Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:17](Cl)(=O)=O)[CH:15]=3)[N:10]([C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[C:1]([N:4]1[CH2:8][CH2:7][C:6]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([SH:17])[CH:15]=3)[N:10]([C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH2:9]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(S(=O)(=O)Cl)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC2(C1)CN(C(=O)C(F)(F)F)c1ccc(S)cc12
Temperature: 50 °C
Reaction time: 4 h
Yield: 30.2 %

Procedure:
The 1′-acetyl-1-(2,2,2-trifluoroacetyl)spiro[indoline-3,3′-pyrrolidine]-5-sulfonyl chloride (101 mg, 0.25 mmol) obtained as an intermediate in Step 2 of Example 236 was dissolved in tetrahydrofuran (3 mL). Thereafter, water (0.1 mL) and triphenylphosphine (0.23 g, 0.86 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred at 50° C. for 4 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous magnesium sulfate, followed by concentration in vacuo. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=20:1) to obtain 1-(1′-acetyl-5-mercaptospiro[indoline-3,3′-pyrrolidin]-1-yl)-2,2,2-trifluoroethanone (26 mg, 31%) in the form of a colorless oily product.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15](C(OCC)=O)=[N:14]2)=[CH:9][CH:8]=1>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=[N:14]2)=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2)c(=O)cc1C(F)(F)F
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1cc(C(F)(F)F)cnn1-c1ccc(Cl)cc1
Temperature: 150 °C
Yield: 45.4 %

Procedure:
Two mililiters (2 ml) of a mixture of sulfuric acid and water (v/v=1/1), and 0.5 g of 2-(4-chlorophenyl)-6-ethoxycarbonyl-5-trifluoromethylpyridazin-3-one (the present compound 1-51) were mixed and heated for 5 hours on a 150° C. oil bath. The reaction solution was cooled to room temperature, poured into water and extracted with 100 ml of ethyl acetate. The organic layer was washed with 50 ml of saturated sodium chloride solution twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the obtained crystals were washed with 50 ml of n-hexane to afford 0.18 g of 2-(4-chlorophenyl)-5-trifluoromethylpyridazin-3-one (yield:45%).
Reaction SMILES: [C:1](OC(C1CCCN1C(=O)C(NC(=O)C1C=CC(N)=C(Cl)C=1)C)=O)(C)(C)C.[O:28]=[C:29]1[O:33][CH:32]([O:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30]1>>[CH2:36]1[C:37]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH2:1][CH:35]1[O:34][CH:32]1[CH:31]([NH:43][C:44]([CH:46]2[CH2:50][CH2:49][CH2:48][N:47]2[C:51](=[O:65])[CH:52]([NH:54][C:55](=[O:64])[C:56]2[CH:61]=[CH:60][C:59]([NH2:62])=[C:58]([Cl:63])[CH:57]=2)[CH3:53])=[O:45])[CH2:30][C:29](=[O:28])[O:33]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)OC(C)(C)C
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OC1Cc2ccccc2C1

Procedure:
Prepared from 97a and [2-(indanol-2-yl]oxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester according to the procedure used to prepare 98a to afford the title compound as a 71:29 mixture of epimers as an off-white solid (0.20 g, 58% yield). 1H-NMR (500 MHz, CDCl3) δ 1.0-1.5 (m, 3H), 1.6-2.3 (m, 4H), 2.42 (m, 1H), 2.6-3.4 (m, 6H), 3.5-4.1 (m, 3H), 4.2-4.9 (m, 4H), 5.65 (d, J=5.0 Hz, 0.80H), 5.8 (m, 0.07H), 5.85 (d, J=5.0 Hz, 0.13H), 6.8-7.3 (m, 6H), 7.4-7.9 (m, 3H) ppm. Analytical HPLC (C18 column) 16.035 (71.4%), 16.476 (28.6%) min. LC-MS (ES+): m/e=555 (M+H).
Reaction SMILES: [OH-].[Na+].[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]\[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([O:13]CC)=[O:12].CO.Cl>O1CCCC1>[O:3]1[CH:7]=[CH:6][CH:5]=[C:4]1/[C:8](=[N:16]\[O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[N:28]=[C:29]([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[O:30][C:31]=2[CH3:32])=[CH:21][CH:20]=1)/[CH2:9][CH2:10][C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)CC/C(=N/OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)c1ccco1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CO/N=C(/CCC(=O)O)c2ccco2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
A 1N aqueous saturated solution of sodium hydroxide (5 ml) was added to a solution of ethyl Z-4-(2-furyl)-4-[4(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyrate (460 mg) in tetrahydrofuran (10 ml)-methanol (5 ml) and stirred at room temperature for 1 hour. 1N hydrochloric acid (5.5 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-hexane to obtain Z-4-(2-furyl)-4-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxyimino]butyric acid (402 mg, yield 93%) as colorless crystals. m.p. 131-133° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]([CH3:19])([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=3)[NH:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29].Cl.CN(C)CC(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[CH3:18][C:17]1([CH3:19])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:20]([OH:22])=[O:21])[CH:14]=2)[NH:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:26]2[CH2:27][CH2:28][N:24]([CH3:23])[C:25]2=[O:29])[CH:3]=1
Reactant: CN1CCNC1=O
Reactant: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(Br)c1
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: Cl
Solvent: CS(C)=O
Product: CN1CCN(c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C1=O
Temperature: 120 °C
Reaction time: 12 h
Yield: 1.1 %

