Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH3:13])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][C:23]([CH3:38])([C:27]([NH:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:24](O)=[O:25]>>[CH3:13][O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:24](=[O:25])[C:23]([CH3:22])([CH3:38])[C:27]([NH:29][CH2:30][C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])=[O:28])[C:3]2[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=2[C:5]2[CH:17]=[CH:16][CH:15]=[CH:14][C:6]1=2
Reactant: COCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: COCCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-methoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (74%). White solid. MS: m/e=528(M+H+).
Reaction SMILES: [NH2:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[O:22][CH3:23])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:24](Cl)(=[O:26])[CH3:25].C(N(CC)CC)C>C(Cl)Cl>[CH:19]([C:16]1[CH:17]=[CH:18][C:13]([C:2]2([NH:1][C:24](=[O:26])[CH3:25])[C:10](=[O:11])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:12])=[C:14]([O:22][CH3:23])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: COc1cc(C(C)C)ccc1C1(N)C(=O)c2ccccc2C1=O
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(C)C)ccc1C1(NC(C)=O)C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62251.7 %

Procedure:
2-Amino-2-(4-isopropyl-2-methoxyphenyl)-2H-inden-1,3-dione (0.10 g, 0.32 mmol) was dissolved in methylene chloride (4 ml). This solution was added with acetyl chloride (0.05 ml, 0.70 mmol), followed by stirring at room temperature for 15 min, and added with triethylamine (0.12 ml, 0.86 mmol), and stirred for 6 hrs. After the reaction mixture was extracted with methylene chloride (50 ml×3), the organic layer was purified using column chromatography (45% ethylacetate in hexane) to afford the title compound (70 g, 62%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([C:9]([OH:11])=O)=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH2:16]([N:18](CC)[CH2:19]C)C.CNC>ClCCl.CN(C=O)C>[CH3:16][N:18]([CH3:19])[C:9]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:8][NH:7][N:6]=1)=[O:11]
Reactant: CCN(CC)CC
Reactant: O=C(O)c1n[nH]cc1[N+](=O)[O-]
Agent: CNC
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1n[nH]cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 24 h
Yield: 29.7 %

Procedure:
A solution of 4-nitro-1H-pyrazole-3-carboxylic acid (1.0 g, 6.4 mmol) in dichloromethane (20 ml) was treated with thionyl chloride (1.4 ml, 19 mmol) and a drop of DMF at ambient temperature. The reaction mixture is stirred at 40° C. overnight whereupon another equivalent of thionyl chloride (0.46 ml, 6.4 mmol) was added and stirring was continued at 40° C. for another 24 h. All volatiles were removed and the acid chloride was suspended in dichloromethane (6 ml) and cooled to 0° C. Triethylamine (4.44 ml, 31.8 mmol) and dimethylamin (4.14 ml, 2M solution in THF) were added. The reaction mixture was allowed to warm-up to ambient temperature and stirring was continued for 3 h. The reaction mixture was partitioned between potassium hydrogen sulfate (20 ml, 10% aqueous solution) and ethyl acetate (40 ml) and extracted. The organic phase was washed with water and brine, dried and the solvent was evaporated. The crude product was triturated with diethylether, sucked off and dried to yield a light brown solid (0.35 g, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[NH2:26])[C:19]([O:21][CH3:22])=[O:20])=[O:12])=[O:7])=[CH:4][CH:3]=1.[N:29]1([C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH2:33][CH:32]=[CH:31][CH2:30]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([CH2:8][CH2:9][O:10][C:11]([CH2:13][NH:14][CH2:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=2[NH:26][CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34]([N:29]3[CH2:33][CH:32]=[CH:31][CH2:30]3)=[O:35])=[CH:43][CH:42]=2)[C:19]([O:21][CH3:22])=[O:20])=[O:12])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(C(=O)N2CC=CC2)cc1
Reactant: COC(=O)c1ccc(N)c(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(NCc2ccc(C(=O)N3CC=CC3)cc2)c(CNCC(=O)OCCC(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
660 mg (1.63 mmol) of methyl 3-[((4-chlorobenzoyl)ethoxycarbonylmethylamino)methyl]-4-aminobenzoate and 431 mg (2.1 mmol) of 4-(2,5-dihydro-1H-pyrrol-1-ylcarbonyl)benzaldehyde were dissolved in 10 ml of dichloromethane. 0.185 ml (3.26 mmol) of acetic acid was added to the solution, and they were stirred at room temperature for 30 minutes. 860 mg (4.1 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([OH:20])[CH:19]=1.[CH3:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH:27]1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.C(Cl)Cl>[F:13][C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([O:20][C@@H:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:26]2[O:25][CH3:24])[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Reactant: COC1CCCCC1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CO[C@H]1CCCC[C@H]1Oc1cc(F)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2.36 ml DEAD were added to an ice-cooled solution of the 1.57 g 5-fluoro-2-nitrophenol, 1.95 ml 2-methoxycyclohexanol and 3.93 g triphenylphosphine in 30 ml THF. The reaction mixture was allowed to warm to rt overnight. The mixture was stirred additional 48 hours. Then the reaction mixture was diluted with methylene chloride and washed with 10% aq. potassium carbonate solution. The organic phase was passed through a hydrophobic frit and evaporated. Purification was achieved by silica gel column chromatography (solvent:10:1 iso-hexane: EtOAc).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[CH3:21][N:22]1[CH:26]=[C:25]([C:27](O)=[O:28])[CH:24]=[N:23]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:27]([C:25]3[CH:24]=[N:23][N:22]([CH3:21])[CH:26]=3)=[O:28])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: Cn1cc(C(=O)O)cn1
Product: Cn1cc(C(=O)NCc2cn(-c3ccccc3)c3cc(Cl)ccc3c2=O)cn1

