Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]=[O:13])=[O:4].Cl.[CH3:15][NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23].C(N(CC)C(C)C)(C)C>C1(C)C=CC=CC=1>[CH3:15][N:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[I:23])[C:12]1[O:13][C:3](=[O:4])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:11]=1
Reactant: COC(=O)c1ccccc1N=C=O
Reactant: CNc1ccccc1I
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: CN(c1nc2ccccc2c(=O)o1)c1ccccc1I

Procedure:
A solution of 2-methoxycarbonylphenyl isocyanate (1.0 g, 5.6 mmol), N-methyl-2-iodoaniline, hydrochloride (1.6 g, 5.9 mmol) and N,N-diisopropylethylamine (1.1 mL, 6.3 mmol) in 100 mL of toluene was refluxed under N2 for 72 hours. The sample was concentrated, and partitioned between chloroform and 10% HCl. The chloroform was dried (MgSO4), filtered, concentrated and chromatographed (silica gel, methylene chloride) to give the title compound as a yellow solid, mp 144°-148° C.
Reaction SMILES: C(N(CC)CC)C.[C:8]1([CH:14]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:15]2[CH2:18][C@@H:17]([OH:19])[C@@H:16]2[CH2:20][CH3:21])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl.C(OCC)(=O)C>[CH3:28][S:29]([O:19][C@@H:17]1[CH2:18][N:15]([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:16]1[CH2:20][CH3:21])(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H]1[C@H](O)CN1C(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@H]1[C@H](OS(C)(=O)=O)CN1C(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 90.9 %

Procedure:
Triethylamine (0.94 mL, 6.74 mmol) was added to a solution of trans(±)-1-(Diphenylmethyl)-2-ethylazetidin-3-ol obtained in Example (234b) (1.20 g, 4.49 mmol) in dichloromethane (8 mL). Then, a solution of methanesulfonyl chloride (0.45 mL, 5.83 mmol) in dichloromethane (1.5 mL) was added dropwise at room temperature, followed by stirring for four hours. The reaction solution was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1) to obtain 1.41 g of the title compound as a pale yellow oily substance (91%).
Reaction SMILES: [F-:1].[K+].[F:3][CH:4]([F:25])[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7](Cl)[C:6]=1[C:21]([O:23][CH3:24])=[O:22].O>CC#N.C1OCCOCCOCCOCCOCCOC1>[F:3][CH:4]([F:25])[C:5]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]([F:1])[C:6]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1Cl
Reactant: [F-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1F
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
The reagent was prepared by dissolving 0.37 g (0.001 mol) of 18-crown-6 in 30 ml of dry CH3CN (distilled over CaH2) and then adding 3.25 g (0.056 mol) of dry KF (dried in an oven at 50° C./67 Pa). After the heterogeneous system was mechanically stirred for 30 minutes, 10 g (0.028 mol) of product of Example 103 was added and the resulting mixture was refluxed for 6 days. The reaction mixture was poured into H2O, extracted with diethyl ether (2X), dried (MgSO4) and solvent removed in acuo affording 9.45 g of a brown oil. The crude product was purified by HPLC using 1ethyl acetate/cyclohexane as eluting solvent affording 6.72 g (70) of product as a white solid; mp 40-41° C.
Reaction SMILES: [N:1]1([C:7]([O:9]C(C)(C)C)=O)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=O)[CH:22](C)[CH3:23]>ClCCl>[C:7]([N:1]1[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1)(=[O:9])[CH:22]([CH3:23])[CH3:21]
Reactant: CC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCNCC1
Reaction time: 0.5 h

Procedure:
Tert-butyl piperazinecarboxylate (2.93 g) and triethylamine (4.39 ml) were dissolved in dichloromethane (60 ml) and then, while being cooled with ice, isobutyryl chloride (1.84 ml) was added thereto. After being stirred for 30 minutes, the reaction mixture was washed with saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, dried over sodium sulfate anhydride, and concentrated under a vacuum. To 1.79 g of part of the resulting residue, trifluoroacetic acid (9 ml) was added and the mixture was stirred for 30 minutes at room temperature. Then, the reaction mixture was concentrated under a vacuum. The residue was dissolved in methanol (20 ml) and then 2N hydrochroric acid methanol solution (10 ml) was added thereto. After being stirred for 10 minutes, the reaction mixture was concentrated under a vacuum. The residue, with 10% aqueous sodium hydroxide solution added thereto, was extracted with chloroform. The extract was washed with water and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum to yield 0.85 g of the aimed compound.
Reaction SMILES: [C:1]1([CH2:11][C:12]([NH2:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.I[C:16]1[CH:20]=[CH:19][S:18][CH:17]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C(OCC)(=O)C>[C:1]1([CH2:11][C:12]([NH:14][C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Ic1ccsc1
Reactant: NC(=O)Cc1cccc2ccccc12
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(Cc1cccc2ccccc12)Nc1ccsc1
Reaction time: 18 h
Yield: 94.9 %

