Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.ClS(O)(=O)=O.[CH3:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH3:27])=[O:25].[Cl:28]([OH:32])(=[O:31])(=[O:30])=[O:29]>>[Cl:28]([OH:32])(=[O:31])(=[O:30])=[O:29].[CH3:17][N:18]1[C:22]([C:3](=[N:2][CH3:1])[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=2)=[CH:21][CH:20]=[C:19]1[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)Cc1cccn1C
Reactant: CN=C(Cl)c1ccc(C)cc1
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CN=C(c1ccc(C)cc1)c1ccc(CC(=O)OC)n1C

Procedure:
The title compound was prepared as in Example X from N-methyl 4-methylbenzimidoyl chloride (5.9 g, 35 mmole), chlorosulfonic acid (0.41 g, 3.5 mmole), methyl 1-methyl-1H-pyrrole-2-acetate (5.4 g, 35 mmole), and 70% perchloric acid (5.5 g, 38.5 mmole) to yield 4.0 g (30%) of a green solid, m.p. 155°-159° C. (dec).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH:3]1[C:8]([O:10]C)=O.[CH3:12][CH:13]([NH2:15])[CH3:14]>>[CH:13]([NH:15][C:8]([CH:3]1[CH2:4][O:5][CH2:6][CH2:7][NH:2]1)=[O:10])([CH3:14])[CH3:12]
Reactant: COC(=O)C1COCCN1
Reactant: CC(C)N
Agent: Cl
Product: CC(C)NC(=O)C1COCCN1
Temperature: 60 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
A mixture of methyl morpholine-3-carboxylate hydrochloride (0.22 g, 1.2 mmol) and propan-2-amine (2.78 g, 47 mmol) was stirred at 60° C. for 12 hours under N2. The mixture was concentrated in vacuo to give the title compound as brownish sticky oil (0.2 g, 95%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[NH:14][N:13]=[C:12]([CH2:15][CH3:16])[CH:11]=1.C(N(CC)C(C)C)(C)C>C1COCC1>[CH2:15]([C:12]1[NH:13][N:14]=[C:10]([NH:9][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:11]=1)[CH3:16]
Reactant: CCc1cc(N)[nH]n1
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(Nc2ccnc(Cl)n2)n[nH]1
Temperature: 60 °C
Yield: 34.7 %

Procedure:
A mixture of 2,4-dichloropyrimidine (2.97 g, 20 mmol), 5-amino-3-ethyl-1H-pyrazole (2.44 g, 22 mmol) and N,N-diisopropylethylamine (3.8 ml, 22 mmol) in dry THF (75 ml) was heated at 60° C. for 18 hours. The volatiles were removed by evaporation, and the residue was triturated with a mixture of DCM and water. The solid product was collected by filtration, washed with water and ether, and dried to give the title compound (1.55 g, 35%) as a colourless crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[OH-].[Li+:24].O1CCCC1.CO>O>[C:1]([C:3]1[CH:4]=[C:5]([CH3:22])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([O-:17])=[O:16])=[CH:19][CH:20]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].[Li+:24]
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C)c3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1cc(C#N)cc2nc(-c3ccc(C(=O)[O-])cc3)oc12
Reaction time: 8 h

