Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH2:22])=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35].[CH2:36]1[O:44][CH:37]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[C:9]([C:13]3[N:23]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[C:16]4=[N:17][CH:18]=[CH:19][C:20]([CH2:21][NH:22][CH:37]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH2:36][OH:44])=[C:15]4[CH:14]=3)=[CH:10][N:11]([CH3:12])[C:6]2=[CH:5][C:4]=1[O:34][CH3:35]
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(CN)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Reactant: c1ccc(C2CO2)cc1
Solvent: CCO
Product: COc1cc2c(nc1OC)c(-c1cc3c(CNC(CO)c4ccccc4)ccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Yield: 7.1 %

Procedure:
To a solution of 0.09 g of [2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-yl]methylamine in 20 cm3 of ethanol, at a temperature in the region of 20° C., is added 0.022 g of styrene oxide. The reaction medium is refluxed for five days. After cooling, the reaction medium is concentrated under reduced pressure. The residue obtained is purified by flash-pack column chromatography (SiO2, dichloromethane/methanol 95/05 by volume as eluents) to give 0.008 g of 2-{[2-(5,6-dimethoxy-1-methyl-1H-pyrrolo[3,2-b]pyridin-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-4-ylmethyl]amino}-2-phenylethanol with the following characteristics:
Reaction SMILES: C(N(CC)CC)C.Br[C:9]([F:21])([F:20])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>C(#N)C>[C:22]([NH:32][CH2:33][C:34](=[O:40])[CH2:35][CH2:36][C:37]([O:39][C:9]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])([F:21])[F:20])=[O:38])([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]
Reactant: O=C(O)CCC(=O)CNC(=O)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)C(F)(F)Br
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(CCC(=O)OC(F)(F)C(=O)OCc1ccccc1)CNC(=O)OCc1ccccc1
Yield: 74.5 %

Procedure:
Triethylamine (3.5 mL; 2.5 g; 25 mmol) was added using a syringe to a stirred mixture of the crude product of 3a (8.6 g; 20 mmol) and 5-(Cbz-amino)-4-oxopentanoic acid (6.63 g; 25 mmol) in dry acetonitrile (100 mL). The mixture was refluxed for 18 h, then the solvent was evaporated and the dark red residue was dissolved in diethyl ether (100 mL) and 0.5 M HCl (100 mL). After mixing thoroughly, the ether layer was washed with water (2×15 mL), saturated NaHCO3 (2×15 mL), and saturated NaCl solution (1×15 mL), then dried (MgSO4). After filtration and evaporation, the residue was purified by flash chromatography on a 60×55 mm silica gel 60 column eluted with dichloromethane-diethyl ether (9:1) (1000 mL), collecting 10×75 mL fractions. After evaporation of fractions 2-5 and vacuum-drying (0.02 mm Hg), 6.7 g (74%) product was obtained (red-orange solid mp 48-50° C.).
Reaction SMILES: C[O-].[Na+].C([NH:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:19]([OH:21])=[O:20])=[S:14])(=O)C1C=CC=CC=1>CO>[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[C:19]([OH:21])=[O:20])(=[S:14])[NH2:12]
Reactant: COc1cc(NC(=S)NC(=O)c2ccccc2)cc(C(=O)O)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(NC(N)=S)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
Sodium methoxide (4.76 mL, 2.38 mmol, 0.5 M solution in methanol) was added to a solution of 3-(benzoylcarbamothioylamino)-5-methoxy-benzoic acid from Step 1 in MeOH (4 mL). The reaction was stirred at ambient temperature for 2 h after which time LCMS indicated complete conversion of the starting material. The solvent was removed in vacuo, the crude partitioned between water and DCM, the organic layer separated and the aqueous layer was acidified to pH 5 with conc HCl resulting in a thick precipitate. The precipitate was extracted into EtOAc which was then washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The product was obtained as an off white solid, 248 mg, 92% yield.
Reaction SMILES: Br[C:2]1[C:3]([CH3:21])([CH3:20])[O:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[C:7]([Cl:19])[CH:6]=2.[CH2:22]([Sn](CCCC)(CCCC)C=C)[CH2:23]CC.[F-].[K+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:7]1[CH:6]=[C:5]2[C:10]([C:11]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[C:2]([CH:22]=[CH2:23])[C:3]([CH3:21])([CH3:20])[O:4]2)=[CH:9][CH:8]=1
Reactant: CC1(C)Oc2cc(Cl)ccc2C(c2ccc(F)cc2)=C1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=CC1=C(c2ccc(F)cc2)c2ccc(Cl)cc2OC1(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-7-chloro-4-(4-fluorophenyl)-2,2-dimethyl-2H-chromen (a compound obtained in Reference Example 8(1); 220 mg), tributyl(vinyl)tin (350 μL) and tetrakis(triphenylphosphine)palladium(0) (140 mg) in dioxane was heated under reflux for 23 hours. After cooling, the reaction solution was diluted with ethyl acetate, a saturated aqueous solution of potassium fluoride was added thereto, and the mixture was stirred at room temperature for an hour. The reaction solution was filtered through Celite and the filtrate was extracted with ethyl acetate. The organic layer was washed successively with water and brine, filtered through a column of porous diatomite (Chem Elut) and the filtrate was concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (Solvent: n-hexane/chloroform=100/0 to 95/5) to give the titled compound (157 mg) as a pale yellow viscous oil.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22]Br)[CH:16]=1>C(O)C>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([CH2:22][O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:16]=1
Reactant: Clc1ccc(Br)cc1CBr
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Clc1ccc(Br)cc1COc1ccccc1
Temperature: 25 °C

