Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([O:23][CH3:24])=[CH:20]2)=[CH:15][CH:14]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].CCCCCC>C1(C)C=CC=CC=1.[Pd]>[CH2:1]([C:13]1[CH:22]=[C:21]2[C:16]([CH:17]=[CH:18][C:19]([O:23][CH3:24])=[CH:20]2)=[CH:15][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC#Cc1ccc2ccc(OC)cc2c1
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCCCCCCCCCCCc1ccc2ccc(OC)cc2c1
Yield: 96 %

Procedure:
Using 7-methoxy-2-naphthyltrifluoromethanesulfonate (30.63 g, 0.10 mol) and 1-dodecyne (20.79 g, 0.125 mol), 7-dodecyn-1-yl-2-methoxynaphthalene was synthesized by the same operation as that in the method for synthesizing 7-decyl-2-methoxynaphthalene according to Example 3, and subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain a light yellow oil product of 7-dodecyn-1-yl-2-methoxynaphthalene (32.0 g, quantitative). The obtained 7-dodecyn-1-yl-2-methoxynaphthalene (total amount) was subjected to catalytic reduction in toluene (316 ml) under a hydrogen atmosphere by adding 10% Pd/C (2.11 g). The obtained product was subjected to column chromatography (silica gel, developed with a mixture of toluene and hexane) to obtain 7-dodecyl-2-methoxynaphthalene (compound (3)-14, 31.10 g, yield of 96%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH2:17][CH2:18]2)[C:13]([Cl:28])=[CH:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2].O1CCCC1.Br.[NH+]1C=CC=CC=1>CC(C)=O>[C:1]([O:4][CH2:5][C:6](=[O:30])[C@@H:7]1[C@:24]2([CH3:25])[C@H:10]([C@H:11]3[C@H:21]([C@@H:22]([OH:26])[CH2:23]2)[C@:19]2([CH3:20])[C:14](=[CH:15][C:16](=[O:27])[CH:17]=[CH:18]2)[C:13]([Cl:28])=[CH:12]3)[CH2:9][C@H:8]1[CH3:29])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C
Agent: Br
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC(=O)OCC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3[C@@H](O)C[C@@]21C

Procedure:
A solution of 10.45 g. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-4,6-pregnadiene-3,20-dione in 80 ml. of tetrahydrofuran is combined with 6.5 g. of pyridinium hydrobromide perbromide in 26 ml. of tetrahydrofuran and agitated for 20 minutes at 25°. Subsequently, 0.6 ml. of acetone is added thereto and the mixture is filtered. The filtrate is concentrated under vacuum to a volume of 10 ml., and combined with 80 ml. of dimethylformamide, 4.5 g. of lithium carbonate, as well as 1.62 g. of lithium bromide. The mixture is heated for 2.5 hours to 105° and concentrated under vacuum at 60° to a volume of 40 ml. The mixture is combined with 10 ml. of acetic acid and 14 ml. of water and stirred into 350 ml. of ice water. The thus-obtained precipitate is filtered off, washed with water, and dried in the air. The crude product, 9.4 g., is chromatographed on silica gel. With 40% ethyl acetate-hexane and after recrystallization from acetone-diisopropyl ether, 1.81 g. of 21-acetoxy-6-chloro-11β-hydroxy-16α-methyl-1,4,6-pregnatriene-3,20-dione is obtained, m.p. 192° [α]D25 =+136° (pyridine). UV: ε228 =11,100, ε256 =10,500, ε299 =9,800 (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)[Cl:15]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:15])=[O:8]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(Cl)cc1C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-2-methoxybenzoic acid (11.3 g, 60.56 mmol) and SOCl2 (9 mL, 123.7 mmol) in toluene (20 mL) were heated gently while vigorous gas evolution occurred. After gas evolution had subsided, the reaction was heated to reflux for 1.5 h, cooled and stirred overnight at room temperature. The volatiles were evaporated in vacuo and the remaining material was treated with toluene and evaporated (2×) to remove excess SOCl2 to provide a white solid that was taken directly on to the next step without purification. 1H NMR (300 MHz, CDCl3) δ 3.92 (s, 3H), 6.95 (d, 1H), 7.53 (dd, 1H), 8.03 (d, 1H).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH:13]1([N:16]2[C:24]3[C:19](=[CH:20][C:21]([CH2:25][NH:26][S:27]([C:30]4[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=4)(=[O:29])=[O:28])=[CH:22][CH:23]=3)[CH:18]=[N:17]2)[CH2:15][CH2:14]1>>[Cl:8][C:7]1[C:2]([N:26]([CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH:13]2[CH2:15][CH2:14]2)[N:17]=[CH:18]3)[S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)(=[O:29])=[O:28])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3C3CC3)c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3C3CC3)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-cyclopropyl-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-5 of Example 28).
Reaction SMILES: [N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:2]1[C:3]([N:5]([CH2:14][CH3:15])[CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[N:1]1([C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:2]1[C:3]([N:5]([CH2:14][CH3:15])[CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CCN(CC(=O)OC(C)(C)C)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCN(CC(=O)O)C(=O)[C@H]1CCCCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 106.5 %

