Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:24][C:25]1[CH:30]=[C:29]([C:2]2[C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[CH:6][CH:5]=[C:4]([CH3:23])[N:3]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3cccc(Cl)c3)c2cc1OC
Temperature: 80 °C
Reaction time: 3 h
Yield: 72.9 %

Procedure:
4-[(2-Iodo-6-methyl-3-pyridyl)oxy]-6,7-dimethoxyquinoline (compound 116) (84 mg), 3-chlorophenylboronic acid (156 mg), tetrakistriphenylphosphine palladium (12 mg) were dissolved in toluene (1 ml) to prepare a solution. A saturated aqueous sodium hydrogencarbonate solution (1 ml) was added to the solution, and the mixture was stirred at 80° C. for 3 hr. The reaction solution was filtered, and the solvent was then removed by distillation under the reduced pressure. The residue was purified by column chromatography using methanol-chloroform to give the title compound (59 mg, yield 73%).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][CH:13]=[C:14]([CH:17]=O)[C:15]=3[CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19]([O:25][CH3:26])(=[O:24])[CH2:20][C:21]([CH3:23])=O.[NH2:27]/[C:28](/[CH3:32])=[CH:29]\[C:30]#[N:31]>C(O)C>[CH3:23][C:21]1[NH:27][C:28]([CH3:32])=[C:29]([C:30]#[N:31])[CH:17]([C:14]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:15]=2[CH:16]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[N:9]3)[C:20]=1[C:19]([O:25][CH3:26])=[O:24]
Reactant: COC(=O)CC(C)=O
Reactant: O=Cc1cccc2ncc(-c3ccccc3)cc12
Reactant: C/C(N)=C/C#N
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C#N)C1c1cccc2ncc(-c3ccccc3)cc12

Procedure:
0.7 g (3 mmol) of 3-phenylquinoline-5-aldehyde in 6 ml of ethanol are boiled with 0.35 g (3 mmol) of methyl acetoacetate and 0.25 g (3 mmol) of 3-aminocrotononitrile for 24 hours. The mixture is cooled and concentrated. The evaporation residue is purified by means of a silica gel column using toluene/ethyl acetate mixtures. The clean fractions are combined and concentrated. 0.5 g of colorless substance of melting point 242° C. are obtained by crystallization from isopropanol.
Reaction SMILES: N1C=CC=CC=1.Cl.[NH2:8][OH:9].[CH3:10][C:11]1[C:15]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=O)=[N:14][O:13][N:12]=1>C(OCC)(=O)C>[CH3:10][C:11]1[C:15](/[C:16](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:8]/[OH:9])=[N:14][O:13][N:12]=1
Reactant: NO
Reactant: Cc1nonc1C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1nonc1/C(=N/O)c1ccccc1
Temperature: 70 °C
Yield: 21.6 %

Procedure:
A pyridine (55 ml) solution of hydroxylamine hydrochloride (5.19 g, 73.0 mmol) was added to (3-methyl-1, 2, 5-oxadiazol-4-yl) phenylmethanone (3.43 g, 18.0 mmol) and heated to 70° C. for 21 hours with stirring. After the reacted solution was condensed, the residue was dissolved in ethyl acetate. After washing with diluted hydrochloride and subsequent washing with water, the residue was dried with magnesium carbonate. After removing the solvent and purifying the residue by column chromatography, (Z)-(3-methyl-1, 2, 5-oxadiazol-4-yl) phenylmethanone oxime (2.13 g) and (E)-(3-methyl-1, 2, 5-oxadiazol-4-yl)phenylmethanone oxime (0.79 g) were obtained.
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][C:7](=[CH2:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>CS(C)=O>[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:33][CH2:32][N:31]([C:3]2[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[C:7](=[CH2:10])[CH2:8][O:9][C:4]=2[C:5]=34)[CH2:30]1)=[O:27])([CH3:24])([CH3:22])[CH3:23]
Reactant: C=C1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Solvent: CS(C)=O
Product: C=C1COc2c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 60.3 %