Procedure:
2-(naphthalen-1-yl)acetamide (14.00 g, 75.6 mmol), 3-iodothiophene (10.15 g, 48.3 mmol), trans-1,2diaminocyclohexane (3.0 ml, 25.0 mmol), cuprous iodide (1.97 g, 10.3 mmol), and potassium carbonate (13.66 g, 98.8 mmol) in dioxane (50 ml) was placed into a preheated oil bath at 95° C. After stirring for 18 h, the heterogenous mixture was diluted with water and extracted with methylene chloride. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was flash chromatographed with 19:1, 9:1, 17:3, and 4:1 methylene chloride:ethyl acetate as the eluant to yield 12.26 g (95% yield) of 2-(naphthalen-1-yl)-N-(thiophen-3-yl)acetamide as a brown solid. Method [7] Retention time 2.07 min by HPLC (MH+ 268).
Reaction SMILES: [S:1](=[O:5])(=[O:4])([OH:3])[OH:2].[CH3:6][O:7][C:8]([C@@H:10]([NH:18][C:19]([C@@H:21]([NH2:26])[CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]>>[CH3:6][O:7][C:8]([C@@H:10]([NH:18][C:19]([C@@H:21]([NH2:26])[CH2:22][C:23]([OH:25])=[O:24])=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[S:1]([O-:5])([O-:4])(=[O:3])=[O:2]
Reactant: O=S(=O)(O)O
Agent: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(=O)O
Product: O=S(=O)([O-])[O-]

Procedure:
Empty capsule and tablet unit dose blisters having five small holes drilled on both the top and bottom of each blister were utilized as the dispensing means. An aspartame sulfate solution was prepared by dissolving 1.66 g of sulfuric acid (96%) and 10.0 g of aspartame (96% pure) in 20 mls. warm distilled water. The aqueous solution was added to 250 mls. of ethanol preheated to 60° C.
Reaction SMILES: [BH4-].[Na+].[Si]([O:10][C:11]1[CH:20]=[CH:19][C:14]2[C:15](=O)[CH2:16][O:17][C:13]=2[CH:12]=1)(C(C)(C)C)(C)C.CC(C)=O.Cl>CO.O>[O:17]1[C:13]2[CH:12]=[C:11]([OH:10])[CH:20]=[CH:19][C:14]=2[CH:15]=[CH:16]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)OCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CO
Solvent: O
Product: Oc1ccc2ccoc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.9 %