Procedure:
Methyl 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate (134 mg, INTERMEDIATE 22) and lithium hydroxide (22 mg) were combined in 10 ml of a 1:1:1 mixture of tetrahydrofuran, methanol, and water. The solution was stirred overnight. The solvents were removed in vacuo to provide the desired intermediate, lithium 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate, as an off-white solid (140 mg). Mass spectrum (ESI) 279.0 (M+1). To a solution of lithium 4-(5-cyano-7-methyl-1,3-benzoxazol-2-yl)benzoate (28 mg) in 2 ml of dichloromethane was added 2.5 ml of a 2M solution of oxalyl chloride in dichloromethane followed by 10 μl of dimethylformamide. The mixture was warmed and stirred until the solids dissolved (about 0.5 h). The mixture was concentrated in vacuo with minimal or no heating (<30° C.) and then dried under high vacuum to remove traces of water. To the residue was added 2 ml of dichloromethane, 28 mg of ({1-[4-(trifluoromethyl)phenyl]piperidin-4-yl}methyl)amine, and 87 μl of diisopropylethylamine. The mixture was stirred at room temperature for 15 min and then was added directly to a 40M samplet. The product was purified via flash chromatography on a Biotage Horizon, 40M column, eluting with 1 column volume of 10% ethyl acetate in hexanes, followed by a linear gradient of ethyl acetate in hexanes from 10 to 100% over 10 column volumes to provide the title compound (38 mg, 73%). Mass spectrum (ESI) 519.0 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.35 (d, J=8.5 Hz, 2H), 7.95 (m, 4H), 7.49 (m, 4H), 6.37 (bs, 2H), 3.83 (d, J=12.6 Hz, 2H), 3.49 (m, 2H), 3.47 (t, J=6.4 Hz, 2H), 2.87 (m, 2H), 2.65 (s, 3H), 1.92 (m, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=O)=[C:5]2[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15].[OH-].CCC[N+](S(=O)(=O)NC(O)=O)(CC)CC>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]#[N:13])=[C:5]2[S:14]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: NC(=O)c1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1
Agent: CCC[N+](CC)(CC)S(=O)(=O)NC(=O)O
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1[nH]c2ccc(Cl)cc2c1S(=O)(=O)c1ccccc1

Procedure:
5-Chloro-3-phenylsulfonylindole-2-carboxamide reacts with methyl (carboxysulfamoyl)triethylammonium hydroxide inner salt (Burgess reagent) in tetrahydrofuran (THF) solvent as described by D. A. Claremon and B. T. Phillips (Tetrahedron Lett., 29, 2155 (1988)) to provide the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([CH3:19])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([I:18])[CH:13]=2)[CH:9]=1)=[O:4].[OH-].[Li+].O>O1CCCC1>[I:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:8]1[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[O:6][C:7]=1[CH3:19]
Reactant: COC(=O)c1cc(COc2cccc(I)c2)c(C)o1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(C(=O)O)cc1COc1cccc(I)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.8 %

Procedure:
A mixture of 4-(3-iodo-phenoxymethyl)-5-methyl-furan-2-carboxylic acid methyl ester (106) (2.7 g, 7.25 mmoles) and lithium hydroxide (1.5 g, 36.25 mmoles) in tetrahydrofuran (25 ml) containing water (2 ml) was stirred at room temperature for 3 h. The tetrahydrofuran was evaporated, the residue was diluted with water and the mixture acidified to pH=1 with 1M aqueous hydrochloric acid. The precipitate was collected washed with water and dried at 70° C. in vacuo to give compound 107(1.76 g) as a white solid. LC/MS System B; Rt=3.51 mins, m/z (ES−)=357 (M−H for C13H11IO4).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:13][CH2:12][C:7]2(OCC[O:8]2)[CH2:6][CH2:5]1>Cl>[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:13][CH2:12][C:7](=[O:8])[CH2:6][CH2:5]1
Reactant: CN(C)C1(c2ccccc2)CCC2(CC1)OCCO2
Agent: Cl
Product: CN(C)C1(c2ccccc2)CCC(=O)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 97 %