Procedure:
Methyl-1H-pyrazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-methyl-1H-pyrazole-4-carboxylic acid. MS calcd. for C21H18ClN4O2 [(M+H)+] 393.1, obsd. 393.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](COCCO)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:27]([O:31][C:32](N1C[C@@H](C)N2[C@H](CC3C2=NC([C@@H](O)C)=CC=3)C1)=O)(C)(C)[CH3:28]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([C@@H:27]([O:31][CH3:32])[CH3:28])=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(COCCO)nc3N21
Reactant: C[C@H](O)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Product: CO[C@@H](C)c1ccc2c(n1)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C

Procedure:
This compound was prepared in analogy to Example 41 intermediate b), from (4R,9aR)-6-(1-(S)-hydroxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H--2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [Cl:1][C:2]1([Cl:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7]Cl.[S-:10][C:11]#[N:12].[K+]>C(O)C>[Cl:1][C:2]1([Cl:9])[C:4]([CH3:6])([CH3:5])[CH:3]1[CH2:7][S:10][C:11]#[N:12]
Reactant: N#C[S-]
Reactant: CC1(C)C(CCl)C1(Cl)Cl
Agent: [K+]
Solvent: CCO
Product: CC1(C)C(CSC#N)C1(Cl)Cl
Yield: 85.9 %

Procedure:
1.87 g of 2,2-dichloro-3,3-dimethyl-1-chloromethylcyclopropane and 1.0 g of potassium thiocyanate were suspended in 20 ml of ethanol, and the suspension was refluxed for 12 hours. Ethanol was evaporated, and 20 ml of water was added. The mixture was extracted with toluene. The toluene layer was washed with water and dried over sodium sulfate. The toluene was then evaporated under reduced pressure to give 1.80 g of 2,2-dichloro-3,3-dimethylcyclopropylmethyl thiocyanate, the desired compound shown above. The boiling point of the product was 115° C. at 200 mmHg.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][CH2:40][NH2:41])[CH:34]=1>>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:21]=[CH:20][C:16]([C:17]([NH:41][CH2:40][CH2:39][C:35]3[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=3)=[O:18])=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)(=[O:24])=[O:25]
Reactant: NCCc1cccnc1
Reactant: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)cc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)NCCc4cccnc4)cc3)oc2C)cc1
Yield: 81 %