Procedure:
130 mg of 9,10-difluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid and 300 mg of 3-tertiary-butoxycarbonylaminopyrrolidine were added to 3 ml of dimethyl sulfoxide and the mixture was allowed to react for 3 hours at 100°-110° C. (bath temperature). The solvent was distilled off in vacuo. The residue was washed with diethyl ether and purified by silica gel column chromatography and then recrystallized from benzene to give 125 mg of 10-(3-tertiary-butoxycarbonylamino-1-pyrrolidinyl)-9-fluoro-3-methylene-7-oxo-2,3-dihydro-7H-pyrido(1,2,3-de)-1,4-benzoxazine-6-carboxylic acid with mp 219°-220° C. as luster yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:13](Cl)(Cl)=[O:14]>O1CCOCC1>[Br:11][C:10]1[C:2]2[NH:1][C:13](=[O:14])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[C:8]([Cl:12])[CH:9]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1c(Br)cc(Cl)cc1C(=O)O
Solvent: C1COCCO1
Product: O=c1[nH]c2c(Br)cc(Cl)cc2c(=O)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 114.2 %

Procedure:
To a solution of 2-amino-3-bromo-5-chlorobenzoic acid (10.0 g, 39.9 mmol) in dioxane (170 mL) was added phosgene (20% in toluene, 42.0 mL, 79.9 mmol) over a period of 15 min. The reaction was stirred at room temperature for 48 h and then concentrated in vacuo. The resulting solid was crushed and further dried in vacuo to yield the title compound (12.6 g, 114%), which was used in the following step without further purification.
Reaction SMILES: [CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([N+]([O-])=O)[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7].[CH2:20]([SH:22])[CH3:21].C([O-])(=O)C.[Na+]>C(OCC)(=O)C>[CH3:1][N:2]=[C:3]([OH:19])[C:4]1[C:5](=[C:9]([S:22][CH2:20][CH3:21])[CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:6]([OH:8])=[O:7]
Reactant: CCS
Reactant: CN=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCSc1cc([N+](=O)[O-])cc(C(O)=NC)c1C(=O)O

Procedure:
5.02 g (20 mmols) of 3,5-dinitrophthalic acid N-methylimide, 2.73 g (44 mmols) of ethylmercaptan, 8.2 g (1 0 mmols) of anhydrous sodium acetate and 50 ml of ethyl acetate are kept at 25° C. overnight and then kept under reflux, again overnight. The reaction mixture is evaporated, the residue is taken up in methylene chloride/water, the extracts are washed with saturated NaHCO3 solution, dried over sodium sulfate and evaporated and the residue is chromatographed with methylene chloride over 20 g of silica gel. After recrystallisation from methylene chloride/n-pentane, 2.40 g (45% of theory) of 3-ethylthio-5-nitrophthalic acid N-methylimide, with a melting point of 193°-4° C., are obtained.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=2)[C:4](=[O:23])[C:3]=1[C:24](=O)[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28](OC(F)(F)F)[CH:27]=1.[OH2:38].[NH2:39][NH2:40].C(=O)([O-])O.[Na+]>CN(C=O)C>[F:20][C:19]([F:22])([F:21])[O:38][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][C:24]1[C:3]2[C:4](=[O:23])[N:5]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][C:19]([F:22])([F:21])[F:20])[CH:13]=3)[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[NH:40][N:39]=1
Reactant: NN
Reactant: O=C(Cc1cccc(OC(F)(F)F)c1)c1c(O)c2cccnc2n(-c2cccc(OC(F)(F)F)c2)c1=O
Reactant: O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2c(Cc3cccc(OC(F)(F)F)c3)n[nH]c2c2cccnc2n1-c1cccc(OC(F)(F)F)c1
Temperature: 105 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a suspension of 4-hydroxy-1-(3-trifluoromethoxyphenyl)-3-(3-trifluoromethoxyphenylacetyl)-1,8-naphthyridin-2(1H)-one (630 mg, 1.2 mmol) produced in Synthesis Example 24 in DMF (5 mL) was added hydrazine monohydrate (purity of 80%, 233 μL), and the mixture was stirred at 100 to 110° C. for 1 hour. To the reaction solution was added a sodium hydrogencarbonate aqueous solution. The resulting precipitate was separated by filtration, recrystallized from ethanol, and dried to give 3-(3-trifluoromethoxybenzyl)-5-(3-trifluoromethoxyphenyl)-1H-pyrazolo[4,3-c][1,8]naphthyridin-4(5H)-one (101 mg, yield 16%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](OCC)=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([NH:22][CH2:18][CH2:19][CH2:20][CH3:21])=[C:8]2[CH:14]=[N:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCCCN
Reactant: CCOC(=O)c1cnc2[nH]ncc2c1OCC
Solvent: O
Product: CCCCNc1c(C(=O)OCC)cnc2[nH]ncc12
Yield: 64.8 %