Procedure:
To a solution of Cbz-D-hPro-N(Et)Gly-O-t-Bu (5 g, 12.4 mmol) in dichloromethane (50 mL) was added anisole (2.5 mL) and trifluoroacetic acid (50 mL). The mixture was allowed to stir for several hours at room temperature. The solvents were removed in vacuo and the resulting oil was partitioned between saturated aqueous NaHCO3 and diethyl ether. The layers were separated and the organic phase was extracted once with saturated aqueous NaHCO3. The combined aqueous phase was adjusted to pH 2 with 5N aqueous HCl and extracted three times with ethyl acetate (150 mL). The combined ethyl acetate extracts were dried with MgSO4, filtered, and concentrated to give a colorless oil (4.6 g, 106%).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9](I)=[CH:8][CH:7]=1)=[O:4].[CH2:15]([OH:21])[CH2:16][CH2:17][CH2:18][C:19]#[CH:20]>CN(C=O)C.C([O-])(=O)C.C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]([F:14])([F:13])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:20]#[C:19][CH2:18][CH2:17][CH2:16][CH2:15][OH:21])=[CH:8][CH:7]=1)=[O:4]
Reactant: O=C(Nc1ccc(I)cc1)C(F)(F)F
Reactant: C#CCCCCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C#CCCCCO)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of Intermediate 32 (2.7 g, 8.5 mmol, prepared according to Melissaris, A. P. and Litt, M. H. J Org Chem 1994, 59, 5818-5821) in DMF (26 mL) was treated successively with tetra-n-butylammonium acetate (3.8 g, 13 mmol) and palladium (II) acetate (57 mg, 0.26 mmol). The mixture was degassed with nitrogen and then treated with 5-hexyn-1-ol (0.93 mL, 8.5 mmol). After four hours of stirring at room temperature, additional quantities of the following reagents were added: tetra-n-butylammonium acetate (1 g), palladium (II) acetate (57 mg), and 5-hexyn-1-ol (1 mL). After stirring overnight at room temperature, the mixture was partitioned between diethyl ether and water. The aqueous phase was extracted four times with diethyl ether. The combined organic extracts were washed twice with water and once with saturated aqueous sodium chloride solution before drying over anhydrous magnesium sulfate, filtration and concentration under reduced pressure to provide the title compound as brown syrup that partially solidified under vacuum. ES/MS calcd. for C14H15F3NO2+: 286.1. Found m/z=286.2 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[FH:14].Cl>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([Cl:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([F:14])=[O:5]
Reactant: O=C(Cl)c1cc(F)c(Cl)c(Cl)c1Cl
Reactant: F
Agent: Cl
Product: O=C(F)c1cc(F)c(Cl)c(Cl)c1Cl

Procedure:
480 g (1.83 mols) of 2,3,4-trichloro-5-fluorobenzoyl chloride are introduced, with 240 g (12 mols) of hydrogen fluoride, at -5° to 0° C. into a stirred autoclave fitted with a pressure-control valve, the apparatus is pressure-sealed and warmed to 70° C. in steps, corresponding to the evolution of HCl. The hydrogen chloride produced is continuously released at 4-5 bar. When the evolution of HCl is complete, the mixture is cooled, the excess pressure is released and the reaction mixture is fractionated.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][NH:12]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]2[CH3:10])[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: CC1CCCCN1
Solvent: ClCCl
Product: CC1CCCCN1Cc1cccc(Br)n1

