Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16](Cl)=[O:17].S(=O)(=O)(O)O>C(O)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[Br:13][C:14]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:17]
Reactant: O=C(Cl)c1cc(F)c(F)cc1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 108.2 %

Procedure:
Magnesium ribbon (7.3 g) is suspended in absolute ethanol (15 ml), and thereto is added carbon tetrachloride (1.5 ml), and thereto is added dropwise a mixture of diethyl malonate (48 g), absolute ethanol (30 ml) and anhydrous ether (120 ml) over a period of one hour. After the addition, the mixture is refluxed for 2 hours. After cooling till room temperature, a solution of 2-bromo-4,5-difluorobenzoyl chloride (92 g) in anhydrous ether (50 ml) is added dropwise to the mixture. After the addition, the mixture is allowed to stand overnight at room temperature. A mixture of ice-water (120 ml) and conc. sulfuric acid (8 ml) is added dropwise to the reaction mixture under ice-cooling. After the addition, the mixture is extracted with ether. The ether layer is washed with saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent is distilled off under reduced pressure to give diethyl (2-bromo-4,5-difluorobenzoyl)malonate (123 g).
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[C:5]([OH:14])(=[O:13])[C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)O.O>C(O)C>[CH3:2][C:1]([O:4][C:12]1[CH:11]=[CH:10][CH:9]=[CH:7][C:6]=1[C:5]([OH:14])=[O:13])=[O:3]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccccc1O
Solvent: O
Solvent: CCO
Product: CC(=O)Oc1ccccc1C(=O)O
Temperature: 22.5 °C

Procedure:
To prepare a suspension, desalted egg phosphatides (Hepar) were dissolved in ethanol at a concentration of 250 mg/ml in a 1000 ml flask. To 400 mg of salicylic acid acetate, 1.6 ml of the above solution containing 400 mg of phosphatides was added and the solution adjusted with absolute ethanol to 4 ml. The final concentration of both ingredients in this pharmacological agent-lipid solution was 100 mg/ml. This procedure was performed at about 22.5° C.+/- about 2.5° C. and atmospheric pressure. Then 0.5 ml of the salicylic acid acetate-lipid solution was added to 9.5 ml of distilled water and briefly shaken by hand, at about 22.5° C.+/- about 2.5° C. and atmospheric pressure forming a suspension. The resulting suspension was milky in appearance and did not contain visable crystals or aggregates after a 30 minute period. Light microscopy of the suspension revealed aggregates, primarily with a diameter below 5 microns and no crystal characteristic for salicylic acid acetate. This suspension contained 0.5 mg salicylic acid acetate/ml.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:10][CH:9]=2)=[C:4]([CH3:18])[CH:3]=1.[Cl:19][CH2:20][CH2:21][N:22]=[C:23]=[O:24]>ClCCl.C1(C)C=CC=CC=1>[Cl:19][CH2:20][CH2:21][NH:22][C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=2)=[C:4]([CH3:18])[CH:3]=1)=[O:24]
Reactant: COC(=O)c1ccc(-c2ccc(N)cc2C)cc1
Reactant: O=C=NCCCl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(-c2ccc(NC(=O)NCCCl)cc2C)cc1
Yield: 69.6 %

Procedure:
Methyl 4'-amino-2'-methylbiphenyl-4-carboxylate (D2) (1.00 g, 4.1 mmol) and 2-chloroethylisocyanate (0.39 ml, 4.5 mmol) were stirred in dichloromethane (20 ml) for 72 h. The suspension was then diluted with toluene (20 ml), and the solid was filtered off and dried. This gave the title compound (0.99 g, 69%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=O)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.ClC(N(C)C)=C(C)C.[NH:22]1[CH2:27][CH2:26][C:25]2([C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:29](=[O:36])[NH:28]2)[CH2:24][CH2:23]1.C(N(CC)CC)C>ClCCl.CN(C)C=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:22]3[CH2:27][CH2:26][C:25]4([C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[C:29](=[O:36])[NH:28]4)[CH2:24][CH2:23]3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1NC2(CCNCC2)c2ccccc21
Reactant: O=C(O)c1c[nH]c2cc(Cl)ccc12
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Reaction time: 1 h
Yield: 26.3 %

