Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.Cl>O1CCCC1.CO>[C:4]1(/[C:10](=[N:17]/[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:31][CH:32]=3)=[CH:22][CH:21]=2)/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)CC/C(=N\OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)CC/C(=N\OCc1ccc(OCc2coc(-c3ccccc3)n2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
Lithium hydroxide monohydrate (49.9 mg) was added to a solution of methyl E-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (280 mg) in tetrahydrofuran (6 ml)-water (4 ml)-methanol (4 ml) and stirred at room temperature for 2 hours. 1N hydrochloric acid (1.3 ml) was added to the reaction mixture and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous saturated solution of sodium chloride, dried (MgSO4) and concentrated. The residue was recrystallized from ethyl acetate-bexane to obtain E-4-phenyl-4-[4-(2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (237 mg, yield 87%) as colorless crystals. m.p. 144-145° C.
Reaction SMILES: [I:1][C:2]1[CH:9]=[C:6]([CH:7]=[O:8])[C:5]([OH:10])=[CH:4][CH:3]=1.[C:11]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:11][O:10][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:9][C:6]=1[CH:7]=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cc(I)ccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccc(I)cc1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.3 %

Procedure:
5-Iodo-salicylaldehyde (1.0 g, 4.0 mmol) was dissolved in DMF (10 mL) and to the stirred solution K2CO3 (0.828 g, 6.0 mmol) and CH3I (1.14 g, 8.0 mmol) were added. The mixture was stirred at room temperature overnight. The suspension was concentrated in vacuo, and the residue was partitioned between water (30 mL) and Et2O (30 mL). The aqueous phase was separated and extracted with ether (20 mL×2). The combined organic phases were dried over Na2SO4, filtered and concentrated to give 67 (1.02 g, 98%). 1H NMR (CDCl3, 300 MHz) δ 10.34(s, 1H), 7.82-7.78 (m, 1H), 7.26 (s, 1H), 6.78 (d, J=8.7 Hz, 1H), 3.91 (s, 3H). MS (m/e) (positive FAB) 262.1 (M+H)+, m.p. 140-142° C.
Reaction SMILES: [CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5]Cl)=[O:4].[C:19]([O-:22])(=[O:21])[CH3:20].[Na+].O>CN(C=O)C>[CH3:1][C:2]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)([CH3:7])[C:3]([CH2:5][O:22][C:19](=[O:21])[CH3:20])=[O:4]
Reactant: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CCl
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC(=O)C(C)(C)NC(=O)c1cc(Cl)cc(Cl)c1
Yield: 47.4 %

Procedure:
N-(1',1'-dimethyl-3'-chloroacetonyl)-3,5-dichlorobenzamide (20 gm, 0.065 m) was dissolved in 100 ml of dry DMF and 10.6 gm (0.128 m) of sodium acetate was added. The slurry was blanketed under a nitrogen atmosphere and then heated to 80°-90° C. for 4 days. The reaction mixture was cooled by adding 100 ml of water. The aqueous solution was extracted four times with 10 ml aliquots of methylene chloride. The combined organic extracts were washed with water (3×100 ml) and brine. The solvent was removed, the resulting white solid dried and then recrystallized from an acetone and hexane (about 1:4) mixture to yield 10.2 gm of the product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]([F:44])([F:43])[F:42])=[C:6]([CH:40]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]CC3C=CC=CC=3)[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1)=[O:8]>CO.C1COCC1.[Pd]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:41]([F:44])([F:42])[F:43])=[C:6]([CH:40]=1)[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:39])[CH2:16][NH:17][C:18]([C:20]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[OH:31])[NH:22][N:21]=2)=[O:19])[CH2:11][CH2:10]1)=[O:8]
Reactant: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2OCc2ccccc2)[nH]n1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2C(F)(F)F)CC1)c1cc(-c2ccccc2O)[nH]n1
Yield: 46.2 %