Procedure:
Dimethyl-(8-phenyl-1,4-dioxaspiro[4.5]dec-8-yl)amine hydrochloride (10.5 g, 35.2 mmol) was dissolved in 7.5 N hydrochloric acid (36 ml) and the solution was stirred at room temperature for 96 h. When the hydrolysis had ended, the reaction mixture was extracted with diethyl ether (2×50 ml). The aqueous phase was rendered alkaline with 5 N sodium hydroxide solution, while cooling with ice, and extracted with methylene chloride (3×50 ml) and the extract was concentrated. It was possible to isolate 4-dimethylamino-4-phenylcyclohexanone (Ket-10) in this way as a yellow solid with a melting point of 104-108° C. in a yield of 97% (7.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32](OC(=O)C(F)(F)F)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[Cl-].[CH3:51][C:52]1[CH:57]=[CH:56][C:55]([Sn](CCCC)(CCCC)CCCC)=[CH:54][N:53]=1>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:10][C@@H:11]1[O:15][C:14]([CH3:17])([CH3:16])[N:13]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C@H:12]1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:55]2[CH:54]=[N:53][C:52]([CH3:51])=[CH:57][CH:56]=2)=[CH:31][CH:30]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@@H]1OC(C)(C)N(C(=O)OCc2ccccc2)[C@H]1Cc1ccc(OC(=O)C(F)(F)F)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc(C[C@H]3[C@H](C[C@H](Cc4ccccc4)NC(=O)OC(C)(C)C)OC(C)(C)N3C(=O)OCc3ccccc3)cc2)cn1
Yield: 83.9 %

Procedure:
A solution containing the product from Example 23I (0.25 g, 0.354 mmol) in DMF (3.5 mL) was treated with LiCl (0.15 g, 3.54 mmol), dichlorobis(triphenylphosphine)palladium(II) (0.075 g, 0.107 mmol), and the product from Example 87A (0.40 mL, 1.67 mmol), heated at 100° C. for 16 hours, cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine and dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-25% ethyl acetate in dichloromethane to give the title compound (0.193 g, 84% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[C:16]3[CH:17]=[C:18](Br)[CH:19]=[CH:20][C:15]=3[S:14][N:13]=1)=[O:11])[CH2:2]2.[C:22](=[O:25])(O)[O-].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2[C:40]2C=CC=C[C:41]=2[N:46](C)[CH3:47])CCCCC1>>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10]([C:12]1[C:16]3[CH:17]=[CH:18][C:19]([N:46]4[CH2:47][CH2:22][O:25][CH2:40][CH2:41]4)=[CH:20][C:15]=3[S:14][N:13]=1)=[O:11])[CH2:2]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1nsc2ccc(Br)cc12
Reactant: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: O=C([O-])O
Agent: [Cs+]
Product: O=C(N[C@H]1CN2CCC1CC2)c1nsc2cc(N3CCOCC3)ccc12
Yield: 180.3 %

Procedure:
In a 5 mL microwave reaction vessel was added N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(bromo)benzo[d]isothiazole-3-carboxamide (133 mg, 0.37 mmol), tris(dibenzlideneacetone)dipalladium (0) (34 mg, 0.04 mmol), caesium bicarbonate (213 mg, 1.1 mmol), and (2′-dicyclohexylphosphanylbiphenyl-2-yl)dimethylamine (30 mg, 0.07 mmol). The vial was then evacuated and back-filled with argon gas. The mixture of solids was then diluted with morpholine (0.7 mL), dioxane (1 mL), and triethylamine (0.5 mL) and the reaction vessel was sealed. The reaction mixture was subjected to microwave irradiation at 120° C. for 1800 s. The reaction mixture was filtered through a plug of celite and concentrated in vacuo. The crude product was purified by chromatography (90/10/1 dichloromethane/methanol/ammonium hydroxide) to provide 47 mg (34%) of 6-morpholin-4-ylbenzo[d]isothiazole-3-carboxylic acid ((3R)-1-azabicyclo[2.2.2]oct-3-yl)amide as a colorless solid.
Reaction SMILES: Cl.N[C:3]1[CH:4]=[C:5]([C:9](C2C=CC=C(N)C=2)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:7][CH:8]=1.N([O-])=[O:26].[Na+].[C:29]1([OH:35])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[OH:35][C:29]1[CH:34]=[C:33]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([OH:26])[CH:4]=2)([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])[CH:32]=[CH:31][CH:30]=1
Reactant: O=N[O-]
Reactant: Nc1cccc(C(c2cccc(N)c2)(C(F)(F)F)C(F)(F)F)c1
Reactant: Oc1ccccc1
Agent: Cl
Agent: [Na+]
Product: Oc1cccc(C(c2cccc(O)c2)(C(F)(F)F)C(F)(F)F)c1
Temperature: 80 °C