Procedure:
2.35 g of 4-ethoxy-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (0.01 mol) is treated with 2.2 g of butylamine (0.03 mol) at 90° for 1 hour. After this period the mixture is cooled, diluted with 20 ml of water and the white crystalline precipitate is filtered off. Recrystallization from diethyl ether yields 1.7 g of 4-butylamino-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester (72%), m.p. 181°.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].O(Cl)[Cl:16].[OH-].[Na+]>O>[Cl:16][C:5]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: ClOCl
Reactant: CCOC(=O)c1c(O)ncnc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1c(Cl)ncnc1CC
Temperature: 90 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
Ethyl 6-ethyl-4-hydroxypyrimidine-5-carboxylate (7.30 g, 37.21 mmol) was stirred under ice-cooling. Phophorus oxychloride (11.41 g, 74.41 mmol) was added dropwise to it. After the addition, the mixture was stirred at 90° C. for 3 hours. After cooling to room temperature, the mixture was poured into ice-cooled water and adjusted to pH 10 with an aqueous solution of sodium hydroxide. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (3.50 g, 44%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:15]=[CH:16]/C(N=[N+]=[N-])=O)[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=1.C([N:26]([CH2:31]CCC)CCCC)CCC.C1([O:41]C2C=CC=CC=2)C=CC=CC=1>>[Br:1][C:2]1[C:3]2[C:31](=[O:41])[NH:26][CH:16]=[CH:15][C:4]=2[N:5]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: CCCCN(CCCC)CCCC
Reactant: C[Si](C)(C)CCOCn1cc(Br)cc1/C=C/C(=O)N=[N+]=[N-]
Product: C[Si](C)(C)CCOCn1cc(Br)c2c(=O)[nH]ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of (2E)-3-(4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrol-2-yl)acryloyl azide (3.39 g) and tributylamine (1.86 g) in diphenyl ether (33.9 mL) was stirred under nitrogen atmosphere at 90-105° C. for 15 min, and then at 155-160° C. for 2 hr. The reaction mixture was allowed to be cooled to room temperature, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.01 g).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH2:20][S:21][CH2:22][CH2:23][C:24]([OH:26])=O)(=[O:17])[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][CH3:16].Cl.[C:47]([O:51][C:52](=[O:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][NH2:57])([CH3:50])([CH3:49])[CH3:48].P(C#N)(OCC)(OCC)=O.O>CN(C)C=O.C(N(CC)CC)C>[C:47]([O:51][C:52](=[O:59])[CH2:53][NH:54][C:55](=[O:58])[CH2:56][NH:57][C:24](=[O:26])[CH2:23][CH2:22][S:21][CH2:20][CH:19]([O:18][C:1](=[O:17])[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][CH3:16])[CH2:27][O:28][C:29](=[O:45])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])([CH3:50])([CH3:48])[CH3:49]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)CNC(=O)CN
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)NCC(=O)NCC(=O)OC(C)(C)C)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 78 %