Procedure:
10% Pd/c (25 mg) was added to a stirred solution of 5-(2-benzyloxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide (94 mg, 0.15 mmol) in a mixture of MeOH (60 mL) and THF (10 mL) and stirred under hydrogen atmosphere. The reaction mixture was then stirred for 1 hrs at room temperature. The mixture was filtered over a bed of celite. The celite was washed with MeOH and the filtrate was concentrated under reduced pressure. The crude was washed with ethyl acetate, filtered and dried to afford 36 mg (45% yield) of 5-(2-hydroxy-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 94.89%. 1H NMR (DMSO-d6): δ 13.2 (s, 1H), 10.4 (s, 1H), 7.9 (m, 2H), 7.5 (m, 2H), 6.9 (m, 3H), 4.1 (d, 2H), 3.4 (m, 6H), 3.1 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH2:18][OH:19]>C(O)C>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]2[CH:15]=[CH:14][C:11](/[C:12](/[NH2:13])=[N:18]/[OH:19])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: NO
Reactant: COc1ccc(Oc2ccc(C#N)cc2)cc1
Solvent: CCO
Product: COc1ccc(Oc2ccc(/C(N)=N/O)cc2)cc1

Procedure:
4-(4-Methoxyphenoxy)benzonitrile (581 mg, 2.58 mmol) was dissolved in ethanol (10.0 mL) and hydroxylamine (630 μL, 10.32 mmol) was added. The mixture was refluxed for 1 hour and the reaction was cooled and then concentrated in vacuo to give the crude product which was taken to the next step without further purification (636 mg, 95%). 1H NMR (500 MHz, CDCL3) δ(ppm): 3.81 (1H, s), 4.87 (1H, bs), 6.88-6.94 (4H, m), 6.99 (2H, d, J=9.2 Hz), 7.55 (2H, d, J=9.0 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 55.8 (CH3), 115.2 (CH), 117.4 (CH), 121.4 (CH), 126.6 (CH), 127.6, 149.5, 152.5, 156.5, 160.4. MS (FAB+): 259 (MH+). HRMS for C14H14N2O3 (MH+): calculated: 259.1083; found 259.1100.
Reaction SMILES: CS[C:3](SC)=[C:4]([C:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[C:8]=1[F:20])=[O:6].[C:31]1([NH2:38])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37]>C(O)C>[NH:37]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[NH:38][C:3]1=[C:4]([C:21]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)=[O:22])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C@@H:13]2[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]2)[C:8]=1[F:20])=[O:6]
Reactant: Nc1ccccc1N
Reactant: CSC(SC)=C(C(=O)c1cccnc1)C(=O)c1cccc([C@@H]2COC(C)(C)O2)c1F
Solvent: CCO
Product: CC1(C)OC[C@@H](c2cccc(C(=O)C(C(=O)c3cccnc3)=C3Nc4ccccc4N3)c2F)O1
Yield: 97 %

Procedure:
A 0.12 g portion of 2-[bis(methylsulfanyl)methylene]-1-[3-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-2-fluorophenyl]-3-pyridin-3-yl-propan-1,3-dione and 36 mg of 1,2-phenylenediamine were dissolved in 8 ml of ethanol and heated under reflux for 3 hours. After concentration of the reaction liquid, the thus formed residue was purified by a silica gel column chromatography to obtain 0.12 g (97%) of 2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-1-{3-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-fluorophenyl}-3-pyridin-3-yl-propane-1,3-dione as a yellow solid from an ethyl acetate-hexane (3:1) eluate. FA: 460
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2.C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O>[Cl:1][CH2:2][C:3]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[CH:10]2)=[O:4]
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)Nc1ccc2[nH]ncc2c1
Yield: 24.2 %

