Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[C:14]([CH3:19])=[N:15][O:16][C:17]=3[CH3:18])O[C:9]=2[CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].Cl.C(N=C=NCCCN(C)C)C.[OH2:52].OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:27])=[CH:29][CH:30]=2)[C:8]2[CH:12]=[C:11]([C:13]3[C:14]([CH3:19])=[N:15][O:16][C:17]=3[CH3:18])[O:52][C:9]=2[CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O
Reactant: Cc1noc(C)c1-c1cc(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)c(C)o1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cc(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
A solution of 4-({cyclohexyl[5-(3,5-dimethylisoxazol-4-yl)-2-methylfuran-3-yl]methyl}amino)benzoic acid (204 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (221 mg, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([N:16]1C2C=CC=CC=2N=N1)[C:13](O)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:31]([C:34]1[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:35]=1[NH2:36])(=O)[CH3:32].CN1CCOCC1.N>O1CCCC1.CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[N:16]=[C:31]([CH3:32])[C:34]2[CH:40]=[CH:39][CH:38]=[C:37]([CH3:41])[C:35]=2[NH:36][C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC(C(=O)O)n1nnc2ccccc21)OCc1ccccc1
Reactant: CC(=O)c1cccc(C)c1N
Agent: N
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC1=NC(NC(=O)OCc2ccccc2)C(=O)Nc2c(C)cccc21
Temperature: 0 °C
Yield: 63.5 %

Procedure:
To a solution of N-benzyloxycarbonyl-2-(benzotriazol-1-yl)glycine (14.11 g) in dry tetrahydrofuran (100 ml) were added oxalyl chloride (3.77 ml) and dimethylformamide (3 drops) under stirring at 0° C. in an ice-salt bath under nitrogen stream. After the mixture was stirred under the same conditions for 2 hours, a mixture of 2-acetyl-6-methylaniline (4.30 g) and N-methylmorpholine (8.74 g) in tetrahydrofuran (20 ml) was added dropwise for 20 minutes. After the addition was completed, the mixture was allowed to warm to ambient temperature with stirring. Tetrahydrofuran was removed in vacuo and the residue was dissolved in ethyl acetate. The mixture was washed with water twice and dried over magnesium sulfate. Removal of the solvent gave an intermediate product as an oil, to which was added 20% methanolic ammonia (75 ml) and stirred at ambient temperature overnight. The resultant precipitate was collected by filtration and washed with cold methanol and diisopropyl ether successively, and dried to give (3RS)-3-benzyloxycarbonylamino-5,9-dimethyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one as a white crystalline powder (6.17 g, 63.5%).
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:17])[F:16])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH2:22])[C:10]=12.[C:23](O)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.O>[Cl:8][C:9]1[C:14]([C:15]([F:18])([F:16])[F:17])=[CH:13][N:12]=[C:11]2[NH:19][CH:20]=[C:21]([NH:22][C:23](=[O:30])[C:24]3[CH:29]=[CH:28][CH:27]=[N:26][CH:25]=3)[C:10]=12
Reactant: O=C(O)c1cccnc1
Reactant: Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1c[nH]c2ncc(C(F)(F)F)c(Cl)c12)c1cccnc1
Reaction time: 0.5 h
Yield: 27.8 %

Procedure:
Triethylamine (“TEA”; 0.50 mL, 3.61 mmol) was added to 4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-amine (0.17 g, 0.72 mmol), nicotinic acid (0.18 g, 1.44 mmol) and BOP—Cl (0.37 g, 1.44 mmol) in DCM (10 mL). The mixture was stirred for 30 minutes, and water was added (10 mL). The solid formed was collected by filtration, washed with DCM (10 mL) and dried to give N-(4-chloro-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)nicotinamide (80 mg, 0.2 mmol, 32% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([OH:35])(=[O:34])=O)=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38].S(Cl)(Cl)=O.CN(C=O)C.[CH3:48][O:49][C:50](=[O:54])[C@@H:51]([CH3:53])[NH2:52]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[N:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:14]([S:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][C:28]([S:32]([NH:52][C@H:51]([CH3:53])[C:50]([O:49][CH3:48])=[O:54])(=[O:35])=[O:34])=[CH:27][C:26]=3[F:36])=[N:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: COC(=O)[C@@H](C)N
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(S(=O)(=O)O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)NS(=O)(=O)c1cc(F)c(CSc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(F)c1
Temperature: 65 °C
Yield: 70.4 %