Procedure:
6] To 6-bromo-2-pyridinecarboxaldehyde (400 mg, 2.15 mmol) was added 2-methylpiperidine (0.4 mL, 3.22 mmol) in dry CH2Cl2 (10 mL) to give 2-bromo-6-[(2-methylpiperidinyl)methyl]pyridine as a pale yellow solid. MS m/z: 269.1(M+H). Calc'd for C12H17BrN2: 269.18.
Reaction SMILES: [OH-].[Na+].[P:3]([O-:20])([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:21]([O:28][C:29](=[O:32])[CH:30]=[O:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][C:29](=[O:32])[CH:30]([P:3]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:20])[OH:31])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=CC(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(OCc1ccccc1)C(O)P(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 20 °C
Yield: 61 %

Procedure:
1.5 ml of a saturated methanolic sodium hydroxide solution are allowed to run rapidly into 45.5 g of dibenzyl phosphite and 28.5 g of glyoxylic acid benzyl ester. The reaction which proceeded is exothermic. The mixture is subsequently stirred at 20° C. for some hours. It is chromatographed on silica gel using methylene chloride containing 5% of methanol. The fraction with a Rf of 0.58 is evaporated, 20 ml of diethyl ether are added to the residue (55.2 g) and 45.0 g of dibenzyloxyphosphinylhydroxy-acetic acid benzyl ester are isolated. Melting point 67°-68° C. Yield: 61%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:15]=2[N+:28]([O-])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:15]=2[NH2:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3)c2[N+](=O)[O-])CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NCc3ccccc3)c2N)CC1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 92.8 %

Procedure:
A solution of 4-(3-benzylamino-2-nitro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (0.200 g, 0.485 mmol) in 5 mL ethanol was added to a solution sodium dithionite (0.565 g, 3.245 mmol) in 10 mL water, and the reaction mixture was heated to 100° C. The mixture was stirred for 5 minutes, cooled to room temperature, and concentrated in vacuo to remove ethanol. A yellow solid precipitates and was filtered and dried under vacuum for 18 hours to give 0.173 g (0.45 mmol, 90%) of 4-(2-amino-3-benzylamino-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. MS: 383 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].N[C:11](N)=[O:12].[OH-].[Na+]>C(O)(=O)C>[N:1]1[C:2]2[CH:6]=[CH:5][S:4][C:3]=2[C:7]([OH:8])=[N:9][C:11]=1[OH:12]
Reactant: NC(=O)c1sccc1N
Reactant: NC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Oc1nc(O)c2sccc2n1

Procedure:
50 mg (0.35 mmol) 3-amino-2-aminocarbonyl-thiophene is covered with urea. The urea is heated until molten. After 5 minutes of heating, the molten mixture is poured into 1 N NaOH (2 mL). Acetic acid is added to neutralize the mixture (pH 7) and the resulting white precipitate is collected. Yield: 39 mg (0.23 mmol, 66%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[CH:7]=[N:8][C:9]3[CH2:10][CH2:11][C:12](=O)[NH:13][C:14]=3[C:5]=2[CH:4]=1>O1CCCC1.B>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[CH:7]=[N:8][C:9]3[CH2:10][CH2:11][CH2:12][NH:13][C:14]=3[C:5]=2[CH:4]=1
Reactant: COc1ccc2cnc3c(c2c1)NC(=O)CC3
Agent: B
Solvent: C1CCOC1
Product: COc1ccc2cnc3c(c2c1)NCCC3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a slightly turbid solution of 3.88 g of 1,4-dihydro-9-methoxybenzo[c]-1,5-naphthyridin-2(3H)-one in tetrahydrofuran (800 ml), 70 ml of borane (0.98M in tetrahydrofuran) was added over approximately one minute. A precipitate formed almost immediately. The suspension was stirred overnight at ambient temperature.
Reaction SMILES: ClC1C=CC=CC=1NC(=O)NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=NC=1.[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:69])[CH3:68])[C:63]([O:65]C)=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[N:50][CH:51]=2)[CH:39]=[CH:40][C:41]=1[F:42]>>[F:35][C:36]1[CH:37]=[C:38]([NH:43][C:44](=[O:70])[NH:45][C:46]2[CH:47]=[CH:48][C:49]([C:52]3[CH:60]=[C:59]4[C:55]([CH2:56][N:57]([C@@H:62]([CH:67]([CH3:68])[CH3:69])[C:63]([OH:65])=[O:64])[C:58]4=[O:61])=[CH:54][CH:53]=3)=[N:50][CH:51]=2)[CH:39]=[CH:40][C:41]=1[F:42]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cn3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccccc4Cl)cn3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)c(F)c4)cn3)cc2C1=O
Yield: 86 %