Procedure:
Chloroacetyl chloride (3.14 ml, 39.4 mmol) was added to a solution of 5-aminoindazole (5.0 g, 37.5 mmol) in tetrahydrofuran (100 ml) at room temperature, followed by adding thereto a solution of triethylamine (5.76 ml, 41.3 mmol) in tetrahydrofuran (30 ml) at 0° C., and the resulting mixture was stirred at 0° C. for 30 minutes. Subsequently, a saturated aqueous sodium carbonate solution and then water were added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent, and the resulting residue was suspended in ethanol and stirred, followed by filtration. To a solution of the solid collected by the filtration and dissolved in a mixture of tetrahydrofuran (25 ml) and methanol (25 ml) was added a 2N-aqueous lithium hydroxide solution (9.3 ml) at 0° C., and stirred at room temperature for 30 minutes. Then, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 2-chloro-N-(1H-indazol-5-yl)acetamide (1.90 g, 46%).
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5][OH:6].S(=O)(=O)(O)O.[C:32](=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CO>[F:13][C:7]1[C:4]([CH2:5][O:6][CH3:32])=[C:3]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)[C:2]([F:1])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(F)c(N2CCN(Cc3ccccc3)CC2)c(CO)c1F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Product: COCc1c(F)c([N+](=O)[O-])cc(F)c1N1CCN(Cc2ccccc2)CC1
Temperature: 25 °C

Procedure:
To a solution of 3,6-difluoro-2-(4-benzyl-1-piperazinyl)-5-nitrobenzyl alcohol (15.4 g) in methanol (400 ml) is added gradually conc. sulfuric acid (80 ml) with stirring under ice cooling. After the addition, the mixture is refluxed for 30 hours, and thereto is further added conc. sulfuric acid (10 ml), and the mixture is further refluxed for 20 hours. After cooling to room temperature, the reaction mixture is adjusted to below pH 8 with aqueous saturated potassium carbonate and aqueous saturated sodium hydrogen carbonate and then extracted with ethyl acetate. The extract is dried over magnesium sulfate, and then the solvent is distilled off. The residue is purified by silica gel column chromatography (solvent, dichloromethane) to give 2,5-difluoro-4-(4-benzyl-1-piperazinyl)-3-methoxymethylnitrobenzene (12.9 g).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[F:6][C:7]([F:18])([F:17])[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[OH-].[Na+].CN([CH:24]=[O:25])C>>[F:18][C:7]([F:6])([F:17])[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH:24]=[O:25]
Reactant: FC(F)(F)c1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Yield: 75 %

Procedure:
Phosphorous oxychloride (7.6 mL, 83.0 mmol) was added dropwise to DMF (150 mL) at 0° C. A solution of 5 (4.5 g, 24.4 mmol) in DMF (30 mL) was added after 15 min. and the reaction mixture was allowed to warm to room temperature for 2 h. The mixture was poured on ice-water (300 g), made alkaline (pH 7-8) with 2 N aq. NaOH, extracted with EtOAc, the extracts were washed with brine, dried (MgSO4), and concentrated. The crude product was purified by flash chromatography on silica gel using 10% MeOH/CHCl3 as eluent. Recrystallization by dissolving yellow solid in hot MeOH and pouring onto cold water afforded 1 (3.9 g, 75% yield) as a white solid. Mp 242-243° C. 1H NMR (300 MHz, MeOH-d4): δ 9.95 (s, 1H), 8.48 (bs, 1H), 8.22 (s, 1H), 7.63 (d, 8.5 Hz, 1H), 7.53 (dd, 8.5, 1.7 Hz, 1H). MS m/z: 212 (M−1). Analysis calcd. for C10H6NOF3; C, 56.35; H, 2.84, N, 6.57; found, C, 56.60; H, 2.92; N, 6.55.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]3[N:15]=[C:16]([CH3:19])[C:17](I)=[C:13]3[N:12]=[C:11]([N:20]3[CH2:24][CH2:23][CH2:22][C@H:21]3[CH2:25][OH:26])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.[F:27][CH:28]([F:38])[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1.C([O-])(O)=O.[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>[F:27][CH:28]([F:38])[C:29]1[CH:34]=[CH:33][C:32]([C:17]2[C:16]([CH3:19])=[N:15][N:14]3[C:9]([C:4]4[CH:3]=[C:2]([F:1])[CH:7]=[C:6]([F:8])[CH:5]=4)=[CH:10][C:11]([N:20]4[CH2:24][CH2:23][CH2:22][C@H:21]4[CH2:25][OH:26])=[N:12][C:13]=23)=[CH:31][CH:30]=1
Reactant: OB(O)c1ccc(C(F)F)cc1
Reactant: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1I
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: Cc1ccccc1
Solvent: CCO
Product: Cc1nn2c(-c3cc(F)cc(F)c3)cc(N3CCC[C@H]3CO)nc2c1-c1ccc(C(F)F)cc1
Temperature: 85 °C
Reaction time: 4 h
Yield: 92.7 %

