Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:17]([F:19])[F:18])=[CH:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH:20]12CC(C=C1)C=[CH:21]2.C(N(CC)CC)C>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1>[F:18][CH:17]([F:19])[O:16][C:13]1[CH:14]=[CH:15][C:10]([N:9]2[CH:21]=[CH:20][C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:8]2)=[CH:11][CH:12]=1
Reactant: C1=CC2C=CC1C2
Reactant: CCOC(=O)C(Cl)=NNc1ccc(OC(F)F)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1ccn(-c2ccc(OC(F)F)cc2)n1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 68.6 %

Procedure:
Ethyl 2-chloro-2-(2-(4-(difluoromethoxy)phenyl)hydrazono)acetate (585 mg, 2 mmol) was dissolved in toluene (4 ml) and 2,5-norbornadiene (906 mg, 1 ml, 9.83 mmol) and triethylamine (587 mg, 808 μl, 5.8 mmol) were added. The reaction mixture was stirred at 70° C. for 30 min and the reaction mixture was allowed to stir at room temperature overnight. The solid was filtered off and washed with toluene. The organic fraction was evaporated and the residue obtained was dissolved in xylene (12 ml) and refluxed for 2 hours. The solvent was evaporated and the residue was purified by column chromatography (50 g Silicagel, dichloromethane) to yield 387 mg (69%) of a light yellow solid. MS (ISP): 283.1 ([M+H]+).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[C:20]([CH3:24])=[N:19][CH2:18][CH2:17]2.C(N(CC)CC)C>ClCCl>[CH2:5]([O:4][C:2]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][CH:23]=[C:14]([O:13][CH3:12])[CH:15]=2)[C:20]1=[CH2:24])=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COc1ccc2c(c1)CCN=C2C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C1c2ccc(OC)cc2CCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Benzyl chloroformate (0.30 mL) was added to an ice-cold solution of 6-methoxy-1-methyl-3,4-dihydroisoquinoline (0.36 g) and triethylamine (0.58 mL) in 10 mL dichloromethane. After 0.5 h, the volatile material was evaporated to furnish 0.66 g of 6-methoxy-1-methylene-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])=[CH:4][CH:3]=1.[N-:24]=[N+:25]=[N-:26].[Na+].[C:28](O)(=O)C>C(OC(OCC)OCC)C>[N:1]1([C:2]2[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]3[C:12](=[O:21])[C:13]4[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=4)[C:19]3=[O:20])=[CH:22][CH:23]=2)[CH:28]=[N:26][N:25]=[N:24]1
Reactant: Nc1ccc(OCCCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: CC(=O)O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(OCC)OCC
Product: O=C1c2ccccc2C(=O)N1CCCCOc1ccc(-n2cnnn2)cc1

Procedure:
To a solution of 17.7 g of 2-[4-(4-amino-phenoxy)butyl]-1H-isoindole-1,3(2H)-dione (Example 37) in a mixture of 250 ml of acetic acid and 80 ml of triethylorthoformate is added 7.0 g of sodium azide and the mixture then stirred and heated on the steam bath for 4 hours. Concentration to dryness in vacuo leaves a residue that is triturated with 250 ml of water. The insolubles are collected, washed with water, and dried. Recrystallization from ethanol gives the title compound, m.p. 143°-145° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([OH:19])[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH:6]=[CH:5]2.[CH3:20]N(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].IC>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH:12]([O:19][CH3:20])[CH2:13][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[CH:6]=[CH:5]2
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Cc1ccc2cc(C(O)Cn3ccnc3)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(Cn1ccnc1)c1ccc2cc(C)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2.38 g. of 1-[2-(6-methyl-2-naphthyl)-2-hydroxyethyl]imidazole in 40 ml. of hexamethylphosphoramide under nitrogen is added 480 mg. of a 56% dispersion of sodium hydride in mineral oil. After stirring for 1 hour at room temperature, the temperature is adjusted to 50° C. and stirring is continued for 1 to 2 hours. The reaction mixture is then cooled to about 5° C. and 0.74 ml. of iodomethane is added dropwise. Thereafter, the solution is stirred at 5° to 10° C. for 1 hour, at room temperature for 4 hours and then heated at 50° C. for 2 hours. The reaction mixture is then poured into water and the resultant aqueous mixture extracted with ether and the ether extracts washed with water. The organic phase is dried over magnesium sulfate and evaporated. The resulting residue may be chromatographed on silica gel to effect purification of the free base. Elution of the gel with 5 to 10% methanol in dichloromethane yields 1-[2-(6-methyl-2-naphthyl)-2-(methoxy)ethyl]imidazole.
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28](O)=[O:29])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]1[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][C:27]=1[C:28]([N:15]1[CH2:16][CH2:17][N:12]([C:3]2[C:2]([F:1])=[CH:7][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:5][N:4]=2)[CH2:13][CH2:14]1)=[O:29])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Reactant: Fc1cc(C(F)(F)F)cnc1N1CCNCC1
Product: CS(=O)(=O)c1ccc(OCc2ccccc2)c(C(=O)N2CCN(c3ncc(C(F)(F)F)cc3F)CC2)c1

