Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][NH:3]1.CN(C)C=O.F[C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25]>O>[N+:24]([C:15]1[CH:16]=[C:17]([C:20]([F:21])([F:22])[F:23])[CH:18]=[CH:19][C:14]=1[N:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C@@H:2]1[CH3:1])([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: C[C@H]1CCCCN1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H]1CCCCN1c1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 99.2 %

Procedure:
(S)-2-methylpiperidine (270 μl, 2.24 mmol, commercially available product) was added at room temperature to an N,N-dimethylformamide (DMF; 0.5 ml) solution of 1-fluoro-2-nitro-4-(trifluoromethyl)benzene (211 mg, 1.00 mmol, commercially available product). The resulting mixture was stirred for two hours. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (20 g, hexane/ethyl acetate=12/1). Thus, (S)-1-[2-nitro-4-(trifluoromethyl)phenyl]-2-methylpiperidine (286 mg, 99.2%) was yielded as an orange-colored oily material.
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Cl:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([N:9]([O:10][CH3:11])[CH3:8])=[O:18])=[CH:15][CH:14]=1
Reactant: CNOC
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Pyridine (27.6 mL, 343 mmol) was added to N,O-dimethylhydroxylamine hydrochloride (16.7 g, 172 mmol) in DCM (400 mL). 4-Chlorobenzoyl chloride (20 mL, 156 mmol) was then added and the mixture was stirred at room temperature for 3 days. Solids were removed by vacuum filtration, washing with DCM. The filtrate was washed with 1 N HCl followed by water. The organic phase was dried (Na2SO4), filtered, and concentrated, affording the crude title compound as a colorless liquid which was used without purification in the next step.
Reaction SMILES: [C:1](=[N:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH3:23])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:24]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:1](=[N:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[CH2:23][Br:24])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1cc(C#N)ccc1N=C(c1ccccc1)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(N=C(c2ccccc2)c2ccccc2)c(CBr)c1
Yield: 56.9 %

Procedure:
To a solution of 4-(benzhydrylidene-amino)-3-methyl-benzonitrile (1.36 g, 4.27 mmol) in 40 mL of CCl4 is added N-bromosuccinimide (0.84 g, 4.7 mmol) and benzoyl peroxide (0.22 g, 0.64 mmol). The solution is heated to reflux for 16 h. The solution is cooled to ambient temperatures. The solution is diluted with CH2Cl2. The solution is washed with 1N NaOH and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude material is purified by column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes. The title compound (0.91 g, 2.43 mmol) is obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][NH2:27])(=[O:23])=[O:22]>CO.C(O)C.[Pd]>[CH3:19][N:20]([CH3:28])[S:21]([CH2:24][CH2:25][CH2:26][NH:27][CH2:11][C:9]1[S:10][C:5]2[C:4]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1)(=[O:23])=[O:22]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CN(C)S(=O)(=O)CCCN
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CN(C)S(=O)(=O)CCCNCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde (280 mg) in methanol (10 mL) was added 3-amino-propane-1-sulfonic acid dimethylamide (284 mg) and the reaction stirred at room temperature for 16 h. The solvent was reduced in vacuo and the residue redissolved in ethanol (50 mL). Palladium on carbon (20 mg) was added and the reaction stirred at room temperature under a hydrogen balloon for 48 h. The reaction was then filtered through Celite and the filtrate reduced in vacuo to give 3-[(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-amino]-propane-1-sulfonic acid dimethylamide as a yellow solid.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[C:27]([CH3:28])=[CH:26][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20])=[C:8]([CH3:29])[CH:7]=1)\[CH2:4][CH3:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:36](Br)[CH2:37][CH3:38]>C(#N)C.O>[CH3:29][C:8]1[CH:7]=[C:6](/[C:3](=[N:2]/[O:1][CH2:36][CH2:37][CH3:38])/[CH2:4][CH3:5])[C:27]([CH3:28])=[CH:26][C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1/[C:18](=[CH:23]\[O:24][CH3:25])/[C:19]([O:21][CH3:22])=[O:20]
Reactant: CC/C(=N\O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CCCO/N=C(\CC)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
