Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][C@H:9]([C:23]1[N:27]([CH2:28][CH2:29][C:30]#[N:31])[N:26]=[N:25][N:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>C(Cl)Cl>[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35].[NH2:8][C@H:9]([C:23]1[N:27]([CH2:28][CH2:29][C:30]#[N:31])[N:26]=[N:25][N:24]=1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2ccccc2)cc1)c1nnnn1CCC#N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CCCn1nnnc1[C@@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.83 h

Procedure:
(S)-3-[5-(1-t-butoxycarbonylamino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile (9.22 g, 22 mmol) is dissolved in methylene chloride (135 mL) under nitrogen. To the stirred solution is added trifluoroacetic acid (50 mL). After 50 minutes, the solution is concentrated under reduced pressure and the residue is treated with ether (200 mL). The amorphous solid is filtered off, washed with ether and dried under vacuum at 45° for 2 hours, then at room temperature for 18 hours to yield (S)-3-[5-(1-amino-2-biphenyl-4-yl-ethyl)-tetrazol-1-yl]-propionitrile trifluoroacetate salt, m.p. 211°-212°, [α]D =+23.35° (c 1.05, DMSO).
Reaction SMILES: C[CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][C:6](F)(F)[C:7](=[O:13])CP(=O)([O-])[O-].C[O-:18].[Tl+]>ClCCl>[CH:16]12[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:6][C:7](=[O:13])[O:18]2
Reactant: C[O-]
Reactant: CC(C)CCCC(F)(F)C(=O)CP(=O)([O-])[O-]
Agent: [Tl+]
Solvent: ClCCl
Product: O=C1CC2CCCC2O1
Yield: 58 %

Procedure:
The compound (9-a) was reacted with dimethyl-3,3-difluoro-2-oxoheptylphosphonate (30.0 g) in dichloromethane in the presence of thallium methoxide (8.23 ml). The crude product obtained by the conventional treatment of the reaction mixture was purified on silica gel column to give the titled compound (10-a) [yield:24.4 g(58%)].
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][N:3]=1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>O.C(O)C.CO>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]=[N:11][OH:12])=[CH:4][N:3]=1
Reactant: NO
Reactant: Cc1ncc(C=O)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: Cc1ncc(C=NO)cn1

Procedure:
As per scheme-4, 2-methyl-pyrimidine-5-carbaldehyde (4-a) is reacted with hydroxylamine hydrochloride in the presence of base such as sodium carbonate or sodiumbicarbonate or potassium carbonate in a suitable solvent such as methanol or ethanol or water or mixture thereof, at a temperature ranging from 0° C. to 35° C., to provide corresponding 2-methyl-pyrimidine-5-carbaldehyde oxime (4-b).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][C:15]#[N:16])[C:4]([CH3:7])=[CH:5][CH:6]=1.[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].CC(C)([O-])C.[Na+]>C(O)C>[C:15]([CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[N:3]1[C:2]([CH3:1])=[CH:6][CH:5]=[C:4]1[CH3:7])[C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])#[N:16]
Reactant: Cc1ccc(C)n1-c1ccccc1CC#N
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1-n1c(C)ccc1C

Procedure:
2-(2,5-Dimethylpyrrol-1-yl)phenylacetonitrile (15 mmol) and diethyl oxalate (4.38 g, 30 mml) were sequentially added neat washing with ethanol (15 mL) to a solution of sodium tert-butoxide (1.73 g, 18 mmol) in ethanol (15 mL). The reaction mixture was heated at reflux under a nitrogen atmosphere for 4.5 hours to provide a solution of ethyl 3-cyano-3-[2-(2,5-dimethylpyrrol-1-yl)phenyl]-2-oxopropionate in ethanol.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][C@@H:15]([CH3:18])[C@H:14]([OH:19])[CH2:13]3)[C:8]([C:20]#[N:21])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.CS(C)=[O:24]>[OH-].[Na+].OO>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([NH:11][C@@H:12]3[CH2:17][CH2:16][C@@H:15]([CH3:18])[C@H:14]([OH:19])[CH2:13]3)[C:8]([C:20]([NH2:21])=[O:24])=[CH:7][N:6]=2)[CH2:2][CH2:3]1
