Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:17](Cl)=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.[NH2:20][C:21]1[C:29]2[O:28][C:27]([CH3:31])([CH3:30])[CH2:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH3:32].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[CH3:30][C:27]1([CH3:31])[CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH3:32])=[C:21]([NH:20][C:17](=[O:18])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:29]=2[O:28]1
Reactant: CCCCCCCCCCCCCCCCC(=O)Cl
Reactant: Cc1ccc2c(c1N)OC(C)(C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Nc1c(C)ccc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 171 mg amount of hexadecanecarboxylic acid chloride was added to a solution of 100 mg of 7-amino-2,2,6-trimethyl-2,3-dihydrobenzofuran and 63 mg of triethylamine in 2 ml of dichloromethane, and the mixture was stirred at room temperature for one hour. A 10 ml amount of a saturated sodium hydrogencarbonate solution was added thereto, and the mixture was extracted twice with 20 ml of ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH2:10][C:11]2([C:19](=[O:20])[O:18]C2=O)[CH2:12][CH2:13][C:14]=1[CH3:15].[CH:21]([O:24]C(C)C)(C)C>>[C:2]1([NH:1][C:21]([CH:12]2[CH:11]([C:19]([OH:18])=[O:20])[CH2:10][C:9]([CH3:8])=[C:14]([CH3:15])[CH2:13]2)=[O:24])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)OC(C)C
Reactant: Nc1ccccc1
Reactant: CC1=C(C)CC2(CC1)C(=O)OC2=O
Product: CC1=C(C)CC(C(=O)Nc2ccccc2)C(C(=O)O)C1
Yield: 96 %

Procedure:
0.9 g (0.01 mol) of aniline was reacted with 1.8 g (0.01 mol) of 3,4-dimethyl-3-cyclohexene dicarboxylic anhydride under reflux for 4 hours in isopropyl ether. The reaction mixture was cooled, and the precipitated crystals were filtered off to provide 2.6 g (yield: 96%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:10]([CH2:11]C2C=CC(Cl)=CC=2)[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:28][Si:29]([CH3:36])([CH3:35])[CH2:30][CH2:31][O:32]CCl>CN(C=O)C>[Br:1][C:2]1[N:10]([CH2:11][O:32][CH2:31][CH2:30][Si:29]([CH3:36])([CH3:35])[CH3:28])[C:9]2[C:8](=[O:19])[NH:7][C:6](=[O:20])[N:5]([CH3:21])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccc(Cl)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.5 %

Procedure:
To a solution of 8-bromo-3-methyl-1H-purine-2,6(3H,7H)-dione (3.5 g, 14.3 mmol, intermediate 8 step 1) in DMF (30 mL) was added potassium carbonate (3.9 g, 28.6 mmol). Then 2-(trimethylsilyl)ethoxymethyl chloride (2.37 g, 14.3 mmol) was added dropwise 0° C., it was stirred room temperature for 3 h. The mixture was partitioned between ethyl acetate and water. The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give a crude product which was washed with ethanol and dried in vacuo to give 8-bromo-3-methyl-7-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (4.0 g, 74.9%) as a white solid. LCMS retention time 1.458 min, LCMS MH+ 377.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][S:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([CH3:38])[N:24]([C:26]3[CH:27]=[C:28]4[C:33](=[C:34]([CH3:36])[CH:35]=3)[NH:32][C:31](=[O:37])[CH:30]=[CH:29]4)[CH:25]=2)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:12][S:13]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:22]=[C:23]([CH3:38])[N:24]([C:26]3[CH:27]=[C:28]4[C:33](=[C:34]([CH3:36])[CH:35]=3)[NH:32][C:31](=[O:37])[CH:30]=[CH:29]4)[CH:25]=2)=[CH:17][CH:16]=1)(=[O:9])=[O:14]
Reactant: Cc1cc(-n2cc(-c3ccc(S(C)=O)cc3)nc2C)cc2ccc(=O)[nH]c12
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(-n2cc(-c3ccc(S(C)(=O)=O)cc3)nc2C)cc2ccc(=O)[nH]c12