Procedure:
To make the desired bisphenol from this diamine, we prepare a solution of 60 milliliters of concentrated hydrochloric acid, 200 milliliters of ice and 33.4 grams (0.1 mole) of 2,2-bis(3-aminophenyl)hexafluoropropane, and add thereto an aqueous solution of sodium nitrite (0.2 mole). We stir the mixture slowly, and heat to 80° C. for two hours. After the desired phenol separates, we extract it three times with 100 milliliters of ether each time, then wash the organic phase with water, sodium bicarbonate, and finally with saturated ammonium chloride. We then distill to obtain 33.6 grams of 2,2-bis(3-hydroxyphenyl)hexafluoropropane. From this bisphenol, we prepare the meta-substituted bisbenzenethiols of this invention following the same sequence of steps that produces the para-substituted bisbenzenethiols.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:47])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([F:45])=[C:41]([CH3:46])[CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: CCCCc1nc(C)n(-c2ccc(F)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CCCCc1nc(C)n(-c2ccc(F)c(C)c2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
A mixture of hydroxylammonium chloride (1.5 g), sodium hydrogen carbonate (2.3 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-fluoro-3-methylphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.11 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (10 mL), N,N′-carbonyldiimidazole (0.58 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.53 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.85 g, 68%).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.[S:18]1[CH2:22][CH2:21][NH:20][C:19]1=[S:23]>C(N(CC)CC)C>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([N:20]2[CH2:21][CH2:22][S:18][C:19]2=[S:23])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: S=C1NCCS1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(c1ccc([N+](=O)[O-])cc1)N1CCSC1=S
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
To a solution of 4-nitrobenzoyl chloride (3.1 g) and tetrahydrofuran (50 ml) were added 1,3-thiazolidine-2-thione (2.0 g) and triethyl amine (2.5 g). The mixture was stirred at 50° C. for 30 minutes under nitrogen atmosphere. The reaction mixture was filtered and the solvent was removed at a reduced pressure. To the residue was added water, and the solution is extracted with dichloromethane. The extract was washed with a saturated aqueous solution of sodium chloride and dried with use of Glauber's salt. The solvent was distilled off and the resulting crystals were purified by silica gel column chromatography (developer: dichloromethane) and recrystallized from dichloromethane to obtain 3.3 g of the desired compound as yellow needle crystals (yield 82.5%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]3[CH2:16][CH2:15]3)[C:7]=12.[CH3:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH2:23])=[CH:20][CH:19]=1>>[ClH:1].[CH:14]1([CH2:13][N:8]2[C:7]3=[C:2]([NH:23][CH2:22][C:21]4[CH:24]=[CH:25][C:18]([CH3:17])=[CH:19][CH:20]=4)[N:3]=[CH:4][CH:5]=[C:6]3[C:10]([CH3:11])=[C:9]2[CH3:12])[CH2:16][CH2:15]1
Reactant: Cc1ccc(CN)cc1
Reactant: Cc1c(C)n(CC2CC2)c2c(Cl)nccc12
Product: Cc1ccc(CNc2nccc3c(C)c(C)n(CC4CC4)c23)cc1
Product: Cl
Yield: 47 %

Procedure:
In accordance with the same procedures as in Step 3 of Example 198, except for using 7-chloro-1-cyclopropylmethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 and 4-methylbenzylamine, the titled compound was obtained as a white solid. (Yield: 47%)
Reaction SMILES: [Na].C[Sn](C)C.C[Sn](C)C.[CH2:10]([O:12][C:13](=[O:21])[C:14]1[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=1)[CH3:11].[C:22](O)(=O)CC(CC(O)=O)(C(O)=O)O.[Sn].[C:36]([Sn:41][C:42]1C=CC=CC=1)(OCC)=O>C(O)COCCO.C(OCC)C.O>[CH3:36][Sn:41]([CH3:42])([CH3:22])[C:17]1[CH:18]=[CH:19][C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:21])=[CH:15][CH:16]=1
Reactant: CCOC(=O)[Sn]c1ccccc1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CCOC(=O)c1ccc(Br)cc1
Agent: C[Sn](C)C
Agent: [Na]
Agent: [Sn]
Solvent: OCCOCCO
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)c1ccc([Sn](C)(C)C)cc1
Temperature: -2 °C