Procedure:
To a solution of 0.060 g (0.31 mmol) 6-chloro-1H-indole-3-carboxylic acid in 3 ml dichloromethane were added 0.045 ml (0.38 mmol) 1-chloro-N,N,2-trimethyl-propenylamine at room temperature. After stirring for 1 h the reaction mixture was concentrated in vacuo. The residue was redissolved in 2 ml dry N,N-dimethylformamide. A solution of 0.062 g (0.31 mmol) spiro[isoindole-1,4′-piperidin]-3(2H)-one and 0.064 ml (0.46 mmol) triethylamine in 1 ml dry N,N-dimethylformamide was added at room temperature. After stirring for 2 h the reaction mixture was quenched with 1 M aqueous sodium hydroxide solution (30 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with water (2×30 ml), 0.5 M aqueous hydrochloric acid solution (1×30 ml) and brine (1×30 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was triturated in warm diethyl ether, filtrated and dried in vacuo to give the title compound (0.031 g, 22%) as light brown solid with a purity of approx. 80% by LC-.MS.
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]([O:9][CH3:10])=[O:8].[CH2:11]1[CH2:16][CH2:15][C:14]([CH2:21][NH2:22])([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][CH2:12]1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>CO>[C:7]([C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[NH:22][CH2:21][C:14]1([CH2:17][C:18]([O-:20])=[O:19])[CH2:15][CH2:16][CH2:11][CH2:12][CH2:13]1)([O:9][CH3:10])=[O:8].[NH2+:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: NCC1(CC(=O)O)CCCCC1
Reactant: COC(=O)C1CCCC1=O
Reactant: C1CCNCC1
Solvent: CO
Product: C1CC[NH2+]CC1
Product: COC(=O)C1=C(NCC2(CC(=O)[O-])CCCCC2)CCC1

Procedure:
Methyl 2-oxocyclopentanecarboxylate (124 μL, 1 mmol), gabapentin (171 mg, 1 mmol), and piperidine (99 μL, 1 mmol) were mixed in anhydrous methanol (10 mL). After heating under reflux for 16 h, the solvent was removed under reduced pressure to afford the title compound with purity greater than 90%. 1H NMR (CDCl3, 400 MHz): δ 1.29-1.60 (m, 12H), 1.72 (m, 4H), 1.79 (m, J=7.6 Hz, 2H), 2.24 (s, 2H), 2.49 (t, J=7.6 Hz, 2H), 2.55 (t, J=7.6 Hz, 2H), 2.99 (m, 4H), 3.24 (d, J=6.8 Hz, 2H), 3.63 (s, 3H), 5.06 (s, br, 2H), 7.93 (s, br, 1H). MS (ESI) m/z 294.36 (M−H−).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].C([N:18]([CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)C(NC)=S)C1C=CC=CC=1.[Cl:30]C1N=CC(NC)=CC=1>>[Cl:30][C:27]1[N:26]=[CH:25][C:24]([CH2:23][NH:18][C:3]([N:2]([CH3:10])[CH3:1])=[CH:4][N+:5]([O-:7])=[O:6])=[CH:29][CH:28]=1
Reactant: CNC(=S)N(Cc1ccccc1)Cc1cccnc1
Reactant: CNc1ccc(Cl)nc1
Reactant: CSC(=C[N+](=O)[O-])N(C)C
Product: CN(C)C(=C[N+](=O)[O-])NCc1ccc(Cl)nc1

