Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH2:8].N([C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=[N+]=[N-]>C(=O)([O-])[O-].[Na+].[Na+].CC(C)=O.O>[CH:30]1[C:31]2[CH:19]([CH2:18][O:17][C:15]([NH:2][C@@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:15]([O:17][CH2:18][CH:19]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=4[C:26]4[C:31]3=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:16])=[O:16])[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:26]=2[CH:27]=[CH:28][CH:29]=1
Reactant: [N-]=[N+]=NC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NCCCC[C@@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OCC1c2ccccc2-c2ccccc21

Procedure:
To a stirred solution of D-lysine hydrochloride (4.5 g) in 175 ml of a sodium carbonate solution (10% in water):acetone (6:1) solution is added dropwise a solution of 9-fluorenylmethyl azidoformate in acetone (150 ml). After 16 hours the mixture is diluted with water and washed three times with hexane. The mixture is then acidified with concentrated hydrochloric acid and extracted three times with ethyl acetate. The ethyl acetate solution is washed successively with dilute hydrochloric acid, water, saturated sodium bicarbonate solution, and brine, dried over magnesium sulfate, then concentrated in vacuo to about 20 ml. The solution is added to hexane (1 l.) and the precipitate is collected and dried to afford the title compound: NMR (dimethylsulfoxide) δ1.0-1.9 (m, 6H), 2.7-3.2 (m,2H), 3.8-4.7 (m,7H), 6.8-8.3 (m,19H).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH3:10])=[O:8])(=[O:5])[CH:2]([CH3:4])[CH3:3].C[O-].[Na+].CO.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][C:25](Cl)=[N:26]O>O1CCCC1>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=1[CH2:24][C:25]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:1]([CH:2]([CH3:4])[CH3:3])[O:5][N:26]=1
Reactant: COC(=O)CC(=O)C(C)C
Reactant: ON=C(Cl)Cc1c(Cl)cccc1Cl
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1c(Cc2c(Cl)cccc2Cl)noc1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
A solution of methyl isobutyrylacetate (1.93 g, 13.4 mmol) in tetrahydrofuran (2.7 mL) was stirred at 0° C. as 0.5 N sodium methoxide in methanol solution (27 mL, 13.5 mmol) was added. A solution of 2-(2,6-dichlorophenyl)-N-hydroxyethanimidoyl chloride (2.60 g, 11.18 mmol) in tetrahydrofuran (8.7 mL) was added and the solution was allowed to warm to room temperature and stir overnight. The mixture was concentrated then partitioned between water and ethyl acetate. The organic layer was dried with magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography (silica gel, 0%-30% ethyl acetate in hexane) to provide the title compound (1.10 g, 30%). 1H NMR (DMSO-d6): 7.48 (d, J=8 Hz, 2H), 7.34 (t, J=8 Hz, 1H), 4.42 (s, 2H), 3.84 (s, 3H), 3.68 (septet, J=7 Hz, 1H), 1.24 (d, J=7 Hz, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([CH2:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:23][C:18]3=[CH:17][CH:16]=2)SCCCS1.CC(C)=[O:30].CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O.Cl[Hg]Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:30])[CH2:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(C)Nc1nc2ccc(CC3(c4ccccc4F)SCCCS3)nc2s1
Reactant: CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl[Hg]Cl
Solvent: CO
Solvent: O
Product: CC(C)Nc1nc2ccc(CC(=O)c3ccccc3F)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
To a solution of 5-((2-(2-fluorophenyl)-1,3-dithian-2-yl)methyl)-N-isopropylthiazolo[5,4-b]pyridin-2-amine (0.61 g, 1.45 mmol, 1.0 eq.) in MeOH (73 mL) and water (6 mL) were added HgO (0.83 g, 3.83 mmol, 2.6 eq.) and HgCl2 (1.83 g, 6.74 mmol, 4.6 eq.). After stirring for 15 min., the solution was refluxed for another 15 min. and cooled to room temperature. The precipitate was removed, and the filtrate was concentrated in vacuo. The residue was diluted with EtOAc and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Acetone (7 mL), water (0.1 mL, 5.56 mmol, 3.8 eq.), and TsOH.H2O (0.0342 g, 0.180 mmol, 0.1 eq.) were added, and the reaction was stirred overnight and concentrated in vacuo. The residue was diluted with CH2Cl2 and water, and the layers were separated. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography using CH2Cl2:MeOH (15:0.1) as eluent afforded 1-(2-fluorophenyl)-2-(2-(isopropylamino)thiazolo[5,4-b]pyridin-5-yl)ethanone as a yellow solid (0.1994 g, 42% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][N:3]=1.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1.Cl.[CH3:41][NH:42][O:43][CH3:44]>CN(C=O)C>[CH3:44][O:43][N:42]([CH3:41])[C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[N:3][CH:4]=1
Reactant: CNOC
Reactant: Cc1ccc(C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(C)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 6-methylnicotinic acid (5.00 g, 36.5 mmol) in DMF (150 mL), 1-hydroxybenzotriazole (4.92 g, 36.5 mmol), N-ethyl-N-(3-dimethylaminopropyl)carbodimide hydrochloride (8.38 g, 45.7 mmol) and 4-methylmorpholine (16.0 mL, 145.8 mmol) were added under argon atmosphere. The mixture was stirred at room temperature for 30 minutes after which N,O-dimethylhydroxylamine hydrochloride was added (3.55 g, 36.5 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was evaporated off. The residue was dissolved in a mixture of CHCl3 and 0.2 N NaHCO3. The phases were separated and the aqueous phase was extracted with CHCl3. The organic phase was dried over Na2SO4 and concentrated to dryness. The product was purified by chromatography on silica gel using hexane-EtOAc mixtures of increasing polarity as eluent, to afford 1.11 g of the desired product (yield: 29%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]([CH:12]=O)=[CH:10][S:9][C:8]=2[CH:14]=1)([O-:3])=[O:2].[NH2:15]/[C:16](/[CH3:23])=[CH:17]\[C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH3:23][C:16]1[NH:15][C:16]([CH3:23])=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:12]([C:11]2[C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:14][C:8]=3[S:9][CH:10]=2)[C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: O=Cc1csc2cc([N+](=O)[O-])ccc12
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1csc2cc([N+](=O)[O-])ccc12
Yield: 38.5 %