Procedure:
(S)-(1-(7-(3,5-Difluorophenyl)-3-iodo-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)pyrrolidin-2-yl)methanol (55 mg), 4-(difluoromethyl)phenylboronic acid (34 mg) and tetrakis(triphenylphosphine)palladium (10 mg) are added to toluene (8 mL), ethanol (3 mL) and 1 N NaHCO3 aqueous solution (1.5 mL) and stirred at 85° C. for 4 hours under argon atmosphere. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The organic layer is washed with brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is concentrated by distillation under reduced pressure and purified by column chromatography to yield the target compound (51 mg).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH:21]=[CH:20][C:19]([CH:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)[OH:23])=[CH:18][CH2:17]2)=[CH:11][CH:10]=1.[BH4-].[Na+]>C(O)C.O>[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[CH2:21][CH2:20][C:19]([CH:22]([C:24]3[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:28][CH:29]=3)[OH:23])=[CH:18][CH2:17]2)=[CH:11][CH:10]=1
Reactant: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)C=C1)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC(C1=CCN(Cc2ccc(Oc3ncccn3)cc2)CC1)c1ccc(C(F)(F)F)cc1
Yield: 47.5 %

Procedure:
A stirred solution of 1.0 gram (0.0021 mole) of {1-[(4-pyrimidin-2-yloxyphenyl)methyl](4-pyridyl)}[4-(trifluoromethyl)phenyl]methanol, hydrochloride salt in 30 mL of ethanol was cooled in an ice-water bath, and 0.1 gram (0.0026 mole) of sodium borohydride was added in one portion. Upon completion of addition, the reaction mixture was stirred at about 10° C. to 20° C. during a three-hour period. After this time the reaction mixture was diluted with 100 mL of water and extracted with two 75 mL portions of ethyl acetate. The combined extracts were washed with one 75 mL portion of aqueous 10% lithium chloride, and the combination was dried with sodium sulfate. The mixture was then filtered and the filtrate was concentrated under reduced pressure to a residue. The residue was purified with column chromatography on neutral alumina (6% water) using 1% to 2% methanol/methylene chloride mixtures as eluants. The appropriate fractions were combined and concentrated under reduced pressure, yielding 0.44 gram of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([Cl:20])=[CH:16][C:17]=2[Cl:19])[N:12]=[C:11]([C:21]([O:23][CH2:24][CH2:25][N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:22])[CH:10]=1)C1C=CC=CC=1.[BrH:33]>C(O)(=O)C>[BrH:33].[Cl:19][C:17]1[CH:16]=[C:15]([Cl:20])[CH:14]=[C:13]2[C:18]=1[C:9](=[O:8])[CH:10]=[C:11]([C:21]([O:23][CH2:24][CH2:25][N:26]([CH:27]([CH3:29])[CH3:28])[CH:30]([CH3:31])[CH3:32])=[O:22])[NH:12]2
Reactant: CC(C)N(CCOC(=O)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1)C(C)C
Agent: Br
Solvent: CC(=O)O
Product: CC(C)N(CCOC(=O)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1)C(C)C