Procedure:
The 1-dimethylamino-1-methylthio-2-nitroethylene (1.0 g) prepared in (1) and 1.0 g of 6-chloro-3-pyridyl- methylamine were refluxed in 30 ml of EtoH for 2 hours. The EtOH was then distilled off and the residue was subjected to silica gel column chromatography using CHCl3 -MeOH (10:1) as an eluent. The crystals obtained were recrystallized from EtOH to recover 0.82 g of the title compound as pale yellow crystals.
Reaction SMILES: O.O.[C:3]([O-:6])(=[O:5])[CH3:4].[Li+].[C:8]([O:11][C:12](=[O:14])[CH3:13])(=[O:10])[CH3:9].[CH2:15]=[CH:16][CH:17]=[CH2:18].O=O>C(O)(=O)C>[C:3]([O:6][CH2:15][CH:16]([O:11][C:8](=[O:10])[CH3:9])[CH:17]=[CH2:18])(=[O:5])[CH3:4].[C:3]([O:6][CH2:15][CH:16]=[CH:17][CH2:18][O:11][C:12](=[O:14])[CH3:13])(=[O:5])[CH3:4]
Reactant: CC(=O)[O-]
Reactant: CC(=O)OC(C)=O
Reactant: C=CC=C
Agent: O=O
Agent: [Li+]
Solvent: O
Solvent: CC(=O)O
Product: C=CC(COC(C)=O)OC(C)=O
Product: CC(=O)OCC=CCOC(C)=O
Temperature: 140 °C
Reaction time: 1 h

Procedure:
Another run was conducted employing the same apparatus as that used in Example I but in this run there was no source of halide in the catalyst system. The reactor was charged with 3.4 grams (20 millimoles) of ceric oxide, 7.6 grams (75 millimoles) of lithium acetate dihydrate, 50 ml of acetic acid, 25 ml of acetic anhydride, and 10.0 grams (185.2 millimoles) of butadiene charged from the vapor phase. The reactor was placed in an oil bath, pressured to 30 psig with oxygen and heated to 140° C. About one hour was required for the oil bath temperature to reach the reaction temperature desired, after which a reaction period of 5.3 hours was employed. During the reaction the reactor was pressured to 120 psig with oxygen intermittently. At the end of the reaction period (5.3 hours) the reactor was vented and 1.8 grams of unreacted butadiene was recovered in a cold trap. The reaction mixture was diluted with ether and 2.67 grams of a solid pecipitate was collected by filtration and dried. The ether solution filtrate was washed with water, neutralized with sodium carbonate solution, dried over magnesium sulfate, filtered, and the ether then removed by distillation. The distillation residue (21.3 g) was a pale brown oil. It was analyzed by gas-liquid chromatography which showed that the residue was 86 per cent. ether with the remainder being the diacetoxy butenes. Specifically, there was produced 11 millimoles of 1,2-diacetoxy-3-butene and 3 millimoles of 1,4-diacetoxy-2 -butene for a total yield of 14 millimoles of diacetoxy butenes which represents a yield of 7 per cent bases on the butadiene charged.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:18])=[C:5]([C:14]([O:16][CH3:17])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].C(Cl)Cl.[Br:22]Br>>[Br:22][CH2:18][C:4]1[C:3]([C:1]#[N:2])=[C:7]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:6][C:5]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1C
Reactant: BrBr
Solvent: ClCCl
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1CBr
Temperature: 25 °C
Reaction time: 96 h
Yield: 96.6 %

