Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[C:8]([C:11]([NH2:13])=O)[CH:9]=2)[C:4]([CH3:16])([CH3:15])[CH:3]1[CH3:17].S(Cl)(Cl)=O.[OH-].[Na+]>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][C:7]([CH3:14])=[C:8]([C:11]#[N:13])[CH:9]=2)[C:4]([CH3:16])([CH3:15])[CH:3]1[CH3:17]
Reactant: Cc1cc2c(cc1C(N)=O)C(C)(C)C(C)C2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1cc2c(cc1C#N)C(C)(C)C(C)C2(C)C

Procedure:
The crude product from Step III was dissolved in 250 ml. of benzene in a 50-ml. flask equipped with mechanical stirrer, cooling bath, thermometer, addition funnel, condenser, and static nitrogen head. Thionyl chloride (72 ml.) was added gradually with cooling over six mimutes at 24° to 30° C. The mixture was then heated to reflux for about 4 hours, and after cooling, 150 ml. of 5% sodium hydroxide solution was added at between 32° and 50° C., with cooling, over 16 minutes. The entire contents of the reaction flask were transferred to a separatory funnel and washed twice with 500 ml. of 5% sodium hydroxide solution. The washings were extracted in succession with 50 ml. of benzene. The organic phases were combined and flash evaporated on a rotary evaporator for one hour at 50° C. 10 mm. Hg to yiedl 30.6 g. of crude nitrile. The infrared spectrum (mineral oil mull) showed a medium intensity nitrile band at 2400 cm-1. The crude nitrile was taken up in 100 ml. of benzene and run onto a 1 1/8 inch by 35 inch chromatography column (wet-packed with 400 g. of MCB grade 923 silica gel using benzene as packing solvent). Pure nitrile was collected after 525 ml. of benzene were eluted from the column. A 5 g. portion of the chromatographed nitrile was recrystallized from hexane. The recrystallized nitrile was dissolved in 30 ml. of methanol, 2 g. of Draco K-9 activated carbon added, and the slurry filtered. After repeating the carbon treatment, the product was again recrystallized from hexane. The recrystallized product melted at 70.2° to 72.8° C. NMR spectrum (CDCl3 with TMS reference):
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].O(CC)[C:12]([S-])=[S:13].[K+].Cl>N1C=CC=CC=1>[CH3:10][O:9][C:7]1[CH:6]=[CH:5][C:3]2[NH:4][C:12](=[S:13])[O:1][C:2]=2[CH:8]=1
Reactant: CCOC(=S)[S-]
Reactant: COc1ccc(N)c(O)c1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Product: COc1ccc2[nH]c(=S)oc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Hydroxy-4-methoxyaniline (1.00 g, 7.19 mmol) and potassium O-ethyl xanthate (1.27 g, 7.91 mmol) were heated to reflux in pyridine (20 mL). After 2 h, the reaction mixture was allowed to cool to rt and was poured into a solution of conc. HCl (10 mL) in ice water (80 mL). The resulting white solid was collected by filtration, washed with water (3×), and dried in a vacuum oven. This gave 0.733 g (56%) of the desired product. LC-MS: RT=6.67 min., [M+H]+=182.1.
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:30]=[N:31][N:32]([CH3:34])[N:33]=2)=[CH:25][CH:24]=1>CS(C)=O.CO.C(OCC)(=O)C>[CH3:34][N:32]1[N:31]=[N:30][C:29]([C:26]2[CH:27]=[CH:28][C:23]([CH2:22][N:1]3[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]3)=[CH:24][CH:25]=2)=[N:33]1
Reactant: Cn1nnc(-c2ccc(CBr)cc2)n1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CO
Product: CCOC(=O)C1CCN(Cc2ccc(-c3nnn(C)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 62.8 %