Reactant: CS(C)=O
Reactant: C[C@@H]1CC[C@@H](Nc2nc(NC3CC3)ncc2C#N)C[C@H]1O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H]1CC[C@@H](Nc2nc(NC3CC3)ncc2C(N)=O)C[C@H]1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
2-(Cyclopropylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carbonitrile (265 mg, 0.922 mmol) was dissolved in DMSO (9.222 mL). To the solution was added 10 drops of 50% aqueous sodium hydroxide followed by 10 drops of 30% aqueous hydrogen peroxide at room temperature. The resulting reaction mixture was stirred at 50° C. for 2 h and was then added slowly to 60 mL of ice water. The resulting precipitate was stirred for 30 min, filtered, and washed with water. The solids were dried in a vacuum oven overnight at 45° C. to afford 2-(cyclopropylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexyl-amino)pyrimidine-5-carboxamide (229 mg, 0.750 mmol, 81% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.73-8.95 (m, 1H), 8.18-8.42 (m, 1H), 7.17-7.37 (m, 1H), 4.39-4.62 (m, 1H), 3.75-3.99 (m, 1H), 2.81-3.06 (m, 1H), 2.53-2.74 (m, 1H), 2.09-2.34 (m, 1H), 1.82-2.05 (m, 1H), 1.50-1.69 (m, 1H), 0.99-1.24 (m, 3H), 0.81-0.98 (m, 4H), 0.50-0.67 (m, 2H), 0.26-0.47 (m, 2H). MS (ESI) m/z 306.3 [M+1]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:46])(=[O:45])[NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([C:16]([OH:18])=O)[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)C(C)C)(C)C.[CH3:56][NH:57][CH2:58][CH2:59][CH2:60][CH3:61].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[CH2:1]([C:5]1[N:6]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34](=[O:45])(=[O:46])[NH:35][C:36](=[O:44])[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])=[CH:24][CH:23]=2)[C:7](=[O:20])[N:8]([C:10]2[CH:15]=[C:14]([C:16](=[O:18])[N:57]([CH2:58][CH2:59][CH2:60][CH3:61])[CH3:56])[CH:13]=[CH:12][C:11]=2[Cl:19])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc(C(=O)O)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCCCNC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCc1nn(-c2cc(C(=O)N(C)CCCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
A solution of 40 mg (0.0589 mmole) of 5-n-butyl-2-(5-carboxy-2-chlorophenyl)-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step A) and 51.3 μL (38.1 mg, 0.295 mmole) of N,N-diisopropylethylamine in 1 mL of CH2Cl2 and 0.3 μL of DMF was stirred at 0° C. under protection from moisture as 27.9 mL (20.5 mg, 0.236 mmole) of N-methylbutylamine was added, followed by 52.1 mg (0.118 mmole) of BOP reagent. The solution was stirred at 0° C. overnight and then concentrated. The residue was reconcentrated twice from toluene. It was then taken up in CH2Cl2 and washed successively twice with 5% citric acid (aqueous), twice with 5% NaHCO3 (aqueous), and then with brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was flash chromatographed on silica gel (gradient elution with 1-5% MeOH in CH2Cl2) and then further purified by HPLC on a semi-preparative Zorbax C8 reverse phase column (elution with 60:40 acetonitrile-H2O) to give a 36% yield of the title compound as a colorless, glassy solid, mp >90° C. (gradual); mass spectrum (FAB) m/e 748 (M+1)+. By NMR the material appeared to exist as a mixture of amide rotamers in a ratio of approximately 1:1.
