Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].CC(C)([O-])C.[K+].Br[CH2:23][C:24]1[C:25]([O:53][CH2:54][CH3:55])=[N:26][O:27][C:28]=1[C:29]1[N:33]=[CH:32][N:31]([C:34]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[N:30]=1>CN1CCCC1=O>[C:1]([NH:4][C:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:23][C:24]1[C:25]([O:53][CH2:54][CH3:55])=[N:26][O:27][C:28]=1[C:29]1[N:33]=[CH:32][N:31]([C:34]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[N:30]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOc1noc(-c2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1CBr
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CCOC(=O)C(Cc1c(OCC)noc1-c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)(NC(C)=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.5 %

Procedure:
A mixture of diethyl acetamidomalonate (1.3 g, 6.0 mmol) and potassium tert-butoxide (0.73 g, 6.5 mmol) in N-methylpyrrolidone (30 mL) was stirred at room temperature for 30 min. 3-[4-(Bromomethyl)-3-ethoxyisoxazol-5-yl]-1-trityl-1H-1,2,4-triazole (2.8 g, 5.4 mmol) in N-methylpyrrolidone (20 mL) was added (temp 22-28° C.) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was poured onto an ice/water mixture (250 mL) and the aqueous phase was extracted with EtOAc (3×250 mL). The organic extracts were washed with an aqueous solution of potassium tert-butoxide and brine, dried (Na2SO4) and concentrated in vacuo. Flash chromatography (silica gel, eluent: EtOAc/heptane/triethylamine=50:50:2) gave the title compound (2.2 g, 62%): mp 145-149° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]1[CH:15]=[C:16]([NH2:24])[C:17](=[CH:21][C:22]=1[F:23])[C:18]([OH:20])=[O:19]>O1CCOCC1>[CH:21]1[CH:17]2[C:16](=[N:24][C:2]([O:19][C:18]2=[O:20])=[O:4])[CH:15]=[C:14]([F:13])[C:22]=1[F:23]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)c(F)cc1C(=O)O
Solvent: C1COCCO1
Product: O=C1N=C2C=C(F)C(F)=CC2C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 828.7 %

Procedure:
Triphosgene (0.65 g, 0.22 mmol) was added to 4,5-difluoroanthranilic acid (0.34 g, 0.2 mmol) in dry 1,4-dioxane (30 ml), and the mixture was stirred at rt. for 1 h. Solvent was slowly distilled off at ca. 50° C., and the residue distributed between ethyl acetate (100 ml) and the pH 7 buffer (50 ml). The aqueous layer was extracted with more ethyl acetate (2×50 ml), and combined organic layers washed with diluted aq. citric acid (pH ca. 4-5), water (30 ml), brine (50 ml), and dried (MgSO4). Solvent was removed in vacuo to yield 0.33 g (83%) of 6,7-difluoroisatoic anhydride. The intermediate thus obtained (0.29 g, 1.45 mmol) was stirred with dry potassium carbonate (0.20 g, 1.45 mmol) in dry methanol (30 ml) for 1 h. Most of the solvent was removed in vacuo, and the residue distributed between ethyl acetate (100 ml) and the pH 7 buffer (50 ml). Aqueous layer was adjusted to pH ca. 7 with additional aq. HCl, and extracted with ethyl acetate (2×30 ml). Combined organic layers were washed with water (2×30 ml), brine (50 ml), and dried (MgSO4). Solvent was removed in vacuo to yield 0.24 g (89%) of methyl 4,5-difluoroanthranilate. 1H NMR in CDCl3 (δ,ppm): 3.86 (s, 3 H), 5.72 (br. s, 2 H), 6.43 (m, 1 H), 7.66 (m, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH:20]([NH:22][NH2:23])=O>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:20]=[N:22][N:23]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: NNC=O
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Solvent: CCCCO
Product: Clc1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2