Procedure:
To a solution of 4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorbenzenesulfonic acid (3.0 g, 5.1 mmol) in DCM (15 mL) was added thionyl chloride (7.5 mL) and DMF (0.1 mL). The mixture was heated at 65° C. for 1 h then concentrated in vacuo and azeotroped with toluene (10 mL) and DCM (10 mL). The pale yellow foam was dissolved in DCM (15 mL) and was added dropwise to a solution of D-alanine methyl ester (2.9 g, 20.6 mmol) in 2M Na2CO3 (30 mL) with vigorous stirring. Upon complete addition the layers were separated and the organics were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography eluting with 0-70% ethyl acetate/hexane to afford a white foam (2.4 g, 77%). MS (EI) m/z 601.3 (M+).
Reaction SMILES: CO.CC(OC[C:8]1[CH2:17][S:16][C@@H:11]2[C@H:12](N)[C:13](=[O:14])N2[C:9]=1C(O)=O)=O.CC(OCC1CS[C@@H]2[C@H](NC(CC3SC=CC=3)=O)C(=O)N2C=1C(O)=O)=[O:23]>O1CCOCC1>[S:16]1[CH:17]=[CH:8][CH:9]=[C:11]1[CH2:12][C:13]([OH:14])=[O:23]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Solvent: C1COCCO1
Solvent: CO
Product: O=C(O)Cc1cccs1

Procedure:
A solution of 15 mM of 7 ACA and 400 mM of thienylactic acid in 50% dioxane/50% acetate 50 mM is prepared at a ph 6. The column is thermostatized at 25° C., the flow and volume of the derivative are the same as in example 1. The moveable phase that we use for HPLC is 30% methanol/70% phosphate, 0.067M at a pH of 4.7, the rest of the conditions are maintained like those in example 1. After attaining the balance, the degree of conversion of 7-ACA into cephalothin is above 95%.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([N:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([N+:12]([O-:14])=[O:13])=[CH:10][CH:11]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(-c2ncc[nH]2)cc1
Reactant: BrCc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2nccn2Cc2ccccc2)cc1

Procedure:
Prepared from 4-(imidazol-2-yl)-nitrobenzene and benzyl bromide
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([CH:7]1[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8]1)=[O:6])[CH3:3].[CH2:21]1COCC1.[OH-].[K+].CI>CN(C=O)C>[CH2:2]([O:4][C:5]([C:7]1([CH3:21])[C:12](=[O:13])[CH2:11][CH2:10][N:9]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCC1=O
Reactant: C1CCOC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CCC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Ethyl-1-benzyl-4-oxo-piperidine-3-carboxylate hydrochloride (150 g, 0.504 mol) was suspended in a solvent mixture of 750 ml THF and 750 ml DMF at room temperature. Addition of powdered KOH (56 g, 1.0 mol) was made in two equal lots keeping half an hour interval between two additions. To a clear reaction mixture methyl iodide (78 g, 0.55 mol) was added over period of 10 minutes and it was stirred for three hours at room temperature. The reaction was quenched by adding 4 ltr water followed by 1.5 ltr diethyl ether. Layers were separated. Organic layer was washed with water and dried over Na2SO4. Evaporation of organic solvent afforded a liquid, which was passed through a silica gel column to give 86 g (61%), titled compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:6](=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:8][C:9]=2[S:11][CH2:12][CH2:13][CH3:14])[CH2:5][CH2:4][CH2:3]1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][CH:3]1[CH2:4][CH2:5][C:6]2=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:8][C:9]([S:11][CH2:12][CH2:13][CH3:14])=[C:10]2[C:2]1=[O:1]
Reactant: CCCSc1sc(C(=O)OCC)c2c1C(=O)CCC2
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: CCCSc1sc(C(=O)OCC)c2c1C(=O)C(Br)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 90.9 %