Procedure:
Following the procedure of Example 16C, 0.5 g of 6-nitrobenzo[b]thiophene-3-carboxaldehyde and 0.7 g of ethyl 3-aminocrotonate were reacted to provide 0.4 g of the desired title product, m.p. 191°-194° C.
Reaction SMILES: [C:1]([N:3]=[C:4](OC)[CH2:5][CH2:6][CH3:7])#[N:2].Cl.[CH3:11][O:12][C:13](=[O:16])[CH2:14][NH2:15].C(N(CC)CC)C>CO>[C:1]([N:3]=[C:4]([NH:15][CH2:14][C:13]([O:12][CH3:11])=[O:16])[CH2:5][CH2:6][CH3:7])#[N:2]
Reactant: COC(=O)CN
Reactant: CCCC(=NC#N)OC
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCC(=NC#N)NCC(=O)OC
Temperature: -5 °C
Reaction time: 17 h

Procedure:
Methyl N-cyanobutyrimidate (240 g, 1.90 mol) from Example 2 was dissolved in absolute methanol (1.5 L) and glycine methyl ester HCl (250 g, 1.99 mol) added to the reaction mixture. The suspension was cooled to -5° C. and triethylamine (211 g, 2.09 mol) added over a period of 15 minutes. The resulting solution was stirred at 20° C. for 17 hours, then concentrated under reduced pressure to an oily-solid residue (690 g). The residue was taken up in ethyl acetate and the insoluble salts removed by filtration. The filtrate was washed with water followed by 10% aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure. This product (370 g) was used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:8]([NH2:11])(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:12]=O.Cl>C(O)(C)C.C(OCC)(=O)C>[S:8]1(=[O:10])(=[O:9])[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][CH2:12][NH:11]1
Reactant: Nc1cccnc1S(N)(=O)=O
Reactant: C=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: O=S1(=O)NCNc2cccnc21