Procedure:
meta-Chloroperbenzoic acid (0.11 g) was added to a stirred solution of 6-(4-[4-methylsulphinylphenyl]-2-methyl-imidazol-1-yl)-8-methyl-2-(1H)-quinolone (0.14 g) in dichloromethane (20 cm3) at room temperature. After 30 minutes the mixture was poured into saturated sodium carbonate solution (30 cm3) and extracted with dichloromethane (3×30 cm3). The combined and dried (MgSO4) extracts were evaporated in vacuo to give a residue which was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with methanol:dichloromethane, 1:19 by volume. Collection and evaporation of appropriate fractions afforded a solid which was recrystallised from ethyl acetate to give the title compound, m.p. 345°-7° (0.06 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[C:8]4[CH2:18][CH2:17][C:16](=[O:19])[C:9]=4[CH:10]=[CH:11][C:12]=3[NH:13][C:14]=2[CH:15]=1.[Al+3].[Cl-].[Cl-].[Cl-].[C:24](Cl)([CH3:26])=[O:25]>ClCCl>[C:24]([C:4]1[C:3]([O:2][CH3:1])=[CH:15][C:14]2[NH:13][C:12]3[CH:11]=[CH:10][C:9]4[C:16](=[O:19])[CH2:17][CH2:18][C:8]=4[C:7]=3[C:6]=2[CH:5]=1)(=[O:25])[CH3:26]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)[nH]c1ccc3c(c12)CCC3=O
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2[nH]c3ccc4c(c3c2cc1C(C)=O)CCC4=O
Temperature: 0 °C
Yield: 80 %

Procedure:
8-Methoxy-1,2-dihydro-6H-cyclopenta[c]carbazole-3-one (82) (27.8 g, 110.8 mmol, 1 eq) was dissolved in dry dichloromethane (300 mL). Anhydrous AlCl3 (29.5 g, 221.5 mmol, 2 eq) was added in portions with stirring and cooling, followed by the dropwise addition of AcCl (24 mL, 332.4 mmol, 3 eq). The reaction mixture was stirred at about 5° C. for 24 h and poured into ice water (violent foaming should be avoided). The precipitated orange solid was filtered off, washed with water (10×100 mL), CH2Cl2 (3×50 mL), acetone (3×50 mL) to give 26 g (80%) of 9-acetyl-8-methoxy-1,2-dihydro-6H-cyclopenta[c]carbazole-3-one (83).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][OH:16])[CH:8]=2)=[CH:4][C:3]=1[F:19].N1C=CN=C1.[CH3:25][C:26]([Si:29](Cl)([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C>[NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH2:15][O:16][Si:29]([C:26]([CH3:28])([CH3:27])[CH3:25])([CH3:31])[CH3:30])[CH:8]=2)=[CH:4][C:3]=1[F:19]
Reactant: Nc1ccc(Oc2ccnc(NCCO)c2)cc1F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCNc1cc(Oc2ccc(N)c(F)c2)ccn1
Yield: 66.7 %