Procedure:
A mixture of 5.74 g. (0.020 mole) of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepine-2-thione, 3.6 g. (0.060 mole) of formic acid hydrazide and 200 ml. of 1-butanol was refluxed for 3.75 hours with a slow stream of nitrogen bubbling through the mixture. The mixture was concentrated, the residue was suspended in water, and the suspension was filtered. The filter cake consisted principally of unchanged starting material. The filtrate was concentrated, ethyl acetate and Skellysolve B hexanes being added during the concentration, giving crude product (2.54 g.) of melting point 220.5°-225° C. Recrystallization of this material from ethyl acetate-Skellysolve B hexanes gave 8-chloro-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine of melting point 228°-229° C. The ultraviolet spectrum (ethanol) had end absorption λ max. 222 (ε = 40,950) and inflections at 245 (ε = 16,200) and 285 mμ(ε = 3,500).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][C:8](=[O:29])[CH:9]([N:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:6])[O:4][CH3:5].C1COCC1.[BH4-].[Na+].Cl>CO>[CH3:1][O:2][P:3]([CH2:7][CH:8]([OH:29])[CH:9]([N:14]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH:11]([CH3:13])[CH3:12])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(CC(=O)C(CC(C)C)N(Cc1ccccc1)Cc1ccccc1)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COP(=O)(CC(O)C(CC(C)C)N(Cc1ccccc1)Cc1ccccc1)OC
Temperature: -2.5 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
Reaction 3: A mixture of the crude oil (3-dibenzylamino-5-methyl-2-oxohexyl)-phosphonic acid dimethyl ester, i.e., compound 3, obtained in reaction 2, was dissolved in about 10% methanol and about 90% THF (v/v) and cooled at −10° C. NaBH4 (68.58 mmol) was added to the mixture in small portions with vigorous stirring. The mixture was stirred at temperature of −10 to 5° C. for 4 h and HCl 5% (v/v) was added. The reaction mixture was concentrated under reduced pressure. The residual oil was dissolved in ethyl acetate, and washed with 30 ml portions of water. The organic phase was dried over anhydrous Na2SO4 and filtered. The solvent was evaporated off to leave (3-dibenzylamino-2-hydroxy-5-methyl-hexyl)-phosphonic acid dimethyl ester as a crude oil. 31P NMR (at 200 MHz, CDCl3) indicated an 80:20 ratio of 2R,3S (δ 34.53) to 2S,3S (δ 35.15) isomers. The diastereomeric mixture was purified by flash chromatography on silica gel using hexane/ethyl acetate as the eluent to afford compound 2R,3S-4 (20.753 g; 64.9% yield; 31P NMR at 200 MHz, CDCl3; δ 34.61).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[CH2:13][N:14]([C:17]1[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=1)[CH2:15][CH3:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O1CCCC1>[CH2:3]([O:10][C:11]1[CH:30]=[CH:29][CH:28]=[CH:27][C:12]=1[CH2:13][N:14]([C:17]1[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1)[CH2:15][CH3:16])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1ccccc1OCc1ccccc1)c1ccc(C(=O)O)cc1

Procedure:
40% Aqueous sodium hydroxide (100 mL) was added to a solution of methyl 4-[N-(2-benzyloxybenzyl)-N-ethylamino]benzoate (44.0 g) in a mixture of methanol (200 mL) and tetrahydrofuran (100 mL) and the resulting mixture was heated under reflux for 6 hours. The reaction mixture was reduced to half its volume on a rotary evaporator and water (300 mL) was added. The mixture was acidified with acetic acid, the precipitate was filtered, washed three times with diethyl ether (50 mL each time) and dried in a vacuum oven at 60° C. to give 4-[N-(2-benzyloxybenzyl)-N-ethylamino]benzoic acid, melting point 165° C., yield 38.0 g (89%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:36])[CH:3]=1.[BrH:37].N([O-])=O.[Na+]>C(#N)C.O>[Br:37][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:13]2[C:32]([CH:33]3[CH2:35][CH2:34]3)=[CH:31][C:16]3[C:17]([C:27]([NH:29][CH3:30])=[O:28])=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[O:19][C:15]=3[CH:14]=2)[S:9]([CH3:12])(=[O:11])=[O:10])=[C:4]([F:36])[CH:3]=1
Reactant: Br
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(Br)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a solution of 6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (360 mg, 0.7 mmol) in acetonitrile (20 mL) was added hydrobromic acid (5 mL, 40% in water) followed by sodium nitrite (49 mg, 0.77 mmol in 2 mL water) dropwise at 0° C. After stirring for 10 minutes at 0° C., cuprous bromide (115 mg, 0.8 mmol) was added. The mixture was warmed to 80° C. and stirred for 1 hour. The mixture was cooled to room temperature and diluted with water (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-bromo-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (240 mg, 0.42 mmol, 60% yield) as an off-white solid. LCMS (m/z, ES+)=575, 577 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=O.[CH:14]([CH:16]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:15]>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][CH2:10][CH2:11]/[CH:12]=[CH:16]/[CH:14]=[O:15]
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCOC1CCCCO1
Product: O=C/C=C/CCCCOC1CCCCO1