Procedure:
A mixture of 1 g of 3-aminopyridine-2-sulfonamide (Preparation 1) and 0.23 g of paraformaldehyde (1.3 eq.) in 10 cm3 of isopropanol to which 10 drops of ethyl acetate saturated with gaseous HCl have been added is brought to reflux for 1 to 2 hours. After cooling, the crystalline precipitate of the title compound is collected on a filter and washed with isopropanol. The product is recrystallized from hot water.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]1>>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([OH:17])[CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OC1CCCNC1
Product: O=[N+]([O-])c1ccc(N2CCCC(O)C2)cc1

Procedure:
1-(4-Nitrophenyl)piperidin-3-ol was synthesized as described in General Procedure A using 1-fluoro-4-nitrobenzene (4.41 g, 31.2 mmol) and piperidin-3-ol (4.3 g, 31.2 mmol) to give an orange solid (6.8 g, 30.6 mmol, 98% yield). Anal. Calcd. for C11H14N2O3 m/z 222.2, found: 223.3 (M+H)+; 1H NMR (500 MHz, CDCl3) δ ppm 8.14-7.98 (m, 2H), 6.83 (d, J=9.35 Hz, 2H), 3.89 (d, J=3.85 Hz, 1H), 3.72 (dd, J=12.92, 3.57 Hz, 1H), 3.53 (ddd, J=13.06, 5.91, 3.02 Hz, 1H), 3.33-3.16 (m, 2H), 2.10-1.97 (m, 2H), 1.96-1.84 (m, 1H), 1.75-1.50 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:18](OCC)(OCC)(OCC)[CH2:19][CH3:20]>C(OCC)(=O)C.CCOCC>[CH3:15][C:14]([CH3:17])([OH:16])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:18]1[CH2:19][CH3:20]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCc1nc2cnc3ccccc3c2n1CC(C)(C)O
Yield: 84.2 %

Procedure:
A mixture containing 15.4 g (0.067 mol) of 1-[(3-amino-4-quinolinyl)amino]-2-methyl-2-propanol (U.S. Pat. No. 4,689,338 example 189) and 14.5 mL (0.07 mol) of triethyl orthopropionate was heated at about 165° C. for about 2 hours. The resulting solid was slurried in a mixture of ethyl acetate and ether, collected and dried to provide 15.2 g of a solid. This material was used without further purification.
Reaction SMILES: Cl.[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][C:26]([C:32](O)=[O:33])=[CH:27][CH:28]=2)[N:23]=1.FC(F)(F)CNC1C=CC2C(=CC(C(O)=O)=CC=2)N=1>>[C:2]([N:6]1[CH:14]=[C:13]2[C:8]([C:9](=[O:20])[NH:10][C:11]3([CH2:19][CH2:18][N:17]([C:32]([C:26]4[CH:25]=[C:24]5[C:29]([CH:30]=[CH:31][C:22]([Cl:21])=[N:23]5)=[CH:28][CH:27]=4)=[O:33])[CH2:16][CH2:15]3)[CH2:12]2)=[N:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCNCC1)C2
Reactant: O=C(O)c1ccc2ccc(Cl)nc2c1
Agent: Cl
Agent: O=C(O)c1ccc2ccc(NCC(F)(F)F)nc2c1
Product: CC(C)(C)n1cc2c(n1)C(=O)NC1(CCN(C(=O)c3ccc4ccc(Cl)nc4c3)CC1)C2

