Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:4][S:3][C:2]1=[C:5]([C:13](C(OOCC)=O)=[O:14])[C:6]([O:8][CH:9]([CH2:11][CH3:12])[CH3:10])=[O:7].[NH2:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1>>[S:3]1[CH2:4][S:1][C:2]1=[C:5]([C:13](=[O:14])[NH:21][C:22]1[S:23][CH:24]=[C:25]([CH3:27])[N:26]=1)[C:6]([O:8][CH:9]([CH2:11][CH3:12])[CH3:10])=[O:7]
Reactant: Cc1csc(N)n1
Reactant: CCOOC(=O)C(=O)C(C(=O)OC(C)CC)=C1SCS1
Product: CCC(C)OC(=O)C(C(=O)Nc1nc(C)cs1)=C1SCS1

Procedure:
Following the procedure of Example 22, the titled compound was prepared as a white solid (67%) from sec-butyl 2-(1,3-dithietan-2-ylidene)-2-(ethoxycarboxycarbonyl)acetate and 2-amino-4-methylthiazole.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11](F)[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH3:17].O>C1COCC1>[NH2:17][C:11]1[C:10]([N+:14]([O-:16])=[O:15])=[CH:9][C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([F:1])[CH:12]=1
Reactant: N
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(F)cc1F
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1F

Procedure:
A mixture of ethyl 2,4-difluoro-5-nitrobenzoate (5.00 g; 21.6 mmol) (see Example 59 (d)) in THF (100 mL) was treated with NH3 in THF (2.7 mL; 8 M; 21.6 mmol) at 0° C. and the mixture was stirred over night. Another portion of NH3 in THF (1.0 mL; 8M; 8 mmol) was added and the mixture stirred over night. Water (100 mL) was added and the mixture was concentrated. The precipitate was filtered off and dried to give the sub-title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[NH2:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([OH:40])[CH2:36][CH2:35]1.C(N(CC)CC)C>C1COCC1>[OH:40][C@H:37]1[CH2:38][CH2:39][C@H:34]([NH:33][C:16]2[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]3[CH:12]=[CH:11][C:10](=[O:31])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:35][CH2:36]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(N[C@H]2CC[C@H](O)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reaction time: 48 h

Procedure:
The product of Example 48 (300 mg, 0.67 mmol), trans-4-aminocyclohexanol hydrochloride (226 mg, 1.5 mmol), and triethylamine (0.42 mL, 3 mmol) were combined in THF (15 mL) and stirred under Ar at 500 for 2 days. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography with 0-20% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a white-crystalline solid. mp 158-160°, LC MS m/z=481 (MH+). Retention time=2.08 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[N+:16]([O-])=O.Cl.C(O)(=O)C.C(=O)(O)[O-].[K+]>C(Cl)(Cl)Cl>[NH2:16][C:3]1[CH:4]=[CH:5][C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:7][C:2]=1[NH2:1]
Reactant: Cc1ccc(Sc2ccc([N+](=O)[O-])c(N)c2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1ccc(Sc2ccc(N)c(N)c2)cc1

Procedure:
3.5 G. of 2-amino-4-(p-methylphenylthio)-1-nitrobenzene in 8 ml. concentrated hydrochloric acid is treated with a solution of 16 g. stannous chloride in 8 ml. concentrated hydrochloric acid in 20 ml. acetic acid. The mixture is heated for 1 hour on a steam bath, cooled and treated with potassium bicarbonate and chloroform. The mixture is filtered and the chloroform layer evaporated. The residue is triturated with hot cyclohexane giving 1,2-diamino-4-(p-methylphenylthio)-benzene.
Reaction SMILES: [Cl:1][C:2]1[C:15]([OH:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][OH:27]>CN(C=O)C>[Cl:1][C:2]1[C:15]([O:16][CH2:25][CH2:26][OH:27])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:17])[C:4]=2[CH:3]=1
Reactant: OCCBr
Reactant: O=c1c2ccccc2oc2cc(O)c(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2oc2cc(OCCO)c(Cl)cc12
Reaction time: 3 h
Yield: 63.6 %