Procedure:
A mixture of Example A8 (0.263 g, 1.0 mmol), imidazole (0.0749 g, 1.1 mmol) and TBSCl (0.181 g, 1.2 mmol) in DMF (10 mL) was stirred at RT overnight. Solvent was removed under reduced pressure. The residue was quenched with H2O (10 mL) and the pH was adjusted to ˜8 by using NaHCO3. The aqueous solution was extracted with EtOAc (3×20 mL) and the combined organic layers were dried (MgSO4), concentrated in vacuo and purified by chromatography to afford 4-(4-amino-3-fluorophenoxy)-N-(2-(tert-butyldimethylsilyloxy)ethyl)pyridin-2-amine (0.252 g, 67% yield) as a light yellow oil. MS (ESI) m/z: 378.3 (M+H+).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][S:16][CH2:17][CH2:18][CH:19]=O.[Cl:21][C:22]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:38])[C@:31]([OH:37])([CH3:36])[C:32]([F:35])([F:34])[F:33].C(=O)([O-])O.[Na+]>ClCCCl>[Cl:21][C:22]1[CH:27]=[C:26]([NH:28][CH2:19][CH2:18][CH2:17][S:16][CH3:15])[CH:25]=[CH:24][C:23]=1[NH:29][C:30](=[O:38])[C@:31]([OH:37])([CH3:36])[C:32]([F:34])([F:33])[F:35]
Reactant: CSCCC=O
Reactant: C[C@@](O)(C(=O)Nc1ccc(N)cc1Cl)C(F)(F)F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CSCCCNc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Reaction time: 16 h

Procedure:
Sodium triacetoxyborohydride (0.297 g) was added to a solution of 3-methylsulphanylpropionaldehyde (0.1 ml) and (R)-N-(2-chloro-4-aminophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 208) (0.282 g) in 1,2-dichloroethane (6 ml). The mixture was stirred for 16 hours. Saturated aqueous sodium hydrogen carbonate (25 ml) was added and the mixture was extracted with ethyl acetate (40 ml). The extracts were washed with brine (15 ml) then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a Varian Isolute silica column eluting with 25% ethyl acetate/hexane. The resulting solid was triturated with ether to give the title compound (0.089 g) as a solid. NMR: 1.54 (s, 3H), 1.78 (m, 2H), 2.05 (s, 3H), 2.55 (q, 2H), 3.09 (q, 2H), 5.93 (t, 1H), 6.54 (dd, 1H), 6.65 (s, 1H), 7.46 (m, 2H), 9.33 (s, 1H); MS (ESP−): 369.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=3)[C:16]([C:17]3[C:26]4[C:21](=[CH:22][C:23](Br)=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[C:10]2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:53]([O-:56])(=[O:55])C.[Na+].[C]=O>CN(C=O)C.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][O:56][C:53]([C:23]1[CH:22]=[C:21]2[C:26]([C:17]([C:16]3[C:15]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:14][N:11]4[CH:12]=[CH:13][C:8]([CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[CH:9][C:10]=34)=[CH:18][CH:19]=[N:20]2)=[CH:25][CH:24]=1)=[O:55]
Reactant: Brc1ccc2c(-c3c(-c4ccccn4)nn4ccc(Cc5ccccc5)cc34)ccnc2c1
Reactant: CC(=O)[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: [C]=O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(-c3c(-c4ccccn4)nn4ccc(Cc5ccccc5)cc34)ccnc2c1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 255 %