Procedure:
The title compound was prepared by a method analogous to that described for Example 3 using 2′-tert-butyl-4′,6′-dihydrospiro[piperidine-4,5′-pyrazolo[3,4-c]pyridin]-7′(2′H)-one hydrochloride salt (Intermediate 4) and 2-chloroquinoline-7-carboxylic acid (Intermediate 44). +ESI (M+H) 452.3; 1H NMR (400 MHz, CDCl3, δ): 8.12 (d, J=8.2 Hz, 1H), 7.98 (br. s., 1H), 7.88 (dd, J=8.4 Hz, 1H), 7.61 (dd, J=8.4, 1.6 Hz, 1H), 7.44 (d, J=8.6 Hz, 1H), 7.39 (s, 1H), 5.91 (br. s., 1H), 4.06-4.22 (m, 1H), 3.38-3.64 (m, 3H), 2.85 (br. s., 2H), 1.67-1.97 (m, 4H), 1.61 (s, 9H).
Reaction SMILES: ClC1C=CC=C[C:3]=1[N:8]1[C:12]([OH:13])=[CH:11][C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9]1.C(O)(=O)C.[CH2:23]([C:27](OCC)(OCC)[O:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26]>C(#N)C>[CH2:29]([O:28]/[C:27](=[C:11]1/[C:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[N:9][N:8]([CH3:3])[C:12]/1=[O:13])/[CH2:23][CH2:24][CH2:25][CH3:26])[CH3:30]
Reactant: COC(=O)Cc1cc(O)n(-c2ccccc2Cl)n1
Reactant: CCCCC(OCC)(OCC)OCC
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCC/C(OCC)=C1/C(=O)N(C)N=C1CC(=O)OC
Temperature: 70 °C

Procedure:
The mixture of the above obtained methyl (5-hydroxy-1-methyl-1H-pyrazol-3-yl)acetate (Compound of Formula (IV), 0.80 g) in acetonitrile (5 mL), glacial acetic acid (21 μl, 0.1 equiv.) and BuC(OEt)3 (3 eq.) was heated at 70° C. for 1 h 15. The resulting red solution was concentrated in vacuo to afford a red syrup that was washed with cyclohexane and then dried in vacuo. Due to its relative instability, no further purification of methyl [(4Z)-4-(1-ethoxypentylidene)-1-methyl-5-oxo-4,5-dihydro-1H-pyrazol-3-yl]acetate was conducted (1.0 g, quantitative yield). MS (ESI+): 283.4; MS (ESI−): 281.3.
Reaction SMILES: [CH3:1]OP(C)(=O)OC.[P:8]([O:25]C1C=CC(C)=CC=1)([O:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[O:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1.CI>>[C:10]1([O:9][P:8]([CH3:1])(=[O:25])[O:17][C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=1
Reactant: COP(C)(=O)OC
Reactant: Cc1ccc(OP(Oc2ccc(C)cc2)Oc2ccc(C)cc2)cc1
Solvent: CI
Product: Cc1ccc(OP(C)(=O)Oc2ccc(C)cc2)cc1
Temperature: 245 °C
Reaction time: 0.5 h
Yield: 263.8 %

Procedure:
A mixture of 64 g of methane phosphonic acid dimethyl ester (0.516 mol), 352 g of tris-p-cresyl phosphite (1.00 mol) and 2 ml of methyl iodide is slowly heated to 245° C. and tempered at this temperature for 30 minutes. Vacuum distillation yields 376 g of methane phosphonic acid di-p-cresyl ester (Bp1 mm 144° C.), 98.6% pure.
Reaction SMILES: P(Br)(Br)[Br:2].O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1.O>CC(OC)(C)C>[Br:2][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]#[N:15])=[CH:9][CH:8]=1
Reactant: N#CCc1ccc(CO)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: COC(C)(C)C
Product: N#CCc1ccc(CBr)cc1