Procedure:
A mixture of 2-chloro-3-hydroxy-9-oxo-9H-xanthene (8.0 g), potassium carbonate (13 g), 2-bromoethanol (12 g) and DMF (200 ml) was stirred at 45°-55° C. for 3 hours. After distilling off the solvent under vacuum, water was added to the residue and the solid crystal was recovered by filtration, washed with water and dried. Recrystallization from a mixed solvent of DMF and water gave 6.0 g of 2-chloro-3-(2-hydroxyethoxy)-9-oxo-9H-xanthene. m.p. 153°-156° C. This compound produced a mass spectrum having a molecular ion peak at m/e 290.
Reaction SMILES: [CH3:1][N:2]([CH2:26][CH:27]=[CH2:28])[S:3]([C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:9]=[CH:8][C:7]=1[Cl:25])(=[O:5])=[O:4].IC.[H][H]>[Pd].C(OCC)(=O)C>[CH3:1][N:2]([CH2:26][CH2:27][CH3:28])[S:3]([C:6]1[CH:11]=[C:10]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:21])([F:22])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[CH:9]=[CH:8][C:7]=1[Cl:25])(=[O:4])=[O:5]
Reactant: [H][H]
Reactant: C=CCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CI
Product: CCCN(C)S(=O)(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
A mixture of 1.6 g of N-methyl-N-(2-propenyl)-2-chloro-5-(3,6-dihydro-3-methyl-4-trifluoromethyl-2,6-dioxo-1(2H)-pyrimidinyl)benzenesulfonamide (Compound #29), prepared byprocess C from Compound #28 and iodomethane, 100 ml of ethyl acetate and 200 mg of 5% palladium/carbon catalyst was hydrogenated in a Paar® apparatus at 28 psi of hydrogen. After 30 minutes, the catalyst was filtered and solvent removed from the filtrate by rotary evaporation. The glassy residue was treated with ethanol to give 1.4 g of the title compound as a light gray powder, m.p. 143.5°-145° C.
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=2)[CH:6]=1.I[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20]>[Cu].CS(C)=O>[CH3:16][C:9]1[CH:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[CH:3]=[N:4]2)[CH:12]=[CH:11][C:10]=1[N+:13]([O-:15])=[O:14]
Reactant: Cc1cc(-n2cc(I)cn2)ccc1[N+](=O)[O-]
Reactant: FC(F)(F)C(F)(F)I
Agent: [Cu]
Solvent: CS(C)=O
Product: Cc1cc(-n2cc(C(F)(F)C(F)(F)F)cn2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
4-Iodo-1-(3-methyl-4-nitrophenyl)-1H-pyrazole (1.98 g), copper powder (1.14 g), iodopentafluoroethane (8.85 g) and DMSO (9 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 100° C. After finishing the reaction, the reaction mixture was poured into ice water and an insoluble matter was filtered with Celite, and then, it was extracted with ethyl acetate. The extracted solution was washed with water and dried with anhydrous sodium sulfate. After distilling off the solvent, the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrophenyl)-4-pentafluoroethyl-1H-pyrazole (0.72 g).
Reaction SMILES: Cl[C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[C:10]([Cl:23])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=1.[CH3:32][O-:33].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:23][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:24]([C:26]3[N:30]([CH3:31])[CH:29]=[N:28][CH:27]=3)=[O:25])[CH:8]=2)[N:3]=[C:2]([O:33][CH3:32])[C:11]=1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: Cn1cncc1C(=O)c1ccc2nc(Cl)c(Cc3ccc(S(C)(=O)=O)cc3)c(Cl)c2c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(C(=O)c3cncn3C)cc2c(Cl)c1Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C