Procedure:
To a solution of 4-(5-benzyl-2-pyridin-2-yl-pyrazolo-[1,5-a]-pyridin-3-yl)-7-bromo-quinoline (118 mg, 0.24 mmol) in DMF (4 mL) and methanol (4 mL), add triphenylphosphine (20 mg, 0.07 mmol) and sodium acetate (28 mg, 0.36 mmol). Bubble nitrogen for 10 minutes. Add palladium acetate (16 mg, 0.07 mmol) and bubble nitrogen for another 10 minutes. Bubble carbon monoxide through the solution for 5 minutes and attach a carbon monoxide balloon. Heat the reaction mixture at 80° C. for 2 days. Cool the reaction mixture to room temperature. Add water (20 mL) and extract the aqueous solution with ethyl acetate (3×20 mL). Dry the combined organic layers with sodium sulfate and concentrate. Purify by flash column chromatography (SiO2, 20-50% ethyl acetate/hexanes) to give the title compound 84 mg (75%) as a yellow solid.
Reaction SMILES: [NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[CH2:19](I)[CH3:20].[H-].[Na+].O>C1COCC1>[C:9]([N:1]([CH2:19][CH3:20])[C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(C(=O)OCc1ccccc1)[C@H](C(=O)O)C(C)C
Temperature: 60 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
To a solution of Z-Val-OH (50 g) in THF (500 ml), ethyl iodide (127.3 ml, 1592 mmol) was added under cooling with ice and then sodium hydride (60% in oil) (23.88 g, 597 mmol) was added slowly, followed by stirring at 60° C. for 12 hours. The reaction mixture was mixed with water and washed with ether. The thus obtained aqueous layer was rendered acidic by the addition of dilute hydrochloric acid and extracted with ethyl acetate. The resultant was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus obtained residue was subjected to silica gel column chromatography (H:EA:AcOH=100:50:1), giving Z-N-Et-Val-OH (V2) (29.29 g, 53%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:14]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-4-nitrophenol (17.5 mmol, 2.75 g) and allyl bromide (17.5 mmol, 1.5 mL) in 10 mL of DMF was added K2CO3 (21 mmol, 2.9 g). The slurry was stirred at ambient temperature overnight, and partitioned into NaHCO3 (aq)/DCM. The organic phase was removed under reduced pressure affording the product as a brown oil. HPLC A: 2.19 min.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([Cl:13])(Cl)=[O:11].[CH2:14]([NH:20][CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(OCC)C>[CH2:14]([N:20]([CH3:21])[C:10]([Cl:13])=[O:11])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCNC
Reactant: O=C(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCCCCN(C)C(=O)Cl
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 0.35 ml of (i-Pr)2NEt in 10 ml of diethyl ether at 0° C. was added phosgene (1.06 ml, 1.93 M solution in toluene) and N-hexylmethylamine (0.31 ml, 2.05 mm). The reaction mixture was allowed to warm up to 25° C., and further stirred at 25° C. for 14 h. The mixture was filtered, and the solvent was removed under vacuum. The product was used for the next step reaction without further purification. 1H NMR (CDCl3): δ 3.42 (m, 2H), 3.07 (s, 3H), 1.59 (m, 2H), 1.31 (m, 6H), 0.90 (m, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10]([C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[O:11])[CH:8]=1)#[N:2].[NH2:22][OH:23]>CCO>[OH:23][N:22]=[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH3:21])=[C:7]([NH:9][C:10]([C:12]2[N:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]3=[N:14][CH:13]=2)=[O:11])[CH:8]=1)[NH2:2]
Reactant: NO
Reactant: Cc1ccc(C#N)cc1NC(=O)c1cnc2ccccn12
Solvent: CCO
Product: Cc1ccc(C(N)=NO)cc1NC(=O)c1cnc2ccccn12
Temperature: 50 °C

Procedure:
To a stirred and cooled (0° C.) suspension of N-(5-cyano-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (8) (10 g, 36.2 mmol) in EtOH (225 ml) was added NH2OH (6 mL, 50% in water solution). After the addition, the reaction was stirred at room temperature for 2 hours then heated at 50° C. for another 2 hours. After cooling to room temperature, the mixture was stored in the fridge overnight. The resulting precipitate was filtered, washed with cold EtOH and dried under vacuum to afford N-(5-(N′-hydroxycarbamimidoyl)-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide (9) as a white solid. 1H NMR (400 MHz, d6-DMSO) δ 9.40 (dt, J=6.8, 1.2 Hz, 1H), 8.15 (s, 1H), 7.88 (d, J=2.0 Hz, 1H), 7.79 (dt, J=9.2, 1.2 Hz, 1H), 7.76 (dd, J=8.0, 1.6 Hz, 1H), 7.52 (ddd, J=9.2, 9.2, 1.2 Hz, 1H), 7.43 (d, J=8.0 Hz, 1H), 7.17 (td, J=6.8, 1.2 Hz, 1H), 2.49 (s, 3H). MS m/z 310.1 (M+1)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:11]([CH3:12])[C:10]2[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7](=[O:17])[N:6]([CH2:18][CH2:19][CH3:20])[C:5]=2[N:4]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:12][N:11]1[C:10]2[C:9](=[O:13])[N:8]([CH2:14][CH2:15][CH3:16])[C:7](=[O:17])[N:6]([CH2:18][CH2:19][CH3:20])[C:5]=2[N:4]=[C:3]1[CH:2]=[O:1]
Reactant: CCCn1c(=O)c2c(nc(CO)n2C)n(CCC)c1=O
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CCCn1c(=O)c2c(nc(C=O)n2C)n(CCC)c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 55.5 %