Procedure:
0.86 mL (9 mmol) of phosphorus tribromide are added dropwise to a solution of 2.6 g (17.66 mmol) of (4-hydroxymethyl-phenyl)-acetonitrile in 25 mL MTBE at 0° C. After the reaction has ended the reaction mixture is combined with water at RT, the organic phase is separated off and these are extracted successively with sodium hydrogen carbonate solution and water. The organic phase is dried over magnesium sulphate and the solvent is distilled off using the rotary evaporator.
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH:4]=O.[C:22]([OH:26])(=[O:25])[CH2:23][SH:24].C(N(CC)CC)C>N1C=CC=CC=1>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[S:24][C:23]([C:22]([OH:26])=[O:25])=[CH:4][C:3]=2[C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=2)=[CH:16][CH:17]=1
Reactant: O=C(O)CS
Reactant: O=CC(=C(Cl)c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(O)c1cc(-c2ccc([N+](=O)[O-])cc2)c(-c2ccc(F)cc2)s1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 3-chloro-3-(4-fluorophenyl)-2-(4-nitrophenyl)propenal (1.5 g), thioglycolic acid (0.36 ml) and triethylamine (1.5 ml) in pyridine (7.6 ml) was stirred at 70° C. for 1 hour and refluxed for 7 hours. Pyridine was evaporated, and the residue was dissolved in ethyl acetate, washed with water and dilute hydrochloric acid, dried and concentrated. The residue (1.6 g) was washed with toluene to give pale brown crystals of 5-(4-fluorophenyl)-4-(4-nitrophenyl)thiophene-2-carboxylic acid (1.1 g).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][CH2:21]4)=[CH:17][C:15]=3[N:16]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C[OH:26]>>[N:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[N:12]=[N+:13]([O-:24])[C:14]3[CH:23]=[C:22]4[C:18]([CH2:19][CH2:20][CH2:21]4)=[CH:17][C:15]=3[N+:16]=2[O-:26])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: [O-][n+]1nc(NCCCN2CCOCC2)nc2cc3c(cc21)CCC3
Reactant: CO
Product: [O-][n+]1nc(NCCCN2CCOCC2)[n+]([O-])c2cc3c(cc21)CCC3

Procedure:
H2O2 (70%, 0.60 mL, ca. 11.9 mmol) was added dropwise to a stirred solution of TFAA (1.7 mL, 11.9 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 60 (412 mg, 1.2 mmol) and TFA (0.46 mL, 6.0 mmol) in DCM (20 mL) at 0° C. The solution was stirred at 20° C. for 4 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give (i) starting material 60 (208 mg, 50%) and (ii) 1,4-dioxide 61 (122 mg, 30%) as a red solid: mp (MeOH) 158-160° C.; 1H NMR δ 8.37 (br s, 1H, NH), 8.11 (s, 1H, H-5), 8.09 (s, 1H, H-9), 3.80-3.84 (m, 4H, 2×CH2O), 3.64-3.69 (m, 2H, CH2N), 3.02-3.10 (m, 4H, H-6, H-8), 2.56 (dd, J=6.2, 6.1 Hz, 2H, CH2N), 2.48-2.52 (m, 4H, 2×CH2N), 2.15-2.22 (m, 2H, H-7), 1.85-1.91 (m, 2H, CH2); 13C NMR δ 155.5, 149.5, 145.6, 138.0, 129.6, 115.8, 111.6, 66.9 (2), 57.7, 53.8 (2), 41.6, 33.3, 32.3, 25.5, 24.5. Anal. calcd for C17H23N5O3.¼CH3OH: C, 58.6; H, 6.9; N, 19.8. Found: C, 58.4; H, 6.7; N, 19.9%.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=2)O1.I[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1.C1(C)C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>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.C(O)C>[N:19]1[CH:20]=[CH:21][N:22]=[CH:23][C:18]=1[C:9]1[CH:10]=[CH:11][C:12]([NH2:15])=[N:13][CH:14]=1
Reactant: Ic1cnccn1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Nc1ccc(-c2cnccn2)cn1
Temperature: 90 °C
Reaction time: 10 h