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C1C(=O)N([I:30])C(=O)C1>>[F:1][C:2]1[C:7]2[N:8]=[N:9][S:10][C:6]=2[CH:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[C:3]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([I:30])=[CH:18][C:17]=1[F:22]
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1cc2snnc2c(F)c1Nc1ccccc1F
Product: COC(=O)c1cc2snnc2c(F)c1Nc1ccc(I)cc1F

Procedure:
Methyl 4-fluoro-5-((2-fluorophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate can be reacted with halogenations reagent (such as NIS) in the presence of acid at ambient temperature in appropriate solvent. The reaction normally completes within several hours (1-12 h, prefer 3-10 h). Methyl 4-fluoro-5-((2-fluoro-4-iodophenyl)amino)benzo[d][1,2,3]thiadiazole-6-carboxylate is obtained after conventional workup.
Reaction SMILES: [C:1]1([C:7]2[CH:21]=[CH:20][C:10]3[N:11]=[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[S:13][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1CCN2C(=NCCC2)CC1.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>CN(C=O)C.O>[CH3:33][S:34]([CH:14]([C:12]1[S:13][C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:21]=[CH:20][C:10]=2[N:11]=1)[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:36])=[O:35]
Reactant: CCOC(=O)Cc1nc2ccc(-c3ccccc3)cc2s1
Reactant: CS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: CCOC(=O)C(c1nc2ccc(-c3ccccc3)cc2s1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73.8 %

Procedure:
To a solution of ethyl 2-(6-phenylbenzo[d]thiazol-2-yl)acetate (390 mg, 1.3 mmol) (described in WO 2011/074560) in DMF (4 mL) at 0° C. was added DBU (0.49 mL, 3.3 mmol) and the reaction mixture was stirred at rt for 10 min. Methanesulfonyl chloride (0.12 mL, 1.6 mmol) was added dropwise and the mixture stirred for 0.5 h. Additional methanesulfonyl chloride (0.030 mL, 0.40 mmol) was added and the reaction mixture stirred for 10 min. The reaction mixture was diluted with H2O then extracted with EtOAc (3×), dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0 to 100% EtOAc/hexane to give Compound 89a (360 mg, 73% yield) as yellow powder. RT=2.06 min using analytical method (Q), 376.9 (M+H). 1H NMR (500 MHz, CDCl3) δ 7.88-7.75 (m, 1H), 7.68-7.53 (m, 3H), 7.53-7.34 (m, 5H), 4.42 (qd, J=7.2, 3.0 Hz, 2H), 3.39-3.21 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:12]=1)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].Cl[C:20]1[C:29]2[C:24](=[CH:25][C:26]([F:30])=[CH:27][CH:28]=2)[N:23]=[C:22]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[C:21]=1[CH3:37].CC(C)([O-])C.[Na+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([NH:1][C:2]3[CH:3]=[C:4]([CH:10]=[C:11]([N:13]4[CH2:14][CH2:15][O:16][CH2:17][CH2:18]4)[CH:12]=3)[C:5]([N:7]([CH3:9])[CH3:8])=[O:6])=[C:21]([CH3:37])[C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[N:23]2)=[CH:28][CH:27]=1
Reactant: CN(C)C(=O)c1cc(N)cc(N2CCOCC2)c1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Nc1cc(C(=O)N(C)C)cc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure Y using 3-amino-N,N-dimethyl-5-morpholinobenzamide (0.046 g, 0.183 mmol), 4-chloro-7-fluoro-3-methyl-2-(pyridin-2-yl)-quinoline (0.050 g, 0.183 mmol), sodium tert-butoxide (0.035 g, 0.367 mmol), XPhos (8.7 mg, 0.018 mmol), XPhos precatalyst (CAS 1028206-56-5; 0.012 g, 0.018 mmol), and toluene (1.0 mL) to afford 3-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)amino)-N,N-dimethyl-5-(4-morpholinyl)benzamide as a yellow amorphous solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.66-8.71 (1H, m), 8.60 (1H, s), 8.09 (1H, dd, J=9.4, 6.3 Hz), 7.99 (1H, td, J=7.7, 1.8 Hz), 7.87 (1H, dt, J=7.8, 1.2 Hz), 7.71-7.77 (1H, m), 7.45-7.52 (2H, m), 6.41-6.46 (1H, m), 6.35-6.41 (1H, m), 5.95-5.98 (1H, m), 3.68-3.73 (4H, m), 3.04-3.11 (4H, m), 2.82-2.91 (6H, m), 2.21 (3H, s). Mass Spectrum (ESI) m/e=486.2 (M+1).