Procedure:
Manganese dioxide (2.48 g, 28.5 mmol) was added to a solution of 800 mg (2.85 mmol) of Compound b obtained in Reference Example 2 in 80 ml of chloroform, and the mixture was stirred at room temperature for 12 hours. Then, the reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (eluent: 1% methanol/chloroform) to give 440 mg (yield 56%) of Compound c as a pale yellow powder.
Reaction SMILES: C[O:2][C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:13][N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[OH-].[Na+].CO.C1COCC1>O>[N:14]1([CH2:13][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=2[C:3]([OH:20])=[O:2])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1c(CN2CCOCC2)cccc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A solution of compound 5 (0.85 g) and NaOH (0.304 g) in a mixture of water (9 mL), methanol (5 mL), and THF (45 mL) was stirred at reflux for 24 h and concentrated to dryness. The residue was dissolved in water, and the solution was cooled to 0° C. and adjusted to pH 7 with 10% potassium hydrogen sulfate. The mixture was concentrated to dryness, the residue was treated with methanol, and filtered to remove solids. The filtrate was concentrated to yield compound 6 as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1[CH:25]=[CH:26][C:27](Cl)=[O:28]>>[Cl:22][C:23]1[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=1/[CH:25]=[CH:26]/[C:27]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:28]
Reactant: O=C(Cl)C=Cc1ccccc1Cl
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)/C=C/c3ccccc3Cl)CC1)O2

Procedure:
Compound 61 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-chlorocinnamoyl chloride and conditions outlined in procedure N. M.p.=110-115° C.; 300 MHz 1H NMR (DMSO) δ 8.0-7.75 (m, 5H), 7.6-7.4 (m, 3H), 7.4-7.25 (m, 1H), 7.2-7.1 (m, 1H), 4.5-4.35 (m, 1H), 3.45-3.05 (m, 5H), 2.25-1.7 (m, 4H); LCMS: 466 [M+H].
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[C:24]([N+:34]([O-])=O)=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[C:12]([CH3:37])[C:11]=1[F:38])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:34][C:24]1[C:23]([C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][N:40]=3)(=[O:9])=[O:8])=[C:11]([F:38])[C:12]=2[CH3:37])=[CH:27][NH:26][N:25]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCC[C@@H]3c3cn(C4CCCCO4)nc3[N+](=O)[O-])c(C)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: Cc1c(O[C@H]2CCCC[C@@H]2c2c[nH]nc2N)ccc(S(=O)(=O)Nc2ccncn2)c1F
Yield: 105.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-2-fluoro-3-methyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (209 mg, 0.294 mmol) prepared in Example 73a, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (139 mg, 99%) as a white solid.
Reaction SMILES: [CH:1]([CH:3]=O)=O.[NH2:5][C:6]1[C:27]([NH2:28])=[CH:26][C:9]2[CH2:10][C@@H:11]3[C:16]([CH3:18])([CH3:17])[C@:15]([CH3:19])([C:8]=2[CH:7]=1)[CH2:14][CH2:13][N:12]3C(=O)C(F)(F)F>C(O)C>[CH3:19][C@@:15]12[C:16]([CH3:18])([CH3:17])[C@@H:11]([CH2:10][C:9]3[CH:26]=[C:27]4[N:28]=[CH:1][CH:3]=[N:5][C:6]4=[CH:7][C:8]=31)[NH:12][CH2:13][CH2:14]2
Reactant: CC1(C)[C@H]2Cc3cc(N)c(N)cc3[C@]1(C)CCN2C(=O)C(F)(F)F
Reactant: O=CC=O
Solvent: CCO
Product: CC1(C)[C@H]2Cc3cc4nccnc4cc3[C@]1(C)CCN2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Glyoxal (40% in water, 95 μL) is added to 1-[(2R,6S)-8,9-diamino-6,11,11-trimethyl-1,2,5,6-tetrahydro-4H-2,6-methano-benzo[d]azocin-3-yl]-2,2,2-trifluoro-ethanone (260 mg) dissolved in ethanol (3 mL) and chilled in an ice bath. The cooling bath is removed and the solution is stirred at ambient temperature overnight. Then, the solution is concentrated and the residue is taken up in methanol (1 mL) and treated with 4 M aqueous NaOH solution (0.38 mL). After stirring at ambient temperature overnight, brine is added and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are washed with brine, dried (MgSO4), and the solvent is removed under reduced pressure to give the crude title compound that is used without further purification.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:13][C:14]1[S:18][C:17]([C:19]([OH:21])=[O:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23].[CH2:25](O)[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>>[O:31]1[C:32]2[CH:33]=[CH:34][C:26]([CH2:25][O:20][C:19]([C:17]3[S:18][C:14]([CH3:13])=[C:15]([N+:22]([O-:24])=[O:23])[CH:16]=3)=[O:21])=[CH:27][C:28]=2[O:29][CH2:30]1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: Cc1sc(C(=O)O)cc1[N+](=O)[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1[N+](=O)[O-]
Yield: 77.8 %