Procedure:
The title compound was prepared in analogy to example 5 from 1-(3-Fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazine (compound 5.5) and 2-Benzyloxy-5-methanesulfonyl-benzoic acid (compound 7.5). MS (m/e): 538.4 (MH+, 100%)
Reaction SMILES: [N:1]([C@@H:4]([C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[F:15])[C:5]([OH:7])=O)=[N+]=[N-].[NH2:23][C:24]1[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=1[CH2:26][CH2:27][C@H:28]1[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:42])([F:41])[F:40])[N:30](C(OC(C)(C)C)=O)[CH2:29]1>>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@H:8]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[F:15])[C@@H:4]([C:5]([NH:23][C:24]2[CH:54]=[CH:53][CH:52]=[C:51]([F:55])[C:25]=2[CH2:26][CH2:27][C@H:28]2[O:33][CH2:32][C@@H:31]([CH2:34][O:35][C:36](=[O:43])[NH:37][CH2:38][C:39]([F:40])([F:42])[F:41])[NH:30][CH2:29]2)=[O:7])[NH:1][C:36]([O:35][CH3:34])=[O:43])=[CH:17][CH:18]=1
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccncc1F
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccncc1F

Procedure:
The title compound was prepared from the product of step 1 and the product of step 4 from Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=714 (M+H)+.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4]1.[F:11][C:12]([F:21])([F:20])[CH2:13][CH2:14][CH:15]([C:18]#[N:19])[C:16]#[N:17].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N+:8]([C:5]1[CH:6]=[CH:7][N:3]([CH2:2][C:15]([CH2:14][CH2:13][C:12]([F:11])([F:20])[F:21])([C:16]#[N:17])[C:18]#[N:19])[CH:4]=1)([O-:10])=[O:9]
Reactant: N#CC(C#N)CCC(F)(F)F
Reactant: O=[N+]([O-])c1ccn(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cn1ccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
0.61 g of 1-chloromethyl-3-nitro-1H-pyrole and 0.65 g of (3,3,3-trifluoropropyl) malononitrile were dissolved in 10 ml of N,N-dimethylformamide. 0.28 g of potassium carbonate was added to the solution under ice cooling, followed by stirring at room temperature for overnight. Water was added to the reaction mixture, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.80 g of [(3-nitro-1H-pyrole-1-yl) methyl](3,3,3-trifluoropropyl) malononitrile (referred as the compound of the present invention (45), hereinafter) shown by below formula.
Reaction SMILES: [K].[CH3:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13].[CH3:18]N(C=O)C>>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:13]([CH3:18])[C:12]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][CH:6]=1)(=[O:4])[CH3:2]
Reactant: CC(=O)c1ccc(O)cc1
Reactant: CN(C)C=O
Reactant: CCOC(C)=O
Agent: [K]
Product: CCOC(=O)C(C)Oc1ccc(C(C)=O)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of the potassium salt of 4-hydroxyacetophenone (17.6 g, 0.1 mol) in DMF (50 mL) is added to a solution of ethyl L-2-[(methylsulfonyl)oxy]propanoate (21.5 g, 0.11 mol) in DMF (40 mL) over 15 minutes at 80° C. and stirred at 80° C. for 2 hours. to the reaction is added ethyl acetate (100 mL) and filtered. The filtrate is concentrated under reduced pressure whereupon the product is analyzed by GLC. The product is dissolved in ethyl acetate (250 mL) and extracted with saturated sodium bicarbonate solution (2×100 mL) and water (2×60 mL). The organic phase is dried and concentrated to give ethyl 2-(4-acetylphenoxy)propanoate (20.2 g).
Reaction SMILES: [CH3:1][C@@:2]12[C:8]([CH3:10])([CH3:9])[C@@H:5]([CH2:6][CH2:7]1)[C:4](=O)[C:3]2=O.COP([CH2:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]=1[C:27]([F:30])([F:29])[F:28])=O)(=O)OC.O.[NH2:39][NH2:40]>>[CH2:31]([N:25]1[C:26]([C:27]([F:30])([F:29])[F:28])=[C:22]([C:20]2[CH:19]=[C:4]3[C:3]([C@:2]4([CH3:1])[C:8]([CH3:10])([CH3:9])[C@H:5]3[CH2:6][CH2:7]4)=[N:40][N:39]=2)[CH:23]=[N:24]1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: NN
Reactant: COP(=O)(CC(=O)c1cnn(Cc2ccccc2)c1C(F)(F)F)OC
Reactant: CC1(C)[C@H]2CC[C@]1(C)C(=O)C2=O
Solvent: O
Product: CC1(C)[C@H]2CC[C@]1(C)c1nnc(-c3cnn(Cc4ccccc4)c3C(F)(F)F)cc12

