Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:26])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH:22][CH:23]([CH3:25])[CH3:24])[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C.[OH-].[Pt+2].[OH-]>[CH3:26][N:14]([CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=1[NH:22][CH:23]([CH3:25])[CH3:24]
Reactant: [H][H]
Reactant: CC(C)Nc1cc(F)ccc1N(C)C1CCN(Cc2ccccc2)CC1
Agent: [Pt+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Nc1cc(F)ccc1N(C)C1CCNCC1

Procedure:
1-Benzyl-4-[N-methyl-N-(2-isopropylamino-4-fluorophenyl)amino]piperidine (EXAMPLE 170, 2.90 g, 8.16 mmol) and platinum hydroxide on carbon (1.0 g) in 50 ml ethanol is hydrogenated at 276 kPa (40 psi) hydrogen for 25 hrs. Filtration and evaporation of the solvent gives the tide compound, NMR (300 MHz, CD3OD) 7.02, 6.32, 6.24, 3.60, 3.15, 2.90, 2.75, 2.54, 1.8-2.0, 1.50 and 1.18δ.
Reaction SMILES: Cl[C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([O:20][CH3:21])=[C:13]([C:2]2[N:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH:12]=1
Reactant: N#Cc1cccnc1Cl
Reactant: COc1ccc(F)cc1B(O)O
Product: COc1ccc(F)cc1-c1ncccc1C#N
Yield: 89 %

Procedure:
Prepared in 89% yield from 2-chloronicotinonitrile and 5-fluoro-2-methoxyphenylboronic acid according to the procedure described for Example 153A. MS (ESI−) m/z 228.9 (M+H)+; 1H NMR (CDCl3) δ 3.86 (s, 3H), 6.98 (dd, J=8.8, 4.0 Hz, 1H), 7.13-7.22 (m, 2H), 7.40 (dd, J=8.0, 4.9 Hz, 1H), 8.04 (dd, J=8.1, 1.7 Hz, 1H), 8.88 (dd, J=5.1, 1.7 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:18])([C:8]([F:17])([F:16])[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[CH2:3][CH2:4][C:5](O)=[O:6].CO>O1CCCC1>[F:1][C:2]([F:18])([C:8]([F:16])([F:17])[C:9]([F:14])([F:15])[C:10]([F:11])([F:12])[F:13])[CH2:3][CH2:4][CH2:5][OH:6]
Reactant: O=C(O)CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
Borane-methyl sulfide complex (5.2 ml, 52.2 mmol) was slowly added to a solution of 4,4,5,5,6,6,7,7,7-nonafluoroheptanoic acid (5.10 g, 17.4 mmol) in anhydrous tetrahydrofuran (50 ml) at −50° C. The reaction mixture was stirred for 4 hours at room temperature and cooled to 0° C., followed by addition of methanol. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/5→1/3) to give 4,4,5,5,6,6,7,7,7-nonafluoroheptan-1-ol (4.7 g, Yield 97%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:22])[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=[C:12]([O:23][CH2:24][O:25][CH3:26])[CH:11]=3)=[CH:4][C:3]=1[O:27][CH2:28][O:29][CH3:30].Br[CH2:32][CH2:33][F:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN1C(=O)CCC1.CCOCC>[F:34][CH2:33][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:15]([C:16](=[O:22])[C:17]=2[O:18][CH2:19][O:20][CH3:21])=[CH:14][CH:13]=[C:12]([O:23][CH2:24][O:25][CH3:26])[CH:11]=3)=[CH:4][C:3]=1[O:27][CH2:28][O:29][CH3:30]
Reactant: FCCBr
Reactant: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(O)c(OCOC)c3)oc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN1CCCC1=O
Product: COCOc1ccc2c(=O)c(OCOC)c(-c3ccc(OCCF)c(OCOC)c3)oc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 85.2 %