Procedure:
The title compound was prepared according to the procedure described for Example 2 using carbonyldiimidazole (0.75 g, 4.3 mmol), 5-methyl-4-nitro-thiophene-2-carboxylic acid (0.6 g, 3.2 mmol), and piperonyl alcohol (0.5 g, 3.3 mmol) to afford 0.8 g of 5-methyl-4-nitro-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester. A sample of the product was triturated in ethanol, cooled, filtered, and dried to give product with a mp 78-79° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[NH:36]1[CH2:39][CH2:38][CH2:37]1.O>C1COCC1>[N:36]1([C:2]2[C:7]([C:8]#[N:9])=[C:6]([C:10]3[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=3)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]3[N:25]=[C:26]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)[S:27][CH:28]=3)[N:3]=2)[CH2:39][CH2:38][CH2:37]1
Reactant: C1CNC1
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At RT, 100 mg (0.19 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 0.015 ml (0.22 mmol) of azetidine were stirred in 2.5 ml of THF overnight. Another 0.025 ml (0.36 mmol) of azetidine was then added, and the mixture was once more stirred at RT overnight. About 10 ml of water were added to the reaction mixture, and the precipitate formed was filtered off, washed with water and dried under high vacuum. This gave 85 mg (82% of theory) of the desired target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([O:13]CC)=[O:12])=[CH:5][C:4]=1[NH:17][C:18](=[O:24])[C:19]([O:21]CC)=[O:20].Cl>[OH-].[Na+].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:16])[C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[NH:17][C:18](=[O:24])[C:19]([OH:21])=[O:20]
Reactant: CCOC(=O)C(=O)Nc1ccc(OC)c(NC(=O)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(NC(=O)C(=O)O)cc1NC(=O)C(=O)O

Procedure:
Diethyl 4-methoxy-N,N'-(m-phenylene)dioxamate (1.0 gm., 0.0029 mole) is stirred in 1.0N NaOH (10 ml.) at room temperature for one hour, then heated at reflux for 30 minutes. The reaction mixture is diluted with water (25 ml.) and the pH adjusted to 3 with hydrochloric acid. The resulting solid is collected and washed with acetone (0.72 gm., 86%, m.p. >320° ).