Procedure:
from 16 g of 5-tetrahydropyranyloxypentanal [E.J. Corey et al., J. Am. Chem. Soc. 92, 6635 (1970)] and 26.1 g of formylmethylenetriphenylphosphorane.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7]O)=[CH:4][CH:3]=1.NC(N)=[S:13].Br.[OH-].[Na+]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][SH:13])=[CH:4][CH:3]=1
Reactant: OCCc1ccc(Cl)cc1
Reactant: NC(N)=S
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: SCCc1ccc(Cl)cc1
Yield: 62.6 %

Procedure:
A mixture of 4-chlorophenethyl alcohol (50.0 g, 0.319 mole), thiourea (24.3 g, 0.319 mole) and 48% hydrobromic acid (161 g, 0.958 mole) was stirred under reflux for 9 hours. The mixture was cooled and a solution of sodium hydroxide (38.3 g, 0.958 mole) in water (380 ml) added, and the resulting mixture was stirred at reflux for 2 hours under a gentle stream of nitrogen. The mixture was cooled and the oily organic layer separated. The aqueous layer was acidified with hydrochloric acid and extracted with 3×50 ml portions of diethyl ether. The ethereal extracts were combined with the oily product and the combination washed with water followed by brine. The ethereal solution was dried (Na2SO4), concentrated and distilled to provide 34.5 g of the title compound, bp 72°-77° (0.03 mm).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].[Br-:11].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([OH:10])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:9]=1
Reactant: [Br-]
Reactant: CCCc1ccccc1O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClC(Cl)Cl
Product: CCCc1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
2-propylphenol (3.0 g, 0.022 mol) was dissolved in CHCl3 (100 mL) and magnetically stirred at room temperature. To this solution was added a solution of Tetrabutyl ammonium tribromide (10.68 g, 0.022 mol) in CHCl3 (100 mL). The resulting yellow solution was allowed to stir at room temperature for 1 hour. The reaction was quenched with a 5% solution of sodium thiosulfate (200 mL). The biphasic mixture was stirred for 15 min. The organics were separated and concentrated. The residue was dissolved in EtOAc (100 mL) and washed with water (2×100 mL) and brine (1×100 mL). The organics were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography (silica gel) eluting with 3% EtOAc in Hexanes. The result was a yellow oil (4.54 g). 1H NMR (CDCl3): δ 1.00 (t, J=8.10 Hz, 3H), 1.52 (m, 2H), 2.50 (t, J=4.56 Hz, 2H), 4.95 (s, 1H), 6.72 (d, J=2.07 Hz 1H)), 6.80 (s, 1H), 6.85 (d, J=2.07 Hz, 1H).
Reaction SMILES: C(O)(=O)/C=C/C(O)=O.[CH:9]([O:12][CH2:13][CH2:14][N:15]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1)[C:16](=[O:19])[CH2:17]Cl)([CH3:11])[CH3:10].[NH:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1>>[CH:9]([O:12][CH2:13][CH2:14][N:15]([C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([Cl:40])=[CH:38][CH:39]=3)[CH2:28][CH2:27]2)=[O:25])=[CH:22][CH:21]=1)[C:16](=[O:19])[CH2:17][N:43]1[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1)([CH3:10])[CH3:11]
Reactant: CC(C)OCCN(C(=O)CCl)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Reactant: C1CCNCC1
Agent: O=C(O)/C=C/C(=O)O
Product: CC(C)OCCN(C(=O)CN1CCCCC1)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
Analogously to Example 51, 1-{4-[N-(2-isopropyloxyethyl)-N-chloroacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine (Example 3) and piperidine are reacted, yielding 1-{4-[N-(2-isopropyloxyethyl)-N-piperidinoacetylamino]benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine. The difumarate thereof melts at 179°-180°.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([C:22]([OH:24])=O)[CH2:18][CH2:17]2)[N:4]=1.[F:25][C:26]([F:36])([F:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH2:34].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:6]=[C:5]([NH:15][C@H:16]2[CH2:17][CH2:18][C@H:19]([C:22]([NH:34][CH2:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:26]([F:25])([F:35])[F:36])=[O:24])[CH2:20][CH2:21]2)[N:4]=1
Reactant: CNc1nc(N[C@H]2CC[C@H](C(=O)O)CC2)nc(-c2ccccc2)n1
Reactant: NCc1ccccc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CNc1nc(N[C@H]2CC[C@H](C(=O)NCc3ccccc3C(F)(F)F)CC2)nc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of trans-4-{[4-(methylamino)-6-phenyl-1,3,5-triazin-2-yl]amino}cyclohexanecarboxylic acid (40 mg, 0.12 mmol) was added 1-[2-(trifluoromethyl)phenyl]methanamine (22 mg, 0.12 mmol), EDCI (24 mg, 0.12 mmol), HOBt (17 mgs, 0.12 mmol), and N-methylmorpholine (13 mg, 0.12 mmol). The mixture was stirred at rt for 20 h. The solvent was removed under vacuum, and the resulting residue was purified by HPLC to provide 20 mg (34% yield) of the desired material. MS (ES+): m/e 485.3 [M+H]+.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[O:11]>>[C:1]1([S:7][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: Sc1ccccc1
Product: COc1ccc(C(=O)CSc2ccccc2)cc1

