Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]1[N:7]2[CH2:8][N:9]3[CH2:11][N:5]([CH2:6]2)[CH2:4][N:3]1[CH2:10]3.[NH4+].[O-][Mo:14]([O-])(=O)=O.[O-][Mo]([O-])(=O)=O>O>[Mo:14].[CH2:2]1[N:7]2[CH2:8][N:9]3[CH2:11][N:5]([CH2:6]2)[CH2:4][N:3]1[CH2:10]3
Reactant: O=[Mo](=O)([O-])[O-]
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: [Mo]

Procedure:
Hexamethylenetetramine molybdate having a 2/1 molybdenum/hexamethylenetetramine molar ratio was prepared in the presence of HCl as follows. 10 grams of hexamethylenetetramine, 14.05 grams of a 37 wt.% aqueous HCl solution, and 100 ml water were dissolved together and heated to reflux in a 500 ml round-bottomed flask equipped with a stirrer and water-cooled condenser. 24.24 grams ammonium dimolybdate was dissolved in 50 ml hot water. The second solution was added to the first solution, and a thin white precipitate formed rapidly.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([O:13]CC)=O)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:19]=[N:20][C:21]([Cl:24])=[CH:22][CH:23]=1.BrC1C=CC=CC=1>CCCCCC>[Cl:24][C:21]1[N:20]=[N:19][C:18]([NH:17][C:11]([C:4]2[C:5](=[O:10])[N:6]([CH3:9])[C:7]([CH3:8])=[C:2]([Cl:1])[C:3]=2[OH:16])=[O:13])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Reactant: Nc1ccc(Cl)nn1
Solvent: CCCCCC
Solvent: Brc1ccccc1
Product: Cc1c(Cl)c(O)c(C(=O)Nc2ccc(Cl)nn2)c(=O)n1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.4 %

Procedure:
168 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 82 mg of 3-amino-6-chloropyridazine were added to 1.5 ml of bromobenzene, and the mixture was stirred for 4 hours under heat refluxing. The reaction mixture was cooled to room temperature, and n-hexane was added to the reaction mixture. The resulting solid was collected by filtration, washed with a mixture of t-butyl methyl ether and n-hexane, and dried to obtain 180 mg of N-(6-chloro-3-pyridazinyl)-5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide (hereafter, referred to as present compound 17) represented by the formula:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH:17]=O>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[CH:17]/[C:13]2[N:12]([CH3:11])[CH:16]=[CH:15][CH:14]=2)/[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: Cn1cccc1C=O
Reactant: N#CCc1ccc(Cl)cc1
Solvent: O
Product: Cn1cccc1/C=C(\C#N)c1ccc(Cl)cc1
Reaction time: 2 h
Yield: 85.2 %

Procedure:
A suspension of 4-chlorophenylacetonitrile (500 mg, 3.30 mmol) and 1-methyl-1H-pyrrole-2-carbaldehyde (370 mg, 3.39 mmol, 1.03 equiv.) in water (5 ml) was treated with 40% aqueous Triton B (1.4 ml, 3.3 mmol). Precipitate began forming almost immediately. After stirring for 2 h, the precipitate was filtered off, washed with water, and dried to afford a yellow solid (682 mg). This is Compound 6 in Table 8.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[Se:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][CH:41]=1>ClCCl>[Cl:39][C:40]1[CH:46]=[CH:45][C:43]([NH:44][C:10](=[Se:11])[C:9]2[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=2[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:42][CH:41]=1
Reactant: OC(=[Se])c1ccccc1Cc1ccccc1
Reactant: Nc1ccc(Cl)cc1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Clc1ccc(NC(=[Se])c2ccccc2Cc2ccccc2)cc1

Procedure:
To a solution of 6 g (0.0206 mol) 2-benzylselenobenzoic acid and 2.1 g (0.0206 mol) triethylamine in 100 ml dichloromethane at 0°-5° C. is added in one portion 5.24 g (0.0206 mol) bis[2-oxo-3-oxazolidinyl]phosphoryl chloride. After stirring for 30 minutes a solution of 2.63 g (0.0206 mol) 4-chloroaniline at 0° C. is added and after 15 minutes a solution of 2.1 g (0.0206 mol) triethylamine in 30 ml dichloromethane (within 21/2 hours). The reaction mixture is then immediately extracted with 100 ml 1N aqueous hydrochloroic acid solution, 100 ml 1N caustic soda solution and 100 ml distilled water. The organic phase is dried with sodium sulfate and the solvent removed under vacuum. The residue is purified by recrystallization from 80 ml 2-propanol.
Reaction SMILES: Br[C:2]1C(Cl)=NC(Cl)=NC=1.[Br:10][C:11]1[C:12]([NH:18][CH:19]([CH:29]([CH3:31])[CH3:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1>>[Br:10][C:11]1[C:12]([NH:18][C@@H:19]([C:29]([CH3:2])([CH3:31])[CH3:30])[CH2:20][NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[N:13][C:14]([Cl:17])=[N:15][CH:16]=1
Reactant: CC(C)C(CNC(=O)OC(C)(C)C)Nc1nc(Cl)ncc1Br
Reactant: Clc1ncc(Br)c(Cl)n1
Product: CC(C)(C)OC(=O)NC[C@@H](Nc1nc(Cl)ncc1Br)C(C)(C)C