Procedure:
NaBH4 (6.0 g, 160 mmol) was added to a solution of 6-(tert-butyldimethylsilyloxy)benzofuran-3(2H)-one (40.0 g, 151 mmol) in MeOH (800 mL) at room temperature. After stirring at room temperature for 2 h, the reaction mixture was treated with acetone. Subsequently 4N HCl were added to the mixture and the stirring was continued for 3 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×1000 mL). The extract was washed with brine, dried, concentrated in vacuo and purified by column chromatography on silica gel (5-10% ethyl acetate in petroleum ether) to afford the pure product (17.0 g, 85.5% yield). 1H NMR (300 MHz, CDCl3) δ: 7.51 (d, J=2.1, 1H), 7.41 (d, J=8.4, 1H), 7.02 (d, J=1.8, 1H), 6.81 (dd, J=8.4, 2.1, 1H), 6.68 (dd, J=2.1, 0.9, 1H), 5.5 (br s, 1H).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:26])[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Br:25])[CH:18]=1.I[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.CN1CCCN(C)C1=O>[CH3:13][O:14][C:15](=[O:26])[CH:16]([C:17]1[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[C:19]([Br:25])[CH:18]=1)[CH2:28][CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: ICC1CCCC1
Reactant: COC(=O)Cc1ccc(SC)c(Br)c1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: COC(=O)C(CC1CCCC1)c1ccc(SC)c(Br)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A solution of diisopropylamine (4.8 mL, 34.27 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) was cooled to −78° C. under nitrogen and then treated with a 2.5M solution of n-butyllithium in hexanes (13.8 mL, 34.27 mmol). The resulting reaction mixture was stirred at −78° C. for 30 min and then treated dropwise with a solution of (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (8.57 g, 31.15 mmol) in dry tetrahydrofuran (30 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL). The resulting reaction mixture was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (7.85 g, 37.38 mmol) in a small amount of dry tetrahydrofuran was added dropwise. The reaction mixture was allowed to warm to 25° C. where it was stirred for 15 h. The reaction mixture was quenched with water (300 mL) and then concentrated in vacuo to remove tetrahydrofuran. The remaining aqueous phase was extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 19/1 hexanes/ethyl acetate) afforded 2-(3-bromo-4-methylsulfanyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (9.20 g, 83%) as a light yellow oil: EI-HRMS m/e calcd for C16H21BrO2S (M+) 356.0446, found 356.0435.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](I)=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:27])[C:17](=[O:18])[C:16]2[C:19]([Sn](C)(C)C)=[CH:20][CH:21]=[CH:22][C:15]=2[O:14]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:19]2[C:16]3[C:17](=[O:18])[C:13]([CH3:12])([CH3:27])[O:14][C:15]=3[CH:22]=[CH:21][CH:20]=2)=[CH:4][N:3]=1
Reactant: CC1(C)Oc2cccc([Sn](C)(C)C)c2C1=O
Reactant: Cc1c(I)cnc(N)c1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(-c2cccc3c2C(=O)C(C)(C)O3)cnc(N)c1C#N
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere, a stirred solution of 1.8 grams (0.007 mole) of 2-amino-3-cyano-5-iodo-4-methylpyridine, 2.3 grams (0.007 mole) of (2,3-dihydro-2,2-dimethyl-3-benzofuranon-4-yl)trimethyltin (prepared in Step D of this Example), and 0.5 gram (catalyst) of tetrakis(triphenylphosphine)palladium(0) in 25 mL of toluene is heated at reflux for about 22 hours. After this time the reaction mixture is cooled to ambient temperature and diluted with 50 mL of ethyl acetate. The mixture is filtered through diatomaceous earth, and the filtrate is concentrated under reduced pressure to a residue. The residue is purified using column chromatography, yielding 2-amino-3-cyano-4-methyl-5-(2,3-di hydro-2,2-dimethyl-3-benzofuranon-4-yl)pyridine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1C=O.[C:17]([O-])(=O)C.[Na+].[BH4-].[Na+]>CO>[CH3:9][C:5]1[CH:4]=[CH:3][C:2]([N:1]([C:11]2[O:10][CH:14]=[CH:13][CH:12]=2)[CH3:17])=[CH:7][C:6]=1[OH:8]
Reactant: CC(=O)[O-]
Reactant: O=Cc1ccco1
Reactant: Cc1ccc(N)cc1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(N(C)c2ccco2)cc1O
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a stirred solution of 5-amino-2-methylphenol (12.30 g, 100 mmole) in methanol (100 mL) at 4° C. was added 2-furaldehyde (14.41 g, 150 mmole) and sodium acetate (16.41 g, 200 mmole). The reaction mixture was stirred for 15 minutes and sodium borohydride (4.73 g, 125 mmole) was added portionwise over 1 hour at 4° C. After the addition was complete, the reaction was allowed to stir for an additional 1.5 hours. The reaction mixture was poured onto crushed ice slurry (200 g) and the resulting precipitate was collected, washed with cold water three times and air-dried to afford 2-methyl-5-(furan-2-yl-methylamino)phenol (16.86 g, 83% yield): mp 126.8-128.5° C.; 1HNMR (400 MHz, DMSO-d6) δ 1.94 (s, 3H), 4.12 (d, 2H, J=6.1 Hz), 5.71 (t, 1H, J=6.1 Hz), 6.00 (dd, 1H, J=2.3, 8.0 Hz), 6.11 (d, 1H, J=2.2 Hz), 6.22 (d, 1H, J=3.0 Hz), 6.36 (m, 1H), 6.70 (d, 1H, J=8.1 Hz), 7.54 (t, 1H, J=0.8 Hz), 8.79 (s, 1H); MS m/z 203 (M+).
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25](O)=[O:26])=[CH:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N:61]1([CH2:66][CH2:67][NH2:68])[CH2:65][CH2:64][CH2:63][CH2:62]1>CN(C)C=O>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([OH:23])[C:9]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)=[CH:10][CH:11]=2)[C:6](=[O:24])[C:5]([C:25]([NH:68][CH2:67][CH2:66][N:61]2[CH2:65][CH2:64][CH2:63][CH2:62]2)=[O:26])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Reactant: NCCN1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCCN2CCCC2)c(=O)c2c(O)c(OCc3ccc(OC)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (1.4 g, 3.79 mmol) in N,N-Dimethylformamide (DMF) (30 mL) was added HATU (1.729 g, 4.55 mmol) and DIPEA (1.655 mL, 9.48 mmol), the resulting mixture was stirred at r.t. for 30 min. Then 2-(pyrrolidin-1-yl)ethanamine (0.656 mL, 4.17 mmol) was added and the resulting mixture was stirred at r.t. for 3 h. The reaction mixture was concentrated and the residue was dissolved in DCM and washed with water, sat. NaHCO3 (aq.) and brine. The organic layer was separated and concentrated, the residue was purified by normal phase silica gel chromatography (CombiFlash), eluting with MeOH/DCM (0-20%) to afford 1-ethyl-5-hydroxy-6-((4-methoxybenzyl)oxy)-4-oxo-N-(2-(pyrrolidin-1-yl)ethyl)-1,4-dihydroquinoline-3-carboxamide (1 g, 2.148 mmol, 56.7% yield) as a yellow solid. LCMS: (M+H)+: 466.3.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][CH:7]([NH:9][C:10](=[O:21])[CH2:11][CH2:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:8].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][CH2:11][C:10]([NH:9][CH:7]([CH3:8])[CH3:6])=[O:21])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(C)NC(=O)CCC(=O)c1ccccc1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)NC(=O)CCC(=NNC(N)=S)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.9 %