Procedure:
Thiophenol and 2-bromo-4′-methoxyacetophenone were converted to the title compound by the procedure of Preparation 1. mp 83° C.-85° C. EA calculated for C15H14O2S: C, 69.74; H, 5.46. Found: C, 69.52; H, 5.48.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[OH:11])([O-])=O.C([Cl:15])(=O)C>>[Cl:15][C:4]1[CH:9]=[CH:8][N+:7]([O-:10])=[CH:6][C:5]=1[OH:11]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1O
Product: [O-][n+]1ccc(Cl)c(O)c1

Procedure:
The starting material was prepared by reaction of 4-nitro-3-hydroxy pyridine-N-oxide with acetyl chloride under reflux for 1 hour. The crude product was purified by rapid chromatography on silica gel using CH2Cl2 /MeOH 7:3 v/v as eluant to give 4-chloro-3-hydroxypyridine-N-oxide. Reduction of this compound with Raney nickel and hydrogen at ambient temperature for 2 hours in MeOH gave 4-chloro-3-hydroxypyridine. This compound was reacted with NaH in DMSO at 50°, the reaction mixture cooled and treated with 4-nitrobenzyl bromide for 1 hour. The reaction mixture was worked up with water and ether and the product treated with HCl/ether to give 4-chloro-3-(4-nitrobenzyloxy)pyridine hydrochloride. Reaction of the free base with excess methyl iodide at ambient temperature for 24 hours gave 4-chloro-1-methyl-3-(4-nitrobenzyloxy)pyridinium iodide. n.m.r. in d6DMSO: 4.35(s, 3H); 5.6(s, 2H); 7.7(d, 2H); 8.3(d, 2H); 8.4(d, 1 H); 8.7(d, 1H); 9.15(s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[N:23][C:24]([O:32]C)=[C:25]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:26]=4)[CH:19]=3)[N:14](C(OC(C)(C)C)=O)[CH:13]=2)[C:8]([CH3:41])=[N:7]1>Cl.CO>[F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[C:25]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[C:24]([OH:32])=[N:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:41])=[N:7]1
Reactant: COc1ncc(-c2cnc3c(c2)c(-c2c(C)nn(Cc4cccc(F)c4)c2C)cn3C(=O)OC(C)(C)C)cc1NS(C)(=O)=O
Agent: Cl
Solvent: CO
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c[nH]c2ncc(-c3cnc(O)c(NS(C)(=O)=O)c3)cc12
Yield: 10.1 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(6-methoxy-5-(methylsulfonamido)pyridin-3-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (61 mg, 0.098 mmol) was deprotected in HCl in MeOH (3 ml) to afford 5 mg (11.3% yield) of the titled compound. 1H NMR (CD3OD, 300 MHz): δ 8.71-8.62 (d, 2H), 7.91-7.88 (d, 2H), 7.68 (s, 1H), 7.47-7.42 (m, 1H), 7.15-7.02 (m, 3H), 6.60 (s, 1H), 5.57 (s, 2H), 3.09 (s, 3H), 2.36 (s, 3H), 2.35 (s, 3H). MS: m/z=506.8 (M+1), HPLC: 90.22% in method B.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:11]([C:12](=[S:14])[NH2:13])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1.Cl[CH:16]([C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[O:30][CH3:31])=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18]>CC(O)C>[CH3:31][O:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:22]1[N:13]=[C:12]([C:11]2[C:3]([CH3:2])=[N:4][N:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=23)[S:14][C:16]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: Cc1nn2ccccc2c1C(N)=S
Reactant: CCOC(=O)C(Cl)C(=O)c1ccccc1OC
Agent: Cl
Solvent: CC(C)O
Product: CCOC(=O)c1sc(-c2c(C)nn3ccccc23)nc1-c1ccccc1OC
Yield: 351.9 %