Procedure:
To a mixture of phenol (7.1 g) and potassium carbonate (11.1 g) in ethanol (100 mL) is added 4-bromo-2-bromomethyl-1-chloro-benzene (19.5 g). The mixture is stirred at ambient temperature over night. The ethanol is evaporated, and water is added to the residue. The resulting mixture is extracted with ethyl acetate, the combined extracts are dried over sodium sulfate, and the solvent is removed. The residue is purified by chromatography on silica gel (cyclohexane/ethyl acetate 70:30).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[N:5]=[C:6]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:7]2[CH2:13][NH:12][CH2:11][CH2:10][C:8]=2[N:9]=1.[CH2:21](Br)[CH:22]=[CH2:23]>>[ClH:20].[ClH:1].[CH2:23]([N:12]1[CH2:11][CH2:10][C:8]2[N:9]=[C:4]([NH2:3])[N:5]=[C:6]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:7]=2[CH2:13]1)[CH:22]=[CH2:21]
Reactant: C=CCBr
Reactant: Nc1nc2c(c(-c3ccc(Cl)cc3)n1)CNCC2
Agent: Cl
Product: C=CCN1CCc2nc(N)nc(-c3ccc(Cl)cc3)c2C1
Yield: 77.3 %

Procedure:
The title compound was prepared as described in Example 17 starting with 2-amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride (1.5 g, 4.5 mmol) and allyl bromide (0.4 mL, 4.6 mmol) instead of iodoethane to produce 0.65 g (39%) of 6-allyl-2-amino-4-(4-chlorophenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine dihydrochloride. m.p. 248°-250° C. MS: 301 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[C:13](Cl)(Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:9][O:8][C:6]([C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:13](=[N:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)=[O:7]
Reactant: COC(=O)c1ccc(N)cc1
Reactant: ClC(Cl)(Cl)c1ccccc1
Product: COC(=O)c1ccc(N=C(Nc2ccc(C(=O)OC)cc2)c2ccccc2)cc1

