Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH:11]([Mg]Cl)=[CH2:12]>O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[CH:11]=[CH2:12]
Reactant: C=C[Mg]Cl
Reactant: O=Cc1ccc(F)cc1F
Solvent: C1CCOC1
Product: C=CC(O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
2,4-Difluorobenzaldehyde (1.42 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to 0° C. Vinyl magnesium chloride (1M in tetrahydrofuran, 12 mL, 12 mmol) was added. The reaction was stirred for 30 minutes then quenched with saturated aqueous ammonium chloride. The mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 10% ethyl acetate/isohexane, to give 1-(2,4-difluorophenyl)prop-2-en-1-ol (1.15 g). 1H NMR (500 MHz, CDCl3) δ 7.45-7.39 (1H, m), 6.90-6.86 (1H, m), 6.81-6.77 (1H, m), 6.07-6.00 (1H, m), 5.48 (1H, d, J=5.1 Hz), 5.35 (1H, d, J=17.1 Hz), 5.23-5.20 (1H, m), 2.06 (1H, s).
Reaction SMILES: [Na].[C:2](OCC)(=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[O:12]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[CH2:26](O)C>CCOCC>[CH3:26][C:16]1[CH:17]=[CH:18][C:13]([O:12][CH:19]([C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:14][CH:15]=1
Reactant: CCOC(=O)COc1ccccc1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCO
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C(=O)C(Oc1ccc(C)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
A sample of ethanol-free sodium ethoxide was prepared by dissolving sodium (3.0 g, 0.13 mole) in ethanol (50 ml) and then evaporating off the excess solvent. The last traces of ethanol were removed by the addition of dry toluene (50 ml), followed by evaporation to dryness. A stirred suspension of the white solid in dry ether (150 ml) under nitrogen, was treated dropwise with diethyl oxalate (17.6 ml, 0.13 mole) and the yellow solution allowed to stir for 21/2 hours at room temperature. A solution of the ethyl phenoxyacetate (0.13 mole, (D28)) in dry ether (50 ml) was added dropwise and the reaction mixture was left to stir overnight, before pouring into water (500 ml). The aqueous layer was separated, washed with ether (1×150 ml) and then acidified with dilute hydrochloric acid. The aqueous mixture was extracted with ether (3×150 ml) and the organic solution then washed with water (2×150 ml), dried (MgSO4) and evaporated to dryness to give the title compound as a yellow oil (28 g, 73%).
Reaction SMILES: C([Li])CCC.[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][CH:16]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[CH2:26][CH2:27][Cl:28].C([O-])([O-])=O.[K+].[K+]>CCCCCC.C1COCC1>[CH2:6]([N:13]1[CH2:19][CH2:18][CH2:17][C:16]([CH2:26][CH2:27][Cl:28])([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:15][CH2:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)C1CCCN(Cc2ccccc2)CC1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1(CCCl)CCCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
To DIPA (3.22 mL) was added dropwise a 2.64 M solution of n-butyl lithium in hexane (7.97 mL) at −78° C., followed by stirring for 30 minutes. To the reaction mixture was added ethyl 1-benzylazepane-4-carboxylate (5.0 g), followed by stirring for 30 minutes. Next, a solution of 1-bromo-2-chloroethane (3.02 g) in THF was added dropwise thereto, followed by warming to room temperature and stirring for 2 hours. To the reaction mixture was added an aqueous K2CO3 solution, followed by extraction with EtOAc. The organic layer was washed with water and brine in this order, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by medium-pressure preparative liquid chromatography (silica gel, YAMAZEN YFLC WPrep2XY, CHCl3:MeOH:aqueous ammonia). Desired fractions were collected, and concentrated under reduced pressure. After concentration under reduced pressure, to the residue, a part of which was solidified, was added EtOAc, followed by purification by silica gel column chromatography (EtOAc) to obtain ethyl 1-benzyl-4-(2-chloroethyl)azepane-4-carboxylate (4.11 g) as a colorless oily substance.