Procedure:
Treatment of 2-diisopropylaminoethyl 4-benzyloxy-5,7-dichloroquinoline-2-carboxylate (0.85 g) with hydrogen bromide in acetic acid (15 ml, 48%) as described in Example 33d gave 2-diisopropylaminoethyl 5,7-dichloro-4-oxo-1,4-dihydroquinoline-2-carboxylate hydrobromide (0.24 g), m.p. 220° C. (dec). δ (360 MHz, DMSO-d6) 1.33 (12H, 2d, CH3), 3.63 (2H, bs, CH2N), 3.74 (2H, m, CH), 4.63 (2H, t, CO2CH2), 6.70 (1H, s, 3-H), 7.46 (1H, d, 6-H), 8.02 (1H, d, 8-H), 8.90 (1H, bs, NH) and 12.14 (1H, bs, NH). (Found: C, 45.44; H, 4.87; N, 5.85%. C18H22Cl2N2O3. HBr.H2O requires C, 45.49; H, 5.09; N, 5.90%).
Reaction SMILES: [CH3:1][C:2]1[C:8](=[O:9])[NH:7][C:5](=[O:6])[N:4]([CH:10]2[O:14][CH:13]([CH2:15][O:16]C(C3C=CC(OC)=CC=3)(C3C=CC(OC)=CC=3)C3C=CC=CC=3)[CH:12]([OH:40])[CH2:11]2)[CH:3]=1.[O:41]([CH2:48][C:49](Cl)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.CS(O)(=O)=O>N1C=CC=CC=1>[O:41]([CH2:48][C:49]([O:40][C@@H:12]1[C@@H:13]([CH2:15][OH:16])[O:14][C@@H:10]([N:4]2[CH:3]=[C:2]([CH3:1])[C:8](=[O:9])[NH:7][C:5]2=[O:6])[CH2:11]1)=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=C(Cl)COc1ccccc1
Reactant: COc1ccc(C(OCC2OC(n3cc(C)c(=O)[nH]c3=O)CC2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](OC(=O)COc3ccccc3)[C@@H](CO)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a solution of 5'-O-dimethoxytritylthymidine (27.23 g, 50.0 mmol) in pyridine (100 mL) at 0° C. was added phenoxyacetyl chloride (8.23 mL, 62.5 mL) dropwise, and the mixture was allowed to warm to ambient temperature over 3 hr. The reaction was quenched with methanol (ME, 25 mL) and concentrated in vacuo. The crude product was extracted with dichloromethane (DCM, 300 mL), washed with saturated aqueous sodium bicarbonate (SASB, 300 mL), dried (Na2 SO4), and concentrated. Toluene (2×100 mL) was added, and the solution was concentrated. The residual oil was dissolved in 10% ME in DCM (275 mL) and treated with methanesulfonic acid (3.24 mL, 50.0 mmol). After 30 min the red solution was quenched with SASB (300 mL), and the organic layer was dried (Na2SO4) and concentrated. The crude product was dissolved in 1:1 ethyl acetate (EA): hexanes (H) (250 mL) and precipitated by cooling to -10° C. for 18 h. The mixture was filtered, and the precipitate dried under vacuum to afford 1 (11.4 g, 60.6%). 1H NMR δ 13C NMR (D6DMSO) δ 12.25, 36.41, 61.29, 64.59, 75.57, 83.68, 84.41, 109.75, 114.52, 121.23, 129.48, 135.77, 150.45, 157.54, 163.65, 168.42. HRMS (FAB) calcd. C18 H21N2O7 (MH+) 377.1349; found 377.1355.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:14][C:15]1[C:16](=[O:34])[N:17]([C:21]2[CH:22]=[C:23]([CH:30]=[CH:31][C:32]=2[CH3:33])[C:24]([NH:26][CH:27]2[CH2:29][CH2:28]2)=[O:25])[CH:18]=[CH:19][N:20]=1)([CH3:13])[CH3:12].