Procedure:
N,N'-Bis(4-methoxycarbonylphenyl)benzamidine (1) was prepared from methyl 4-aminobenzoate and α,α,α-trichlorotoluene; pale-yellow crystals: mp 180°-182° C. 1H-NMR (CDCl3) 8.0-7.0 (m, 14H), 3.8 (s, 6H); IR (CDCl3) 3330, 1705, 1585; MS (m/e) 388 (M+), 238 (base).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:33]=[CH:32][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([O:29]CC)=[O:28])=[CH:13]3)=[CH:7][CH:6]=1)(=[O:4])=[O:3]>O1CCCC1.C(O)C.[OH-].[Na+]>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[C:17]([O:19][CH2:20][CH:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[CH:18]=2)[NH:15][C:14]([C:27]([OH:29])=[O:28])=[CH:13]3)=[CH:32][CH:33]=1)(=[O:3])=[O:4]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cc3)cc(OCC3CCOCC3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(Oc2cc(OCC3CCOCC3)c3[nH]c(C(=O)O)cc3c2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
Ethyl 5-[4-(methylsulfonyl)phenoxy]-7-(tetrahydro-2H-pyran-4-ylmethoxy)-1H-indole-2-carboxylate (3.5 g) was dissolved in a mixed solvent of tetrahydrofuran (30 mL)-ethanol (30 mL), 1M aqueous sodium hydroxide solution (15 mL) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction solution was allowed to cool to room temperature, and concentrated under reduced pressure. Water was added to the residue, and the mixture was neutralized with 1M hydrochloric acid, and subjected to extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained crude product was crystallized from a mixed solvent of ethanol-hexane-diethyl ether. The obtained colorless crystals were recrystallized from acetone-hexane to give the title compound (1.1 g) as colorless crystals. melting point 256-258° C. (decomposition).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:18])=[N:4][CH:5]=[C:6]([C:13](OCC)=[O:14])[C:7]=1[C:8](OCC)=[O:9].O.[NH2:20][NH2:21]>>[NH2:1][C:2]1[C:7]2[C:8](=[O:9])[NH:21][NH:20][C:13](=[O:14])[C:6]=2[CH:5]=[N:4][C:3]=1[CH3:18]
Reactant: NN
Reactant: CCOC(=O)c1cnc(C)c(N)c1C(=O)OCC
Solvent: O
Product: Cc1ncc2c(=O)[nH][nH]c(=O)c2c1N
Temperature: 100 °C

Procedure:
To 57 mg of 3-amino-4,5-diethoxycarbonyl-2-methylpyridine was added 0.5 mL of hydrazine monohydrate, and the mixture was heated at 100° C. in a stream of nitrogen for 30 minutes. After the solvent was distilled off, the resulting crystals were collected by filtration with ethanol. Water was added to the crystals, and the mixture was neutralized with 1N hydrochloric acid, followed by collection of the crystals by filtration.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].[F:10][CH:11]([CH3:30])[CH2:12][CH2:13][CH2:14][Si:15]1(C2C=CC=CC=2)[CH2:20][CH2:19][CH:18]([C:21](O)=[O:22])[CH2:17][CH2:16]1>>[F:10][CH:11]([CH3:30])[CH2:12][CH2:13][CH2:14][Si@H:15]1[CH2:16][CH2:17][C@H:18]([C:21]([O:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[O:22])[CH2:19][CH2:20]1
Reactant: Oc1ccc(F)c(F)c1
Reactant: CC(F)CCC[Si]1(c2ccccc2)CCC(C(=O)O)CC1
Product: CC(F)CCC[Si@H]1CC[C@H](C(=O)Oc2ccc(F)c(F)c2)CC1

Procedure:
The general procedure of Example 3 was repeated using (3,4-difluorophenol and 4-(4-fluoropentyl)-4-phenyl-4-silacyclohexanecarboxylic acid, thereby obtaining the intended product.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[N:4][C:3]=1[C:17]([NH2:19])=[O:18].Br[C:21]1[N:26]=[C:25]([CH2:27][C:28]#[N:29])[CH:24]=[CH:23][CH:22]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[K+].[K+].C(O)(CC)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:28]([CH2:27][C:25]1[N:26]=[C:21]([NH:1][C:2]2[S:6][C:5]([C:7]3[CH:8]=[CH:9][C:10]([C:13]([OH:16])([CH3:15])[CH3:14])=[CH:11][CH:12]=3)=[N:4][C:3]=2[C:17]([NH2:19])=[O:18])[CH:22]=[CH:23][CH:24]=1)#[N:29]
Reactant: N#CCc1cccc(Br)n1
Reactant: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(N)s2)cc1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: CC(C)(O)c1ccc(-c2nc(C(N)=O)c(Nc3cccc(CC#N)n3)s2)cc1