Procedure:
A mixture of 2-(3-bromo-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (360 mg, 1 mmol), 1-methyl-imidazolidin-2-one (300 mg, 3 mmol), copper(I) iodide (115 mg, 0.6 mmol), N,N-dimethylglycine hydrochloride (112 g, 0.8 mmol) and potassium carbonate (415 mg, 3 mmol) in dimethyl sulfoxide (5 mL) was stirred at 120° C. for 12 h. Then the reaction mixture cooled to room temperature. The reaction mixture was extracted with ethyl acetate (2×150 mL), washed with water (2×50 mL) and saturated aqueous ammonium chloride solution (2×50 mL), dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 3,3-dimethyl-2-[3-(3-methyl-2-oxo-imidazolidin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (4 mg, 1%) as a white solid: LC/MS m/e calcd for C22H25N3O3 (M+H)+: 380.46, observed: 380.1.
Reaction SMILES: [C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15][CH3:16])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>>[C:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([O:17][CH3:18])[C:13]([S:15]([CH3:16])=[O:27])=[CH:14][C:7]=2[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1SC)CCN(C(C)=O)CC2
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1cc2c(cc1S(C)=O)CCN(C(C)=O)CC2

Procedure:
Following the general procedure of Example 4 Method B, 3-acetyl-8-methoxy-7-methylthio-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with one equivalent of 3-chloroperbenzoic acid to give 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine. Following the procedure of Example 4, 3-acetyl-8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine is reacted with 3N hydrochloric acid to give 8-methoxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride. This methoxy compound is treated with pyridine hydrochloride to give 8-hydroxy-7-methylsulfinyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:19])[F:18])[N:11]([CH3:21])[C:10]=1[CH3:22])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][C:17]([F:20])([F:18])[F:19])[N:11]([CH3:21])[C:10]=1[CH3:22]
Reactant: Cc1c(OCc2ccccc2)c(=O)cc(CC(F)(F)F)n1C
Agent: [Pd]
Solvent: CO
Product: Cc1c(O)c(=O)cc(CC(F)(F)F)n1C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
To a suspension of 3-benzyloxy-2-hydroxymethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.34 g, 1.04 mmol) in acetonitrile (15 mL), was added thionyl chloride (0.38 mL, 5.19 mmol) at room temperature. A clear solution resulted and the reaction was completed within 10 min. The reaction mixture was evaporated to dryness to give the crude 3-benzyloxy-2-chloromethyl-1-methyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil, which was taken up in ethanol (15 mL) to give a clear solution. Sodium borohydride (430 mg, 11.4 mmol) was added to the solution portionwise. The reaction mixture was stirred for another 10 min, and the progress of the reaction was monitored by TLC (methanol/dichloromethane, 1/10 v/v as eluant). There was still some unreacted chloride derivative present at this time. Additional sodium borohydride (360 mg, 9.5 mmol) was added in several portions. The reaction mixture was stirred for another 10 min. The reaction mixture was purified by column chromatography on silica gel (methanol/dichloromethane, 1/20 v/v as eluant) to give 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as an oil (0.20 g, 61% for the two combined steps, HPLC Method 1 (Example 24), RT=15.1 min, HPLC purity (peak percent area): 92% at λ=280 nm). This material, 3-benzyloxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one (0.20 g, 0.64 mmol) was taken up in methanol (25 mL) to give a clear solution. To the solution was added Pd/C (10 wt. %, dry basis, on activated carbon, wet, Degussa type E101 NE/W, 90 mg). The hydrogenation reaction was conducted under a hydrogen pressure of 50 psi. The reaction was completed in 30 min. A CELITE™ bed was prepared on a sintered glass, and washed with 6M HCl (100 mL), followed by water (7×50 mL) and then methanol (2×50 mL) under suction. The reaction mixture was filtered through the pre-treated CELITE™ bed. The filtrate was evaporated to give the first crop of 3-hydroxy-1,2-dimethyl-6-(2,2,2-trifluoro-ethyl)-1H-pyridin-4-one as a solid product (free base, 74 mg, 52% yield), HPLC Method 1 (Example 24), RT=9.9 min, HPLC purity (peak percent area): 96.4% at λ=280 nm). 1H NMR (DMSO-d6) δ ppm: 6.25 (s, 1H), 3.94 (q, J=11 Hz, 2H), 3.57 (s, 3H), 2.32 (s, 3H). MS-ESI (m/z) 222.2 ([M+1]+, 100%), 202.3, 153.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([F:13])[CH:6]=1)[CH3:15]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1ccc(C#N)c(F)c1
Temperature: 25 °C