Procedure:
Thiosemicarbazide (2.08 g, 22.8 mmol) was added to a solution of N-(1-methylethyl)-4-oxo-4-phenyl-butyramide (5.0 g, 22.8 mmol), prepared in the previous step, in 80 ml of methanol plus 6.2 ml of 1 N HCl plus 6.2 ml of water and the reaction stirred at room temperature for 2 days. An additional 1.04 g (11.4 mmol) of thiosemicarbazide was added and the reaction stirred at room temperature for 24 hours. The reaction was cooled in an ice bath and a white solid precipitated. The solid was collected by filtration and dried. Recrystallization of the solid from isopropyl alcohol gave the title compound (4.73 g, 53%) as a white solid, mp 66-71° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=1>CN(C=O)C>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:25])=[O:26])[CH:20]=[CH:21][CH:22]=2)[N:7]=1
Reactant: COc1ccccc1-c1ccnc(Cl)n1
Reactant: Nc1cccc(CS(N)(=O)=O)c1
Solvent: CN(C)C=O
Product: COc1ccccc1-c1ccnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
A solution of 2-chloro-4-(2-methoxy-phenyl)-pyrimidine (0.882 g, 0.004 mol), and (3-amino-phenyl)-methanesulfonamide (0.865 g, 0.005 mol) in DMF (12 ml) was stirred for 2 hours at 80° C. (TLC control). The solvent was removed under reduced pressure to afford {3-[4-(2-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-methanesulfonamide.
Reaction SMILES: CC1(C)[O:9][CH2:8][CH2:7][C@H:6]2[N:3]1[C:4](=[O:27])[C@H:5]2[C:10]([CH3:26])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=1)=[O:14])[CH3:11]>C(O)(=O)C.O>[OH:9][CH2:8][CH2:7][C@H:6]1[NH:3][C:4](=[O:27])[C@H:5]1[C:10]([CH3:26])([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1)=[O:14])[CH3:11]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2[C@@H]1CCOC2(C)C
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N[C@@H]1CCO
Temperature: 65 °C
Yield: 84.1 %

Procedure:
A solution of (6R,7R)-2,2-dimethyl-7-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-1-aza-3-oxabicyclo[4.2.0]octan-8-one (200 mg) in a mixture of acetic acid (3.2 ml) and water (0.8 ml) was heated at 65° C. for 1 hour. The mixture was cooled to room temperature and evaporated in vacuo. The crystalline residue was washed with ether to give (3R,4R)-4-(2-hydroxyethyl)-3-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]azetidin-2-one (151 mg).
Reaction SMILES: C(Cl)(Cl)(Cl)Cl.BrN1C(=[O:12])CCC1=O.[C:14]1([C:23]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19]CCNN=1.O.[C:33]([O:36][CH2:37]C)(=[O:35])[CH3:34]>>[C:33]([C:34]1[CH:19]=[CH:20][C:21]2[C:22](=[O:12])[C:14]3[CH:23]=[CH:31][CH:30]=[CH:29][C:28]=3[CH:27]=[CH:26][C:25]=2[CH:24]=1)([O:36][CH3:37])=[O:35]
Reactant: C1=C(C2=NNCCCCCC2)CCCCCCC1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(C)=O
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
4.68 G. of 2-carbomethoxy-5-oxo-5H-dibenzo[a,d]cycloheptane is refluxed in 100 ml. of carbon tetrachloride containing 3.56 g. (1 eq.) of N-bromosuccinimide while being irradiated with a 100 watt incandescent lamp. After 2 hrs. the solution is cooled, filtered and evaporated to dryness. The residue is dissolved in 30 ml. of dimethylformamide and 2.48 g. (1 eq.) of diazabicylononene is added. The mixture is heated briefly to 60° C, and water and ethyl acetate are added. The organic layer is washed with dilute hydrochloric acid and water, then dried and evaporated to give 2-carbomethoxy-5-oxo-5H-dibenzo[a,d]cycloheptene. Hydrolysis in eight to one aqueous methanol, 5% potassium hydroxide, followed by acidification with dilute hydrochloric acid yields 5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid (m.p. 261°-262° C).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1([C:15]([OH:17])=O)[CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N:19](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.C(=O)([O-])O.[NH4+]>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1([C:15](=[O:17])[NH2:19])[CH2:14][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NC1(C(=O)O)CC1)OCc1ccccc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)C1(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 82.2 %