Procedure:
Ethyl 4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (25.29 g) was dissolved in chloroform (380 ml); a solution of bromine (13.81 g) in chloroform (20 ml) was added dropwise at room temperature over a period of 20 minutes. After the reaction mixture was stirred at room temperature for 40 minutes, it was washed with a 2% aqueous solution of sodium sulfite (400 ml), water, a saturated aqueous solution of sodium hydrogen carbonate and water in that order, and dried (MgSO4), after which the solvent was distilled off to yield ethyl 5-bromo-4,5,6,7-tetrahydro-4-oxo-3-propylthiobenzo[c]thiophene-1-carboxylate (29.07 g, 90.9%), which was then recrystallized from ethyl acetate-hexane. Light-yellow prisms. Melting point 93-94° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([NH2:16])=[CH:12][CH:13]=[CH:14][CH:15]=1.[S:17](N)(N)(=[O:19])=[O:18].S(=O)(=O)(O)N>COCCOCCOC>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][S:17]1(=[O:19])=[O:18]
Reactant: Cc1ccc(Nc2ccccc2N)c(F)c1
Reactant: NS(N)(=O)=O
Agent: NS(=O)(=O)O
Solvent: COCCOCCOC
Product: Cc1ccc(N2c3ccccc3NS2(=O)=O)c(F)c1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution of N-(2-fluoro-4-methylphenyl)benzene-1,2-diamine (3.9 g, 18 mmol) in diglyme (36 mL) was treated with sulfamide (2.1 g, 22 mmol) and added dropwise over 10 min to a refluxing solution of sulfamic acid (0.9 g, 9 mmol) in diglyme (36 mL), and the reaction mixture was kept at reflux for an additional 15 minutes, then cooled to room temperature and concentrated. The residue was dissolved in ethyl ether (300 mL), washed with 2 N hydrochloric acid (100 mL), evaporated, and flash chromatographed (SiO2, 050% ethyl acetate/hexanes) provided 1-(2-fluoro-4-methylphenyl)-1,3-dihydro-2,1,3-benzothiadiazole2,2-dioxide (2.6 g) as a red solid:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1.[CH3:16][NH2:17].C(Cl)Cl.CO>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:17][CH3:16])[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccccc2)c(Cl)n1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CNc1nc(SC)ncc1-c1ccccc1

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-phenyl-pyrimidine by reacting with methylamine in ethanol at 90° C., Rf value: 0.63 (silica gel; methylene chloride/methanol=20:1)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([O:24]C)=O)=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH3:28]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]([NH2:28])=[O:24])=[CH:17][CH:16]=3)[CH:11]=[C:10]([CH2:26][CH3:27])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCc1cc(Oc2ccc(CC(=O)OC)cc2)nc(-c2cccc(Cl)c2)n1
Reactant: N
Solvent: CO
Product: CCc1cc(Oc2ccc(CC(N)=O)cc2)nc(-c2cccc(Cl)c2)n1
Yield: 64 %