Reaction SMILES: O=[C:2]1[CH2:21][NH:20][CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[NH:13][CH2:12][C:11](=O)[NH:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.O>O1CCCC1>[CH:9]12[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[NH:3][CH2:2][CH2:21][NH:20][CH:19]1[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]1)[NH:13][CH2:12][CH2:11][NH:10]2
Reactant: O=C1CNC2CCCCC2NCC(=O)NC2CCCCC2N1
Solvent: C1CCOC1
Solvent: O
Product: C1CCC2NCCNC3CCCCC3NCCNC2C1
Reaction time: 24 h

Procedure:
A 1M solution of BH3 in tetrahydrofuran (265 ml.) was slowly added to 10.2 g. (33.1 mmol.) of compound (A). The solution was boiled for 24 hours. Water was then added dropwise to destroy the excess BH3 and the reaction mixture was brought to dryness. The solid residue was added to 265 ml. of a 6M hydrochloric acid solution and the mixture was refluxed overnight. Hydrochloric acid was eliminated under vacuum. The residue was digested in ethanol, filtered and dissolved in water. Concentrated ammonia was added until the pH became strongly basic. The inorganic precipitate that formed was filtered off and the filtrate was extracted with methylene chloride yielding 6.3 g. of compound (B) as a white solid after elimination of the solvent.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C(O)(=O)CC.Cl.[N:29]([O-])=O.[Na+].[CH3:33][N:34]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[N+:1]([C:4]1[CH:10]=[C:9]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH:8]=[CH:7][C:5]=1[N:6]=[N:29][C:38]1[CH:39]=[CH:40][C:35]([N:34]([CH3:33])[CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[CH:36][CH:37]=1)([O-:3])=[O:2]
Reactant: O=N[O-]
Reactant: CN(CCC(=O)O)c1ccccc1
Reactant: CCCCCCCCCCCCc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCC(=O)O
Product: CCCCCCCCCCCCc1ccc(N=Nc2ccc(N(C)CCC(=O)O)cc2)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4 %

Procedure:
2-Nitro-4-dodecylaniline (3.06 g) was dissolved in acetic acid (15 ml) and propionic acid (15 ml) and warmed whilst dilute hydrochloric acid (5 ml) was added. The mixture was cooled to 0° C. and sodium nitrite (0.7 g) was added at 0° C. The diazotised amine was then added to N-methyl-N-(2-hydroxycarbonylethyl)aniline (1.79 g) in water (100 ml) with dilute hydrochloric acid (3 ml). Sodium acetate was added until colour developed and the mixture was stirred for 0.5 hours. The crude product was recrystallised from CH2Cl2 to give a red solid (0.2 g).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH2:5][C:6]1[C:14]2[S:13][C:12]([Cl:15])=[N:11][C:10]=2[C:9]([Cl:16])=[CH:8][C:7]=1[Cl:17]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:15][C:12]1[S:13][C:14]2[C:6]([N:5]=[C:1]=[O:2])=[C:7]([Cl:17])[CH:8]=[C:9]([Cl:16])[C:10]=2[N:11]=1
Reactant: Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C=Nc1c(Cl)cc(Cl)c2nc(Cl)sc12
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
Under a nitrogen atmosphere 25 mL of ethyl acetate was stirred and cooled in an ice bath. To this was added via syringe 9.5 mL (18 mmole) of 1.9M phosgene in toluene. During 25 minutes, a solution of 3.0 grams (11.8 mmole) of 7-amino-2,4,6-trichlorobenzothiazole in 75 mL of ethyl acetate was added dropwise. Upon completion of the addition the reaction mixture was warmed to ambient temperature and then gently heated at reflux for 2.5 hours. After this time the reaction mixture was concentrated under reduced pressure, yielding (2,4,6-trichlorobenzothiazol-7-yl)isocyanate, which was stored in a refrigerator.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8](=[O:35])[CH2:9][CH:10]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:5]=[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:10]=2[CH2:9][C:8]([O:7][CH3:6])=[O:35])=[CH:14][CH:15]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)c1ccc(Br)cc1
Agent: CC(=O)[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: COC(=O)Cc1[nH]c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc1-c1ccc(Br)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