Procedure:
Method E. Reaction of oxalyl chloride (71.2 μL, 0.82 mmol) and benzoic acid 4 (202 mg, 0.54 mmol) with subsequent reaction with 2-(3-pyridinyl)ethylamine (71 λL, 0.59 mmol) gave benzamide 12 (208 mg, 81%) as a white powder: mp (EtOAc) 207-208° C.; 1H NMR δ 8.68 (t, J=5.6Hz, 1 H, CONH), 8.46 (d, J=1.7Hz, 1 H, H-2′), 8.41 (dd, J=4.7, 1.6Hz, 1 H, H-6′), 7.93 (dd, J=8.6, 2.0Hz, 2 H, H-2, H-6), 7.87 (dd, J=8.6, 2.0Hz, 2 H, H-3, H-5), 7.65-7.69 (m, 3 H, H-4′, H-2″, H-6″), 7.42 (d, J=8.3Hz, 2 H, H-3″, H-5″), 7.31 (ddd, J=7.8, 4.7, 0.7Hz, 1 H, H-5′), 4.62 (s, 2 H, CH2SO2), 3.54 (dt, J=7.0, 5.8 Hz, 2 H, CH2N), 2.89 (t, J=7.1Hz, 2 H, CH2), 2.40 (s, 3 H, CH3), 2.13 (s, 3 H, CH3); 13C NMR δ 165.4, 158.0, 149.9, 149.8, 147.4, 144.5, 136.2, 135.8, 135.6, 134.9, 129.6 (2), 128.7, 128.3 (2), 127.9 (2), 126.0, 125.4 (2), 123.4, 53.0, 40.4, 32.0, 21.0, 9.7; MS m/z 476.6 (MH+, 100%). Anal. calcd for C26H25N3O4S: C, 65.67; H, 5.30; N, 8.84. Found: C, 65.53; H, 5.18; N, 8.75%.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.C(O)(=O)C.[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1>N1C=CC=CC=1>[NH2:12][C:13]1[N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:5](=[O:7])[CH3:6])=[CH:22][CH:21]=2)[C:17](=[O:27])[N:16]([CH3:28])[C:15](=[O:29])[CH:14]=1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1c(=O)cc(N)n(Cc2ccc(N)cc2)c1=O
Solvent: c1ccncc1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Cn2c(N)cc(=O)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Using the general procedure for Intermediate 1, (4-nitro-benzyl)-urea [J. Med. Chem. 1996, 39, 1924] is converted into 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione, [MH]+ 277. A solution of calcium chloride (4.94 g, 45 mmol) in water (100 ml) is added to a solution of 6-amino-3-methyl-1-(4-nitro-benzyl)-1H-pyrimidine-2,4-dione (19.08 g, 69.0 mmol) in acetic acid (300 ml). Zinc dust (58.8 g, 900 mmol) is then added portionwise with external cooling. The reaction is stirred at room temperature for 1.5 hours, filtered through a celite plug and washed successively with ethanol and acetic acid. Evaporation of the combined filtrate and washings affords 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine-2,4-dione acetic acid salt, [M-3H]− 243. Acetic anhydride (7.2 ml, 76.0 mmol) is added to a cooled (0° C.) suspension of 6-amino-1-(4-amino-benzyl)-3-methyl-1H-pyrimidine -2,4-dione acetic acid salt (17.0 g, 69.0 mmol) in pyridine (260 ml). The reaction mixture is warmed to room temperature, stirred for 6 hours and the solvent evaporated. The residue is triturated with water and the solid collected by filtration and dried to afford N-[4-(6-amino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 289. Using the general procedure for Intermediate 1, this compound is converted into N-[4-(5,6-diamino-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-phenyl]-acetamide, [MH]+ 304.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=2)[CH:7]=1)=[O:5].[CH3:26][C:27]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=1[Mg]Br>C1COCC1>[Br:24][C:20]1[N:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:15](=[O:16])[C:6]([C:4](=[O:5])[C:28]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:27]=3[CH3:26])=[CH:7]2)[CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccc([Mg]Br)c(C)c1
Reactant: CON(C)C(=O)c1cn(Cc2cccc(Br)n2)c2ccccc2c1=O
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)c2cn(Cc3cccc(Br)n3)c3ccccc3c2=O)c(C)c1

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60 from 90 mg (0.22 mmol) of 1-(6-bromo-pyridin-2-ylmethyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid methoxy-methyl-amide in 1 mL THF and 0.98 mL 0.5M 2,4-dimethylphenylmagnesium bromide. Yield: 57 mg of a white solid. LC-MSD, m/z for C24H19BrN2O2 [M+H]+=447.0, 449.0; HPLC retention time: 2.7 min.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:26])([F:25])[F:24])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([O:19]C)=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:27])[C:5]=2[NH:4][N:3]=1.O.O.[OH-].[Li+].Cl>CO.O1CCCC1>[Br:1][C:2]1[C:10]2[C:9]3[CH2:11][N:12]([CH2:22][C:23]([F:24])([F:25])[F:26])[C:13](=[O:21])[C@H:14]([CH2:16][C:17]([OH:19])=[O:18])[CH2:15][C:8]=3[CH:7]=[C:6]([Br:27])[C:5]=2[NH:4][N:3]=1
Reactant: COC(=O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C[C@@H]1Cc2cc(Br)c3[nH]nc(Br)c3c2CN(CC(F)(F)F)C1=O
Temperature: 60 °C
Reaction time: 1.25 h
Yield: 96 %