Procedure:
To a reaction vessel equipped with a mechanically driven agitator, water-cooled condenser, addition funnel, thermometer, and nitrogen inlet was added 80 cc. of anhydrous diethyl ether of diethylene glycol and 8 g. (0.35 mole) of freshly cut sodium pieces. The mixture was cooled to -2° C. and a solution of 52.4 g. (0.16 mole) of hexamethylditin in 80 cc. of anhydrous diethyl ether of diethylene glycol was added over 20 minutes. The hazy green mixture was stirred for one additional hour at 0° C. and then allowed to warm to room temperature over three hours. The mixture was filtered and then added dropwise over a 2.5 hour period to a solution of 36.6 g. (0.16 mole) ethyl-p-bromobenzoate in 160 cc. of the diethyl ether of diethylene glycol, cooled to -15° C. The solution was stirred 2 hours at -2° C. and 16 hours at room temperature. The solution was then hydrolyzed using 300 cc. of a 5% aqueous citric acid solution. The water phase was separated from the organic phase and washed twice with 200 cc. portions of ether. The organic layers were combined, dried over a quantity of magnesium sulfate, and concentrated under reduced pressure. The solvent was removed at 50 mm. pressure (mercury manometer) and the residue distilled at 0.15 mm. A clear liquid fraction boiling at 88°-90° C. was isolated and analyzed. The tin content was found to be 37.54%. The calculated tin content for carbethoxyphenyltin is 37.92%. Gas chromatographic analysis indicated a purity of 97.6%. The refractive index was recorded as 1.5362 at 23° C. The nuclear magnetic resonance spectrum contained a singlet at 0.38 ppm. (CH3 --Sn, 9H's), a triplet at 1.46 ppm. (CH3 --,3H's), a quartet at 4.50 ppm. ##STR5## and a doublet of doublets at 7.86 ppm. ##STR6##
Reaction SMILES: [NH:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:8])=[CH:5][N:4]=1)[NH2:2].CN(C)[CH:21]=[C:22]([N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]1=[O:34])[C:23](OCC)=[O:24]>>[OH:24][C:23]1[N:1]([C:3]2[CH:18]=[CH:17][C:6]([C:7]([NH:9][CH2:10][CH:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[O:8])=[CH:5][N:4]=2)[N:2]=[CH:21][C:22]=1[N:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]1=[O:34]
Reactant: CCOC(=O)C(=CN(C)C)n1ccccc1=O
Reactant: NNc1ccc(C(=O)NCC2CCOCC2)cn1
Product: O=C(NCC1CCOCC1)c1ccc(-n2ncc(-n3ccccc3=O)c2O)nc1

Procedure:
The title compound was prepared in a manner similar to Example 188 using 6-hydrazinyl-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide and ethyl 3-(dimethylamino)-2-(2-oxopyridin-1(2H)-yl)acrylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10-1.32 (m, 2H) 1.62 (d, J=12.9 Hz, 2 H) 1.81 (ddd, J=11.1, 7.3, 4.0 Hz, 1 H) 3.20 (t, J=6.3 Hz, 2 H) 3.24-3.31 (m, 2 H) 3.86 (dd, J=11.2, 2.7 Hz, 2 H) 6.31 (t, J=6.6 Hz, 1 H) 6.44-6.59 (m, 1 H) 7.48 (t, J=7.8 Hz, 1 H) 7.80 (br. s., 1 H) 8.27-8.61 (m, 2 H) 8.73 (br. s., 1 H) 8.92 (s, 1 H) 13.12 (br. s., 1 H). MS m/z 396 [M+H]+.
Reaction SMILES: Cl.Cl.COC1C=CC(N2CCNCC2)=CC=1.C(Cl)(=O)CC(C)C.[F:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([F:33])=[CH:27][C:26]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[C:40]([C:44]1[CH:52]=[CH:51][C:47]([C:48](Cl)=[O:49])=[CH:46][CH:45]=1)([CH3:43])([CH3:42])[CH3:41]>>[C:40]([C:44]1[CH:45]=[CH:46][C:47]([C:48]([N:37]2[CH2:38][CH2:39][N:34]([C:26]3[CH:27]=[C:28]([F:33])[C:29]([O:31][CH3:32])=[CH:30][C:25]=3[F:24])[CH2:35][CH2:36]2)=[O:49])=[CH:51][CH:52]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)c1ccc(C(=O)Cl)cc1
Reactant: COc1cc(F)c(N2CCNCC2)cc1F
Agent: CC(C)CC(=O)Cl
Agent: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Product: COc1cc(F)c(N2CCN(C(=O)c3ccc(C(C)(C)C)cc3)CC2)cc1F

