 g, 21.2 mmol). The mixture was heated at reflux for 3 hours. The reaction mixture was cooled, poured into water (100 mL) and extracted twice with EtOAc. The organic phases were combined and washed with water, brine, dried (Na2SO4), concentrated and dried under high vacuum overnight to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.C1COCC1.C1(C)C=CC=CC=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34](=[O:39])N(OC)C)=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C:34](=[O:39])[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: CON(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.4 %

Procedure:
At 0° C. 4-chlorophenylmagnesiumbromide 0.9 molar in THF/toluene (66.7 ml, 60 mmol) was added over 15 minutes to a solution of (S)-2-(Methoxy-methyl-carbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester CAS 115186-37-3 (5.16 g, 20 mmol) in dry THF (50 ml). The reaction mixture was warmed to ambient temperature and stirred for another 4 hours. The reaction mixture was poured on 1N HCl/ice (150 ml) and then extracted with ethyl acetate (2×100 ml). The organic layers are washed with water (2×50 ml), saturated NaCl (50 ml) and then dried over Na2SO4. After evaporation of the solvent, the crude product (7.5 g in the form of a yellow oil) was purified by flash chromatography over silica gel 150 g, (eluent:cyclohexane/ethyl acetate 9:1) to afford 4.3 g (69.4% of theory) of (S)-2-(4-chloro-benzoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester as a as a white solid m.p. 117-122° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1Cl)([O-:3])=[O:2].[CH2:14]([CH2:16][NH2:17])[OH:15]>O>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[NH:17][CH2:16][CH2:14][OH:15])([O-:3])=[O:2]
Reactant: NCCO
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Solvent: O
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1NCCO