Procedure:
To a solution of 6,7-bis(palmitoyloxy)-4-thiaheptanoic acid as obtained in Reference Example 4 (200 mg) and glycylglycine t-butyl ester hydrochloride (80 mg) in dimethyl formamide (3 ml), triethylamine (0.099 ml) and diethyl cyanophosphate (73 mg) were added, followed by stirring at room temperature for 17 hours. After addition of water, the reaction mixture was extracted with chloroform. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:3) to yield the title compound (191 mg, yield 78%) as a wax-like substance.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.ClC(Cl)(Cl)[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]=[N:25][CH:24]=[CH:23]2)=[O:16].C1CCN2C(=NCCC2)CC1>>[CH:26]1[C:27]2[C:22](=[CH:21][CH:20]=[CH:19][C:18]=2[NH:17][C:15]([NH:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=2)=[O:16])[CH:23]=[CH:24][N:25]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: O=C(Nc1cccc2ccncc12)C(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2ccncc12

Procedure:
The title compound was prepared using 4-(trifluoromethyl)benzylamine, the product from Example 57D, DBU and the procedure described in Example 1B. MS (ESI+) m/z 346 (M+H)+; 1H NMR (DMSO-d6) δ 9.58 (s, 1H), 9.10 (s, 1H), 8.49 (d, 1H), 8.12 (d, 1H), 7.81-7.54 (m, 7H), 7.20 (t, 1H), 4.47 (d, 2H); Anal. Calcd for C18H14F3N3O.0.2H2O: C, 61.96; H, 4.16; N, 12.04. Found: C, 62.06; H, 4.23; N, 11.91.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6]1)=[O:4].C(#N)C.C(N(CC)CC)C.[CH:34]1[CH:39]=[CH:38][C:37]([O:40][C:41](OC2C=CC=CC=2)=[N:42][C:43]#[N:44])=[CH:36][CH:35]=1>>[C:43](/[N:42]=[C:41](\[O:40][C:37]1[CH:38]=[CH:39][CH:34]=[CH:35][CH:36]=1)/[N:7]1[CH2:8][CH2:9][C@H:10]([C:11]([N:13]2[CH2:17][CH2:16][C@H:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14]2)=[O:12])[C@@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1)#[N:44]
Reactant: COC(=O)[C@H]1CNCC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)[C@H]1CN(/C(=N/C#N)Oc2ccccc2)CC[C@@H]1C(=O)N1CC[C@H](c2ccccc2)C1
Temperature: 85 °C
Yield: 88.2 %

Procedure:
To a stirred solution of (3R,4S)-4-((R)-3-Phenyl-pyrrolidine-1-carbonyl)-piperidine-3-carboxylic acid methyl ester (654 mg, 0.00207 mol) in anhydrous acetonitrile (11.0 mL, 0.211 mol) at rt was added triethylamine (0.579 mL, 0.00413 mol) and diphenyl cyanocarbonimidate (762 mg, 0.00310 mol). The reaction mixture was heated to reflux (oil bath temperature: 85° C.) for 18 h. The reaction mixture was concentrated in vacuo. The residue was purified by Combiflash with 40-90% EtOAc/Hex to give the product as a colorless solid (841 mg, 88% in yield). MS (ESI): (M+H)+=461.1.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][C:27]=2[CH3:35])=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:36][C:37]1[CH:38]=[C:39]([CH:43]=[CH:44][CH:45]=1)[C:40]([NH2:42])=[O:41].O.[C:47]([OH:51])(=[O:50])[CH:48]=O>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:14]1[CH:15]=[C:16]([NH:20][C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH:48]([NH:36][C:37]3[CH:45]=[CH:44][CH:43]=[C:39]([C:40](=[O:41])[NH2:42])[CH:38]=3)[C:47]([OH:51])=[O:50])=[CH:28][C:27]=2[CH3:35])=[O:22])[CH:17]=[CH:18][CH:19]=1)[CH3:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CC(=O)O
Reactant: Cc1cc(B(O)O)ccc1CCOC(=O)Nc1cccc([C@@H](C)NC(=O)OCc2ccccc2)c1
Reactant: NC(=O)c1cccc(N)c1
Solvent: O
Product: Cc1cc(C(Nc2cccc(C(N)=O)c2)C(=O)O)ccc1CCOC(=O)Nc1cccc([C@@H](C)NC(=O)OCc2ccccc2)c1
Yield: 70 %