Ammonium acetate (9.4 g, 157 mmol) was added to a solution of Example J7, (2S)-tert-butyl 2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate (7.6 g, 15.7 mmol) in xylene (80 mL) and stirred for 4 hours at 140° C. in a screw capped 150 mL pressure vessel. After being cooled, the reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3 and brine before being concentrated by rotory evaporation under high vacuum. The crude product was taken up in CH2Cl2 and charged to a 40 (M) Biotage silica gel cartridge. Gradient elution 15-100% B over 2 L (A=CH2Cl2; B=ethyl acetate) gave Example J8, (S)-tert-butyl 2-(4-(4-bromophenyl)-5-(2-methoxy-2-oxoethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 3.38 g (46%). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (s, 4H), 4.83-4.73 (m, 1H), 3.81 (br. s, 1H), 3.62 (s, 3H), 3.53-3.51 (m, 1H), 3.38-3.31 (m, 2H), 2.25-2.15 (m, 1H), 1.99-1.83 (m, 3H), 1.41/1.16 (s, 9H). RT=1.6 minutes (Condition 1). LCMS: Anal. Calcd. for C21H26BrN3O4 464.11; found: 464.40 (M+H)+.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:5]=[C:6]([OH:13])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11].[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([F:12])[C:9]=1[CH2:10][OH:11]
Reactant: O=C([O-])[O-]
Reactant: OCc1c(F)cc(O)cc1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cc(F)c(CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Methyl iodide (0.13 mL, 2.08 mmol) was added dropwise to a solution of 3-chloro-5-fluoro-4-(hydroxymethyl)phenol (334 mg, 1.89 mmol) and potassium carbonate (287 mg, 2.08 mmol) in DMF (5 mL) and the reaction mixture stirred for 4 h at rt. The reaction mixture was partitioned between DCM and H2O, the organic layer separated and the aqueous further extracted with DCM. The combined organic phases were concentrated in vacuo to yield the title compound as a yellow oil (360 mg, 1.89 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH:32]C(C)(C)C)(=[O:31])=[O:30])[CH:8]=2)[N:3]=1.CCCCCCC>FC(F)(F)C(O)=O>[NH2:1][C:2]1[N:11]=[C:10]([C:12]([N:14]2[CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[S:29]([NH2:32])(=[O:31])=[O:30])[CH:8]=2)[N:3]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc2nc(N)nc(C(=O)N3Cc4ccccc4C3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: Nc1nc(C(=O)N2Cc3ccccc3C2)c2cc(-c3ccccc3S(N)(=O)=O)ccc2n1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
1 g of 2-[2-amino-4-(1,3-dihydroisoindole-2-carbonyl)quinazolin-6-yl]-N-tert-butylbenzenesulfonamide is dissolved in 10 ml of trifluoroacetic acid and stirred at 22° C. for 16 h. 10 ml of n-heptane are subsequently added and evaporated to dryness in vacuo. The crude product obtained in this way is purified by column chromatography.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH2:27]([O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41](=[O:44])[CH2:42]Br)=[CH:37][CH:36]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([C:41](=[O:44])[CH2:42][N:11]2[CH2:10][CH2:9][N:8]([CH:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12]2)=[CH:39][CH:40]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
To 90 ml of an ethyl acetate solution containing 7.56 g (30 mmol) of 1-diphenylmethylpiperazine and 3.33 g (33 mmol) of triethylamine was added 9.15 g (30 mmol) of p-benzyloxy-α-bromoacetophenone. The resultant mixture was stirred at room temperature for 45 minutes. After addition of 100 ml of ice water, the thus obtained mixture was stirred for about 10 minutes. Precipitated crystals were collected by filtration and then washed successively with water, ethanol and ethyl acetate and thereafter dried to give 12.5 g of 1-(4-benzyloxyphenyl)-2-(4-diphenylmethylpiperazinyl)ethanone (yield: 87.4%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[O:33]1[C:37](B(O)O)=[CH:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]1=2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C>[O:33]1[C:34]2=[CH:44][CH:43]=[CH:42][C:41]2=[CH:35][CH:36]=[C:37]1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:14][C:12](=[O:13])[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(I)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: COCCOC