Procedure:
Intermediate J was hydrogenated using 10% Pd/C under hydrogen at 50 psi in a pressure vessel to afford tert-butyl N-[(2S)-2-amino-3,3-dimethyl-butyl]carbamate which was then reacted with 5-bromo-2,4-dichloro-pyrimidine using analogous reaction conditions as described using analogous reaction conditions as described for tert-butyl N-[2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3-methyl-butyl]carbamate to afford tert-butyl N-[(2S)-2-[(5-bromo-2-chloro-pyrimidin-4-yl)amino]-3,3-dimethyl-butyl]carbamate. LCMS (ESI) 407 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([SH:16])=[N:14][N:15]=1.[OH-].[Na+].I[CH3:20]>O.ClCCl>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[NH:9][CH2:10][C:11]1[O:12][C:13]([S:16][CH3:20])=[N:14][N:15]=1
Reactant: CI
Reactant: Cc1cccc(C)c1NCc1nnc(S)o1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CSc1nnc(CNc2c(C)cccc2C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.3 %

Procedure:
To a stirred mixture of 16.2 g (0.0688 mol) 2-(2,6-dimethylphenylaminomethyl)-5-mercapto-1,3,4-oxadiazole in 200 ml water and 200 ml dichloromethane was added quickly 2.8 g (0.0688 mol) sodium hydroxide. To the resulting reaction mixture was then added 9.9 g (0.0688 mol) iodomethane. The reaction mixture was stirred at about 25° C. for 1 hour and then heated under reflux for 1 hour. After the reaction mixture was allowed to stand overnight at 25° C., the organic layer was separated, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a yellow solid. Trituration with ethyl ether/petroleum ether gave 8.8 g of 2-(2,6-dimethylphenylaminomethyl)-5-methylthio-1,3,4-oxadiazole, m.p. 84°-85° C. The product is tabulated in Table I as Compound No. 24-A.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN(C=O)C.C(N(CC)C(C)C)(C)C.[F:49][C:50]([F:60])([F:59])[C:51]1[CH:58]=[CH:57][C:54]([CH2:55][NH2:56])=[CH:53][CH:52]=1>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:56][CH2:55][C:54]2[CH:53]=[CH:52][C:51]([C:50]([F:49])([F:59])[F:60])=[CH:58][CH:57]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(C(=O)NCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a mixture of p-aminobenzoic acid (5.0 g, 36 mmol) and HBTU (14 g, 36 mmol) in DMF (50 mL, 600 mmol) at 0° C. were added N,N-diisopropylethylamine (19 mL, 110 mmol) and 4-(trifluoromethyl)benzylamine (6.2 mL, 44 mmol). The reaction mixture was slowly warmed to ambient temperature. The reaction mixture was quenched with an equal volume of saturated aqueous sodium bicarbonate and extracted with ethyl acetate (3×). The combined organic layers were washed successively with water, aqueous lithium chloride, and brine, dried over sodium sulfate, filtered and concentrated in vacuo (8.2 g, 70%).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:26])[CH:23]([CH3:24])[CH3:25])=[O:19]
Reactant: [H][H]
Reactant: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)C(=O)NNC(=O)[C@H]1CC[C@H]2CN1C(=O)N2O
Yield: 93.3 %

Procedure:
To a solution of (2R,5S)-6-(benzyloxy)-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 194 (0.30 g, 0.83 mml) in methanol (20 mL) was added 5% Pd/C (0.40 g). The mixture was hydrogenated under 10 psi hydrogen atmosphere at room temperature for 1 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give (2R,5S)-6-hydroxy-N′-(2-methylpropanoyl)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 195 (0.21 g, 95%) as a colorless foam.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12](=[O:19])[C:11]([C:20]([C:22]3[CH:23]=[N:24][C:25]([N:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)=[CH:26][CH:27]=3)=[O:21])=[CH:10]2)[CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: O=C(c1ccc(N2CCCC2)nc1)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O