Procedure:
0.05 mol (10.125 g) of 2,6-dinitrochlorobenzene is added gradually, whilst stirring, to 25 ml of ethanolamine, the reaction medium being cooled so that the temperature does not exceed 50° C. The reaction medium is poured into 100 ml of iced water. The expected product precipitates. It is filtered off, washed with water and recrystallised from ethanol. After drying in vacuo, it melts at 100° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([NH2:17])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=1[Cl:16].[F:19][C:20]([F:31])([F:30])[C:21]([F:29])([F:28])[C:22]([F:27])([F:26])[C:23](O)=O.Cl>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[CH:6][C:5]2[NH:17][C:23]([C:22]([F:26])([F:27])[C:21]([F:28])([F:29])[C:20]([F:31])([F:30])[F:19])=[N:18][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2cccc(Cl)c2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Agent: Cl
Product: FC(F)(F)C(F)(F)C(F)(F)c1nc2cc(Cl)c(Oc3cccc(Cl)c3Cl)cc2[nH]1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Compound number 140 (i.e., 6-chloro-5-(2,3-dichlorophenoxy)-2-heptafluoropropylbenzimidazole) was prepared as follows. 4-chloro-5-(2,3-dichlorophenoxy)benzene-1,2-diamine (150 mg, 0.49 mmol, 1.00 equiv), heptafluorobutanoic acid (15 mL) and hydrogen chloride (3 mL) was placed into a 100-mL round-bottom flask. The resulting solution was stirred overnight at 110° C. in an oil bath. The reaction mixture was cooled to room temperature. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×100 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The crude product was re-crystallized from EA/hexane in the ratio of 1/1. This resulted in 63.4 mg (27%) of 6-chloro-5-(2,3-dichlorophenoxy)-2-heptafluoropropylbenzimidazole as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[CH:11][C:10]=1[CH3:20])[C:6]([OH:8])=O.[C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])[NH:22][NH2:23].C(N(CC)C(C)C)(C)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][CH:5]([C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12]([O:18][CH3:19])=[CH:11][C:10]=1[CH3:20])[C:6]([NH:23][NH:22][C:21]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:8]
Reactant: COc1cc(C)c(C(CCCCl)C(=O)O)cc1C(C)C
Reactant: CC(C)(C)OC(=O)NN
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(C(CCCCl)C(=O)NNC(=O)OC(C)(C)C)cc1C(C)C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
5-Chloro-2-(5-isopropyl-4-methoxy-2-methylphenyl)pentanoic acid (6.2 g), tert-butyl carbazate (4.1 g) and N,N-diisopropylethylamine (10.8 mL) were dissolved in dichloromethane (120 mL). Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (7.9 g) was added under ice-cooling. After addition of the reagent, the mixture was brought back to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure. A sodium bicarbonate solution and tert-butyl methyl ether were added and the organic layer was separated. The resulting organic layer was washed with brine and then dried over anhydrous sodium sulfate. The drying agent was separated by filtration, and then the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain the title compound (6.1 g). The property values of the compound are as follows.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[C:13]([NH2:17])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[CH2:9]([O:8][C:7]1[C:6](=[O:11])[C:5](=[O:12])[C:4]=1[NH:17][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:10]
Reactant: CC(C)(C)N
Reactant: CCOc1c(OCC)c(=O)c1=O
Solvent: C1CCOC1
Product: CCOc1c(NC(C)(C)C)c(=O)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a room temperature solution of 5.81 g (34 mmol) of 3,4-diethoxy-3-cyclobutene-1,2-dione and 50 mL of THF was added 2.9 g (34 mmol) of tert-butyl amine. After stirring at room temperature for 12 hours, the reaction mixture was evaporated to a yellow oil. Flash chromatography on silica gel, eluting with 0 to 5% MeOH/CH2Cl2 gave 6.2 g (34 mmol, a 100% yield) of the title compound as a white solid: mp: 80°-82° C.; 1H NMR: (300 MHz, DMSO-d6): δ1.30-1.62 (m, 12H), 4.70-4.93 (m, 2H), 5.50-6.42 (brm, 1H); IR (KBr, cm-1): 3214w, 3144m, 3071w, 2973m, 2941m, 1794m, 1702s, 1606s, 1577s, 1500-1442brs; MS (CI) m/z (relative intensity): 198 (M+H, 100); Anal. Calcd. for C10H15NO3 : C, 60.90; H, 7.67; N, 7.10. Found: C, 61.03; H, 7.66; N, 6.98.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][Cl:5].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[Na+].Cl>O.C(#N)C>[ClH:5].[Cl:5][CH2:4][CH2:3][CH2:2][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: ClCCCBr
Reactant: C1COCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: ClCCCN1CCOCC1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
5 ml acetonitrile, 2.3 ml (23 mmol) of 1-bromo-3-chloropropane and 1 ml (11.5 mmol) of morpholine were added successively into a reaction flask. The mixture was stirred for 1 h, and 0.5 ml of 5% NaOH solution was added. After stirring at room temperature for 12 h, 3 ml concentrated hydrochloric acid and 10 ml water were added into the mixture. The lower layer was discarded, and the upper layer was alkalified with 5% NaOH and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution and dried over anhydrous sodium sulfate, then filtrated. The filtrate was concentrated to dry in a reduced pressure, and a small amount of ethanol/NaOH solution was added dropwise into the residue. The mixture was shaken and placed in a refrigerator for standing, then concentrated to dry in a reduced pressure to obtain 1.4 g white solid with the yield of 60%. m.p. 168-170° C.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].[CH3:42][S:43]([CH2:46][CH2:47][CH2:48]O)(=[O:45])=[O:44].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:41][O:40][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:21]=1[O:20][CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:45])=[O:44])[N:28]=[CH:27][N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[C:25]2=[O:39]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: CS(=O)(=O)CCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCS(C)(=O)=O
Yield: 90.7 %

Procedure:
Triphenylphosphine (8.9 g, 35.2 mmol) was added to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 19.6 mmol), (prepared as described for the starting material in Example 12), in methylene chloride (150 ml). This was followed by the addition of 3-(methylsulphonyl)-1-propanol (3.5 g, 25.4 mmol) and diethyl azodicarboxylate (5.55 ml, 35.2 mmol) in portions. The reaction was complete once the reaction became homogeneous. Silica was added and the volatiles were removed by evaporation. The free flowing powder was placed on the top of a flash chromatography column pre-equilibrated with ethyl acetate (100%). Elution was done using ethyl acetate (100%) followed by methylene chloride/ethyl acetate/methanol (60/35/5). The volatiles were removed by evaporation to give 6-methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7.58 g, 91%) as a white solid.