Procedure:
The title compound was prepared as described in Example 1, Step 2 using 5-amino-2-[4-(1-hydroxy-1-methylethyl)phenyl]-1,3-thiazole-4-carboxamide (Example 5, Step 3) (150 mg, 0.54 mmol), (6-bromopyridin-2-yl)acetonitrile (107 mg, 0.54 mmol), Pd2(dba)3 (30 mg, 0.032 mmol), X-PHOS (77 mg, 0.16 mmol), potassium carbonate (82 mg, 0.60 mmol), and tert-amyl alcohol (1.2 ml) as starting materials. 1H NMR (600 MHz, d6-DMSO) δ 11.31 (s, 1H), 7.86 (d, 2H), 7.73 (m, 2H), 7.62 (s, 1H), 7.53 (d, 2H), 7.16 (d, 1H), 6.94 (d, 1H), 5.08 (s, 1H), 4.27 (s, 2H), 1.42 (s, 6H). LRMS (APCI) calc'd for C20H20N5O2S [M+H]+ 394.1, found 394.0.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH:18]=O>C(O)(C)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:18]/[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: O=Cc1ccccn1
Solvent: CC(C)O
Product: O=C1Nc2cc(Cl)ccc2/C1=C/c1ccccn1

Procedure:
In a manner similar to the method described in example 1, 6-chlorooxindole (4.12 g, 24.7 mmol) (Avocado) and pyridine-2-carbaldehyde (2.96 g, 24.7 mmol) (Aldrich) in isopropanol to give a mixture of E/Z-6-chloro-3-pyridi-2-ylmethene-1,3-dihydro-indol-2-one as a bright yellow solid (Yield 6.0 g, 94.6%) and used for the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[N+:20]([O-:22])=[O:21])=[CH:7][CH:8]=[C:9]([C:11](=[S:13])[NH2:12])[CH:10]=1)=[O:4].Br.Br[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)=O>>[N+:20]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:6]1[C:5]([C:3]([OH:2])=[O:4])=[CH:10][C:9]([C:11]2[S:13][CH:25]=[C:26]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[N:12]=2)=[CH:8][CH:7]=1)([O-:22])=[O:21]
Reactant: O=C(CBr)c1ccncc1
Reactant: COC(=O)c1cc(C(N)=S)ccc1-c1ccccc1[N+](=O)[O-]
Agent: Br
Product: O=C(O)c1cc(-c2nc(-c3ccncc3)cs2)ccc1-c1ccccc1[N+](=O)[O-]
Yield: 77 %

Procedure:
2′-Nitro-4-(4-pyridin-4-yl-thiazol-2-yl)-biphenyl-2-carboxylic acid (195 mg, 77%) was prepared from 2′-nitro-4-thiocarbamoyl-biphenyl-2-carboxylic acid methyl ester (which may be prepared as described for Intermediate 4) and 4-(bromoacetyl)pyridine hydrobromide (available from Oakwood Products, Inc.) using the procedure described for the preparation of Example 1. 1H NMR (300 MHz, DMSO-d6) δ 13.14 (s, 1H), 8.68 (d, J=5.2 Hz, 2H), 8.61 (s, 1H), 8.58 (d, J=1.1 Hz, 1H), 8.28 (dd, J=7.9, 0.9 Hz, 1H), 8.14 (d, J=8.2 Hz, 1H), 8.02 (d, J=5.4 Hz, 2H), 7.78 (t, J=7.5 Hz, 1H), 7.65 (t, J=7.6 Hz, 1H), 7.41-7.49 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[N:7](COCCOC)[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:10])=[O:9].Cl>CO>[Cl:1][C:2]1[C:3]([CH3:36])=[N:4][O:5][C:6]=1[NH:7][S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH2:20][C:21]1[CH:26]=[CH:25][C:24]2[O:27][CH2:28][O:29][C:23]=2[CH:22]=1)(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(Cc2ccc3c(c2)OCO3)sc2ncccc12
Agent: Cl
Solvent: CO
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc4c(c3)OCO4)sc3ncccc23)c1Cl
Yield: 75.4 %