Procedure:
Experimental conditions analogous to those described for Example 141, from 103 mg (0.23 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 0.5 mL pyrrolidine in 2 mL THF. Yield: 50 mg of a yellow powder. LC-MSD, m/z for C25H21BrN4O2 [M+H]+=489.0, 491.0; HPLC retention time: 1.1 min.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.P(=O)(O)(O)O.[NH2:20][C:21]1[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=[C:23]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=2)[CH:22]=1.[C:36]([CH2:39][C:40](=O)[CH3:41])(=O)[CH3:37].[OH-].[Na+]>>[Cl:35][C:31]1[CH:30]=[C:29]([C:23]2[C:22]3[C:21](=[N:20][C:36]([CH3:37])=[CH:39][C:40]=3[CH3:41])[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1c(N)cc(-c2cccc(Cl)c2)cc1=O
Agent: O=P(O)(O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Product: Cc1cc(C)c2c(-c3cccc(Cl)c3)cc(=O)n(C)c2n1
Temperature: 140 °C
Yield: 70.6 %

Procedure:
A mixture of diphosphorus pentoxide (10.5 g) and phosphoric acid (5 ml) was stirred at 140° C. until it became transparent. Then, 6-amino-4-(3-chlorophenyl)-1-methyl-2(1H)-pyridone (2.34 g, 10 mmol) and acetylacetone (1.05 ml, 10 mmol) were added to this solution, and the mixture was stirred at 140° C. for 3 hours. The reaction solution was poured into ice water, made alkaline by adding 1N sodium hydroxide aqueous solution and then extracted with ethyl acetate. After drying the organic layer with anhydrous magnesium sulfate, magnesium sulfate was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was then purified by silica gel column chromatography (benzene-ethyl acetate) to give 4-(3-chlorophenyl)-1,5,7-trimethyl-1,8-naphthyridin-2(1H)-one (2.11 g, 71%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](Br)=[C:4](Cl)[C:5]([F:8])([F:7])[F:6].[OH-].[Na+]>O1CCCC1.[Ni]>[F:1][C:2]([F:12])([F:11])[CH2:3][CH2:4][C:5]([F:8])([F:7])[F:6]
Reactant: FC(F)(F)C(Cl)=C(Br)C(F)(F)F
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: FC(F)(F)CCC(F)(F)F
Yield: 58.5 %

Procedure:
1,1,1,4,4,4-Hexafluoro-2-bromo-3-chloro-2-butene (10 g, 36 mmole) in 50 ml tetrahydrofuran was hydrogenated in the presence of sodium hydroxide (3.0 g) and Raney nickel (5 g) at a temperature of 20° to 40° C. and under a hydrogen pressure of 20 to 40 bar. The reaction mixture was worked up as in Example B, producing 3.5 g (59% of theory) of 1,1,1,4,4,4-hexafluorobutane.
Reaction SMILES: CS(O[CH2:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=1)[OH:8])(=O)=O.[OH-].[Na+]>CS(C)=O>[Cl:15][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[C@H:7]1[O:8][CH2:6]1
Reactant: CS(=O)(=O)OC[C@H](O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: 0 °C

Procedure:
Into dimethyl sulfoxide (30 ml) were added (R)-2-(3-chlorophenyl)-2-hydroxyethyl methanesulfonate obtained in 2) above (10 g) and, under ice-cooling, a 5N aqueous NaOH solution (15 ml), and then the resulting mixture was stirred at the same temperature for 12 hours. The reaction mixture was added into ice water and extracted with 50% diethyl ether/pentane. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desiccant was filtered off, then the solvent was distilled off under reduced pressure, and the oily substance obtained was distilled under reduced pressure to obtain a colorless oily compound mentioned above (3.62 g, 76.5%). The optical purity of the product obtained was 97.5% e.e. as determined by HPLC.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1CCCCC1>C1C=CC=CC=1.CS(O)(=O)=O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH3:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(C)(c1ccccc1)C2
Agent: CS(=O)(=O)O
Solvent: c1ccccc1
Solvent: C1CCCCC1
Product: CC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A solution of tert-butyl (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetate (1.0 g., 0.00237 mole) in benzene (25 ml.) is treated with methanesulfonic acid (2 drops) and refluxed for 1/2 hour. The reaction mixture is treated with cyclohexane (20 ml.) and cooled affording (1-oxo-2-methyl-2-phenyl-6,7-dichloro-5-indanyloxy)acetic acid which is filtered and dried.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13][CH3:14])[C:10](=[O:15])[C:9]([F:17])([F:16])[CH2:8][N:7]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[C:6]=2[N:23]=1.[NH2:24][C:25]1[CH:39]=[CH:38][C:28]([C:29]([NH:31][CH:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:30])=[CH:27][CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH:18]1([N:7]2[CH2:8][C:9]([F:17])([F:16])[C:10](=[O:15])[N:11]([CH2:12][CH2:13][CH3:14])[C:5]3[CH:4]=[N:3][C:2]([NH:24][C:25]4[CH:26]=[CH:27][C:28]([C:29]([NH:31][CH:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[O:30])=[CH:38][CH:39]=4)=[N:23][C:6]2=3)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: Nc1ccc(C(=O)NC2CCOCC2)cc1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCOCC4)cc3)ncc21
Yield: 25.2 %