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccccc2-c2ccc3cccc-3o2)cc1
Temperature: 125 °C
Reaction time: 0.1 h
Yield: 80 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-N-(4-iodo-phenyl)-3-(4-nitro-phenyl)-propionamide (1056 mg, 2 mmol) in 8 ml 1,2-dimethoxyethane, 4 ml ethanol, and 2 ml water was added benzo[b]furan-2-boronic acid (972 mg, 6 mmol), bis(tri-o-tolylphosphine)palladium(II)dichloride (158 mg, 0.2 mmol), and sodium carbonate (1060 mg, 10 mmol). The reaction mixture was stirred at 125° C. for 6 min, filtered, and concentrated. Chromatography of the residue (20% ethyl acetate in hexane) afforded N-(4-Benzofuran-2-yl-phenyl)-2-(4-tert-butyl-phenyl)-3-(4-nitro-phenyl)-propionamide as a yellow foam (830 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1.S(Cl)(Cl)=O.Cl.[CH2:20](OCC)[CH3:21]>C(O)C>[CH3:1][C:2]1[C:3]([C:12]([O:14][CH2:20][CH3:21])=[O:13])=[CH:4][C:5]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:11]=1
Reactant: Cc1cc2c(cc1C(=O)O)OCCO2
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc2c(cc1C)OCCO2
Temperature: 0 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
A mixture of 7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (1.72 g, 8.8 mmol) in ethanol (100 mL) was cooled to 0° C. and stirred for 1 h prior to dropwise addition of thionyl chloride (3.9 mL, 53.2 mmol) over 1 h. After this time, the mixture was warmed to room temperature for 1 h, then transferred to an oil bath, and heated to 70° C. overnight. The mixture was then cooled to room temperature and 2 N hydrochloric acid (50 mL) added slowly followed by diethyl ether (50 mL). The aqueous layer was extracted twice with diethyl ether (50 mL), the combined organic layers washed with brine (100 mL), dried over magnesium sulfate, and concentrated under reduced pressure to afford ethyl 7-methyl-2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylate (1.7 g, 89%) as a white solid: 1H NMR (500 MHz, CDCl3) δ 7.51 (s, 1H), 6.70 (s, 1H), 4.30 (q, J=7.0, 7.5 Hz, 2H), 4.26 (m, 4H), 2.49 (s, 3H), 1.36 (t, J=7.0, 7.5 Hz, 3H).
Reaction SMILES: [C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35]C)=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:37].C(=O)([O-])[O-].[NH4+:42].[NH4+]>CO>[ClH:37].[C:1]1([N:7]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[C:8]([C:10]2[CH:29]=[CH:28][C:13]3[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]4[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH2:42])=[CH:23][CH:24]=4)=[N:16][C:12]=3[CH:11]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Yield: 87 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-ethoxycarbonylethyl)-amide and methanolic hydrochloric acid, methanol and ammonium carbonate. Yield: 87% of theory, Rf value: 0.11 (silica gel; dichloromethane/ethanol=4:1) C27H28N6O3 (484.6) ##EQU31##
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].[C:19]([O-])([O-])=O.[K+].[K+].CI.O>C(#N)C>[CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][N:14]([CH3:19])[N:13]=2)=[CH:8][CH:7]=1)([CH3:2])[CH3:4]
Reactant: O=C([O-])[O-]