Procedure:
To 2-(4-hydroxy-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one (20 mg, 0.048 mmol) and 1-bromo-2-fluoroethane (18 mg, 0.14 mmol) in 0.3 mL NMP was added Cs2CO3 (39 mg, 0.12 mmol). The mixture was stirred at rt for 15 h under Ar atmosphere and diluted with ether (30 mL). It was washed with NaH2PO4 (sat. 30 mL) and water (2×30 mL) and dried over MgSO4 and concentrated. The crude product was purified with chromatography (hexane/EtOAc) to afford 2-(4-(2-fluoroethoxy)-3-(methoxymethoxy)phenyl)-3,7-bis(methoxymethoxy)-4H-chromen-4-one as a white solid (19 mg, 85%). 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.8 Hz, 1H), 7.91 (d, J=2.0 Hz, 1H), 7.76 (dd, J=8.4 Hz, 2.0 Hz, 1H), 7.13 (d, J=2.4 Hz, 1H), 7.05 (dd, J=8.8, 2.4 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 5.29 (s, 4H), 5.22 (s, 2H), 4.89 (m, 1H), 4.78 (m, 1H), 4.40 (m. 1H), 4.32 (m, 1H), 3.56 (s, 3H), 3.51 (s, 3 H) 3.20 (s, 3H); MS (ESI) m/z 465 (M+H+).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:6]=[CH:5][N:4]=1>Cl>[CH2:9]([C:7]1[CH:6]=[CH:5][NH:4][C:3](=[O:2])[N:8]=1)[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: COc1nccc(CCc2ccccc2)n1
Agent: Cl
Product: O=c1nc(CCc2ccccc2)cc[nH]1
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A solution of 2-methoxy-4-phenethylpyrimidine (0.50 g, 2.3 mmol) in concentrated HCl (4.0 mL) was heated under reflux for 16 h. The reaction solution was cooled to room temperature and filtered. The filter cake was washed with water and dried under reduced pressure to give the title compound (0.34 g, 74%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 8.52 (d, J=6.5 Hz, 1H), 7.33-7.24 (m, 5H), 6.78 (d, J=6.0 Hz, 1H), 3.12-3.07 (m, 4H).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[O:12][C:10](=O)[NH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH3:13][N:14]([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C([O-])=O)=NC([O-])=O.[OH-].[Na+]>O1CCCC1>[CH3:13][N:14]([CH3:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:10][NH:9][C:7](=[O:8])[C:5]1[C:4](=[CH:3][CH:2]=[CH:1][CH:6]=1)[OH:12]
Reactant: O=c1[nH]c(=O)c2ccccc2o1
Reactant: CN(C)CCCCCCO
Agent: O=C([O-])N=NC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)CCCCCCNC(=O)c1ccccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
A slurry of 18.02 g (110 mmol) of carsalam, 18.0 ml (15.84 g, 109 mmol) of 6-dimethylamino-1-hexanol, 29.12 g (111 mmol) of triphenylphosphine, and 150 ml of tetrahydrofuran was treated with a solution of 21.8 ml (22.39 g, 111 mmol) of disopropyl azodicarboxylate and 40 ml of tetrahydrofuran, added dropwise over 20 minutes, causing the temperature of the slurry to rise to about 67° C. The reaction mixture was allowed to cool back to about 25° C. and stir for about 20 hours. The solution was treated with 150 ml (300 mmol) of aqueous 2 N sodium hydroxide and warmed to about 60° C. for about 90 minutes. The reaction mixture was washed with ethyl acetate (2×60 ml). The aqueous phase was acidified with 4% aqueous hydrochloric acid to a pH slightly less than about 0 and washed with ethyl acetate (2×60 ml). The pH of the aqueous phase was raised to about 4.5 with 50% aqueous potassium carbonate and washed with ethyl acetate (2×60 ml). The aqueous phase was treated with solid sodium bicarbonate and extracted with ethyl acetate (14×60 ml). The combined 14 ethyl acetate extracts were dried over sodium sulfate and concentrated to a viscous liquid. The liquid was taken up into a minimum amount of ethyl acetate, diluted with 100 ml of hexanes and treated in an ice bath with 150 ml of hexanes, causing a white solid to develop. A total of 13.65 g of N-(6-dimethylaminohexyl)salicylamide was isolated by filtration.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:23](=[O:24])[C:22]4[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:21]=4[C:20]3=[O:30])=[C:15]([CH3:31])[CH:14]=2)=S)=O)=[CH:4][CH:3]=1.Cl.Cl.[NH2:34][NH2:35]>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:21]2[C:20](=[O:30])[N:19]([C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:10]4[NH:9][C:7]([C:5]5[S:6][C:2]([Cl:1])=[CH:3][CH:4]=5)=[N:35][N:34]=4)=[CH:14][C:15]=3[CH3:31])[C:23](=[O:24])[C:22]=2[CH:25]=1
Reactant: Cc1cc(NC(=S)NC(=O)c2ccc(Cl)s2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Reactant: NN
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nnc(-c3ccc(Cl)s3)[nH]2)ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 14.2 %