Procedure:
A solution of 30.0 grams (0.191 mole) of ethyl isonipecotate in 75 mL of DMSO and 99 mL of methanol was stirred and 61.7 grams (0.477 mole) of N,N-diisopropylethylamine, followed by 40.2 grams (0.159 mole) of 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetraazole (known compound—U.S. Pat. No. 5,639,763) were added. Upon completion of addition the reaction mixture was stirred at ambient temperature for about 72 hours. The reaction mixture was then diluted with 175 mL of ethyl acetate and washed with 175 mL of a solution comprised of one part of an aqueous solution saturated with sodium chloride and one part of water. The organic layer was concentrated under reduced pressure to a residue. NMR analysis of the residue indicated the presence of some of the starting ethyl isonipecotate. The residue was dissolved in 370 mL of methanol and water was added to precipitate a solid material. After standing for about 20 minutes, the solid was collected by filtration and was washed with a cold solution of one part methanol and one part of water. The solid was dried, yielding 32.9 grams of the subject compound. A second crop of solid was collected from the filtrate, yielding an additional 11.0 grams of the subject compound. The NMR spectra were consistent with the proposed structure.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][NH2:12])=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[CH3:13][N:14]1[CH:19]=[C:18]([CH2:20]Cl)[C:17]([C:22](OC)=[O:23])=[C:16]([Cl:26])[C:15]1=[O:27]>CC#N>[Cl:26][C:16]1[C:15](=[O:27])[N:14]([CH3:13])[CH:19]=[C:18]2[CH2:20][N:12]([CH2:11][CH2:10][C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)[C:22](=[O:23])[C:17]=12
Reactant: NCCc1cn2ccccc2n1
Reactant: COC(=O)c1c(CCl)cn(C)c(=O)c1Cl
Solvent: CC#N
Product: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1cn3ccccc3n1)C2
Temperature: 100 °C
Yield: 48 %

Procedure:
TEA (5 ml, 36 mmol) was added to a suspension of 2-(imidazo[1,2-a]pyridine-2-yl)ethanamine (1.934 g, 12 mmol) and 1-methyl-2-oxo-1,2-dihydro-3-chloro-4-methoxycarbonyl-5-chloromethyl-pyridine (3 g, 12 mmol, see compound (6) of Example b1)) in MeCN (5 ml). The reaction was heated in a CEM microwave at about 100° C. for about 40 min. The solvent was removed and the resulting mixture was deposited onto silica gel, loaded onto a silica gel column and eluted with DCM/MeOH (50:1) to give 2.9 g of crude product. The crude product was washed with water, dried to afford the title compound (2 g, 5.76 mmol, 48.1% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[CH:22]=[O:23]>CC(O)=O>[N:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]=[CH:14][C:13]=1[CH:22]([OH:23])[CH2:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cnc2ccccc2n1
Reactant: O=Cc1cnc2ccccc2n1
Solvent: CC(=O)O
Product: OC(Cc1cnc2ccccc2n1)c1cnc2ccccc2n1
Yield: 26.3 %

Procedure:
A solution of 2-methyl quinoxaline (0.11 g, 0.76 mmol) and quinoxaline-2-carbaldehyde (0.16 g, 0.63 mmol) in AcOH (2 mL) was stirred for 1 hour at 70° C. The reaction mixture was concentrated and purified with reverse phase column chromatography to afford 1,2-di(quinoxalin-2-yl)ethanol (0.05 g) as a yellow solid. MS (ESI) m/z 303.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.Br[CH2:10][CH:11]=O.C(OC(OCC)CBr)C.Br.C(=O)(O)[O-].[Na+]>O>[F:8][C:7]1[C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1F
Reactant: O=CCBr
Agent: Br
Agent: CCOC(CBr)OCC
Agent: O=C([O-])O
Solvent: O
Product: Fc1cccn2ccnc12