Procedure:
A mixture of 0.05 g (0.15 mmole) of 2-chloro-9-cyclopentyl-7,7-difluoro-5-propyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-144), 0.04 g (0.17 mmole) of 4-amino-N-(tetrahydro-pyran-4-yl)-benzamide, 0.04 g (0.22 mmole) of p-toluenesulfonic acid monohydrate and 4.0 mL of 2-propanol was heated at 160 degrees for 2 hours in a microwave reactor. The cooled mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phases were extracted with dichloromethane, and the combined organic layers washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75), to give 0.020 g of 4-(9-cyclopentyl-7,7-difluoro-6-oxo-5-propyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(tetrahydro-pyran-4-yl)-benzamide (I-149).
Reaction SMILES: ClC1C=CC=[C:4]([C:8]([O:10]O)=O)[CH:3]=1.C(O[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]#[N:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)C=C>C(Cl)Cl>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([CH2:3][CH:4]3[O:10][CH2:8]3)=[CH:21][CH:20]=2)=[CH:27][CH:26]=1)#[N:29]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCOc1ccc(-c2ccc(C#N)cc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(-c2ccc(CC3CO3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.4 %

Procedure:
20 g of m-chloroperbenzoic acid divided into portions was added in a few times to a solution prepared by dissolving 19 g of 4-allyloxy-4′-cyanobiphenyl in 150 ml of methylene chloride, and stirred at room temperature for 24 hours. The deposited insoluble was filtered away, water was added to it for liquid-liquid separation, and the organic layer was washed with an aqueous saturated sodium hydrosulfite solution and then dried with anhydrous magnesium sulfate. The solvent was evaporated away, and the residue was purified through silica gel column chromatography and further recrystallized from ethanol to obtain 13 g of 4-cyano-4′-glycidylbiphenyl.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:25][CH:26]([CH3:28])[CH3:27])(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:18][CH2:19][CH2:20][CH:21]1[CH2:23][CH:22]1[C@@H:24]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CC1CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C1CC1CCO
Temperature: 25 °C
Reaction time: 9 h
Yield: 87.9 %

Procedure:
To a solution of the crude TBDPS-protected alcohol 11a (464 mg, 0.742 mmol) in dry THF (6 mL) at 0° C. was added TBAF (1.0M/THF, 0.93 mL, 0.927 mmol), and the reaction mixture was allowed to warm to rt while stirring under N2. Since TLC showed uncomplete reaction after 5 h, 0.75 eq. TBAF (0.56 mL) was added. After 9 h, the reaction mixture was quenched with sat. aq. NH4Cl and diluted with EtOAc. The aqueous phase was separated and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography (SiO2, 5:5, hexanes/EtOAc) afforded 177 mg (88%) of the title compound as a colorless oil which solidified upon high vacuum to give a white powder. mp 49.8-50.2° C.; [α]D22-30.8 (c 1.0, DCM); 1H NMR (300 MHz, CDCl3) δ 4.50 (appbd, 1 H, J=4.5 Hz), 3.66 (bs, 2 H), 2.94 (m, 1 H), 2.36 (bs, 1H), 1.82 (m, 1 H), 1.71 (m, 1 H), 1.45 (s, 9 H), 1.39 (t, 2 H, J=7.2 Hz), 1.01 (bs, 2 H), 0.90 (dd, 6 H, J=10.2, 6.6 Hz), 0.50 (m, 1 H), 0.43-0.27 (m, 2 H); HRMS (ESI) m/z calcd for C15H29NO3Na 294.2045. found 294.2064.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18].[CH:21]([NH2:25])([CH2:23][CH3:24])[CH3:22]>>[CH:21]([NH:25][C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[C:17]([F:20])([F:19])[F:18])([CH2:23][CH3:24])[CH3:22]
Reactant: CCC(C)N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c2[nH]c(C(F)F)nc12
Product: CCC(C)Nc1c(C(F)(F)F)cc([N+](=O)[O-])c2nc(C(F)F)[nH]c12