Procedure:
Using a procedure analogous to that used to prepare 2D, 64D (175 mg, 0.37 mmol) was reacted with 3-aminobenzamide and glyoxylic acid monohydrate to afford 64E (175 mg, 70%) as an oil. MS (ESI) m/z 625.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:15]O>>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: CO
Reactant: Cc1c(C(=O)O)cc(Br)cc1[N+](=O)[O-]
Product: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1C

Procedure:
reacting 5-bromo-2-methyl-3-nitrobenzoic acid with methanol to form methyl 5-bromo-2-methyl-3-nitrobenzoate;
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][CH2:8][CH2:9][C:10](O)=[S:11])=[N:5][N:4]=[N:3]1.N1C=CC=CC=1.BrC(OC)=O.[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]1>O1CCCC1>[CH3:24][CH:25]1[CH2:30][CH2:29][CH:28]([NH:31][C:10](=[S:11])[CH2:9][CH2:8][CH2:7][C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)[CH2:27][CH2:26]1
Reactant: Cn1nnnc1CCCC(O)=S
Reactant: CC1CCC(N)CC1
Agent: COC(=O)Br
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC1CCC(NC(=S)CCCc2nnnn2C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To tetrahydrofuran (50 ml) are added 4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyric acid (45 mmole) and pyridine (50 mmole), and thereto is added dropwise with stirring methyl bromoformate (50 mmole) with keeping the inner temperature at 5°-15° C. by ice-cooling, and thereafter, the mixture is stirred at room temperature for one hour. To the mixture is added 4-methylcyclohexylamine (55 mmole), and the mixture is further stirred for 3 hours. After the reaction, the solvent is distilled off under reduced pressure, and the residue is dissolved in chloroform. The chloroform layer is washed with dilute aqueous sodium hydroxide solution, diluted hydrochloric acid and water in order, and dried over sodium sulfate. Inorganic materials are filtered off and the mother liquor is concentrated. The resulting residue is subjected to column chromatography (Wakogel C-200, eluting solvent, benzene:chloroform=4:1, V/V) to isolate N-(4-methylcyclohexyl)-4-(1-methyl-1,2,3,4-tetrazol-5-yl)thio-butyramide (yield: 45%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17](Cl)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][NH:26][CH3:27]>CO.C(Cl)Cl.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([N+:21]([O-:23])=[O:22])=[CH:19][CH:18]=[C:17]([N:26]([CH3:27])[CH3:25])[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2nc(Cl)ccc2[N+](=O)[O-])CC1
Reactant: CNC
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)c1ccc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 104.3 %