To a solution of 0.12 g (0.3 mmol) of (E)-methyl 2-(2-((4-((E)-1-(hydroxyimino)propyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 4 and 0.2 g (0.61 mmol) of cesium carbonate in 10 mL of acetonitrile (CH3CN) was added propyl bromide (0.05 mL, 0.55 mmol), followed by stirring at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure and the residue thus obtained was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate and concentrated in a vacuum and the concentrate was purified by silica gel chromatography to afford 0.1 g of (E)-methyl 2-(2-((2,5-dimethyl-4-((E)-1-(propoxyimino)propyl)phenoxy)-methyl)phenyl)-3-methoxyacrylate as a white oil (yield: 77%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:4][CH:3]=1.[Na+].[I-:18].[OH-].[Na+]>CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[C:10]([CH3:16])[CH:9]=2)=[CH:6][C:7]=1[I:18]
Reactant: [I-]
Reactant: Cc1cc(-c2ccc(O)cc2)ccc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-c2ccc(O)c(I)c2)ccc1C#N
Temperature: 0 °C
Reaction time: 1.33 h
Yield: 52 %

Procedure:
The product from Example 106B (4.67 g, 22.3 mmol), NaI (3.343 g, 22.3 mmol), and NaOH (892 mg, 22.3 mmol) were combined in methanol (70 mL) at 0° C. and treated with bleach (5.25%, 31.6 g) dropwise over 30 minutes. After being stirred at 0° C. for 80 minutes, the mixture was quenched with 10% aqueous sodium thiosulfate (10 mL). The mixture was acidified with 1M aqueous HCl (25 mL), neutralized with dipotassium hydrogen phosphate, recooled to 0° C., and filtered. The solids were rinsed with water, then mostly dissolved in 50% EtOAc/hexanes and filtered. When this filtrate was mostly concentrated crystals began to form. The solids were slurried with 20% EtOAc/hexanes, collected by filtration, and washed with 10% EtOAc/hexanes followed by hexanes to provide the impure title compound as a light tan powder (52% yield). MS (ESI APCI negative ion detection) m/z 334 (M−H)−; 1HNMR (300 MHz, d6-DMSO) δ 2.52 (s, 3H), 6.98 (d, 1H), 7.58-7.63 (m, 2H), 7.73 (s, 1H), 7.78 (d, 1H), 8.06 (d, 1H), 10.66 (s, 1H).
Reaction SMILES: N1C=CC=CC=1.CS(O)(=O)=O.[CH:12]1([C:18]2[C:26]3[C:25](=[O:27])[NH:24][C:23]([C:28]4[CH:33]=[CH:32][C:31](N5CCC(O)CC5)=[CH:30][C:29]=4OC)=[N:22][C:21]=3[N:20]([CH3:43])[N:19]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[Br:44]C1C=CC(C(Cl)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:44][C:31]1[CH:32]=[CH:33][C:28]([C:23]2[NH:24][C:25](=[O:27])[C:26]3[C:18]([CH:12]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[N:19][N:20]([CH3:43])[C:21]=3[N:22]=2)=[CH:29][CH:30]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: COc1cc(N2CCC(O)CC2)ccc1-c1nc2c(c(C3CCCCC3)nn2C)c(=O)[nH]1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cn1nc(C2CCCCC2)c2c(=O)[nH]c(-c3ccc(Br)cc3)nc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
To a 30 ml pyridine solution of 2.2 g (10 mmol) of the compound obtained in Example 32, 2.8 g (13 mmol) of p-bromobenzoyl chloride was added, and the mixture was stirred at room temperature for 3 hours. Further, 1.0 g (4.5 mmol) of p-bromobenzoyl chloride was added, and the mixture was stirred at room temperature for 4 hours. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, followed by distilling off the solvent under reduced pressure. To the residue, 80 ml of ethanol and 40 ml of a 1M aqueous solution of sodium hydroxide were added, and the mixture was heated under reflux for 8 hours. Then, the reaction mixture was cooled to room temperature, and acetic acid was added. Precipitated solids were collected by filtration, the solids obtained were dissolved in chloroform, and the solution was washed with sodium hydrogen carbonate, water and a saturated aqueous solution of sodium chloride in this order. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was recrystallized (ethanol) to obtain 590 mg (15%) of the captioned compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[N+:13]([C:11]1[C:2](=[O:1])[NH:3][C:4]2[C:9]([C:10]=1[OH:12])=[CH:8][CH:7]=[CH:6][CH:5]=2)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Oc1cc(O)c2ccccc2n1
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]c2ccccc2c(O)c1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
To a mixture of 1.45 g (9.00 mmol) of 2,4-dihydroxyquinoline (Aldrich) in 10 mL of glacial acetic acid was added 2.5 mL of HNO3 (69-71%). The mixture was heated at 90° C. for 5 min to become a red solution, then a precipitate was observed in the solution. The mixture was cooled to room temperature, then was added 40 mL of water and the mixture was stirred for 20 min. The mixture was filtered and washed with water, dried to leave 1.54 g (83%) of title compound as a yellow solid, mp 216° C. (decomposed, lit: Buckle, D. R., et al., J. Med. Chem. 18:726-732 (1975), 216° C.). 1H NMR (CDCl3 +DMSO-d6), 7.013 (t, 1, J=7.5), 7.105 (d, 1, J=7.5), 7.396 (t, 1, J=7.2), 7.877 (d, 1, 7.8), 11.72 (mb 1).