Reaction SMILES: [C:1]1([C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([CH3:13])[C:8]([N:10]=[C:11]=[O:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:20]([OH:22])[CH3:21]>>[CH2:20]([O:22][C:11](=[O:12])[NH:10][C:8](=[O:9])[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:13])[CH3:21]
Reactant: CCO
Reactant: CC(C(=O)N=C=O)(c1ccccc1)c1ccccc1
Product: CCOC(=O)NC(=O)C(C)(c1ccccc1)c1ccccc1

Procedure:
The title compound, colorless gum, MS: m/e=297.4 (M+H+) was prepared in accordance with the general method of example 1 from crude 2,2-diphenylpropionyl isocyanate and ethanol.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[CH:7]=[CH:8][N:9]([CH:16]([CH3:18])[CH3:17])[C:10]=2[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1)=[O:4].O[Li].O>C1COCC1.O>[CH:16]([N:9]1[C:10]2[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=[C:5]([C:3]([OH:4])=[O:2])[C:6]=2[CH:7]=[CH:8]1)([CH3:18])[CH3:17]
Reactant: COC(=O)c1cc(OC)cc2c1ccn2C(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Yield: 69.8 %

Procedure:
To a stirred solution of 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid methyl ester (320 mg, 1.29 mmol) in THF (2 mL) was added LiOH.H2O (160 mg, 3.88 mmol) in water (2 mL) at room temperature and heated at reflux for 2 h. The THF was removed under reduced pressure and the resulting aqueous layer was acidified with 1N HCl (pH 6) and extracted with ethyl acetate (2×5 mL). The combined organic layer was dried over anhydrous Na2SO4 and concentrated to afford 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (210 mg). 1H NMR (400 MHz, DMSO-d6): δ 1.42 (d, 6H), 3.88 (s, 3H), 4.85 (m, 1H), 6.81 (d, J=2.8 Hz, 1H), 7.26 (s, 2H), 7.45 (s, 1H), 12.68 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[CH:4][CH:3]=1.[CH2:10]([C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([S:21]([NH:24][CH3:25])(=[O:23])=[O:22])=[C:14]([NH:26][CH2:27][CH2:28][CH3:29])[C:13]=1[N+:30]([O-:32])=[O:31])[CH3:11].N1C=CC=CC=1>ClCCl>[CH2:10]([C:12]1[C:17]([N+:18]([O-:20])=[O:19])=[CH:16][C:15]([S:21]([N:24]([S:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:25])(=[O:23])=[O:22])=[C:14]([NH:26][CH2:27][CH2:28][CH3:29])[C:13]=1[N+:30]([O-:32])=[O:31])[CH3:11]
Reactant: ClSc1ccc(Cl)cc1
Reactant: CCCNc1c(S(=O)(=O)NC)cc([N+](=O)[O-])c(CC)c1[N+](=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCNc1c(S(=O)(=O)N(C)Sc2ccc(Cl)cc2)cc([N+](=O)[O-])c(CC)c1[N+](=O)[O-]
Reaction time: 0.33 h

Procedure:
A 2.2 g (0.012 mol) sample of p-chlorophenylsulfenyl chloride was added dropwise to a cooled (-5° C. to 0° C.) solution of 3.5 g (0.1 mol) 4-ethylpropylamino-N-methyl-3,5-dinitrobenzenesulfonamide and 1.1 g (0.014 mol) pyridine in 25 ml dichloromethane. The reaction was stirred for 20 minutes and then diluted with 50 ml dichloromethane, washed with water, washed with aqueous sodium bicarbonate solution, and dried over magnesium sulfate. The dichloromethane was then evaporated under reduced pressure to give a solid residue. Recrystallization from ethanol gave the product as red-orange plates, m.p. 89°-91° C. Elemental analysis for C18H21ClN4O6S2 showed: % S, calc. 13.1, found 13.3; % Cl, calc. 7.3, found 7.8.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][CH:9]=2)[N:3]=1.C(Cl)(=O)C([Cl:20])=O>ClCCl.CN(C)C=O>[CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([Cl:20])=[O:13])=[CH:10][CH:9]=2)[N:3]=1