Procedure:
2-Amino-3-fluoropyridine (21.1 g) is added to a solution of bromoacetaldehyde prepared from 74 g of bromoacetaldehyde diethylacetal, 18.5 ml of aqueous hydrogen bromide solution and 18.5 ml of water and made to react in the presence of sodium bicarbonate in aqueous ethanolic solution giving 12 g of the above-identified compound, bp. 91°-100° C./1-1.5 mmHg, which solidifies at room temperature.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH:26]=O)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:31]([NH:33][CH3:34])[CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[CH2:31]([N:33]([CH2:26][C:24]1[S:23][CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:28]([NH2:30])=[O:29])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7][CH2:8]2)[CH:25]=1)[CH3:34])[CH3:32]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(C=O)c4)cc23)CC1
Reactant: CCNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Temperature: 25 °C
Reaction time: 5 h
Yield: 55.8 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-3-thienyl)-1H-indole-7-carboxamide (50 mg, 0.11 mmol) in DMSO (2.0 mL) was added 2 drops of acetic acid, ethyl(methyl)amine (59 mg, 1.0 mmol), and stirred at room temperature for 5 h. To this was then added sodium triacetoxyborohydride (212 mg, 1.0 mmol) and reacted overnight. It was then purified by Gilson Preparatory HPLC to give 30.0 mg of the title compound (61.4%).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[OH2:11]>>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: C1=Cc2ccccc2NC1
Reactant: O
Product: O=C1CCc2ccccc2N1

Procedure:
A mixture of 46.8 g (1.2 moles) of sodamide. 400 cc of toluene containing 0.5 cc of oleic acid and 129.2 g (1.0 mole) of quinoline was placed in a liter Magne Drive, equipped as described in Example 15. The autoclave was closed and purged of air with ammonia, pressurized to 30 psig with ammonia and then to 200 psig with nitrogen. The pressure relief valve was set at 350 psig. Cooling water was turned on the reflux condenser. The autoclave was heated with stirring for 2 hours within a range of 138°-148° C. No hydrogen evolution was observed. The autoclave was cooled and vented to atmospheric pressure. The reaction mixture was carefully hydrolyzed (external cooling) with 150 cc of water. The maximum temperature was 30° C. The hydrolyzed mixture contained organic crystalline material. In order to dissolve the crystals, 200 cc of 4-picoline was added and the mixture thoroughly stirred. The aqueous phase was allowed to settle and was removed. The organic phase was placed under vacuum at 40° C. to remove most of the residual ammonia. It was then treated with dry ice and filtered to remove carbonates. The filtrate was topped to a liquid temperature of 110° C. at 50 mm Hg. To the residue was added about 2 parts of toluene and the solution was allowed to crystallize. The mixture was filtered to give 57.4 g of 2-amino-3,4-dihydroquinoline, m.p. of 134.9°-136.3° C. The dihydroquinoline was hydrolyzed in boiling water to give 3,4-dihydrocarbostyril m.p. 165.7°-167.1° C. It is reported in Tetsuji et al., J. Heterocycle Chem., 2, 330 (1965) that the Chichibabin amination of quinoline in toluene at atmospheric pressure gave only 2-aminoquinoline. Derivatives of 3,4-dihydrocarbostryril have anti-inflammatory and blood platelet coagulation activities as claimed by Nakagawa et al., Japan. Kokai 77 73,866.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][NH:7][C:8](=O)[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]=[C:8]([Cl:20])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[N+:16]([O-:18])=[O:17]
Reactant: O=C(NCc1ccc(Cl)c([N+](=O)[O-])c1)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cc(CN=C(Cl)C(F)(F)F)ccc1Cl
Temperature: 100 °C