Procedure:
Methyl 2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetate (0.075 g, 0.20 mmol) and ammonia in methanol (7 M, 3 mL) were heated at 100° C. for 72 h. After this time, the crude reaction solution was cooled, evaporated, and purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.048 g, 64%) as a white solid. MW=367.83. 1H NMR (DMSO-d6, 500 MHz) δ 8.16-8.13 (m, 1H), 8.14-8.11 (m, 1H), 7.59-7.55 (m, 1H), 7.51 (t, J=7.9 Hz, 2H), 7.39-7.36 (m, 2H), 7.24-7.21 (m, 2H), 6.92 (s, 1H), 6.90 (s, 1H), 3.44 (s, 2H), 2.80 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H); APCI MS m/z 368 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[C:10](=[O:13])([O-])[O-].[Cs+].[Cs+].C[N:17]1[CH2:21][CH2:20][CH2:19][C:18]1=O>O>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:10]=[O:13]
Reactant: CN1CCCC1=O
Reactant: O=C([O-])[O-]
Reactant: Clc1cncc(Cl)c1Cl
Agent: [Cs+]
Solvent: O
Product: O=Cc1cccn1-c1c(Cl)cncc1Cl
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 2.6 g of 2-pyrrolecabaldehyde, 5.0 g of 3,4,5-trichloropyridine, 10.7 g of cesium carbonate and 30 ml of N-methylpyrrolidone was stirred at 100° C. for 2 hours, and then allowed to cool to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate two times. The organic layers were combined, washed successively water and an aqueous saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was subjected to silica gel chromatography to obtain 2.14 g of 1-(3,5-dichloro-4-pyridinyl)-1H-pyrrole-2-carbaldehyde of the formula:
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:6][C@H:5]([CH2:7][O:8][C:9]2[CH:16]=[C:15]([CH3:17])[C:12]([CH:13]=O)=[C:11]([CH3:18])[CH:10]=2)[CH2:4][O:3]1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:35]=[CH:36][C:37]=1[NH2:38])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=1)=[O:25].C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Yb+3].O>CS(C)=O.CCOC(C)=O>[CH3:34][C:29]1[CH:28]=[C:27]([NH:26][C:24]([C:23]2[CH:35]=[CH:36][C:37]3[N:38]=[C:13]([C:12]4[C:15]([CH3:17])=[CH:16][C:9]([O:8][CH2:7][C@@H:5]5[CH2:4][O:3][C:2]([CH3:19])([CH3:1])[O:6]5)=[CH:10][C:11]=4[CH3:18])[NH:20][C:21]=3[CH:22]=2)=[O:25])[CH:32]=[CH:31][C:30]=1[CH3:33]
Reactant: Cc1ccc(NC(=O)c2ccc(N)c(N)c2)cc1C
Reactant: Cc1cc(OC[C@@H]2COC(C)(C)O2)cc(C)c1C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)c2ccc3nc(-c4c(C)cc(OC[C@@H]5COC(C)(C)O5)cc4C)[nH]c3c2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylbenzaldehyde (145 mg, 0.55 mmol) and 3,4-diamino-N-(3,4-dimethylphenyl)-benzamide (153 mg, 0.55 mmol) in DMSO (8 mL) was added Yb(OTf)3 (68 mg, 0.11 mmol) and the mixture was stirred at ambient temperature overnight. The reaction mixture was partioned between water and EtOAc and the aqueous layer was extracted with EtOAc. The organic layer was washed with water, brine, dried with MgSO4, filtered and concentrated. Purification by flash chromatography using heptane/EtOAc (1:2) as eluent gave 2-[4-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2,6-dimethylphenyl]-3H-benzoimidazole-5-carboxylic acid (3,4-dimethylphenyl)-amide as a pale yellow solid 1H NMR (Methanol-d4, 400 MHz): δ 8.30 (d, 1H), 7.90 (d, 1H), 7.77 (dd, 1H), 7.47 (s, 1H), 7.44 (dd, 1H), 7.13 (d, 1H), 6.79 (s, 2H), 4.51 (m, 1H), 4.19 (q, 1H), 4.07 (d, 2H), 3.91 (q, 1H), 2.29 (s, 3H), 2.26 (s, 3H), 2.15 (s, 6H), 1.44 (s, 3H), 1.38 (s, 3H). MS (m/z) 500.3 (M+1); Retention time: 1.51 min (Method 10).
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH3:13])[CH:9]=[CH:8][C:7]=1[N:14]1[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[N:15]1)(=O)=O.Cl.O>CO>[CH3:20][C:16]1[CH:17]=[C:18]([CH3:19])[N:14]([C:7]2[CH:8]=[CH:9][C:10]([CH2:12][CH3:13])=[CH:11][C:6]=2[OH:5])[N:15]=1
Reactant: CCc1ccc(-n2nc(C)cc2C)c(OS(C)(=O)=O)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: CCc1ccc(-n2nc(C)cc2C)c(O)c1
Yield: 36 %

Procedure:
28 mg of 2-(3,5-dimethyl-1H-pyrazol-1-yl)-5-ethylphenyl methanesulfonate was dissolved in 0.1 ml of methanol, and 0.07 ml of 5N-hydrochloric acid was added and heated at reflux for 30 minutes. To the reaction mixture added 15 ml of water, and extracted with 15 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified using preparative thin-layer silica gel column chromatography (hexane:ethyl acetate=4:1) to yield 7.4 mg of the title compound.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=3)[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1>C1(C)C=CC=CC=1.CC(C)=O>[N:20]1([C:2]2[C:3]3[CH:10]=[C:9]([C:11]4[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=4)[NH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH2:22][CH2:21]1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Cl)ncnc3[nH]2)cc1
Reactant: c1ccc2c(c1)CCCN2
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(-c2cc3c(N4CCCc5ccccc54)ncnc3[nH]2)cc1