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([O:13][CH3:14])[CH:7]=1)C>CO.O>[OH:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4]([OH:15])=[O:3])=[CH:7][C:8]=1[O:13][CH3:14]
Reactant: CCOC(=O)Cc1ccc(O)c(OC)c1
Solvent: CO
Solvent: O
Product: COc1cc(CC(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 14 h
Yield: 96.4 %

Procedure:
A mixture of (4-hydroxy-3-methoxy-phenyl)-acetic acid ethyl ester (2 g, 9.51 mmol) and LiOH monohydrate (1.2 g, 28.5 mmol) in MeOH (20 ml) and water (10 ml) was stirred at RT for 14 h. The reaction mixture was concentrated under vacuum, diluted into water and neutralized by the addition of HCl 2 M in water (14.3 ml). The resulting slurry was extracted with DCM (3×) and AcOEt (2×) and the combined organic fractions were dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (1.67 g, 9.17 mmol, 96%) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=0.77 min; LC-MS: m/z 183.4 [M+H]+; NMR (400 MHz, DMSO-d6): 3.43 (s, 2H), 3.74 (s, 3H), 6.61-6.66 (m, J=8.1, 2.0, 1H), 6.67-6.72 (m, 1H), 6.81 (d, J=2.0, 1H), 8.81 (s, 1H), 12.17 (s, 1H).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:8]=[C:9]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:10][Si](C(C)C)(C(C)C)C(C)C.CN([CH:28]=[O:29])C.Cl>CCCCCC.C1COCC1>[Cl:24][C:22]1[CH:21]=[C:9]([OH:10])[CH:8]=[C:7]([Cl:6])[C:23]=1[CH:28]=[O:29]
Reactant: CC(C)[Si](Oc1cc(Cl)cc(Cl)c1)(C(C)C)C(C)C
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1c(Cl)cc(O)cc1Cl
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
A solution of 2.50 M n-butyllithium in hexane (13.3 mL) was added to a stirred solution of (3,5-dichlorophenoxy)(triisopropyl)silane (10.1 g, 31.6 mmol) in THF (40 mL) under an atmosphere of nitrogen at −78° C. After stirring for 45 min at −78° C., DMF (5 mL) was added slowly. The mixture was allowed to warm to −10° C. After hydrolysis with 2 N HCl, the layers were separated and the aqueous layer separated and extracted with ethyl acetate twice. The combined organic solutions were dried over Na2SO4, filtered and concentrated. To the residue was added hexane (30 mL) and the precipitate was filtered and washed with hexane to give the desired product as a white precipitate. (5.50 g, 91%). LCMS for C7H5Cl2O2(M+H)+: m/z=191.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:5]([C:18]([O:20]CC)=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2>C(O)C.O>[OH:3][C:4]1[C:5]([C:18]([OH:20])=[O:19])=[N:6][C:7]2[C:12]([N:13]=1)=[CH:11][C:10]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:9][CH:8]=2
Reactant: CCOC(=O)c1nc2ccc(S(C)(=O)=O)cc2nc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)c1ccc2nc(C(=O)O)c(O)nc2c1

Procedure:
Potassium hydroxide (1.0 mL, 1.8 mmol, 1.0 N solution) was added to a suspension of ethyl 3-hydroxy-6-(methylsulfonyl)quinoxaline-2-carboxylate (249 mg, 0.84 mmol) in ethanol (30 mL) and the resulting mixture was heated at reflux for 2 h. The cooled mixture was diluted with water (10 mL), acidified to pH 1 and the resulting solids were collected by filtration under reduced pressure to provide 3-hydroxy-6-(methylsulfonyl)quinoxaline-2-carboxylic acid as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.6 Hz, 1H), 7.87-7.84 (m, 2H), 3.31 (s, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:11][CH3:12])[NH:10][C:5]2=[C:4]([CH3:13])[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:8]1[C:6]2=[N:7][C:2]([Br:1])=[CH:3][C:4]([CH3:13])=[C:5]2[N:10]=[C:9]1[CH2:11][CH3:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CCc1nc2nc(Br)cc(C)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc2c(C)cc(Br)nc2n1Cc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-2-ethyl-7-methylimidazo[4,5-b]pyridine (10 g, 39 mmol) in DMF (70 mL) at room temperature was added NaH (1.3 g of an 80% dispersion, 43 mmol). After 20 min benzyl bromide (5.15 mL, 43 mmol) was added and the reaction was stirred for 16 h. The mixture was poured onto 500 g of ice and the solid residue was filtered, washed with water and air dried to afford 3-benzyl-5-bromo-2-ethyl-7-methylimidazo[4,5-b]pyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:14])[F:13].I[C:20]1[CH:25]=[CH:24][C:23]([S:26]([N:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)(=[O:28])=[O:27])=[CH:22][CH:21]=1.C[O-].[Na+]>CC(N(C)C)=O.[Cu]Cl>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:20]2[CH:25]=[CH:24][C:23]([S:26]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:18])[C@:11]([OH:17])([CH3:16])[C:12]([F:15])([F:13])[F:14]
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)cc1Cl)C(F)(F)F
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCCC1
Agent: Cl[Cu]
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccc(S(=O)(=O)N3CCCC3)cc2)cc1Cl)C(F)(F)F
Temperature: 150 °C
Reaction time: 4 h
Yield: 44.9 %

Procedure:
Copper(I) chloride (0.038 g) was added to a mixture of (R)-N-(2-chloro-4-mercaptophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 210) (0.21 g), N-(4-iodobenzenesulphonyl)pyrrolidine (0.258 g) and sodium methoxide (0.042 g) in DMA (5 ml). The mixture was heated at 150° C. with stirring for 4 hours then cooled and the DMA removed by evaporation. Ethyl acetate (20 ml) and water (20 ml) was added and the mixture was filtered. The aqueous layer was extracted with ethyl acetate (3×20 ml) and the organic layers were combined and dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column, eluting with methanol/DCM 0-10% to give the title compound (0.16 g) as a solid. NMR (CDCl3): 1.75 (s, 3H), 1.75-1.85 (m, 4H), 3.2-3.3 (m, 4H), 4.0 (s, 1H), 7.2-7.3 (m, 2H), 7.4-7.45 (m, 1H), 7.6 (s, 1H), 7.7 (d, 2H), 8.45 (d, 1H), 9.15 (s, 1H); MS (ESP−): 507.
Reaction SMILES: [O:1]([C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH2:17]([S:19][CH2:20][CH2:21][NH2:22])[CH3:18]>>[CH2:17]([S:19][CH2:20][CH2:21][NH:22][CH2:12][C:11]1[CH:14]=[CH:15][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][CH:10]=1)[CH3:18]
Reactant: CCSCCN
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Agent: Cl
Product: CCSCCNCc1ccc(Oc2ccccc2)cc1
Yield: 94.6 %

Procedure:
Following the procedure described in Example 68A, 4-phenoxybenzaldehyde (1.98 g, 10 mmol) and 2-(ethylthio)ethylamine hydrogen chloride (1.42 g, 10 mmol) were combined to give the title compound (2.72 g, 95%). 1H NMR (300 MHz, CDCl3), δ 7.33 (m, 4 H), 7.09 (t, 1 H), 6.98 (m, 4 H), 3.78 (s, 2 H), 2.84 (t, 2 H), 2.71 (t, 2 H), 2.54 (q, 2 H), 1.26 (t, 3 H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:19](=[O:21])[CH3:20])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc(O)cc1
Reactant: CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(OC(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4-isopropoxy-phenol (800 mg, 5.26 mmol, 1.0 eq.) and triethylamine (1.47 mL, 10.5 mmol, 2.0 eq.) in DCM (22 mL), acetyl chloride (0.45 mL, 6.36 mmol, 1.2 eq.) was added dropwise. The reaction mixture was stirred at r.t. for 4 days. Sat. aq. NaHCO3 soln. was added and the layers were separated. The org. phase was dried over MgSO4, filtered, and concentrated in vacuo to give acetic acid 4-isopropoxy-phenyl ester as a yellow oil. The product was used without further purification.