Procedure:
To a suspension of (5-chloro(2-thienyl))-N-({[4-(5-chloro-1,3-dioxobenzo[c]azolin-2-yl)-3-methylphenyl]amino}thioxomethyl)carboxamide (15 mg, 0.030 mmol) and hydrazine dihydrochloride (4 mg, 0.038 mmol) in DMF (0.3 mL) was added HgO (7 mg, 0.032 mmol). The reaction was stirred at room temp for 17 hr, and HPLC purified to give the desired product 5-chloro-2-(4-{[5-(5-chloro(2-thienyl))(4H-1,2,4-triazol-3-yl)]amino}-2-methylphenyl)benzo[c]azoline-1,3-dione (2 mg) (ES-MS (M+H)+=470, 472) and the aminoguanidine intermediate N-((1E)-2-aza-1-{[4-(5-chloro-1,3-dioxobenzo[c]azolidin-2-yl)-3-methylphenyl]amino}-2-aminovinyl)(5-chloro(2-thienyl))carboxamide (2 mg) ES-MS (M+H)+=488, 490 (2Cl).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[C:3]=1[NH2:18].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1.O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[C:4]([C:14]([F:15])([F:16])[F:17])[C:3]=1[NH:18][C:27](=[O:28])[CH2:26][C:23]1[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Reactant: Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Solvent: CC#N
Solvent: O
Product: O=C(Cc1ccc(F)cc1)Nc1c(Br)cc(N2CCOCC2)cc1C(F)(F)F
Temperature: 150 °C
Yield: 9 %

Procedure:
2-Bromo-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.236 g) and 4-fluorophenylacetyl chloride (0.105 mL) were dissolved in acetonitrile (5 mL) and heated to 150° C. for 10 minutes in a sealed microwave process vial. Water (25 mL) was added and the product was extracted with ethyl acetate (3×25 mL). The organic phases were washed with brine (50 mL), dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to furnish 0.027 g (9%) of the title compound as an off-white solid. LC-MS (m/z) 462 (MH+); tR=2.84, (UV, ELSD) 96%, 100%. 1H NMR (500 MHz, DMSO-d6): 3.23 (m, 4H), 3.62 (s, 2H), 3.72 (m, 4H), 7.14 (dd, 2H), 7.19 (d, 1H), 7.35 (dd, 2H), 7.46 (d, 1H), 9.78 (s, 1H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([O:25][CH3:26])=[N:19][C:20]([O:23][CH3:24])=[N:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=1>>[CH3:24][O:23][C:20]1[N:19]=[C:18]([O:25][CH3:26])[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([F:35])[CH:30]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2cccc(-n3cnc(C(=O)N(C)OC)c3)c2)c(OC)n1
Reactant: Fc1cccc(Br)c1
Product: COc1ncc(-c2cccc(-n3cnc(C(=O)c4cccc(F)c4)c3)c2)c(OC)n1

Procedure:
This compound is prepared by method C using compound 12m and 1-bromo-3-fluorobenzene
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1.Br[C:22]1[C:30]2[N:29]=[CH:28][N:27]([CH3:31])[C:26]=2[CH:25]=[C:24]([CH3:32])[CH:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C(OCC)(=O)C.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:22]4[C:30]5[N:29]=[CH:28][N:27]([CH3:31])[C:26]=5[CH:25]=[C:24]([CH3:32])[CH:23]=4)[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: Cc1cc(Br)c2ncn(C)c2c1
Reactant: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cc(C)cc2c1ncn2C
Temperature: 100 °C
Reaction time: 72 h

Procedure:
A mixture of 10-chloro-7-(1-ethylpropyl)-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (100.0 mg, 0.343 mmol), 4-bromo-1,6-dimethyl-1H-benzimidazole (154.9 mg), xantphos (20.0 mg, 0.0343 mol), sodium tert-butoxide (40.0 mg, 0.412 mmol), tris(dibenzylideneacetone) dipalladium (31.0 mg, 0.0343 mmol) and toluene (2.0 mL) was stirred at 100° C. for 3 days. After cooling, the mixture was diluted with ethyl acetate and the precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-80% ethyl acetate/n-hexane gradient mixture to give the mixture containing the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (51.0 mg, 0.117 mmol, 34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[O:35]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].CCO>[Pd].C1COCC1.CCO>[C:1]([O:5][C:6](=[O:43])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:34])[CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:22][C:21]=1[OH:35])(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(=O)CCCN(C)C)cc1O
Reaction time: 19.5 h
Yield: 83 %