Procedure:
yellow oil. MS (EI): 413.2 (M+). Prepared from (1S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]heptane-2,3-dione, [2-(1-Benzyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester, hydrazine monohydrate.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[C:11]3([CH2:25][C:16]4=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]4[CH2:14]3)[N:10]([CH3:26])[C:9]2=[O:27])=CC=1.[N+]([O-])([O-])=O.[NH4+]>C(#N)C.O>[CH3:26][N:10]1[C:11]2([CH2:25][C:16]3=[N:17][CH:18]=[C:19]([C:21]([O:23][CH3:24])=[O:22])[CH:20]=[C:15]3[CH2:14]2)[C:12](=[O:13])[NH:8][C:9]1=[O:27]
Reactant: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)N(Cc2ccc(OC)cc2)C(=O)N1C
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC(=O)c1cnc2c(c1)CC1(C2)C(=O)NC(=O)N1C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 1′-(4-methoxybenzyl)-3′-methyl-2′,5′-dioxo-5,7-dihydrospiro[cyclopenta[b]pyridine-6,4′-imidazolidine]-3-carboxylate (100 mg, 0.25 mmol) in acetonitrile (8.4 mL) at ambient temperature was added eerie ammonium nitrate (4.1 g, 7.6 mmol) as a solution in H2O (5 mL). After 20 min, the reaction mixture was partitioned between H2O (50 mL) and 9:1—CH2Cl2:i-PrOH (50 mL). The aqueous was extracted further with 9:1—CH2Cl2:i-PrOH (5×50 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude solid was washed with MTBE (3×10 mL) then partitioned between saturated aqueous sodium bicarbonate (5 mL) and EtOAc (10 mL). The aqueous layer was extracted further with EtOAc (10 mL) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound in sufficient purity for use in the next step. MS: m/z 276.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][C:37]([C:41]([F:44])([F:43])[F:42])([OH:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][C:37]([C:41]([F:44])([F:42])[F:43])([OH:40])[CH2:36][CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(O)(C(F)(F)F)CC1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(O)(C(F)(F)F)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4-(trifluoromethyl)piperidin-4-ol. MS (ESI): mass calcd. for C22H20F4N4O3S, 496.12; m/z found, 497.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.23 (d, J=1.1, 1H), 8.15-8.11 (m, 1H), 7.94 (m, 1H), 7.75-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.45-7.41 (m, 1H), 7.35-7.27 (m, 2H), 3.29-3.22 (m, 2H), 2.79-2.64 (m, 2H), 1.65-1.48 (m, 4H).
Reaction SMILES: [Cl:1][CH:2]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][C:10]=1[Cl:11])[NH2:7].[CH3:17][CH:18]1[CH2:28][CH2:27][C:21]2[C:22]([O:24][C:25](=O)[C:20]=2[CH2:19]1)=[O:23]>>[Cl:11][C:10]1[CH:9]=[CH:8][C:6]([N:7]2[C:25](=[O:24])[C:20]3[CH2:19][CH:18]([CH3:17])[CH2:28][CH2:27][C:21]=3[C:22]2=[O:23])=[CH:5][C:4]=1[CH2:3][CH:2]([Cl:1])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CC1CCC2=C(C1)C(=O)OC2=O
Reactant: CCOC(=O)C(Cl)Cc1cc(N)ccc1Cl
Product: CCOC(=O)C(Cl)Cc1cc(N2C(=O)C3=C(CC(C)CC3)C2=O)ccc1Cl