Procedure:
To a solution of 1-benzyloxycarbonylamino-cyclopropanecarboxylic acid (7.0 g, 29.8 mmol) in DMF (30 mL) was added HATU (11.3 g, 29.8 mmol) and Et3N (4.3 mL, 29.8 mmol). The mixture was allowed to stir at room temperature for 20 min, then ammonium hydrogen carbonate (7.06 g, 89.3 mmol) was added in one portion. The reaction was heated at 60° C. for 12 h. The mixture was cooled to room temperature, diluted with water and extracted with EtOAc (2×100 mL). The combined extracts were washed with satd NaHCO3, water, brine and dried with MgSO4. The mixture was filtered and the solvent removed to give (1-carbamoyl-cyclopropyl)-carbamic acid benzyl ester (5.5 g, 24.5 mmol) as a white solid.
Reaction SMILES: CO[C:3]([CH:5]1[C:10](=O)[CH2:9][CH2:8][O:7][CH2:6]1)=[O:4].C(N(CC)CC)C.[Cl:19][CH2:20][C:21]([NH2:23])=[NH:22].C(Cl)Cl>CO>[Cl:19][CH2:20][C:21]1[NH:23][C:3](=[O:4])[C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:10]=2[N:22]=1
Reactant: COC(=O)C1COCCC1=O
Reactant: N=C(N)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(CCl)nc2c1COCC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
A mixture of crude 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester (1780 g, 11 mol) and triethylamine (830 g, 8.2 mol) in MeOH (3560 mL) was cooled to 0° C. under N2. A solution of 2-chloro-acetamidine (567 g, 4.4 mol) in 890 mL of MeOH was added dropwise over 50 minutes. The reaction mixture was stirred at 0° C. for 30 minutes and then at about 20° C. for 16 hours. LCMS at 215 nm and TLC (DCM:MeOH=10:1) analysis showed that most of 4-oxo-tetrahydro-pyran-3-carboxylic acid methyl ester was consumed. The mixture was then filtered and concentrated to give black oil, which was subsequently purified by flash column chromatography on silica gel and eluted with DCM to give yellow solid/oil mixture, which was further triturated with MTBE (˜1200 mL) and H2O:CH3CN:EA=1:1:2 (˜600 mL) to give the title compound as a white solid (318 g). MS m/z 201.2 (M+H). CHN analysis: calculated (results). C, 47.89 (47.95), H, 4.52 (4.401), N, 13.96 (13.76).
Reaction SMILES: N1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])CC1.N1([CH:15]=[CH:16][C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)=[O:18])CCCCC1.[CH2:32]1COC[CH2:33]1>>[O:8]([CH:15]=[CH:16][C:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:24][CH:25]=1)=[O:18])[C:7]1[CH:4]=[CH:5][CH:6]=[CH:33][CH:32]=1
Reactant: OCC1CCNCC1
Reactant: C1CCOC1
Reactant: O=C(C=CN1CCCCC1)Oc1ccc(-c2ccccc2)cc1
Product: O=C(C=COc1ccccc1)Oc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.62 h

Procedure:
4-Piperidinemethanol (0.06 g, 0.5 mmol) and compound 3 (0.11 g, 0.5 mmol) [4 (0.22 g, 0.5 mmol) or 5 (0.19 g, 0.5 mmol)] were dissolved in dry THF (5 mL), and the solution was stirred at room temperature for 30-45 min. The solvent was removed under reduced pressure at room temp to give the crude product which was then purified by column chromatography using ethyl acetate:hexane (7:3 or 8:3) to give compound 6 (7 or 8).