Procedure:
(S)-Methyl 2-(1,4-dibromo-8-oxo-9-(2,2,2-trifluoroethyl)-3,6,7,8,9,10-hexahydroazepino[3,4-e]indazol-7-yl)acetate (220 mg, 0.429 mmol) was dissolved in a mixture of methanol (5.0 mL) and tetrahydrofuran (5.0 mL). Water (5.0 mL) was added to the mixture followed by lithium hydroxide hydrate (66.0 mg, 1.573 mmol). Reaction was warmed to 60° C. and held with stirring for 1.25 hours. Mixture was cooled to room temperature and then neutralized with 1.6 mL 1N hydrochloric acid. Mixture was concentrated by roto-vap. Residue was partitioned between ethyl acetate and water. Layers were separated and the aqueous phase was discarded. Material was washed with brine and the aqueous phase was discarded. Organics were dried MgSO4, filtered and then concentrated to dryness. Title compound was obtained as white solid in 96% yield. MS (M−H)−=498.1, 496.1, 500.1.
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]2[N:8]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:21]=[CH:20][C:7]2[N:8]([CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: CC(c1ccccc1)n1c(=O)oc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CCO
Product: CC(c1ccccc1)n1c(=O)oc2cc(N)ccc21
Reaction time: 2 h
Yield: 62.2 %

Procedure:
Into a solution of 6-nitro-3-(1-phenylethyl)benzo[d]oxazol-2(3H)-one (40-2, 7.89 g, 27.8 mmol) in EtOH (139 ml) was added Pd/C (295 mg, 2.78 mmol). The reaction was stirred under 1 atm of H2 for 2 h, filtered through celite, concentrated and purified using a 50 g SCX column (eluting with 2 N NH3 in MeOH) to yield 6-amino-3-(1-phenylethyl)benzo[d]oxazol-2(3H)-one (4.4 g, 17.3 mmol). LRMS C15H14N202 [M+H] calc 255.1, obs 255.4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=C2C(=[CH:11][CH:12]=1)C(=O)CCC2)#[N:2].Cl.[CH2:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31]N)[CH:26]=2)=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([C:19]1[CH:24]=[CH:23][C:22]([C:25]2[C:26]3[C:27]4[NH:31][C:19]5[C:24]([C:28]=4[CH2:29][CH2:30][C:11]=3[CH:12]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:23][CH:22]=[CH:21][CH:20]=5)=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CCCCc1ccc(-c2cccc(NN)c2)cc1
Reactant: N#Cc1ccc2c(c1)CCCC2=O
Agent: Cl
Product: CCCCc1ccc(-c2cc(C#N)cc3c2-c2[nH]c4ccccc4c2CC3)cc1

Procedure:
This material is prepared from commercially available 6-cyanotetralone and (4′-Butyl-biphenyl-3-yl)-hydrazine hydrochloride (example 70, step 1) in the same manner and similar yield as example 1, step 3. LC/MS calculated for [M+H]+ C27H25N2: 377.2, found: 377.1.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[OH:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:28])([CH3:25])([CH3:24])[CH3:23]>CC(N(C)C)=O>[C:22]([O:26][C:27]([N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH:30]1[CH2:35][CH2:36][O:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: Oc1ccccc1CCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCCCN2C(=O)OC(C)(C)C)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CCCCC1CCOc1ccccc1CCc1ccccc1
Yield: 75.6 %

Procedure:
Following a procedure similar to that described in Example 40(a), 0.930 g of 2-(2-phenylethyl)phenol (prepared as described in Preparation 19), 0.527 g of potassium t-butoxide and 1.66 g of 1-t-butoxycarbonyl-2-[2-(p-toluenesulfonyloxy)ethyl]piperidine were reacted in 20 ml of dimethylacetamide. The mixture was then worked lap as described in Example 40(a), and the crude product thus obtained was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.34 g (yield 75%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5]Br.[NH:11]1[CH2:21][CH2:20][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][N:11]1[CH2:12][CH2:13][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:20][CH2:21]1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Clc1ccc(CBr)cc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Reaction time: 17 h
Yield: 88.5 %