Reactant: Cc1cc(C)n(-c2ccc(C(=O)O)cc2)n1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C)n(-c2ccc(C(=O)Cl)cc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55 %

Procedure:
To a suspension of 4-(3,5-dimethylpyrazol-1-yl)benzoic acid (1.34 g) in dichloromethane (25 ml) was added oxalyl chloride (1.0 g) and one drop of dimethylformamide. The mixture was stirred at room temperature for 18 hours and the volatile material was removed under reduced pressure. The residue was dissolved in hexane and filtered through diatomaceous earth. Evaporation of the solvent in vacuo yielded 4-(3,5-dimethylpyrazol-1-yl)benzoyl chloride (0.80 g), which was used without further purification.
Reaction SMILES: Cl([O-])=O.[Na+].[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[CH:9]=[O:10].P([O-])(O)(O)=[O:19].[Na+].C([O-])(O)=O.[Na+]>O.CS(C)=O.O>[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[C:9]([OH:19])=[O:10]
Reactant: O=P([O-])(O)O
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1cc(O)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of sodium chlorite (47.6 g, 526 mmol) in water (350 mL) was added drop wise to a solution of 3,4-dihydroxy-5-nitrobenzaldehyde (68.8 g, 376 mmol) and sodium dihydrogen phosphate (45.1 g, 376 mmol) in DMSO/H2O mixture (375 mL/150 mL) at room temperature for 1.5 h. The reaction mixture was stirred at room temperature for 1 h and poured into a separatory funnel containing a 5% solution NaHCO3 (500 mL). The product was extracted with dichloromethane (3×100 mL). The water layer was acidified with concentrated HCl to pH˜1 and extracted with ether (3×250 mL). The combined organic layers were washed with brine (200 mL), dried over Na2SO4, and evaporated to afford the desired acid (70.3 g, 353 mmol, 94% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:17][CH3:18])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:15][CH3:16])([OH:14])[CH2:12][CH3:13])[S:5][CH:6]=1.CN(C1C=CC=CN=1)C.C(N(CC)CC)C.FC(F)(F)S(O[Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])(=O)=O>ClCCl.O>[Br:1][C:2]1[CH:3]=[C:4](/[C:7](/[CH2:17][CH3:18])=[CH:8]/[CH2:9][CH2:10][C:11]([CH2:15][CH3:16])([CH2:12][CH3:13])[O:14][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[S:5][CH:6]=1
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC/C(=C\CCC(O)(CC)CC)c1cc(Br)cs1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC/C(=C\CCC(CC)(CC)O[Si](CC)(CC)CC)c1cc(Br)cs1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
11.8 g (35.6 mmol) of (E)-7-(4-bromo-2-thienyl)-3-ethylnon-6-en-3-ol are dissolved in 150 mL of dichloromethane. 130 mg (1.1 mmol) of dimethylaminopyridine and 14.9 mL (107 mmol) of triethylamine are added. The reaction medium is cooled to 0° C. and 12.1 mL (53.4 mmol) of triethylsilyl trifluoromethanesulphonate are added dropwise. The medium is warmed to room temperature and stirred for 15 minutes, after which it is poured into 150 mL of water and extracted with dichloromethane. After chromatography on silica gel (eluent: heptane), the desired product is obtained in the form of a colourless oil (m=15 g; Y=100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#N)=[CH:4][N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.CO.S(=O)(=O)(O)[OH:23]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:23])=[CH:4][N:3]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: CO