Procedure:
(S)-3-[2-Benzyloxy-4-(4-dimethylamino-butanoylamino)-benzenesulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester (0.62 g, 1.0 mmol) was shaken with 20% palladium on carbon (0.06 g) in THF-EtOH (1:1) under H2 (50 psi) for 16 h using a Parr apparatus. Mass spectrometry and NMR analysis indicated only starting material to be present. An additional 0.28 g of 20% Pd/C and EtOH (50 mL) were added and allowed to stir for 19.5 h. TLC analysis showed complete consumption of starting material. The reaction mixture was filtered through celite and concentrated to yield (S)-3-[4-(4-dimethylamino-butanoylamino)-2-hydroxy-benzensulfonylamino]-4,4-diethoxy-butyric acid tert-butyl ester (0.44 g, 0.83 mmol, 83%). MS (APCI) m/z 532.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][C:13]2[O:14][CH:15]=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][C:13]2[O:14][C:15]([CH2:22][OH:21])=[C:16]([OH:20])[C:17](=[O:19])[CH:18]=2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Reactant: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)occ1O
Product: O=c1cc(CNS(=O)(=O)c2ccc(Cl)cc2)oc(CO)c1O
Yield: 45.62 %

Procedure:
4-Chloro-N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-07) (7.01 g, 45.62%) was synthesized as a light yellow solid from 4-chloro-N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (8-07) (14.0 g, 44.44 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([Br:15])=[C:11](Br)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][OH:23])=[CH:20][CH:19]=1.[OH-].[K+].O>CN(C)C=O>[Br:15][C:12]1[C:13](=[O:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=[CH:10][C:11]=1[O:23][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=1
Reactant: O=c1c(Br)c(Br)cnn1-c1ccc(Cl)cc1
Reactant: OCc1ccc(Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c(Br)c(OCc2ccc(Cl)cc2)cnn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.8 %

Procedure:
In 35 ml of N,N-dimethylformamide were dissolved 1.5 g (4.1 m mol) of 2-(4-chlorophenyl)-4,5-dibromo-3(2H)-pyridazinone and 0.59 g (4.1 m mol) of p-chlorobenzyl alcohol, and thereto was added 0.27 g of powdery potassium hydroxide. The reaction mixture was stirred for one day at room temperature. The resulting solution was poured into water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and freed of solvent by distillation under reduced pressure. The crystals thus obtained were recrystallized from ethyl acetate-benzene to give 1.4 g of the intended compound.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:16].C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>CN(C)C=O>[CH3:24][C:25]1[C:30]([CH3:31])=[CH:29][CH:28]=[CH:27][C:26]=1[N:32]1[CH2:33][CH2:34][N:35]([CH2:3][CH:2]([OH:1])[CH2:4][CH2:5][N:6]2[C:14](=[O:15])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7]2=[O:16])[CH2:36][CH2:37]1
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: O=C1c2ccccc2C(=O)N1CCC1CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(N2CCN(CC(O)CCN3C(=O)c4ccccc4C3=O)CC2)c1C
Temperature: 110 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a mixture of 2-(2-(oxiran-2-yl)ethyl)isoindoline-1,3-dione obtained in step 2 (0.30 g, 1.38 mmol) and potassium carbonate (0.48 g, 3.45 mmol) in N,N-dimethylformamide (3.0 ml), was added 1-(2,3-dimethylphenyl)piperazine hydrochloride (0.31 g, 1.38 mmol) at room temperature. The resulting reaction mixture was stirred at 110° C. for 18 hours. After the reaction complete, the reaction mixture thus obtained was filtered through a plug of Celite. The filtrate was concentrated under reduced pressure to obtain the title compound (0.26 g). The compound was used for the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:3]2[C:8]([CH:9]=[CH:10][CH:11]=1)=[C:7]([C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:19])[C:6](=[O:20])[CH:5]=[CH:4]2.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:7]1[C:6](=[O:20])[CH:5]=[CH:4][N:3]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:2]2[N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CCNC1
Reactant: O=c1ccn2c(Cl)cccc2c1-c1c(Cl)cccc1Cl
Product: O=c1ccn2c(N3CCCC3)cccc2c1-c1c(Cl)cccc1Cl
Temperature: 90 °C