Procedure:
(4-Cyano-3-fluoro-phenyl)-acetic acid methyl ester (3.06 g, 15.84 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL) and cooled in a dry ice-acetone bath. Lithium bis(trimethylsilyl)amide (1.0 M in tetrahydrofuran, 17.42 mL) was added under a nitrogen atmosphere. The solution was stirred for 1 h, at which point methyliodide (4.91 mL) was added dropwise. The reaction was allowed to warm to ambient temperature while stirring. Upon reaction completion satd. aq. ammonium chloride (100 mL) was added and the bulk of the tetrahydrofuran evaporated under a nitrogen stream. The aqueous layer was then extracted with ethyl acetate (3×300 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude was purified by silica gel chromatography with ethyl acetate:hexanes (3:17) to give the title compound (1.73 g).
Reaction SMILES: C[Sn](C)(C)[C:3]1[S:7][C:6]([S:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[CH:5][CH:4]=1.Br[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[N:22]=1>CN1CCCC1=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:27][C:23]1[N:22]=[C:21]([C:3]2[S:7][C:6]([S:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)(=[O:10])=[O:9])=[CH:5][CH:4]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1cccc(Br)n1
Reactant: C[Sn](C)(C)c1ccc(S(=O)(=O)Oc2ccccc2)s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(-c2ccc(S(=O)(=O)Oc3ccccc3)s2)n1
Temperature: 90 °C

Procedure:
A mixture of phenyl 5-(trimethylstannanyl)-2-thiophenesulfonate (1.3 g, 3.2 mmol) (WO 9827069), 2-bromo-6-methylpyridine (550 mg, 3.2 mmol) and dichlorobis(triphenylphosphine)palladium (II) (100 mg) in 1-methyl-2-pyrrolidinone (10 ml) was heated at 90° C. under argon for 4 hours. After cooling to room temperature the mixture was diluted with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by chromatography (1:10 ethyl acetate:pentane) to afford the title product (D11). MS (ES+) m/e 332 [M+H]+.
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@@H:6]1[N:19]1[CH:23]=[N:22][C:21]([C:24]([O:26]C)=O)=[N:20]1)(=[O:3])[CH3:2].[NH3:28]>CO>[C:1]([O:4][C@H:5]1[C@@H:14]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([CH2:9][O:10][C:11](=[O:13])[CH3:12])[O:7][C@@H:6]1[N:19]1[CH:23]=[N:22][C:21]([C:24]([NH2:28])=[O:26])=[N:20]1)(=[O:3])[CH3:2]
Reactant: N
Reactant: COC(=O)c1ncn([C@H]2O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H]2OC(C)=O)n1
Solvent: CO
Product: CC(=O)OC[C@@H]1O[C@H](n2cnc(C(N)=O)n2)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
Methyl 1,2,4-triazole-3-carboxylate and 1,2,3,5-tetra-O-acetyl-β-L-ribofuranose are heated under reduced pressure in the presence of trifluoromethanesulfonic acid or bis(p-nitrophenyl)-phosphate. The residue is recrystallized from ethanol or methanol to obtain methyl 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate. Subsequently, the obtained methyl 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxylate is treated with ammonia in a methanol solvent, and the resultant mixture is then recrystallized from ethanol to obtain a crude product of 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide. The obtained compound is further recrystallized from an ethanol aqueous solution, so as to obtain high-purity 1-(2,3,5-tri-O-acetyl-β-L-ribofuranosyl)-1,2,4-triazole-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Br:9])[NH2:5].Cl.Cl[CH2:12][CH2:13][CH2:14][N:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH3:16][N:15]([CH3:17])[CH2:14][CH2:13][CH2:12][NH:5][C:4]1[CH:6]=[CH:7][C:8]([Br:9])=[C:2]([Br:1])[CH:3]=1
Reactant: CN(C)CCCCl
Reactant: Nc1ccc(Br)c(Br)c1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CN(C)CCCNc1ccc(Br)c(Br)c1