Procedure:
A mixture of (2,4-dichloro-3-(4-(methylsulfonyl)benzyl)quinolin-6-yl)(1-methyl-1H-imidazol-5-yl)methanone (1 g, 2.085 mmol, Intermediate 38: step a) and solid sodium methoxide (0.56 g, 10.42 mmol) in toluene (10 mL) was heated in a sealed tube at 105° C. for 12 hours, cooled to room temperature, diluted with DCM and the resulting suspension filtered through Celite® rinsing several times with CH2Cl2. The solvents were removed under reduced pressure and the residue chromatographed (Heptane/EtOAc) to provide the title compound as a white solid.
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH3:26])=[N:4][C:3]=1[CH2:27][CH3:28].[OH:29][CH2:30][C:31]([CH3:41])([CH3:40])[O:32][C:33]1[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=1.[OH-].[K+].CS(C)=O>C(OCC)(=O)C>[CH2:27]([C:3]1[N:4]=[C:5]([CH2:24][CH2:25][CH3:26])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]=1[O:39][C:36]1[CH:35]=[CH:34][C:33]([O:32][C:31]([CH3:41])([CH3:40])[CH2:30][OH:29])=[CH:38][CH:37]=1)[CH3:28]
Reactant: CCCc1nc(CC)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(CO)Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)c(Oc2ccc(OC(C)(C)CO)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 150 °C
Reaction time: 12 h
Yield: 56.2 %

Procedure:
A mixture of 4′-[(5-bromo-4-ethyl-6-oxo-2-propylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.52 g), 4-(2-hydroxy-1,1-dimethylethoxy)phenol (0.32 g), 8 M potassium hydroxide solution (0.22 mL) and dimethyl sulfoxide (8 mL) was stirred at 150° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.36 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:17])OC2C=CC=CC=2)=[C:4]([C:18]#[N:19])[CH:3]=1.O1CCCC1.[CH3:25][NH2:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:26][CH3:25])=[O:17])=[C:4]([C:18]#[N:19])[CH:3]=1
Reactant: N#Cc1cc(Cl)ccc1NC(=O)Oc1ccccc1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc(Cl)cc1C#N

Procedure:
(Step 1) Using phenyl (4-chloro-2-cyanophenyl)carbamate obtained in Example 47, Steps 1 and 2N methylamine tetrahydrofuran solution, and in the same manner as in Example 47, Step 2, 1-(4-chloro-2-cyanophenyl)-3-methylurea was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:3]=1.C([Li])CCC.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>O1CCCC1.[Cl-].[Na+].O>[C:11]([O:10][C:9]([NH:8][C:4]1[CH:3]=[C:2]([CH2:1][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:7]=[CH:6][N:5]=1)=[O:15])([CH3:12])([CH3:14])[CH3:13]
Reactant: COC(=O)CBr
Reactant: Cc1ccnc(NC(=O)OC(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CCc1ccnc(NC(=O)OC(C)(C)C)c1
Temperature: -78 °C
Yield: 59 %