Procedure:
2.60 g of 3-(2-chloro-2-ethoxycarbonyleth-1-yl)-4-chloroaniline and 1.65 g of 4-methyl-3,4,5,6-tetrahydrophthalic anhydride were refluxed for 6 hours. After the mixture had been cooled and evaporated down, the residue was taken up in ethyl acetate and the solution was washed three times with water. The organic phase was dried over Na2SO, and then evaporated down. Yield 3.0 g (75%); 1H-NMR (in d6-DMSO/TMS): δ [ppm]=0.96 (d; 3H), 1.05 (t; 3H), 1.64-2.08 (m; 3H), 2.15-2.70 (m; 4H), 3.20-3.55 (m; 2H), 4.14 (q; 2H), 4.78 (dd; 1H), 7.26 (d; 1H), 7.34 (s; 1H), 7.55 (d; 1H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26](O)=[O:27])=[CH:21][CH:20]=1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.O>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:26]([NH:17][CH2:16][CH2:15][C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:10]=2)=[O:27])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1ccc(O)cc1
Reactant: NCCc1cccc(OCc2ccccc2)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccc(O)cc1)NCCc1cccc(OCc2ccccc2)c1
Yield: 56.2 %

Procedure:
A solution of 2-[3-(phenylmethoxy)phenyl]ethylamine (2.80 g, 12.3 mmol), 4-hydroxyphenylacetic acid (2.25 g, 14.8 mmol), N,N-diisopropylethylamine (2.79 mL, 16 mmol), and EDCI (3.07 g, 16 mmol) in 20 mL of DMF was stirred at room temperature for 10 h. The reaction mixture was poured into 100 mL of water and the aqueous layer was extracted with CH2Cl2. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography (SiO2, hexanes/ethyl acetate, 1:1) to provide the title compound (2.50 g, 56% yield): ES−MS, (m/z) 362 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[O-:14][CH2:15][CH3:16].[Na+].N1C=CC=CC=1C1C=CC=CN=1.C(OCC)(=O)C>CO>[CH2:15]([O:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:16]
Reactant: CCOC(=O)Nc1ccccc1Br
Reactant: CC[O-]
Agent: [Na+]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)Nc1ccccc1OCC
Yield: 83.7 %

Procedure:
2.44 g of the 2-bromo-1-ethoxycarbonylaminobenzene was added to a solution containing 680 mg of sodium ethoxide, 170 mg of cupric chloride dihydrate, and 156 mg of 2,2'-bipyridine in 40 ml of methanol, and the mixture was heated under reflux for 1.5 hours. After the temperature was brought to room temperature, ethyl acetate was added thereto, and the resulting mixture was washed with water and dried over Glauber's salt. The solvent was distilled off, and the obtained crude crystals were recrystallized from a n-hexane/ethyl acetate solvent mixture, to obtain 1.75 g (yield: 84%) of the desired compound. The spectrum data of the compound was in agreement with the spectrum data of the separately synthesized reference compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29]/[C:30](=[N:33]/[H])/[NH:31]O)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]>CS(C)=O>[CH2:11]([N:15]1[C:23]2[N:22]=[C:21]([Cl:24])[NH:20][C:19]=2[C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[N:31]=[C:8]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[O:10][N:33]=2)[C:16]1=[O:35])[CH2:12][CH2:13][CH3:14]
Reactant: Cc1cccnc1C(=O)O
Reactant: [H]/N=C(/CCCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCCc2noc(-c3ncccc3C)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 12.2 %

Procedure:
3-Methyl-2-pyridinecarboxylic acid (35 mg, 0.25 mmol) and CDl (45 mg, 0.28 mmol) were stirred in anhydrous DMSO (0.9 ml) at rt for 1 h. (1Z)-5-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxypentanimidamide (100 mg, 0.28 mmol) was added and the mixture was stirred at 90° C. for 16 h. The reaction mixture was purified by MDAP. The product fraction was combined and concentrated to give the title compound as a white solid 14 mg, 12%).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:11]([OH:14])(=O)[CH3:12].N1C2C=CC=CC=2NC=1.[NH2:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>C1COCC1>[NH2:28][C:27]1[C:26]2[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:24][C:11](=[O:14])[CH:12]=1
Reactant: N#Cc1ccccc1N
Reactant: CC(=O)O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Product: Nc1cc(=O)[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3-4 eq) was added to the benzimidazole acetate (1.0 eq) in THF (at a constant temperature ranging from −78° C. to 0° C.). After 20 minutes, a solution of the 2-aminobenzonitrile (1.1 eq) in THF was then added. The resulting mixture was allowed to warm to room temperature, stirred for 1-3 hours and was then heated to approx. 40° C.-65° C. (1 hour to 12 hours). The mixture was cooled to 0° C. and quenched with NH4Cl (aq, saturated). The aqueous phase was extracted with CH2Cl2 or EtOAc, and the organic extracts were collected, dried (Na2SO4), and filtered. Evaporation of the solvent under reduced pressure and purification of the residue by silica gel chromatography or HPLC provided the 4-amino quinolinone products.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=O.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[CH:12]=[CH:13][C:14]3[C:19]([C:8]=2[S:7](=[O:20])(=[O:21])[NH:6][C:5]=1[C:3]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:2])=[CH:18][CH:17]=[CH:16][CH:15]=3
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: O=C(Nc1nccs1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1