Procedure:
The compound of example 400 was prepared analogous to the compound of example 394 by hydrolysis of the compound of example 399.
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:22][CH2:23][C:24]([NH2:26])=[NH:25])[C:5]([C:7]1[NH:8][CH:9]=[C:10]([N:12]([CH3:21])[C:13]([C:15]2[NH:16][CH:17]=[C:18]([NH2:20])[CH:19]=2)=[O:14])[CH:11]=1)=[O:6].C(N(C(C)C)CC)(C)C.[Cl:36]C1C=C(Cl)C(Cl)=CC=1[CH2:45][N:46]([N:50]=[O:51])[C:47](=O)[O-:48]>CN(C=O)C>[ClH:36].[CH3:3][N:4]([CH2:22][CH2:23][C:24]([NH2:26])=[NH:25])[C:5]([C:7]1[NH:8][CH:9]=[C:10]([N:12]([CH3:21])[C:13]([C:15]2[NH:16][CH:17]=[C:18]([NH:20][C:47]([N:46]([CH3:45])[N:50]=[O:51])=[O:48])[CH:19]=2)=[O:14])[CH:11]=1)=[O:6]
Reactant: O=NN(Cc1cc(Cl)c(Cl)cc1Cl)C(=O)[O-]
Reactant: CN(CCC(=N)N)C(=O)c1cc(N(C)C(=O)c2cc(N)c[nH]2)c[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCC(=N)N)C(=O)c1cc(N(C)C(=O)c2cc(NC(=O)N(C)N=O)c[nH]2)c[nH]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
To an ice-cooled solution of β-[N-methyl-4-(N-methyl-4-aminopyrrole-2-carboxamido)pyrrole-2-carboxamido]propionamidine dihydrochloride (0.404 g) in 5 ml of DMF and 320 mg of 2,4,5-trichlorophenyl-N-methyl-N-nitrosocarbamate [prepared according to J. Med. Chem. 25, 178 (1982)], a solution of diisopropylethylamine (0.164 ml) in 8 ml of DMF was added dropwise. The resulting solution was stirred 1 hour at 0° C. The reaction mixture was concentrated under vacuum and the residue was purified by column chromatography to yield 251 mg of β-[N-methyl-4-[N-methyl-4-(3 -methyl-3-nitrosoureido)pyrrole-2-carboxamido]pyrrole-2-carboxamido]propionamidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SC)[NH:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][NH:36][CH3:37])[CH3:32]>>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]([CH2:35][CH2:34][N:33]([CH2:38][CH3:39])[CH2:31][CH3:32])[CH3:37])=[N:19][C:18]4=[O:24])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:27]([F:29])([F:30])[F:28])[CH:3]=1
Reactant: CSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CCN(CC)CCNC
Product: CCN(CC)CCN(C)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-[(2-diethylamino-ethyl)-methyl-amino]-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-methylsulfanyl-thiazolidin-4-one and N,N-Diethyl-N′-methyl-ethane-1,2-diamine following General Procedure B.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[CH:40]=[N:39][CH:38]=[CH:37][N:36]=1>C(Cl)Cl.CN(C)C=O.O1CCCC1.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:34][C:35]2[CH:40]=[N:39][CH:38]=[CH:37][N:36]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1cnccn1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1cnccn1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.8 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichloro-phenyl)-propionic acid (prepared as in Example 38A, 100 mg, 0.35 mmol) in methylene chloride (5 mL) and one drop of N,N-dimethylformamide was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (0.20 mL, 0.39 mmol). Gas evolution began immediately. The reaction mixture was stirred for 30 min at 0° C. After this time, the reaction mixture was treated with a solution of N,N-diisopropylethylamine (0.15 mL, 0.84 mmol) and 2-aminopyrazine (69 mg, 0.73 mmol) in tetrahydrofuran (4 mL) in one portion. The resulting reaction mixture was stirred for 16 h at 25° C. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 90/10 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichloro-phenyl)-N-pyrazin-2-yl-propionamide (38 mg, 30%) as a yellow solid: mp 46.5–51.3° C.; EI-HRMS m/e calcd for C18H19Cl2N3O (M+) 363.0905, found 363.0907.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=[N:8][OH:9])[NH2:7])=[CH:4][CH:3]=1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.[OH-].[Na+].[S:26]1[CH:30]=[CH:29][CH:28]=[C:27]1[C:31](Cl)=O>CC1CCCO1.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:7]=[C:31]([C:27]3[S:26][CH:30]=[CH:29][CH:28]=3)[O:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1cccs1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC1CCCO1
Solvent: O
Product: Clc1ccc(-c2noc(-c3cccs3)n2)cc1
Temperature: 50 °C
Yield: 86.2 %