Procedure:
Using 2-methylpyrazolo[1,5-a]pyridine-3-carbothioamide hydrochloride (300 mg, 1.3 mmol) produced in Example 11-B(v), ethyl 2-chloro-3-(2-methoxyphenyl)-3-oxopropanoate (600 mg, 2.3 mmol) produced above and 2-propanol (40 mL) as starting materials and in the same manner as in Example 11-B(vi), the title compound (1.8 g, 71%) was obtained as a yellow solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>>[N+:1]([C:8]1[CH:9]=[CH:10][C:5]([CH3:11])=[CH:6][CH:7]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccccc1
Product: Cc1ccc([N+](=O)[O-])cc1

Procedure:
reacting toluene with nitric acid in a single liquid phase reaction in a first reaction zone at an elevated temperature to provide a single phase mononitrotoluene-containing product mixture, using a reaction mixture that is free of sulfuric acid and that comprises a molar ratio of said nitric acid to said toluene of from 20:1 to 30:1, said reaction being conducted using a combination of fresh and recycled aqueous nitric acid, said combination having a nitric acid concentration not exceeding 75% based upon the weight of nitric acid plus water in said dilute aqueous nitric acid,
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N+:11]([O-])=O.[H][H]>C(O)C.[Pd]>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([NH:2][CH3:1])=[C:4]([NH2:11])[CH:5]=1
Reactant: [H][H]
Reactant: CNc1ccc(OC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: CNc1ccc(OC)cc1N
Yield: 120.7 %

Procedure:
A solution of 1.16 g of N-methyl-4-methoxy-2-nitroaniline (prepared as described in Preparation 24) in 50 ml of ethanol was shaken in an atmosphere of hydrogen and in the presence of 0.3 g of 10% w/w palladium-on-charcoal for 3 hours. At the end of this time, the palladium-on-charcoal was filtered off, and the filtrate was freed from the solvent by evaporation under reduced pressure, to give 1.17 g of the title compound having an Rf value=0.50 (on thin layer chromatography on silica gel; developing solvent: a 1:3 by volume mixture of ethyl acetate and hexane).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:26]4[CH2:29][CH:28]([C:30]([O:32]C)=[O:31])[CH2:27]4)=[CH:22][C:21]=3[CH3:34])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.O.[OH-].[Li+].C(O)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([C:15]2[O:19][N:18]=[C:17]([C:20]3[S:24][C:23]([CH2:25][N:26]4[CH2:27][CH:28]([C:30]([OH:32])=[O:31])[CH2:29]4)=[CH:22][C:21]=3[CH3:34])[N:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COC(=O)C1CN(Cc2cc(C)c(-c3noc(-c4ccc(Oc5ccccc5)c(F)c4)n3)s2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(CN2CC(C(=O)O)C2)sc1-c1noc(-c2ccc(Oc3ccccc3)c(F)c2)n1
Yield: 76.1 %

Procedure:
The title compound (0.17 g) was synthesized in a yield of 74% as a white crystalline solid by conducting the reaction similar to that mentioned in Example 2 (2e) using methyl 1-({5-[5-(3-fluoro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-4-methyl-2-thienyl}methyl)azetidine-3-carboxylate (0.23 g, 0.48 mmol) that was obtained in Example 11 (11g), lithium hydroxide monohydrate (46 mg, 1.1 mmol), and acetic acid (60 μL, 1.1 mmol).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[Cl:24])=[O:16].[OH-].[Na+]>COCCOC>[Cl:24][C:18]1[CH:19]=[C:20]([F:23])[CH:21]=[CH:22][C:17]=1[C:15](=[O:16])[CH2:14][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][N:5]=1
Reactant: CC(=O)c1ccc(F)cc1Cl
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.7 %

Procedure:
A reaction vessel was charged with sodium hydride (as a 60% oil dispersion, 5.0 g, 125 mmol), DME (40 ml) and 2-chloro-5-trifluoromethylpyridine (6.93 g, 38.2 mmol). 2-Chloro-4-fluoroacetophenone (6.8 g, 39.4 mmol) in DME (10 ml) was added in portions to the mixture under nitrogen at room temperature. The mixture was stirred at ambient temperature for one hour then at 40-45° C. overnight. Upon the completion of the reaction, the mixture was cooled to 5° C. and 10% aqueous sodium hydroxide solution (20 ml) was slowly added to the reaction mixture. The mixture was partitioned between diethylether (300 ml) and water (300 ml). The layers were separated, the organics dried over magnesium sulfate and concentrated to dryness. The residue was purified by column chromatography on silica eluting with diethylether-cyclohexane (1:3). Concentration of the appropriate fractions afforded 8.10 g (67%) of the title compound.