Procedure:
4-Chloro-7-nitro-5-trifluoromethyl-2-difluoromethylbenzimidazole is reacted with sec-butylamine to obtain 4-secbutylamino-7-nitro-5-trifluoromethyl-2-difluoromethylbenzimidazole, m.w., 352.3.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48]>CN(C=O)C.O>[C:50]([O:49][C:47](=[O:48])[CH2:46][NH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)[N:7]([CH:9]([C:13]2[N:22]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21](=[O:30])[C:20]3[C:15](=[CH:16][C:17]([Cl:31])=[CH:18][CH:19]=3)[N:14]=2)[CH:10]([CH3:12])[CH3:11])[CH:8]=1)([CH3:53])([CH3:52])[CH3:51]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1ccc(-c2nc(CCN)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(-c2nc(CCNCC(=O)OC(C)(C)C)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 49.6 %

Procedure:
A solution of 2-{1-[4-(2-Amino-ethyl)-2-p-tolyl-imidazol-1-yl]-2-methyl-propyl}-3-benzyl-7-chloro-3H-quinazolin-4-one (181 mg, 0.343 mmol), potassium carbonate (47 mg., 0.343 mmol), and tert-butyl bromoacetate (67 mg., 0.343 mmol) in DMF (2.0 mL) was stirred at room temperature for 4.5 h. The reaction was diluted with water and the resulting white precipitate was filtered and purified by flash chromatography (silica gel, 95:5 methylene chloride:methanol) to provide the title compound as a white solid (109 mg., 50%). MS(ES+) m/e 640 [M+H]+.
Reaction SMILES: FC(F)(F)S(O/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])(=O)=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[C:24]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)#[N:25]>O1CCOCC1>[C:24]([C:26]1[CH:31]=[C:30](/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:29]=[CH:28][CH:27]=1)#[N:25]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CCOC(=O)/C=C/OS(=O)(=O)C(F)(F)F
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)/C=C/c1cccc(C#N)c1
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of ethyl (E)-3-{[(trifluoromethyl)sulfonyl]-oxy}-2-propenoate (390 mg, 1.49 mmol) in 5 ml anhydrous dioxane was added potassium phosphate (474 mg, 2.24 mmol), 3-cyanophenyl boronic acid (217 mg, 1.49 mmol), and tetrakis (triphenylphosphine)palladium(0) (43 mg, 0.038 mmol). Reaction mixture was heated to reflux and stirred overnight. Mixture was filtered through a pad of Celite, diluted with 50 ml ethyl acetate, washed with 2×50 ml water, 2×50 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated in vacuo. Residue was chromatographed on silica gel using 5% EtOAc in hexane as the eluent to give ethyl (E) 3-(3-cyanophenyl)-2-propenoate (240 mg, 71%) as a clear yellow oil after drying. H1NMR (CDCl3): 1.2-1.32 (t, 3H); 2.547 (s, 3H); 4.18-4.24 (m, 2H); 6.113 (s, H); 7.47-7.725 (m, 4H). NOE confirmed stereo orientation.
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:7]([CH3:13])=[C:8]([CH:11]=O)[NH:9][CH:10]=1)([OH:3])=[O:2].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([CH2:26][C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1>N1CCCCC1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([C:22]2[CH:30]=[C:29]3[C:25]([C:26](=[CH:11][C:8]4[NH:9][CH:10]=[C:6]([CH2:5][CH2:4][C:1]([OH:3])=[O:2])[C:7]=4[CH3:13])[C:27](=[O:31])[NH:28]3)=[CH:24][CH:23]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: COc1cccc(-c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1c(CCC(=O)O)c[nH]c1C=O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]cc(CCC(=O)O)c2C)c1
Yield: 97 %

Procedure:
4-(2-carboxyethyl)-2-formyl-3-methylpyrrole (90.5 mg), 120 mg 6-(3-methoxyphenyl)-2-oxindole, and 3 drops piperidine in 3 mL of ethanol were heated at 90° C. overnight. The reaction mixture was cooled and concentrated. The residue was suspended in 6 N aqueous hydrochloric acid. The precipitate was filtered, washed with water to pH 6 and dried in a vacuum oven overnight to give 195 mg (97%) of the title compound as a brown solid.