Procedure:
A mixture of N-(4-chloro-3-nitrobenzyl)-2,2,2-trifluoroacetamide (6.0 g, 0.0212 mol) and phosphorus pentachloride (8.9 g, 0.0427 mol) is heated to 100° C. for three hours, concentrated in vacuo to remove excess phosphorus pentachloride and triturated with methylene chloride to obtain a solution of N-(4-chloro-3-nitrobenzyl)-2,2,2-trifluoroacetimidoyl chloride in methylene chloride. The methylene chloride solution is treated with 2-chloroacrylonitrile (2.5 mL, 0.0319 mol) and triethylamine (5.9 mL, 0.0422 mol), stirred overnight at room temperature, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a residue. Chromatography of the residue using silica gel and a 4:1 hexanes/ethyl acetate solution gives the title product as a yellow solid (0.65 g, mp 258°-260° C.).
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].O=[C:9]([CH2:21][CH2:22][CH3:23])[CH:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C([O-])(=O)C.[NH4+].C1(C)C=CC=CC=1>C(O)(=O)C>[O:6]=[C:5]1[C:7](=[C:9]([CH2:21][CH2:22][CH3:23])[CH:10]=[CH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[S:1][C:2](=[S:3])[NH:4]1
Reactant: O=C1CSC(=S)N1
Reactant: CCCC(=O)C=Cc1ccc(C(=O)O)cc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCC(C=Cc1ccc(C(=O)O)cc1)=C1SC(=S)NC1=O

Procedure:
A mixture of 0.73 g (0.0055 mol) of rhodanine, 1.09 g (0.005mol) of 4-(3-oxo-hexen-1-yl)benzoic acid, 0.39 g (0.005 mol) of ammonium acetate and 10 ml of toluene was heated under reflux for 5 hours. After cooling, acetic acid was added to the reaction mixture and the precipitate was recovered by filtration. The precipitate was recrystallized from chloroform-methanol to give 0.10 g of the isomer A of the desired 4-[3-(4-oxo-2- thioxo-5-thiazolidinylidene)-1-hexen-1-yl]benzoic acid. To the filtrate was added water and the resulting mixture was extracted with chloroform (100 ml×3). The chloroform layer was washed three times with water and then once with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate and then filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (eluent, chlorform : methanol=10:1) to give 0.10 g of the isomer B of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)=[O:6])[CH3:2].Cl[C:16]1[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=1.Cl>C(O)C.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:14])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:16]2[C:21]([N+:22]([O-:24])=[O:23])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:9][CH:8]=1)=[O:6])[CH3:2]
Reactant: CCOC(=O)C(=O)c1ccc(N)cc1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CCOC(=O)C(=O)c1ccc(Nc2ncccc2[N+](=O)[O-])cc1
Temperature: 25 °C