Procedure:
tert-Butyl N-(4-methyl-2-pyridyl)carbamate (5 g, 24.0 mmol) was dissolved in tetrahydrofuran (120 ml), cooled to −78° C., and then added dropwise with n-butyl lithium (40 ml, 60 mmol). Then, the reaction solution was warmed and stirred at room temperature. The reaction mixture was stirred for 1 hour, then again cooled to −78° C., and added dropwise with methyl bromoacetate (3.4 ml) dissolved in tetrahydrofuran (10 ml). After the reaction mixture was stirred for 30 minutes, the reaction was stopped with saturated brine and the reaction mixture was extracted with ethyl acetate. The resulting organic layer was dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:ethyl acetate=3:1→5:1) to obtain 3.95 g (59%) of the title compound as pale yellow crystals.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=O.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].CO.[H-].[Na+]>CN(C=O)C>[Cl:14][C:8]1[CH:9]=[C:10]([Cl:13])[CH:11]=[CH:12][C:7]=1[C:5]1[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:3][C:4]=1[C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=1
Reactant: N#CCC(N)=O
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
To a solution of the product of Step A, cyanoacetamide (1.33 g, 15.8 mmol), and MeOH (1.3 mL, 32 mmol) in DMF (35 mL) was added dropwise to a suspension of NaH (60% in mineral oil) (1.45 g, 36 mmol) in DMF (16 mL) at rt. After the slow addition was complete, the reaction was heated to 95° C. for 2.5 h. Most of the DMF was then removed in vacuo before the reaction was diluted with aq 18% citric acid solution. The mixture was extracted twice with CH2Cl2 and the organic layers were washed with brine. The combined organic layers were dried (Na2SO4) and concentrated. The solid residue was triturated with ether, filtered, and air dried to afford the product. (LC-2) HPLC/MS: 375 (M+1), 377 (M+3); Rt=3.47 min.
Reaction SMILES: [C:1]([C:5]1[C:6](=[O:27])[C:7]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:9](=[N:11][C:12]2[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=2)[O:15][CH2:16][C:17]([OH:19])=[O:18])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(O)C>[Pd].C1C=CC=CC=1>[C:23]([C:7]1[CH:8]=[C:9]([CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:27])[NH:11][C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([OH:19])=[O:18])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C1=CC(=Nc2cccc(OCC(=O)O)c2)C=C(C(C)(C)C)C1=O
Agent: [Pd]
Solvent: CCO
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(Nc2cccc(OCC(=O)O)c2)cc(C(C)(C)C)c1O
Reaction time: 5 h

Procedure:
A mixture of 5.0 g of 3-(2,6-di-tertiary-butylcyclohexadienon-4-ylideneamino)phenoxyacetic acid, 250 ml of ethanol and 10 mg of 5% palladium on charcoal catalyst was placed on a Paar apparatus. Hydrogenation was complete after five hours. The reaction mixture was filtered to remove the catalyst and the filtrate was evaporated to give a thick brown oil. The oil was dissolved in 20 ml of benzene, filtered, diluted with 20 ml of cyclohexane and 10 ml of hexane, and chilled to give 1.4 g of light tan crystalline 3-(3,5-di-tertiary-butyl-4-hydroxyanilino)phenoxyacetic acid, m.p. 127°-127.5° C. Analysis: Calculated for C22H29NO4 ; % C, 71.1; % H, 7.9; % N, 3.8; Found: % C, 70.3; % H, 7.6; % N, 3.7.
Reaction SMILES: [CH:1](NC1CCCCC1)(C)C.[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[CH2:20][C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:11][C:12]([CH3:26])=[C:13]([N:18]1[C@H:21]([CH2:22][CH:23]=[CH2:24])[C@H:20]([CH3:1])[C:19]1=[O:25])[C:14]([O:16][CH3:17])=[O:15]
Reactant: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Reactant: CC(C)NC1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@H](C)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: -70 °C
Reaction time: 0.33 h