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[S:7][C:8]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([C:21]4[C:22]([C:45]5[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=5)=[N:23][N:24]([C:26]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:25]=4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)=[CH:9][CH:10]=1)(=[O:5])=[O:4].[H-].[Na+].[CH3:54][O:55][C:56]1[CH:65]=[CH:64][C:59]([C:60](=[O:63])[CH2:61]Br)=[CH:58][CH:57]=1.O>CN(C)C=O>[CH3:54][O:55][C:56]1[CH:65]=[CH:64][C:59]([C:60](=[O:63])[CH2:61][N:2]([CH3:1])[S:3]([C:6]2[S:7][C:8]([C:11]3[C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:21]5[C:22]([C:45]6[CH:46]=[CH:47][C:48]([F:51])=[CH:49][CH:50]=6)=[N:23][N:24]([C:26]([C:39]6[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=6)([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)[C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=6)[CH:25]=5)[CH:19]=4)[N:14]=[CH:13][N:12]=3)=[CH:9][CH:10]=2)(=[O:5])=[O:4])=[CH:58][CH:57]=1
Reactant: CNS(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)CN(C)S(=O)(=O)c2ccc(-c3ncnc4ccc(-c5cn(C(c6ccccc6)(c6ccccc6)c6ccccc6)nc5-c5ccc(F)cc5)cc34)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
50 mg 5-{6-[3-(4-fluorophenyl)-1-trityl-1H-pyrazol-4-yl]quinazolin-4-yl}thiophen-2-sulfonic acid methylamide (compound in Example 745) was dissolved in 3 mL N,N-dimethylformamide, then 3.1 mg sodium hydride was added thereto and stirred at room temperature for 0.5 hour. Under ice-cooling, a solution of 18 mg 4-methoxyphenacyl bromide in 2 mL N,N-dimethylformamide was added thereto and stirred for 1.0 hour under ice-cooling. Water was added to the reaction solution which was then extracted with ethyl acetate, and the organic layer was washed with brine and dried over sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 47 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:13][CH:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:34](F)(F)C(O)=O>O.C(OCC)(=O)C>[CH3:34][C:10]1([O:13][C@@H:14]([CH2:24][O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@@H:9]1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:11]
Reactant: COC1O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(O)O[C@@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
Methyl 2,3,5-tri-O-benzyl-L-xylofuranoside (22.7 g, 56.30 mmol) is dissolved at 0° C. in a 9:1 mixture of trifluoroacetic acid and water (200 mL) and stirred at 0° C. overnight. The mixture is put to dryness under reduced pressure. The oily residue is dissolved in ethyl acetate and washed three times with a saturated solution of sodium bicarbonate. The organic layer is dried over sodium sulfate, filtered and put to dryness under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 7:3 mixture of cyclohexane and ethyl acetate yield methyl 2,3,5-tri-O-benzyl-L-xylofuranose as an oil (11.7 g, 53%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:13]([O-])=O.[NH4+].[Cl-]>C1COCC1>[Cl:12][C:11]1[C:6]([Cl:5])=[C:7]2[C:8]([CH:1]=[CH:2][NH:13]2)=[CH:9][CH:10]=1
Reactant: C=C[Mg]Br
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Clc1ccc2cc[nH]c2c1Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
800 ml of a 1M solution of vinylmagnesium bromide in THF are cooled to −45° C. under a nitrogen atmosphere, a solution of 51.2 g of 2,3-dichloronitrobenzene in 1000 ml of THF is then added dropwise and the mixture is left stirring at −30° C. for 1 hour. The reaction mixture is poured onto 1000 ml of a saturated NH4Cl solution and extracted with ether, the combined organic phases are washed with water and with a saturated NaCl solution and dried over MgSO4, and the solvents are evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a cyclohexane/EtOAc mixture (95/5; v/v). 27.75 g of the expected compound are obtained.