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2nn(C)cc2C=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 22.4 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)-phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (400 mg, 1.5 mmol) and K2CO3 (624 mg, 4.5 mmol) in acetonitrile (6 mL) was stirred at 0-5° C. for 1 h. Methyl iodide (310 mg, 2.2 mmol) was added and the mixture stirred at ambient temperature for 48 h. The reaction was poured into water (200 mL) and extracted with EtOAc (50 mL×3). The combined extracts were washed with brine (100 mL), dried, and concentrated under vacuum. The residue was purified by prep-TLC using Hexane:EtOAc (210:90) as eluent to afford the 3-(4-isopropoxyphenyl)-1-methyl-1H-pyrazole-4-carbaldehyde (82 mg, Yield: 19%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 9.94 (s, 1H), 8.00 (s, 1H), 7.68-7.64 (m, 2H), 7.02-6.97 (m, 2H), 4.69-4.59 (t, J=6.0 Hz, 1H), 4.00 (s, 3H), 1.38 (d, J=6.0 Hz, 6H) ppm. LCMS (method C RT=2.08 min, m/z=245.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.Cl.[NH2:14][CH2:15][C:16]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=O.[OH2:25]>>[NH2:14][C:15]1[C:16]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:7][C:8]2[C:4]([C:5]=1[C:6]([OH:11])=[O:25])=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2
Reactant: NCC(=O)c1ccc(Cl)cc1
Reactant: O
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Agent: Cl
Product: Nc1c(-c2ccc(Cl)cc2)nc2ccc(Cl)cc2c1C(=O)O

Procedure:
A solution of 4.54 g of 5-chloroisatin in water was reacted with 6.8 g of 2-amino-1-(4-chlorophenyl)ethanone hydrochloride by the procedure described in example 33, giving 6.27 g of the desired compound as a yellow solid,mp 240°-241° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([S:33][C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)[NH:23][C:24]=2[C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[CH:16][CH:15]=1>ClCCl>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]2[N:23]=[C:22]([S:33]([C:34]3[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=3)=[O:9])[NH:21][C:20]=2[C:17]2[CH:16]=[CH:15][C:14]([O:13][CH3:12])=[CH:19][CH:18]=2)=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1ccc(-c2nc(Sc3ccc(C(C)(C)C)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Solvent: ClCCl
Product: COc1ccc(-c2nc(S(=O)c3ccc(C(C)(C)C)cc3)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.5 %

Procedure:
A solution of 2.164 g of 3-chloroperbenzoic acid (80%) in 150 ml of dichloromethane is added dropwise to a solution of 4.45 g of 4,5-bis(4-methoxyphenyl)-2-(4-tert-butylphenylthio)imidazole in 100 ml of dichloromethane. The solution is stirred for 3 hours at room temperature, washed with sodium bicarbonate solution, dried over sodium sulfate, and concentrated to dryness under vacuum. The residue is chromatographed on 150 g of silica gel with acetone/hexane, thus producing 4.17 g of 4,5-bis(4-methoxyphenyl)-2-(4-tert-butylphenylsulfinyl)imidazole as an amorphous foam.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][OH:6].C(N(CC)CC)C.Cl[C:15]([O:17][CH:18]([Cl:20])[CH3:19])=[O:16].[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1>ClCCl>[C:21]([O:6][CH2:5][CH2:4][CH2:3][N:2]([C:15]([O:17][CH:18]([Cl:20])[CH3:19])=[O:16])[CH3:1])(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: CC(Cl)OC(=O)Cl
Reactant: CNCCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCCCN(C)C(=O)OC(C)Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
Under a nitrogen atmosphere, 3-methylamino-propan-1-ol (343.4 mg, 3.85 mmol) was dissolved in dichloromethane (5.0 mL), and triethylamine (588.2 μL, 4.24 mmol) was added. The mixture was cooled to 0° C. While maintaining the reaction temperature at 0° C., 1-chloroethyl chloroformate (415.7 μL, 3.85 mmol) was then added and the mixture was stirred for 1 hour. While maintaining the reaction temperature at 0° C., acetic anhydride (400 μL, 4.24 mmol) and pyridine (314.4 μL, 3.85 mmol) were then added, and the mixture was stirred at room temperature for 15 hours. After completing the reaction, the mixture was extracted with dichloromethane. The organic layer was washed with 1.0 M hydrochloric acid, water, and a saturated brine, dried over anhydrous sodium sulfate, and filtered. The solvent was distilled off. The residue was then purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1, Rf=0.6) to obtain 479.5 mg (52% yield) of 3-[(1-chloro-ethoxycarbonyl)-methyl-amino]-propyl acetate.