Procedure:
A mixture of (4-amino-phenyl)-oxo-acetic acid ethyl ester (347 mg, 1.8 mmol), 2-chloro-3-nitropyridine (294 mg, 1.8 mmol) and 4M HCl in dioxane (0.45 mL, 1.8 mmol) in ethanol (4 mL) is refluxed for 14 h. An additional 0.45 mL of 4M HCl in dioxane is added and the mixture refluxed for 5 h. The reaction mixture is cooled down to room temperature and the resulting precipitate is filtered off. [4-(3-Nitro-pyridin-2-ylamino)-phenyl]oxo-acetic acid ethyl ester is obtained as an orange solid. Title compound: ES-MS: 315.99 [M+H]+; tR=1.7 min (System 2).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=O)[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2].Cl.[NH2:34][OH:35].C(=O)(O)[O-].[Na+]>CO>[C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:31]=[N:34][OH:35])[CH:8]=[C:9]2[C:17]=1[CH:16]([CH2:18][O:19][C:20](=[O:22])[NH2:21])[C:15]1([O:24][C:25](=[O:27])[CH3:26])[O:23][N:10]2[CH2:11][CH:12]2[CH:14]1[N:13]2[C:28](=[O:30])[CH3:29])(=[O:3])[CH3:2]
Reactant: NO
Reactant: CC(=O)Oc1cc(C=O)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(=O)Oc1cc(C=NO)cc2c1C(COC(N)=O)C1(OC(C)=O)ON2CC2C1N2C(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
To a solution of 11-acetyl-8-carbamoyloxymethyl-4-formyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (40 mg) in methanol (2 ml) were added hydroxylamine hydrochloride (10 mg) and sodium bicarbonate (8 mg). The mixture was stirred for 2 hours at ambient temperature and evaporated in vacuo. The residue was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (10:1, v/v) to afford 11-acetyl-8-carbamoyloxymethyl-4-hydroxyiminomethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]2[NH:9][C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:36]1CCOC[CH2:37]1>>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]2[N:9]([CH2:37][OH:36])[C:10](=[O:14])[CH:11]([CH3:13])[O:12][C:7]=2[CH:6]=1
Reactant: C1COCCO1
Reactant: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2NC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC1Oc2cc(Oc3ccc(C(F)(F)F)cc3Cl)ccc2N(CO)C1=O
Temperature: 80 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
First, 7-(2-chloro-4-trifluoromethylphenoxy)-2-methyl-2H-1,4-benzoxazine-3 (4H)-one (0.4 g) prepared in Example 1 was dissolved in dioxane (5 ml), p-formaldehyde (0.1 g) and p-toluenesulfonic acid (0.1 g) were added to the solution, and the mixture was stirred at 80° C. for 3 hr. After the completion of the reaction, the reaction mixture was concentrated in vacuo, and the resultant residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=1/1) to prepare the title compound (0.2 g) as a colorless crystal (yield: 50%).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[NH:5][N:4]=1)[CH3:2].[CH3:14][O:15][CH2:16][CH2:17]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([C:11]([NH2:13])=[O:12])[N:5]([CH2:17][CH2:16][O:15][CH3:14])[N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c(C(N)=O)c1[N+](=O)[O-]
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCc1nn(CCOC)c(C(N)=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 20 h
Yield: 39 %

Procedure:
A mixture of 3-ethyl-4-nitro-1H-pyrazole-5-carboxamide (prepared as in WO 98/49166) (1.7 g, 8.8 mmol), 2-bromoethyl methyl ether (0.85 mL, 8.85 mmol) and cesium carbonate (2.9 g, 9.0 mmol) in dimethylformamide (20 mL) was stirred at room temperature for 20 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (125 mL) and brine (100 mL). The phases were separated, and the organic layer was dried (Na2SO4), and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel, using ethyl acetate:methanol (97:3) as eluant to afford 3-ethyl-1-(2-methoxyethyl)-4-nitro-pyrazole-5-carboxamide (831 mg, 39%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]2[S:26][C:25](=[O:27])[NH:24][C:23]2=[O:28])=[CH:19][CH:18]=1)=[O:16].[BH4-].[Na+]>C(O)(C)C>[C:7]1([C:5]2[O:6][C:2]([CH3:1])=[C:3]([CH2:13][CH2:14][CH:15]([C:17]3[CH:30]=[CH:29][C:20]([CH2:21][CH:22]4[S:26][C:25](=[O:27])[NH:24][C:23]4=[O:28])=[CH:19][CH:18]=3)[OH:16])[N:4]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(=O)c1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 2 h
Yield: 45.5 %