Procedure:
3,4-Dichlorobenzyl bromide (1.83 g, 7.63 mmol) was added to a solution of ethyl isonipecotate (1 g, 6.36 mmol) and triethylamine (1.33 ml, 9.54 mmol) in methylene chloride solution (10 ml) at room temperature. After 17 h, the reaction mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution (10 ml). The organic layer was dried over magnesium sulfate, filtered, and concentrated. Flash chromatography with 9:1, hexanes/ethyl acetate followed by 6:1 hexanes/ethyl acetate gave ethyl 1-(3,4-dichlorobenzyl)isonipecotate (1.78 g) as a pale yellow oil.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([C:23]1[NH:24][C:25](=O)[C:26]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28][C:27]=2[N:40]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:16]([C:23]1[N:24]=[C:25]([O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[C:26]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:37])[CH3:39])=[O:34])[CH2:29][CH2:28][C:27]=2[N:40]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)[nH]c(=O)c2CC1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)nc(OS(=O)(=O)C(F)(F)F)c2CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
Triflic anhydride (516 mg, 0.30 mL, 1.83 mmol) was added dropwise to a solution of the product of Step A (500 mg, 1.41 mmol) and pyridine (167 mg, 0.17 mL, 2.11 mmol) in CH2Cl2 (5.0 mL) at 0° C. The resulting solution was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was quenched by addition of water then partitioned between 5% citric acid and ethyl acetate. The organic layer was washed with sodium bicarbonate (sat.), dried over magnesium sulfate and concentrated under vacuum to yield the crude product as a yellow gum (670 mg). This material was taken on without further purification.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1.OS(O)(=O)=O.[CH3:24]O>>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([O:15][CH3:24])=[O:14])(=[O:9])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1

Procedure:
3-(Morpholinosulfonyl)benzoic acid (100 mg, 0.369 mmol) was refluxed overnight in methanol in the presence of catalytic concentrated H2SO4 at 65° C. The reaction was monitored by TLC. After completion of the reaction, the solvent was removed by vacuum and then compound was purified by column chromatography to yield the title compound as an off white solid (60 mg). 1H NMR (400 MHz, CDCl3): δ 8.38 (t, 1H, J=1.6 Hz), 8.27 (m, 1H), 7.92 (m, 1H), 7.64 (t, 1H, J=8.0 Hz), 3.95 (s, 3H), 3.73 (m, 4H), 3.00 (m, 4H). ESI-MS: 286.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH2:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([CH2:19][NH:20][C:21](=[O:36])[O:22][CH:23]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14]2)=[O:6].[CH3:37]I>CN(C)C=O>[CH3:37][N:20]([CH2:19][CH:13]1[CH2:12][CH2:11][C:10]2[C:15](=[CH:16][CH:17]=[CH:18][C:9]=2[O:8][CH2:7][C:5]([O:4][CH3:3])=[O:6])[CH2:14]1)[C:21](=[O:36])[O:22][CH:23]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CI
Reactant: COC(=O)COc1cccc2c1CCC(CNC(=O)OC(c1ccccc1)c1ccccc1)C2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1CCC(CN(C)C(=O)OC(c1ccccc1)c1ccccc1)C2
Reaction time: 7 h
Yield: 59.1 %

Procedure:
60% Sodium hydride (10.2 mg) was added to a stirred solution of benzhydryl N-[[1,2,3,4-tetrahydro-5-(methoxycarbonylmethoxy)-2-naphthyl]methyl]carbamate (117 mg) and methyl iodide (36 mg) in N,N-dimethylformamide (1.2 ml) under ice cooling and the mixture was stirred at the same temperature for 7 hours, then another 60% sodium hydride (10.2 mg) and methyl iodide (36 mg) was added thereto. The resulting mixture was stirred at room temperature for 3 days and extracted with ethyl acetate. The extract was washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene-ethyl acetate) over silica gel to afford benzhydryl N-methyl-N-[[1,2,3,4-tetrahydro-5-(methoxycarbonylmethoxy)-2-naphthyl]methyl]carbamate (71 mg) as an oil.