Procedure:
In the manner given in Example 1, 3,4-dibromoaniline, 1-chloro-3-dimethylaminopropane hydrochloride, sodium carbonate and sodium bicarbonate are heated in toluene to give N,N-dimethyl-(3,4-dibromophenyl)trimethylenediamine.
Reaction SMILES: [C:1](OC)(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[CH2:16]([N:23]([CH3:37])[C:24](=[O:36])[CH2:25][CH2:26][CH2:27][C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CCCCCC.O1CCCC1>[CH2:16]([N:23]([CH3:37])[C:24](=[O:36])[CH2:25][CH2:26][CH2:27][C:28]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:5][C:3]([OH:4])=[CH:2][C:1](=[O:6])[O:35]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: CN(Cc1ccccc1)C(=O)CCCC(=O)c1ccccc1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN(Cc1ccccc1)C(=O)CCCC1(c2ccccc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 1 using 5.6 mmol of methyl acetoacetate, 6.1 mmol of NaH 60% dispersion in oil, 5.9 mmol of 1.6M n-butyl lithium in hexane, 5.6 mmol of 5-oxo-5-phenylpentanoic acid benzyl-methyl amide and 25 mL of tetrahydrofuran. The product was flash chromatographed using CH2 Cl2 /MeOH (98/2) to give a solid (m.p. 47°-51° C.). 1H NMR (DMSO-d6) δ 1.1-1.3 (m, 1 H), 1.4-1.6 (m, 1 H), 1.8-2.0 (m, 2 H), 2.2-2.4 (m, 2 H), 2.75/2.81 (s/s 3 H), 2.85-3.1 (m, 2 H), 4.4/4.5 (s/s, 2 H), 4.85/4.9 (s/s 1 H), 7.1-7.4 (m, 10 H), 11.36/11.38 (s/s, 1 H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20]Cl)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+]>C(O)CCC.O>[Cl:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: O=Cc1ccc(OCCCCl)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Solvent: O
Product: CN1CCN(CCCOc2ccc(C=O)c(Cl)c2)CC1
Yield: 63.6 %

Procedure:
N-Methylpiperazine (2.16 g, 21.5 mmol), 2-chloro-4-(3-chloro-propoxy)-benzaldehyde (3.19 g, 10.8 mmol), K2CO3 (4.46 g, 32.3 mmol), and KI (1.02 g, 5.38 mmol) were stirred in n-butanol (22 mL) at 90° C. for 18 h. The reaction mixture was diluted with water and then extracted three times with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated, yielding the crude product, which was purified by Method 1 to afford 2.04 g (63%) of an orange oil. 1H NMR (400 MHz, CD3OD): 10.3 (s, 1H), 7.86 (d, J=8.0, 1H), 7.08 (d, J=2.0, 1H), 7.00 (dd, J=8.0, 2.0, 1H), 4.15 (t, J=8.0, 2H), 3.00-2.30 (br s, 10H), 2.29 (s, 3H), 2.05-1.90 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:21]=[C:20]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:19]=[CH:18][C:17]=3[N+:28]([O-])=O)[CH:11]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C(O)(=O)C>O1CCCC1.CCO.[Zn]>[NH2:28][C:17]1[CH:18]=[CH:19][C:20]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:21][C:16]=1[C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([CH3:1])[CH:3]=2)[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3[N+](=O)[O-])c2)cc1C
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc(Nc2ccnc(-c3cc(N4CCCCC4)ccc3N)c2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
Into a 50-mL 3-necked round bottom flask, was placed a solution of N-(3,4-dimethylphenyl)-2-(2-nitro-5-(piperidin-1-yl)phenyl)pyridin-4-amine (300 mg, 0.75 mmol, 1.00 equiv) in tetrahydrofuran/EtOH (10/1 mL), Zn (485 mg, 7.46 mmol, 10.00 equiv), and acetic acid (1 mL). The resulting solution was stirred for 30 min at room temperature. The solids were filtered out. The solution was adjusted to pH 7-8 with sodium bicarbonate (aq). The resulting solution was extracted with 3×25 mL of dichloromethane and the organic layers combined. The resulting mixture was washed with 1×25 mL of brine, dried over sodium sulfate, and concentrated under vacuum. The product was obtained as 270 mg (97%) of a yellow solid.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][CH:8]([N+:12]([O-:14])=[O:13])[N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+].[OH-].[Na+]>>[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]([N:15]=[N+:16]=[N-:17])([N+:12]([O-:14])=[O:13])[N+:9]([O-:11])=[O:10])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCCC([N+](=O)[O-])[N+](=O)[O-]
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)OCCCC(N=[N+]=[N-])([N+](=O)[O-])[N+](=O)[O-]
Reaction time: 5.25 h