Procedure:
Production Example 3 was repeated except that 1-(4-methoxyphenyl)piperazine dihydrochloride and isovaleryl chloride were replaced with 1-(2,5-difluoro-4-methoxyphenyl)-piperazine (228 mg) and 4-tert-butylbenzoyl chloride (234 μL), respectively, to provide crude 1-(4-tert-butylbenzoyl)-4-(2,5-difluoro-4-methoxyphenyl)piperazine (433 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[O:31]=[C:32]1[NH:41][C:40]2[N:39]=[CH:38][C:37](/[CH:42]=[CH:43]/[C:44](O)=[O:45])=[CH:36][C:35]=2[CH2:34][CH2:33]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)[C:44](=[O:45])/[CH:43]=[CH:42]/[C:37]1[CH:38]=[N:39][C:40]2[NH:41][C:32](=[O:31])[CH2:33][CH2:34][C:35]=2[CH:36]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Reactant: CNCc1cccc2ncccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cccc2ncccc12)C(=O)/C=C/c1cnc2c(c1)CCC(=O)N2

Procedure:
According to the procedure of Example 1, except substituting methyl-quinolin-5-ylmethyl-amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.387 g, quantitative) was prepared as a tan solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.69-10.63 (m, 1H), 9.26-9.13 (m, 2H), 8.39-8.25 (m, 2H), 8.11-7.93 (m, 3H), 7.77-7.45 (m, 2H), 7.30-7.17 (m, 1H), 5.50-5.22 (m, 2H), 3.15-3.01 (m, 3H), 2.94-2.78 (m, 2H), 2.56-2.44 (m, 2H); MS (ESI) m/e 373 (M+H)+.
Reaction SMILES: [Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([Cl:5])=[O:4].S(=O)(=O)(O)O.[N+:17]([O-])([OH:19])=[O:18].C(Cl)(=O)C(Cl)=O>CN(C)C=O.C(Cl)Cl>[Cl:1][CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:17]([O-:19])=[O:18])[CH:7]=1)[C:3]([Cl:5])=[O:4]
Reactant: O=C(Cl)C(Cl)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=C(Cl)C(=O)Cl
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C(Cl)c1cccc([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
To a methylene chloride (i000 mL) solution of 2-chloro-2-phenylacetyl chloride (50.0 grams, 0.26 mol) and concentrated sulfuric acid (100 mL) cooled in an ice bath was added dropwise fuming nitric acid (20.0 grams, 0.32 mol). The mixture was allowed to stir for two hours and then poured into ice (500 mL). The organic layer was washed with saturated sodium chloride solution (2×200 mL), dried with magnesium sulfate and filtered through a thin pad of silica gel. To this methylene chloride solution was added oxalyl chloride (13.2 grams, 0.52 mol) and N,N-dimethylformamide (9 drops). The mixture was stirred at room temperature for 1.5 hours, was heated under reflux for 20 minutes, and concentrated in a rotary evaporator to give the desired 2-chloro-2-(3-nitrophenyl)acetyl chloride (50.2 grams, 81% yield whose structure was confirmed by nuclear magnetic resonance, infra-red spectroscopy, and mass spectroscopy analysis.