Procedure:
The title compound was prepared by the method of Example 4(D) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxymethyl)-2-[3,4-(methylenedioxy)benzyl]thieno[2,3-b]pyridine-3-sulfonamide (0.14 g, 0.26 mmoles), methanol (6 ml) and 4N HCl (2 ml). Recrystallization from chloroform/hexanes provided 91 mg (76%) of the title compound as a tan crystalline solid, m.p. 163.5°-165° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:7](O)(=O)[C:8](O)=O.CN(CCC1C=CC=C(C)N=1)CCC([C:19]1[CH:24]=[CH:23][C:22]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=1)=O.C(O)(=O)C(O)=O.C(O)(=O)C(O)=O.[CH2:51]([N:53]([CH2:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=C(C)[N:73]=1)CCCC(C1C=CC(NS(C)(=O)=O)=CC=1)=O)C.C(O)(=O)C(O)=O.C(O)(=O)C(O)=O.CS(N)(=O)=O>>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:51][N:53]([CH2:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[C:7]([CH3:8])[N:73]=1)[C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([CH3:29])(=[O:27])=[O:28])=[C:23]([C:1](=[O:6])[CH3:2])[CH:24]=1
Reactant: CCN(CCCC(=O)c1ccc(NS(C)(=O)=O)cc1)CCc1cccc(C)n1
Reactant: Cc1cccc(CCN(C)CCC(=O)c2ccc(NS(C)(=O)=O)cc2)n1
Agent: CS(N)(=O)=O
Agent: O=C(O)C(=O)O
Product: CC(=O)c1cc(N(C)CCc2cccc(C)n2)ccc1NS(C)(=O)=O

Procedure:
##STR27## Compound B: Compound prepared in Example 2: N-[4-[3-{N-methyl-(6-methyl-2-pyridyl)-ethylamino}propionyl]phenyl]methanesulfonamide dioxalate: ##STR28## Compound C; Compound prepared in Example 4: N-[4-[4-{N-methyl-2-(6-methyl-2-pyridyl)-ethylamino}butyrul]phenyl]methanesulfonamide dioxalate: ##STR29## Compound D: Compound prepared in Example 5: N-[4-[4-{N-ethyl-2-(6-methyl-2-pyridyl)-ethylamino}butyryl]phenyl]methanesulfonamide dioxalate: ##STR30## Compound E: Compound prepared in Example 6: N-[4-[5-{6-methyl-2-pyridyl)ethylamino}valeryl]-phenyl]methanesulfonamide dioxalate: ##STR31##
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[CH:15]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([F:27])([F:26])[C:18]([F:29])([F:28])[C:17]2[CH:30]=[CH:31][CH:32]=[CH:33][C:16]1=2>>[CH2:10]([O:9][C:1](=[O:8])[CH:2]([CH:15]1[C:16]2[CH:33]=[CH:32][CH:31]=[CH:30][C:17]=2[C:18]([F:29])([F:28])[C:19]([F:26])([F:27])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]1=2)[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11]
Reactant: FC1(F)c2ccccc2C(Cl)c2ccccc2C1(F)F
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C(=O)OCC)C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21
Reaction time: 1 h