Procedure:
A divided electrochemical H-cell was charged with 4,4-dinitrobutyl acetate (10.2 g), 30% aqueous NaN3 (25 mL) and 12N NaOH (4 mL) in the anode compartment and 30% NaN3 (35 mL) in the cathode compartment. This solution was electrolyzed at 650 mA using a platimum foil anode (6.5 cm2) and a stainless steel cathode. After 5.25 h the reaction was stopped, and the anolyte was extracted with CH2Cl2 (3×25 mL). Brine-washing, drying, and concentrating the extracts yielded a product which displayed a weak hydroxyl absorption in the infrared spectrum. The product was reacetylated by stirring with acetyl chloride (1 mL) in CH2Cl2 (30 mL) for 2 h. This reaction was quenched in ice water, dried, and concentrated. The crude yellow oil was purified by column chromatography on silica gel eluting with 10% ethyl acetate in hexanes. The purified product was a clear light yellow oil which was greater than 95% pure by HPLC: nD =1.4649 (25° C.); IR: 2165, 1735, and 1590 cm-1 ; NMR (CDCl3): 4.07 (q, 2H), 2.58 (m, 2H), 2.07 (s, 3H), 1.73 (m, 2H). Elemental analyses calculated for C6H9N5O6 : C, 29.15; H, 3.64; N, 28.34. Found: C, 29.59; H, 3.90; N, 27.89.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=O)[CH:6]=[CH:5]2.S(Cl)([Cl:17])=O>>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([Cl:17])=[O:14])[CH:6]=[CH:5]2
Reactant: O=C(O)c1ccc2cc(F)ccc2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2cc(F)ccc2c1

Procedure:
6-fluoro-2-naphthoic acid (2 g, 10.52 mmol) was stirred in thionyl chloride (21.03 ml) at 80° C. for 4 h in pressure vessel. The mixture was cooled and concentrated. The acid chloride was dried and used as is for next step.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[CH3:26][O:27][C:28]1[C:33]([CH3:34])=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[F:21][C:19]1([F:22])[O:18][C:17]2[CH:23]=[CH:24][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[N:29][C:28]([O:27][CH3:26])=[C:33]([CH3:34])[CH:32]=5)[C:3]([CH3:25])=[CH:4][CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:15][C:16]=2[O:20]1
Reactant: COc1ncc(B2OC(C)(C)C(C)(C)O2)cc1C
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C
Temperature: 80 °C
Yield: 50.7 %

Procedure:
N-(6-Chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (73 mg, 0.20 mmol) was dissolved in 2 mL of 1,2-dimethoxyethane in a reaction tube. 2-Methoxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (65 mg, 0.26 mmol), 0.2 mL of an aqueous 2 M sodium carbonate solution, and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol) were added and the reaction mixture was heated at 80° C. overnight. The reaction was diluted with ethyl acetate (5 mL) and washed with water (5 mL). The organics were dried over sodium sulfate and evaporated to dryness. The resulting residue was purified by silica gel chromatography eluting with 0-100% ethyl acetate in hexane to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6′-methoxy-3,5′-dimethyl-2,3′-bipyridin-6-yl)cyclopropanecarboxamide (46 mg, 51%). ESI-MS m/z calc. 453.4. found 454.3 (M+1)+. Retention time 2.16 minutes.