[CH3:35][NH2:36]>O1CCOCC1.C(OCC)(=O)C>[CH:27]1([NH:26][C:24](=[O:25])[C:23]2[CH:30]=[CH:31][C:32]([CH3:33])=[C:21]([N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][C:11]([CH3:13])([C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[O:4][CH2:3][CH2:2][NH:36][CH3:35])[CH3:12])[C:16]3=[O:34])[CH:22]=2)[CH2:29][CH2:28]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC(C)(C)c2ccccc2OCCCl)c1=O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNCCOc1ccccc1C(C)(C)Nc1nccn(-c2cc(C(=O)NC3CC3)ccc2C)c1=O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-[3-[[1-[2-(2-Chloroethoxy)phenyl]-1-methylethyl]amino]-2-oxo-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 198e, 17.5 g) in dioxane (50 mL) was treated with 40% Methylamine solution (50 ml) under nitrogen. The resulting suspension was heated in a sealed system at 100° C. for 4 h. After cooling to room temperature, the solution was evaporated to dryness. The crude product was purified by flash chromatography (SiO2, eluent 10% methanol in dichloromethane and 1% triethylamine). Evaporation of the relevant fractions to dryness and trituration of the residue in diethyl ether gave a solid which was filtered off. The filtrate was collected and evaporated. This residue was purified by preparative HPLC (Waters X-Terra column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent). The fractions containing the desired compound were evaporated to dryness. Further purification by preparative HPLC (phenomenex column, aqueous 0.2% ammonia in acetonitrile as eluent) and freeze-drying of the relevant fractions gave a solid. This freeze dried material readily dissolved in ethyl acetate (30 mL) at room temperature and after stirring for 1 h some solid precipitated. The mixture was then heated to at 85° C. for 1 h to effect dissolution and then cooled and stirred at room temperature for 1 week. The solid was filtered off and dried in vacuo at 40° C. to afford the title compound (2.20 g).
Reaction SMILES: [C:1](/[C:5]1[C:6]([C:12]([F:15])([F:14])[F:13])=[N+:7]([O-:11])[CH:8]=[CH:9][CH:10]=1)(=[N:3]\[NH2:4])\[NH2:2].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:29](=O)[CH:30]=O)[CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]=1[O:24][CH3:25]>C(O)C>[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:29]2[N:2]=[C:1]([C:5]3[C:6]([C:12]([F:13])([F:15])[F:14])=[N+:7]([O-:11])[CH:8]=[CH:9][CH:10]=3)[N:3]=[N:4][CH:30]=2)[CH:21]=[C:22]([N+:26]([O-:28])=[O:27])[C:23]=1[O:24][CH3:25]
Reactant: COc1cc(C(=O)C=O)cc([N+](=O)[O-])c1OC
Reactant: N/N=C(\N)c1ccc[n+]([O-])c1C(F)(F)F
Solvent: CCO
Product: COc1cc(-c2cnnc(-c3ccc[n+]([O-])c3C(F)(F)F)n2)cc([N+](=O)[O-])c1OC
Temperature: 25 °C

Procedure:
To a stirred solution of (Z)-3-carbamohydrazonoyl-2-(trifluoromethyl)pyridine 1-oxide (1.10 g, 5 mmol) in ethanol (30 mL) was added 2-(3,4-dimethoxy-5-nitrophenyl)-2-oxoacetaldehyde (1.19 g, 5 mmol). The reaction mixture was heated to reflux for 5 hours, and then cooled to room temperature and the solvent was removed by evaporation. The residue was dissolved in dichloromethane (30 mL) and the organic phase was washed with water and dried over anhydrous magnesium sulphate, filtered and evaporated. The crude product was recrystallized from isopropanol to give 3-(5-(3,4-dimethoxy-5-nitrophenyl)-1,2,4-triazin-3-yl)-2-(trifluoromethyl)pyridine 1-oxide, 1.69 g (80%).