Procedure:
A mixture of 6-chloro-1-(2,6-dichlorophenyl)-2H-quinolizin-2-one (Example 1, 15 mg) in pyrrolidine (0.5 mL) was heated to 90° C. for 2½ hr and then concentrated. The residue was purified by silica gel (methylene chloride/acetone=3/1) to give title compound as a yellow solid (12 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][N:4]=1.[CH2:14]([S:16][C:17]1[C:22]([C:23](O)=[O:24])=[CH:21][N:20]=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=1)[CH3:15].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>O.N1C=CC=CC=1>[CH3:1][NH:2][C:3]1[C:8]([NH:9][C:23]([C:22]2[CH:21]=[N:20][C:19]([C:26]([F:28])([F:29])[F:27])=[CH:18][C:17]=2[S:16][CH2:14][CH3:15])=[O:24])=[CH:7][C:6]([C:10]([F:13])([F:11])[F:12])=[CH:5][N:4]=1
Reactant: CNc1ncc(C(F)(F)F)cc1N
Reactant: CCSc1cc(C(F)(F)F)ncc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: c1ccncc1
Product: CCSc1cc(C(F)(F)F)ncc1C(=O)Nc1cc(C(F)(F)F)cnc1NC
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
A mixture of 428 mg of N2-methyl-5-trifluoromethylpyridine-2,3-diamine, 562 mg of 4-ethylsulfanyl-6-trifluoromethylnicotinic acid, 645 mg of EDCI hydrochloride, 30 mg of HOBt and 2.5 ml of pyridine was stirred at room temperature for 5 hours, then allowed to stand at room temperature overnight. Water was poured to the reaction mixture, and the precipitated solid was filtered. The resulting solid was washed with water and n-hexane and then dried to obtain 786 mg of 4-ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide. 4-Ethylsulfanyl-6-trifluoromethylpyridine-3-carboxylic acid (2-methylamino-5-trifluoromethylpyridin-3-yl)-amide
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][N:8]([CH3:18])[C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=O.[NH2:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:39])=[C:24]([NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=2)[CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CN(C)C1C=CN=CC=1>[Cl:39][C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[C:9]([N:8]([CH3:7])[CH3:18])[CH:10]=2)=[CH:25][C:24]=1[NH:26][C:27](=[O:38])[C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=1
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C(=O)Nc2cc(N)ccc2Cl)cc1OC
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc(NC(=O)c3cccc(N(C)C)c3)ccc2Cl)cc1OC
Reaction time: 4 h
Yield: 24.1 %

Procedure:
Oxalyl chloride (0.11 ml) was added dropwise to a stirred suspension of 3-dimethylaminobenzoic acid (0.18 g) in methylene chloride (10 ml) at 20° C. DMF (2 drops) was added and the reaction mixture was stirred for 4 hours. The solvent was evaporated to give a solid. The solid was dissolved in methylene chloride (15 ml) and added dropwise over 5 minutes to a stirred mixture of N-(5-amino-2-chlorophenyl)-3,4-dimethoxybenzamide (0.306 g), triethylamine (0.4 ml), 4-dimethylaminopyridine (0.005 g) and methylene chloride (5 ml). The resultant mixture was stirred at 20° C. for 18 hours. The reaction mixture was washed with water and with a saturated, aqueous sodium bicarbonate solution, dried (MgSO4) and evaporated. The residual oil was purified by column chromatography on silica gel using a 99:1 mixture of methylene chloride and methanol as eluent. There was thus obtained the title compound (0.109 g), m.p. 98-99° C.;
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.Cl>C1COCC1>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[O:11][CH:12]([CH2:15][CH2:16][OH:17])[C:13]=1[O:14][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccc1
Reactant: O=C1OC(CCO)C(O)=C1OCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1OC(CCO)C(OCc2ccccc2)=C1OCc1ccccc1
Yield: 58.8 %

Procedure:
A mixture of 1.25 g (5 mmol) of 3-benzyloxy-4-hydroxy-5-(2-hydroxyethyl)-2(5H)-furanone, 15 mL of THF, 871 μL (5.0 mmol) of diisopropylethylamine and 631 μL (5.2 mmol) of benzyl bromide were combined under argon. The reaction mixture was warmed to reflux for 5 hours, and upon cooling, a suspension formed which was poured into 50 mL of 5% aqueous HCl solution and extracted with 100 mL of ether. The ether fraction was separated and sequentially washed with 30 mL of 5% aqueous HCl, 30 mL of H2O, 30 mL of saturated NaHCO3 solution, 30 mL of H2O, 30 mL of brine, dried (MgSO4) and concentrated to a colorless oil. Purification over silica gel using EtOAc/hexanes (2/3) provided 3,4-dibenzyloxy-5-(2-hydroxyethyl)-2(5H)-furanone as a faint pink colored oil (1.0 g, 60% yield).