Procedure:
1.55 M Butyl lithium-hexane solution (1.66 ml) was added to a solution of N-isopropylcyclohexylamine (0.29 ml) in tetrahydrofuran (3 ml) at -70° C., and the mixture was stirred for 20 minutes at -70° C. and allowed to warm up to 0° C. This mixture was added to a solution of methyl 3-methyl-2-[(4R)-2-oxo-4-allylazetidin-1-yl]but-2-enoate (100 mg) in tetrahydrofuran (3 ml) at -70° C., and the mixture was stirred for 1 hour at -70° C. and allowed to warm up to -30° C. during 30 minutes. 1 N Hydrochloric acid (3.6 ml) was added to the reaction mixture at -70° C., and the mixture was diluted with ethyl acetate (30 ml). The solution was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (5:1-2:1) to give methyl 3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-2-enoate (20 mg); IR (CH2Cl2): 1740, 1715 cm-1 ; NMR (CDCl3) δ: 1.23 (d, 3H, J=8 Hz), 1.95 (s, 3H), 2.19 (s, 3H), 1.36 (t, 2H, J=7 Hz), 3.36 (dq, 1H, J=6, 8 Hz), 3.75 (s, 3H), 4.04 (dt, 1H, J=6, 7 Hz), 4.9-5.2 (m, 2H), 5.4-5.9 (m, 2H); and methyl 3-methyl-2-[(3R,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (28 mg); IR (CH2Cl2): 1740 cm-1 ; NMR (CDCl3) δ: 1.27 and 1.29 (a pair of d, 3H, J=8 Hz), 1.83 (broad s, 3H), 2.1-2.9 (m, 2H), 2.85 (dq, 1H, J=2, 8 Hz), 3.2-3.4 (m, 1H), 3.74 and 3.76 (a pair of s, 3H), 4.8-5.2 (m, 5H), 5.5-6.0 (m, 1H); and a mixture of methyl 3-methyl-2-[(3R,4R)-3-methyl-2-oxo- 4-allylazetidin-1-yl]but-2-enoate and methyl 3-methyl-2-[(3S,4R)-3-methyl-2-oxo-4-allylazetidin-1-yl]but-3-enoate (36 mg): IR (CH2Cl2): 1740 cm-1.
Reaction SMILES: NC1C=CNN=1.O/[CH:8]=[C:9]1\[C:10](=[O:18])[NH:11][C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:19]([C:23]1[NH:27][N:26]=[C:25]([NH2:28])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([C:23]1[NH:27][N:26]=[C:25]([NH:28][CH:8]=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH:24]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: O=C1Nc2ccccc2/C1=C/O
Agent: Nc1cc[nH]n1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(NC=C2C(=O)Nc3ccccc32)n[nH]1

Procedure:
The named compound is prepared by substituting 5-tert-butyl-1H-pyrazol-3-ylamine for 3-aminopyrazole in the reaction of Example 1. Specifically, E & Z-3-[(hydroxy)-methylene]-1,3-dihydro-indol-2-one (0.100 gms.) is reacted with 0.1920 gms. of 5-tert-butyl-1H-pyrazol-3-ylamine by refluxing in tetrahydrofuran (2.5 mL).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][N:6]1[C:15](=[O:16])[CH2:14][C:9]2([CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][C:7]1=[O:17].[CH3:18][S:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.C(N(C(C)C)CC)(C)C>CC#N>[CH3:18][S:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][O:5][N:6]3[C:15](=[O:16])[CH2:14][C:9]4([CH2:13][CH2:12][CH2:11][CH2:10]4)[CH2:8][C:7]3=[O:17])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C1CC2(CCCC2)CC(=O)N1OCCCBr
Reactant: CSc1cccc(N2CCNCC2)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CSc1cccc(N2CCN(CCCON3C(=O)CC4(CCCC4)CC3=O)CC2)c1

Procedure:
A mixture of 8-(3-bromopropyloxy)-8-azaspiro[4.5]decan-7,9-dione (4.0 g), 1-(3-methylthiophenyl)piperazine (2.75 g) and diisopropylethylamine (4.6 ml) was stirred in 100 ml of dry CH3CN at room temperature under N2.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[CH3:17])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[OH:28])=[CH:23][CH:22]=2)(=[O:20])=[O:19])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[C:10]([CH3:17])=[CH:11][C:12]([CH3:16])=[CH:13][C:14]=2[CH3:15])[C:5]([S:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:28])=[CH:23][CH:22]=2)(=[O:19])=[O:20])=[CH:4][CH:3]=1
Reactant: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C(O)c3ccccc3)cc2)c(C)c1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: Cc1cc(C)c(Nc2nc(C)ccc2S(=O)(=O)c2ccc(C(=O)c3ccccc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99 %