Procedure:
3.2 gm (0.01 mol) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide and 1.5 gm (0.015 mol) of 2-amino-thiazole were heated for 16 hours in 200 ml of dry xylene analogous to Example 35. After cooling, the precipitate which had formed was suction-filtered off, and the mother liquor was evaporated in vacuo, whereby another crop of crude 4-hydroxy-N-(2-thiazolyl)-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxamide-1,1-dioxide was obtained. The two crops of crude product were combined and recrystallized three times from acetonitrile, yielding 0.85 gm (23% of theory) of the desired compound, m.p. 238° C (decomp.).
Reaction SMILES: [C:1]([OH:10])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][C:6](O)=O.O[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O>CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Co+2].[Co].C1CCCCC1>[CH:1]1([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[C:17]1(=[O:19])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C(O)CCCCC(=O)O
Reactant: O=C(O)CCCCCO
Agent: [Co+2]
Agent: [Co]
Agent: CCCCC(CC)C(=O)[O-]
Solvent: C1CCCCC1
Product: O=C1CCCCC1
Product: OC1CCCCC1
Reaction time: 1488 h

Procedure:
Cyclohexane was oxidized in the liquid phase with air, in the presence of cobalt octoate catalyst at a pressure of about 170 psi. The cobalt content of the stream was about 0.1 ppm. Two of the components of the "other oxidation products" were measured: the stream contained about 0.13 weight % adipic acid and about 0.26 wt percent 6-hydroxy caproic acid. A commercial alkyl phosphate (Emphos PS-400) was injected into the oxidizer tails at 6 ppm concentration. The mixture was extracted with water, 2.5% by volume, at 127° C. in two mixer/separator stages and then flashed to remove water. The resulting mixture contained cyclohexane, 1.212 weight % cyclohexylhydroperoxide, 0.087 weight % dicyclohexylperoxide, 0.029 weight % 2-cyclohexyl-2-methylfuranylperoxide, 0.886 weight % cyclohexanone, 2.32 weight % cyclohexanol, 128 ppm cyclohexenone and about 0.02 ppm cobalt. Analysis showed that between about 65 and 85 weight % of the adipic acid and 6-hydroxy caproic acid were extracted. This mixture was hydrogenated at 150° C. and 165 psia in a 6-inch×9-foot long fixed bed containing 60 pounds of 1/12-inch spheres of 0.5% palladium on silica catalyst. After 62 days of operation (56,000 pounds of feed per pound of catalyst), the hydrogenation rate remained high for cyclohexylhydroperoxide (99%), 2-cyclohexyl-2-methylfuranylperoxide (81%), cyclohexenone (98%), and dicyclohexylperoxide (60%). The ratio of cyclohexanol to cyclohexanone produced across the hydrogenator remained high at 5.5. A high percentage of peroxide exiting the air oxidizer (>80%) reached the hydrogenator. The yield of cyclohexanol and cyclohexanone was 92% based on converted peroxide. The moles of hydrogen consumed per mole of peroxide consumed was 0.60, with the remaining hydrogen dissolved in the hydrogenator tails stream. The catalyst removed at the end of the run was clean and free flowing.
Reaction SMILES: [Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:11](=[O:17])[N:10]([CH2:18][C:19]([OH:21])=O)[N:9]=1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[Cl:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]1[N:12]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:11](=[O:17])[N:10]([CH2:18][C:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([C:23]([F:22])([F:32])[F:33])[CH:25]=2)=[O:21])[N:9]=1
Reactant: Cc1csc(-c2nn(CC(=O)O)c(=O)n2CC(C)C)c1Cl
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(-c2nn(CC(=O)NCc3cccc(C(F)(F)F)c3)c(=O)n2CC(C)C)c1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
40.0 mg (0.121 mmol) of 2-[3-(3-chloro-4-methyl-2-thienyl)-4-isobutyl-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]-acetic acid from Example 249A and 23.4 mg (0.133 mmol) of 3-trifluoromethyl-benzylamine are placed in 1.5 ml of DMF and treated with 19.7 mg (0.146 mmol) of HOBt. 30.2 mg (0.158 mmol) of EDC hydrochloride are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with about 15 ml of water and the resulting precipitate filtered off, washed with water and dried in vacuo. 43 mg (73% of theory) of the target compound are thus obtained.