Procedure:
To a stirring solution of 6 g (0.016 mol) of 4-(6-chloro-3-nitro-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester in MeOH/CH2Cl2 (84 mL/15 mL) was added 2.2 g (0.05 mol) of dimethylamine in THF (25 mL). The reaction mixture was stirred at room temperature for 16 h, and was then concentrated. The crude product was then dissolved in CH2Cl2 (400 mL) and washed with saturated NaHCO3 (2×200 mL). The washes were combined and extracted with EtOAc (100 mL). The combined organic layers were dried over Na2SO4 and concentrated to afford 6.1 g (99%) of the desired product as a bright yellow solid. MS (electrospray): exact mass calculated for C17H27N5O4, 365.21; m/z found, 388.19 [M+Na]+. 1H NMR (400 MHz, CDCl3): 8.74 (d, J=7.07 Hz, 1H), 8.18 (d, J=9.4 Hz, 1H), 5.97 (d, J=7.3 Hz, 1H), 4.28-4.16 (m, 1H), 4.07-3.93 (m, 2H), 3.17 (s, 6H), 3.01 (t, J=11.9 Hz, 2H), 2.05 (dd, J=12.4 Hz and 3.03 Hz, 2H), 1.60-1.50 (m, 2H), 1.47 (s, 9H).
Reaction SMILES: N[C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].C(ON=O)(C)(C)C.[C:24](#[N:27])[CH:25]=[CH2:26].[Cl:28]C1C=CC(Cl)=CC=1C(C1C=CC=CC=1)=O>C(#N)C.Cl.O.CCOCC>[Cl:28][CH:25]([CH2:26][C:2]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:3]=1[C:4](=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:24]#[N:27]
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: O=C(c1ccccc1)c1cc(Cl)ccc1Cl
Reactant: C=CC#N
Agent: CC(C)(C)ON=O
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: O
Product: N#CC(Cl)Cc1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 92.7 g (0.4 mole) of 2-amino-5-chlorobenzophenone in 250 ml of acetonitrile was added to a mixture of 70 g (0.52 mole) of cupric chloride, 65 g (0.63 mole) of t-butylnitrite, 500 ml of acrylonitrile, and 500 ml of acetonitrile. When the addition was complete stirring at room temperature was continued for 2 hr. The mixture was diluted with 80 ml of 6 N hydrochloric acid and 1500 ml of water, extracted with ether and dried over anhydrous sodium sulfate. The ether solution was concentrated at reduced pressure to give a brown oil, which contained the end product and 2,5-dichlorobenzophenone. Trituration of the oil with a mixture of ether and petroleum ether gave the end product as a tan solid. Recrystallization of a small portion of the end product from a mixture of ether and petroleum ether gave pale yellow needles, mp 69°-71°.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:6][CH2:7][C@H:8]1[O:27][C@H:11]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[OH:28])([CH3:4])[CH3:3].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][S:42]([O:28][C@@H:9]1[C@@H:8]([CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:27][C@H:11]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)(=[O:44])=[O:43]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1OS(C)(=O)=O)(c1ccccc1)c1ccccc1

Procedure:
The title compound is prepared by the procedure of Example 277 using 3.39 g of product from Example 284, 0.57 ml of methanesulfonyl chloride, 1.03 ml of triethylamine, and 30 ml of methylene chloride to give, after chromatography, 3.0 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:6]([Cl:7])=[N:5][C:4](=[C:8](Cl)Cl)[N:3]=1.[CH3:11][NH:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[O:21]1CCOCC1>>[C:13]([N:12]([CH3:11])[C:8]([C:4]1[NH:5][C:6]([Cl:7])=[C:2]([Cl:1])[N:3]=1)=[O:21])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C1COCCO1
Reactant: ClC1=NC(=C(Cl)Cl)N=C1Cl
Reactant: CNC(=O)c1ccccc1
Product: CN(C(=O)c1ccccc1)C(=O)c1nc(Cl)c(Cl)[nH]1
Temperature: 0 °C
Yield: 20 %

Procedure:
A solution of 21.8 g (0.1 mol) of 4,5-dichloro-2-dichloromethylene-imidazole was added to a solution of 15 g (0.11 mol) of N-methyl-benzamide in 100 ml of dioxane. The mixture was then heated briefly to the boil and discharged into ice water. The oil which first precipitated out became solid after a few hours. After the product had been filtered off, washed with water and dried, 6.0 g (20% of theory) of N-benzoyl-N-methyl-4,5-dichloro-imidazole-2-carboxylic acid amide with a melting point of 168° C. (acetonitrile) were obtained.