Procedure:
This product is prepared in a manner analogous to that described in Example 6 from 4-chloro-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]pyrimidine and 1,2,3,4-tetrahydroquinoline (2.1 equivalents). FAB-MS: (M+H)+ =372 (corresponds to C21H17N5O2); Rf value (toluene-acetone--4:6)=0.36.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]3([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[O:18][CH2:17][CH2:16][O:15]3)[C:9]2=[O:29])[C@H:4]([CH2:30][S:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH2:3]1.[C:40](O)(=O)[CH3:41].[C:44](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CCOC(C)=O.CC(C)=O>[CH:40]([NH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[CH2:12][CH2:11][C@H:10]([CH2:13][C:14]3([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=4)[O:15][CH2:16][CH2:17][O:18]3)[C:9]2=[O:29])[C@H:4]([CH2:30][S:31]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:32])=[O:33])[CH2:3]1)([CH3:41])[CH3:44]
Reactant: CC(=O)O
Reactant: N[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: CC(C)N[C@@H]1CC[C@H](N2CC[C@H](CC3(c4cccc(C(F)(F)F)c4)OCCO3)C2=O)[C@H](CS(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
A mixture of 39h-b (170 mg, 300 μmol), acetone (871 μL, 11.9 μmol), acetic acid (69.1 μL, 1.20 mmol), and sodium triacetoxyborohydride (255 mg, 1.20 mmol) in dichloroethane (17 mL) was stirred at room temperature for 2 h. The reaction was diluted with EtOAc (500 mL), washed with saturated NaHCO3 (3×150 mL), water (2×100 mL), and brine (150 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by CombiFlash chromatography (silica, 0–10% MeOH/CH2Cl2) to provide (R*)-1-((1S*,2R*,4R*)-4-(isopropylamino)-2-(phenylsulfonylmethyl)cyclohexyl)-3-((2-(3-(trifluoromethyl)phenyl)-1,3-dioxolan-2-yl)methyl)pyrrolidin-2-one (39i-b, 106 mg, 58%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J=7.2 Hz, 2H), 7.68 (s, 1H), 7.64–7.39 (m, 6H), 4.20 (s, 1H), 4.05–3.90 (m, 2H), 3.81–3.60 (m, 3H), 3.48–3.11 (m, 4H), 3.10–2.88 (m, 1H), 2.60–2.10 (m, 5H), 2.09–1.60 (m, 8H), 1.43–1.00 (m, 6H); 19F NMR (282 MHz, CDCl3) δ −62.9; ESI MS m/z 609 [C31H39F3N2O5S+H]+.
Reaction SMILES: [N:1]#[C:2][NH2:3].[N:4]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19]C3CC3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)=[C:5]=[S:6].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)=[O:26]>>[NH2:1][C:2]1[N:3]=[C:5]([NH:4][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)=[CH:11][CH:12]=2)[S:6][C:24]=1[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([OH:33])[CH:28]=1)=[O:26]
Reactant: S=C=Nc1ccc(N2CCN(CC3CC3)CC2)cc1
Reactant: N#CN
Reactant: O=C(CBr)c1cccc(O)c1
Product: CN1CCN(c2ccc(Nc3nc(N)c(C(=O)c4cccc(O)c4)s3)cc2)CC1

Procedure:
This compound was prepared from cyanamide, 1-(4-isothiocyanato-phenyl)-4-cyclopropylmethylpiperazine (of Example 1) and 2-bromo-1-(3-hydroxyphenyl)ethanone (of Example 14N) following the procedure used in Example 24. Mass spectrum (ES) MH+=410.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1.[C:16]([O:20][CH3:21])(=[O:19])[NH:17][NH2:18].Cl>C(O)C>[CH3:21][O:20][C:16](=[O:19])[NH:17][N:18]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: NC(=O)NC1CCC(=O)c2ccccc21
Reactant: COC(=O)NN
Agent: Cl
Solvent: CCO
Product: COC(=O)NN=C1CCC(NC(N)=O)c2ccccc21
Temperature: 25 °C

Procedure:
A mixture of 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea (4.5 g), methyl carbazate (4.0 g), 95% ethanol (150 ml) and concentrated hydrochloric acid (2 ml) is heated at reflux for an overnight period. The mixture is cooled to room temperature and the crystals are collected. The product melts at 230° C to 233° C (dec). On recrystallizing from aqueous methanol, the title compound melts at 223° C to 225° C (dec).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH:2]([CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Reaction time: 12 h

Procedure:
To a solution of Example 1B (5 g, 23.22 mmol) in dichloromethane (50 mL) was added pyridinium chlorochromate (10.01 g, 46.4 mmol) and the mixture was stirred for 12 hours. The mixture was filtered and concentrated to afford crude product which was purified by column chromatography (silica gel, 40% ethyl acetate in hexane) to afford the title compound. 1H NMR (300 MHz, CDCl3): δ 1.44 (s, 9H), 1.5-1.54 (m, 1H), 1.66-1.69 (m, 2H), 1.9-2.0 (m, 1H), 2.38-2.46 (m, 1H), 3.04-3.12 (m, 1H), 2.38-3.36 (m, 1H), 3.6-3.68 (m, 1H), 3.88-4.0 (m, 1H), 9.7 (s, 1H).