Procedure:
{4-[6-Methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-phenyl-methanol, prepared as described in Example 53, (60 mg, 0.127 mmol) was dissolved in CHCl3 (2 mL) and Des-Martin periodinane (59 mg, 0.140 mmol) was added. The reaction was stirred at 25° C. for 1.5 h, dissolved in EtOAc (100 mL), and the EtOAc was washed with sat. sodium thiosulfate solution (20 mL), water (20 mL) and brine, dried and stripped in vacuo. The residue was chromatographed on silica gel using 20% EtOAc/hexanes eluent to give {4-[6-methyl-2-(2,4,6-trimethylphenylamino)-pyridine-3-sulfonyl]-phenyl}-phenyl-methanone (59 mg, 99% yield) as a solid, mp 222–225° C. mass spec. (AP+): m/z 471 (M+1).
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][NH:14][CH2:13][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11]2)=[CH:6][CH:5]=1)[CH3:3].C(N(CC)CC)C.[CH:28]1([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1>ClCCl>[CH:28]1([C:33]([N:14]2[CH2:15][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:2]([CH3:1])[CH3:3])=[CH:9][CH:8]=3)[CH2:11][CH:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:13]2)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C1CNCC(c2ccc(C(C)C)cc2)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(c2ccc(C(C)C)cc2)CN(C(=O)C2CCCC2)C1

Procedure:
1.5 g (5.3 mmol) of ethyl 5-[4-(1-methylethyl)phenyl]piperidine-3-carboxylate were dissolved in 18 ml of dichloromethane, and 0.81 g (7.9 mmol) of triethylamine was added at 0° C. 1.43 g (10.5 mmol) of cyclopentanecarbonyl chloride were then added dropwise.
Reaction SMILES: Cl.[C:2](N)(=[O:9])[C:3]1C=C[CH:6]=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:35][C:36]([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[O:37])=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25].O1CCC(=O)CC1>>[ClH:18].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([NH:35][C:36]([CH:38]2[CH2:39][CH2:40][N:41]([CH:4]3[CH2:3][CH2:2][O:9][CH2:6][CH2:5]3)[CH2:42][CH2:43]2)=[O:37])=[C:23]([CH:34]=1)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1)=[O:25]
Reactant: NC(=O)c1ccccc1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)C1CCNCC1
Agent: Cl
Agent: O=C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc(Cl)cn1)c1cc(Cl)ccc1NC(=O)C1CCN(C2CCOCC2)CC1

Procedure:
Using methods substantially equivalent to those described in example 27, 5-chloro-N-(5-chloropyridin-2-yl)-2-[1-(tetrahydropyran-4-yl)piperidin-4-ylcarbonyl]amino]-benzamide hydrochloride (0.25 g, 56%) was prepared from 5-chloro-N-(5-chloropyridin-2-yl)-2-[(piperidin-4-ylcarbonyl)amino]benzamide trifluoroacetate and tetrahydro-4H-pyran-4-one. The preparative RPHPLC (C18) purification procedure was elution with a linear gradient of 90/10 to 50/50 (0.01% HCl/acetonitrile) over 180 min.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:26]1(O)[CH2:31]CCC[CH2:27]1.Cl>CCO.CCO.CCO.CCO.[Ti].O>[Br:1][C:2]1[C:7]2[C:8](=[O:25])[N:9]3[CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:20][CH2:31][CH2:26][CH2:27][CH2:22]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Reactant: OC1CCCCC1
Agent: [Ti]
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2

Procedure:
8 g (20 mmol) of tert.butyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate, 25 g (250 mmol) of cyclohexanol and 1.8 g (8 mmol) of tetraethyl orthotitanate are stirred at 120° overnight, the excess cyclohexanol is removed in a water-jet vacuum and the residue is taken up in chloroform. The solution obtained is stirred for 0.5 hour with 40 ml of a 1:1 mixture of concentrated hydrochloric acid and water, the organic phase is separated, washed once with 1N hydrochloric acid and once with saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. By recrystallization from ethanol there is obtained cyclohexyl (S)-8-bromo-12,12a-dihydro-9-oxo-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carboxylate of melting point 203°-204°.