Solvent: Cc1ccccc1
Product: O=Cc1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cooled 5° C., stirred solution of 2-chloro-5-cyanopyridine (25.0 grams) in anhydrous toluene (540 mL) was added a 1M solution of diisobutylaluminum hydride (189 mL) over a 30 minute period. The resulting red-colored solution was treated with methanol (50 mL) and 2M sulfuric acid (150 mL), sequentially. The resulting biphasic solution was allowed to warm to ambient temperature and stirred for 1 hour. The reaction mixture was extracted with ethyl acetate, the combined organic layers were washed with saturated aqueous sodium bicarbonate and saturated aqueous brine. The organic phase was stirred over activated charcoal for 20 minutes, dried over anhydrous sulfate and concentrated in vacuo to afford the title compound as a light-yellow colored solid, 23.5 grams 1H NMR (400 MHz, CDCl3) δ=10.08 (s, 1H); 8.85 (s, 1H); 8.12 (d, 1H); 7.50 (d, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[O:6][CH:5]([CH2:7][O:8][CH2:9][CH2:10][C:11]2[C:16]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([F:27])[CH:20]=3)[OH:18])=[C:15]([O:28][CH2:29][O:30][CH3:31])[CH:14]=[C:13]([O:32][CH2:33][O:34][CH3:35])[C:12]=2[CH2:36][CH3:37])[CH2:4][O:3]1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>ClCCl.C(OCC)C>[F:27][C:21]1[CH:20]=[C:19]([C:17]([C:16]2[C:11]([CH2:10][CH2:9][O:8][CH2:7][CH:5]3[CH2:4][O:3][C:2]([CH3:1])([CH3:38])[O:6]3)=[C:12]([CH2:36][CH3:37])[C:13]([O:32][CH2:33][O:34][CH3:35])=[CH:14][C:15]=2[O:28][CH2:29][O:30][CH3:31])=[O:18])[CH:24]=[CH:23][C:22]=1[O:25][CH3:26]
Reactant: CCc1c(OCOC)cc(OCOC)c(C(O)c2ccc(OC)c(F)c2)c1CCOCC1COC(C)(C)O1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCc1c(OCOC)cc(OCOC)c(C(=O)c2ccc(OC)c(F)c2)c1CCOCC1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
2-Bromo-3-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-4-ethyl-1,5-bis(methoxymethoxy)benzene (390 mg, 0.84 mmol) obtained in the step 3 in Example 173 was dissolved in tetrahydrofuran (10 mL), and with stirring at −78° C., tetrahydrofuran solution of 1.5 mol/L n-butyllithium (1.0 mL, 1.5 mmol) was dropwise added thereto. The resulting mixture was stirred at −78° C. for 30 minutes, then 2-fluoro-4-methoxybenzaldehyde (130 mg, 0.8 mmol) was dropwise added thereto and further stirred for 30 minutes. Aqueous saturated ammonium chloride solution was added to the reaction mixture, and extracted twice with ethyl acetate. The organic layers were combined, washed with aqueous saturated sodium chloride solution, then dried over anhydrous sodium sulfate, and the solvent was evaporated away to obtain 1-(6-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5-ethyl-2,4-bis(methoxymethoxy)phenyl)-1-(3-fluoro-4-methoxyphenyl)methanol. Thus obtained, 1-(6-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5-ethyl-2,4-bis(methoxymethoxy)phenyl)-1-(3-fluoro-4-methoxyphenyl)methanol was dissolved in dichloromethane (10 mL), and pyridinium dichromate (160 m, 0.43 mmol) was added thereto and stirred at room temperature for 8 hours. The reaction mixture was diluted with diethyl ether, filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (ethyl acetate/hexane=1/4 to 1/1) to obtain 6-{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethyl}-5-ethyl-2,4-bis(methoxymethoxy)phenyl 3-fluoro-4-methoxyphenyl ketone (210 mg, 46%).