Procedure:
Diethyl malonate, 90 ml., is stirred, cooled in an ice bath, and treated with 1.51 g. of 55.7% sodium hydride in mineral oil in several portions. The mixture is stirred approximately 5 minutes at room temperature and then treated with 10.03 g. (0.0334 mole) of 5-chloro-10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene. Stirring is continued for 16 hours at approximately 40° C., 1 hour at 50° C., 1 hour at 60° C. and 1 hour at 70° C. The excess diethyl malonate is distilled at 70°-75° C. and 0.1 mm. and the residue is triturated with hexane. The insoluble mixture of product and sodium chloride is collected, washed with hexane and petroleum ether, and dried at 80° C. and 0.1 mm. The mixture is triturated with benzene and the insoluble sodium chloride is removed by filtration. Evaporation of the benzene solution under reduced pressure and recrystallization of the residual white solid from absolute ethanol affords purified product, m.p. 144°-146° C.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[N:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][NH:57][CH2:56][CH:55]1[CH3:60])=[O:53])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52]([N:54]1[CH2:59][CH2:58][N:57]([C:12]([C:9]2[N:10]=[CH:11][N:7]([C:3]3[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=3)[N:8]=2)=[O:14])[CH2:56][CH:55]1[CH3:60])=[O:53])([CH3:50])([CH3:48])[CH3:49]
Reactant: CC1CNCCN1C(=O)OC(C)(C)C
Reactant: Cc1cccc(-n2cnc(C(=O)O)n2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(-n2cnc(C(=O)N3CCN(C(=O)OC(C)(C)C)C(C)C3)n2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.00 g (9.84 mmol) 1-m-tolyl-1H-[1,2,4]-triazole-3-carboxylic acid was stirred with 3.30 g (10.3 mmol) TBTU and 2.50 mL (14.6 mmol) DIPEA in 30 mL DCM at RT. After 10 min, 2.05 g (9.84 mmol) 2-methyl-piperazine-1-carboxylic acid tert-butyl ester was added and the reaction mixture was stirred at RT for 12 h. The solvent was removed by distillation. The residue was taken up in water and extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (EtOAc).
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11].P([O-])(O)(O)=O.[K+]>CS(C)=O>[F:1][C:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: [F-]
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1cnccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
Anhydrous potassium fluoride (5.5 g, 93 mmol) was suspended in anhydrous dimethylsulfoxide (200 ml) and the solvent reduced to half its volume by distillation under an atmosphere of nitrogen. The resulting suspension was cooled to room temperature and 4-chloro-3-nitropyridine (14 g, 88 mmol) was added. The reaction mixture was stirred at 120° C. for three hours under an atmosphere of nitrogen, cooled and then poured into a saturated aqueous solution of potassium dihydrogen phosphate. The resulting mixture was extracted with ethyl acetate. The organic phase was washed three times with water and then brine before being dried over anhydrous magnesium sulphate. The solvent was removed in vacuo to yield as an oil, 4-fluoro-3-nitropyridine (6.5 g), (δ(CDCl3) 7.32 (1H, 4 lines), 7.86 (1H, t, J=5 Hz) and 8.29 (1H, d, J=9 Hz), represented by the structural formula: ##STR21##
Reaction SMILES: C[O:2][C:3](=[O:19])[C@@H:4]([N:11]1[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]1=[O:18])[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[CH:13][C:12]2=[O:18])[C:3]([OH:19])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCC1)N1CC(OC)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1=CC(=O)N([C@@H](CC2CCCC2)C(=O)O)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 64.9 %

Procedure:
To a solution containing (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid methyl ester (1.42 g, 5.20 mmol) in tetrahydrofuran (10 mL) was treated with an aqueous solution of lithium hydroxide monohydrate (273 mg, 6.4 mmol) in water (10 mL). The mixture was stirred at 25° C. for 2.5 h, it was then acidified with 2N aqueous hydrochloric acid. The mixture was extracted with dichloromethane (2×30 mL). The combined organic layers was dried over magnesium sulfate and concentrated to afford (S)-3-cyclopentyl-2-(4-methoxy-2-oxo-2,5-dihydro-pyrrol-1-yl)-propionic acid, (855 mg, 65%), as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.08 (m, 2H), 1.36-1.88 (m, 9H), 3.78 (s, 3H), 3.95 (J=17.7 Hz, 2H), 4.54 (dd, J=4.5 Hz, 11.0 Hz, 1H), 5.16 (s 1H), 12.80 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Br[C:10]#[N:11]>O>[NH:8]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][N:1]=[C:10]1[NH2:11]
Reactant: NCC1(N)CCCC1
Reactant: N#CBr
Solvent: O
Product: NC1=NCC2(CCCC2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 138.8 %

Procedure:
3.35 g of 1-(aminomethyl)cyclopentanamine are solubilized in 20 mL of water, cooled beforehand in an ice bath. 3.52 g of BrCN are added and the mixture is then stirred for 3 h at RT. The solvent is evaporated. 5.67 g (yield=88%) of 1,3-diazaspiro[4.4]non-2-en-2-amine are obtained as a brown oil.