Procedure:
The title product of Example 9 (0.70 g) was suspended in 50 ml of isopropanol at room temperature. NaBH4 (0.15 g) was added and the mixture stirred for 2 hours, concentrated in vacuo to low volume, diluted with 50 ml of water and extracted 2×200 mL ethyl acetate. The organic layers were combined, washed with brine, dried (MgSO4), stripped in vacuo and the residue chromatographed using 1:1 ethyl acetate:hexane-1% acetic acid to yield 0.32 g of present title product; mp 50°-55° C.; tlc Rf 0.40 (1:1 hexane:ethyl acetate-2.5% acetic acid), 0.28 (2:1 CH2Cl2 :ether).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17]C3C=NC=CC=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=1>>[F:25][C:2]([F:1])([F:26])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([F:35])[CH:29]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Product: Cc1ccc(Nc2cc(F)cc(F)c2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) in accordance with the general method of example 20 using 1-Bromo-3,5-difluorobenzene instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=414.6 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=2)=[O:15])[C:5]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)=[N:6][CH:7]=1.[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([Cl:35])[CH:34]=1.C1(CNCC2CCCCC2)CCCCC1>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=3)=[O:15])[C:5]([C:8]3[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=3)=[N:6][CH:7]=2)[CH:32]=[C:33]([Cl:35])[CH:34]=1
Reactant: COc1ccc(CNC(=O)c2cc(Cl)cnc2-c2cccnc2)cc1OC
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C1CCC(CNCC2CCCCC2)CC1
Solvent: C1COCCO1
Product: COc1ccc(CNC(=O)c2cc(-c3cc(Cl)cc(Cl)c3)cnc2-c2cccnc2)cc1OC
Temperature: 110 °C
Reaction time: 0.33 h

Procedure:
To a solution of methyl 5-chloro-2,3′-bipyridine-3-carboxylate (1-2, 0.500 g, 2.01 mmol) in tetrahydrofuran (5 mL) and methanol (5 mL) was added potassium hydroxide (0.200 g, 3.61 mmol) and water (1.25 mL) and the system was stirred at room temperature overnight. The reaction mixture was then neutralized with 6N HCl to a pH of 2.0 and then concentrated in vacuo to afford 5-chloro-2,3′-bipyridine-3-carboxylic acid as a bone powder in the form of a bis HCl salt. ESI+ MS [MH]+C11H7ClN2O2=234.9. To a solution of the bis HCl salt form of 5-chloro-2,3′-bipyridine-3-carboxylic acid (0.613 g, 2.00 mmol) and 3,4-dimethoxybenzylamine (0.367 g, 2.2 mmol) in dimethylformamide (10 mL) was added EDC (0.764 g, 4.00 mmol), HOBt (0.612 g, 4.00 mmol) and triethylamine (0.6 mL, 10 mmol) and the system was stirred in an oil bath at 100° C. for 3 h. The system was cooled to room temperature, extracted with EtOAc, washed with water and dried over magnesium sulfate. The crude reaction mixture was then tritirated with ether to afford 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide as a bone powder. ESI+ MS [MH]+ C20H18ClN3O3=234.9. To a solution of 5-chloro-N-(3,4-dimethoxybenzyl)-2,3′-bipyridine-3-carboxamide (0.600 g, 1.56 mmol) in dioxane (5.2 mL) was added 3,5-dichlorophenyl boronic acid (1.50 g, 7.82 mmol), N,N-dicylohexylmethylamine (0.368 mL, 1.72 mmol), and bis(tri-t-butylphosphine)palladium (0.023 g, 0.047 mmol) and the system was stirred at 110° C. for 20 minutes in the microwave. The reaction was then cooled to room temperature, and partitioned between ethyl acetate and water. The reaction mixture was filtered and purified via normal phase chromatography (0→6% MeOH in DCM) followed by reverse phase chromatography (10%→65% 0.1% TFA in water: 0.1% TFA in ACN) followed by free basing with saturated sodium carbonate afforded the title compound (2-1) as a white powder. 1H NMR (500 MHz, CDCl3) δ 9.00 (s, 1H), 8.95 (s, 1H), 8.66-8.68 (m, 1H), 8.15 (s, 1H), 7.98-8.00 (m, 1H), 7.53-7.54 (m, 2H), 7.46-7.47 (m, 1H), 7.28-7.30 (m, 1H), 6.77 (d, J=5 Hz, 1H), 6.39-6.66 (m, 2H), 5.69 (br s, 1H), 4.42 (d, J=5.5 Hz, 2H), 3.85 (s, 3H), 3.88 (s, 3H). HRMS [M+H] C26H21Cl2N3O3 calc'd 494.1033, found 494.1023.