Procedure:
To a sealed tube was added 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine 86-1 (2.2 g, 10 mmol), 2-iodopyrazine 86-2 (2.06 g, 10 mmol), Pd(PPh3)4 (577 mg, 0.5 mmol), toluene (70 mL), ethanol (15 mL) and 2M Na2CO3 (15 mL). The reaction mixture was bubbled with nitrogen for 2 minutes and stirred at 90° C. for 10 hours. After cooling to room temperature, the solvents were evaporated and the residue was redissolved in dichloromethane (200 ml) and treated with 1M HCl aqueous solution (50 mL). The two layers were separated and the aqueous layer was treated with 10% NaOH aqueous solution to adjust the pH to around 13. The resulting suspension was extracted with ethyl acetate (100 mL×3). The combined organic phases were washed with H2O (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated to give 5-(pyrazin-2-yl)pyridin-2-amine 86-3 as white solid. MS m/z 173.1 (M+1); 1H NMR 400 MHz (DMSO-d6) δ 9.12 (d, 1H, J=1.6 Hz), 8.73 (m, 1H), 8.60 (m, 1H), 8.46 (d, 1H, J=2.8 Hz), 8.12 (dd, 1H, J1=8.8 Hz, J2=2.4 Hz), 6.55 (d, 1H, J=8.8 Hz), 6.46 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:20]=3[NH2:21])[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][N:33]([CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1)[C:34]([C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=1)[C:39](O)=[O:40])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]4)[CH:23]=[CH:22][C:20]=3[NH:21][C:39](=[O:40])[C:38]3[CH:42]=[CH:43][CH:44]=[C:36]([C:34]([N:33]([CH3:32])[CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)=[O:35])[CH:37]=3)[CH:14]=2)[N:10]=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)O)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(-c2cn(Cc3ccccc3)nn2)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(-c3cn(Cc4ccccc4)nn3)ccn2)c1
Yield: 37.6 %

Procedure:
A solution of 22 mg of 2-(4-(1-benzyl-1H-1,2,3-triazol-4-yl)pyridin-2-yl)-4-(piperidin-1-yl)aniline 24d, 15.2 mg of 3-(methyl(2-morpholinoethyl)carbamoyl)benzoic acid, 22.6 mg of HATU, and 27.9 mg of diisopropylethylamine in 0.3 mL of DMF was stirred for 1 h. The solution was filtered and the product was isolated from the filtrate by reverse phase chromatography eluting with 0.05% TFA in a water/acetonitrile gradient. This procedure gave 13.4 mg of product. 1H NMR (400 MHz, DMSO-d6, ppm): δ 8.97 (s, 1H), 8.78 (d, J=5.0 Hz, 1H), 8.35 (s, 1H), 8.32-8.26 (m, 1H), 8.03-7.94 (m, 2H), 7.91 (d, J=5.2 Hz, 1H), 7.70-7.50 (m, 3H), 7.35 (mj, 4H), 7.28-7.19 (m, 1H), 5.69 (s, 2H), 4.09-3.90 (m, 3H), 3.85-3.76 (m, 2H), 3.71-3.53 (m, 4H), 2.91 (s, 3H), 1.69 (s, 4H), 1.55 (s, 2H). MS (ESI, m/z) 685.3 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Cs+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Oc1cc(Cl)nnc1Cl
Reactant: Cc1cccc(C2CC2)c1O
Agent: [Cs+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.4 %

Procedure:
To a mixture of 12.8 g (86.4 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 15.3 g (86.4 mmol) of 95% cesium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95.0%; 28.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 180° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 2 hours, the reaction mixture was cooled to room temperature, and 100 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous phase containing a cesium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was added dropwise to a 4% aqueous hydrochloric acid solution at 0° C. to deposit solids, followed by filtration. The resultant solids were washed with pure water and dried under a reduced pressure, and dissolved in an organic solvent and quantitatively determined by an HPLC internal standard analysis method, which showed that 7.92 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (purity: 76.1%; yield: 76%) and 166 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 2.1%) were obtained.