Procedure:
The 4-chlorobenzamidoxime (1.00 g, 5.8 mmol) was dissolved in 2-methyltetrahydrofuran (10.0 mL) and water (1.0 mL). A 40% aqueous solution of benzyltrimethylammonium hydroxide (100 uL) was added and the solution heated to 50° C. A 50% aqueous solution of sodium hydroxide (720 mg, 9.00 mmol) and 2-thiophenecarbonyl chloride (939.0 mg, 6.4 mmol) were added dropwise simultaneously over 15 minutes. The temperature of the mixture warmed to 70° C. The mixture was cooled to room temperature and water (40 mL) added. Solids formed and the 2-methyltetrahydrofuran was removed at reduced pressure. The solids were isolated by vacuum filtration. The 3-(4-chlorophenyl)-5-(2-thienyl)-1,2,4-oxadiazole (1.32 g, 5.0 mmol) was obtained as a white solid. (86% yield).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH:6](O)[CH:7]2[C:11](=[O:12])[C:10]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])=[C:9]([O:22]C)[CH2:8]2)=[CH:2]1.Cl>CC(C)=O>[O:1]1[CH:5]=[CH:4][C:3](/[CH:6]=[C:7]2/[C:11](=[O:12])[CH:10]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:9](=[O:22])[CH2:8]/2)=[CH:2]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)c2ccoc2)C1
Agent: Cl
Solvent: CC(C)=O
Product: Cc1cc(C)c(C2C(=O)C/C(=C\c3ccoc3)C2=O)c(C)c1
Temperature: 120 °C

Procedure:
To a solution of 5-(furan-3-yl-hydroxy-methyl)-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (770 mg) in acetone (2 ml) is added 2N hydrochloric acid (2 ml) and the resulting suspension heated to 120° C. for 30 minutes. The crude reaction mixture is concentrated in vacuuo and purified by flash chromatography to give 4-[1-furan-3-yl-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[C:25]([CH3:26])=[C:24]([CH3:27])[S:23][C:10]=3[C:11]3[C:21]([CH3:22])=[N:20][O:19][C:12]=3[C@H:13]([CH2:15][C:16](=S)[NH2:17])[N:14]=2)=[CH:4][CH:3]=1.CO[CH:30](OC)[CH2:31][NH2:32]>CC#N.Cl[Hg]Cl>[NH:32]1[CH:31]=[CH:30][N:17]=[C:16]1[CH2:15][C@H:13]1[C:12]2[O:19][N:20]=[C:21]([CH3:22])[C:11]=2[C:10]2[S:23][C:24]([CH3:27])=[C:25]([CH3:26])[C:9]=2[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14]1
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(c1ccc(Cl)cc1)=N[C@H]2CC(N)=S
Reactant: COC(CN)OC
Agent: Cl[Hg]Cl
Solvent: CC#N
Product: Cc1noc2c1-c1sc(C)c(C)c1C(c1ccc(Cl)cc1)=N[C@H]2Cc1ncc[nH]1
Yield: 6.2 %

Procedure:
To a solution of 2-((6S)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)ethanethioamide (0.080 g, 0.19 mmol) and 2,2-dimethoxyethanamine (0.200 g, 1.90 mmol) in CH3CN (5 mL) was added HgCl2 (0.515 g, 1.90 mmol). The mixture was refluxed overnight. The reaction mixture was filtered, concentrated in vacuo and the residue was purified by column chromatography (silica-gel, petroleum:ethyl acetate=2:1) to give (6S)-6-((1H-imidazol-2-yl)methyl)-4-(4-chlorophenyl)-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepine as a yellow solid (0.005 g, 6.2% yield): 1H NMR (300 MHz, DMSO-d6) δ 8.26 (br, 1H), 7.42 (d, J=4.8 Hz, 2H), 7.24 (d, J=4.8 Hz, 2H), 6.82 (d, J=1.2 Hz, 2H), 4.40-4.30 (m, 1H), 3.84-3.74 (m, 2H), 2.50 (s, 3H), 2.42 (s, 3H), 1.64 (s, 3H); LC/MS m/z 423 [M+H]+.