Procedure:
To the solution of methyl 4-cyano-3-methyl-5-(morpholin-4-yl)thiophene-2-carboxylate (0.500 g, 1.88 mmol) in anhydrous methylene chloride (15 mL, 230 mmol) was added a solution of bromine (0.409 g, 2.56 mmol) in anhydrous methylene chloride (5.0 mL, 78 mmol). The mixture was stirred at room temperature for 4 days. The mixture was evaporated under reduced pressure and dried in vacuum to give a crude product that was used without further purification (0.658 g, contained 3.4% starting material, yield 96.6%). LC/MS: (FA) ES+ 345, 347. 1H NMR (400 MHz, d-chloroform) δ 4.83 (s, 2H), 3.87 (s, 3H), 3.85 (m, 4H), 3.62 (m, 4H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH2:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl[C:16]1[N:24]=[CH:23][N:22]=[C:21]2[C:17]=1[N:18]=[CH:19][N:20]2[C@H:25]1[C@H:32]2[C@H:28]([O:29][C:30]([CH3:34])([CH3:33])[O:31]2)[C@@H:27]([CH2:35][F:36])[CH2:26]1.CCN(CC)CC>CCO>[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][C:16]3[N:24]=[CH:23][N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4[C@H:25]3[C@H:32]4[C@H:28]([O:29][C:30]([CH3:33])([CH3:34])[O:31]4)[C@@H:27]([CH2:35][F:36])[CH2:26]3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(Cl)ncnc43)[C@@H]2O1
Reactant: N[C@H]1CCN(c2cccc(Cl)c2)C1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H]2[C@@H](CF)C[C@@H](n3cnc4c(N[C@H]5CCN(c6cccc(Cl)c6)C5)ncnc43)[C@@H]2O1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
1-(3-Chloro-phenyl)-pyrrolidin-3(S)-ylamine hydrochloride (300 mg, 1.29 mmoles) prepared as in step 4 of example 1 and 6-chloro-9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl-tetrahydro-cyclopenta-1,3-dioxol-4-yl)-9H-purine (420 mg, 1.29 mmoles) prepared as described above were combined in EtOH (12 ml), NEt3 (730 μl, 5.15 mmoles) was then added and the resulting brown solution was stirred at reflux under an argon atmosphere. After 22 h, the reaction mixture was cooled to room temperature, evaporated to dryness, the residue was partitioned between water and EtOAc, the aqueous layer was separated and extracted two times with EtOAc. The combined organic layers are washed with brine and dried over magnesium sulfate. The filtrate is concentrated under reduced pressure to give a residue which is purified by flash chromatography on silica gel eluting with 40% EtOAc in cyclohexane followed by 5% MeOH in CH2Cl2 to yield [(S)-1-(3-chloro-phenyl)-pyrrolidin-3-yl]-[9-((3aS,4R,6S,6aR)-6-fluoromethyl-2,2-dimethyl -tetrahydro-cyclopenta-1,3-dioxol-4-yl)-9H-purin-6-yl]-amine
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH:9](Br)Br)=[CH:4][N:3]=1.C([OH:14])C>[N+]([O-])([O-])=O.[Ag+].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:9]=[O:14])=[CH:6][C:7]=1[F:8]
Reactant: Fc1cc(C(Br)Br)cnc1Cl
Reactant: CCO
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: O
Product: O=Cc1cnc(Cl)c(F)c1

Procedure:
A suspension 2-chloro-5-(dibromomethyl)-3-fluoropyridine (2.3 g, 7.58 mmol), silver nitrate (5.15 g, 30.3 mmol) in a mixed solvents of ethanol (10 mL) and water (10 mL) was stirred for 1 h at 100° C., then filtrated, and concentrated. The residue was dissolved in ethyl acetate, washed with water and brine, dried over sodium sulfate, concentrated. Purification via ISCO system afforded the title product (1.0 g) as a pale solid. LC-MS (ESI): m/z 159 [M+H]+; 2.01 min (ret time).
Reaction SMILES: [OH:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.[H-].[Na+].Br[CH2:21][CH2:22][F:23]>CN(C=O)C>[F:23][CH2:22][CH2:21][O:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[CH:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: FCCBr
Reactant: COC(=O)C1CC(O)CN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1CC(OCCF)CN1C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 72.1 %

Procedure:
A solution of 2.45 g (10.0 mmol) of 1-tert-butyl 2-methyl 4-[hydroxy]pyrrolidine-1,2-dicarboxylate (24) in DMF (10 ml) was added to a suspension of 0.65 g (15 mmol) of sodium hydride in DMF (20 ml). After 15 min, a solution of 1.90 g (15.0 mmol) of 1-bromo-2-fluoroethane in DMF (10 ml) was added. The batch was subsequently reacted in 3 portions at 100° C. in a microwave for 45 minutes. The batch was concentrated and treated with water and ethyl acetate. After phase separation, the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. The crude product was purified by column chromatography (silica gel, hexane/ethyl acetate). 2.10 g (48%) of 1-tert-butyl 2-methyl 4-(2-fluoroethoxy)-pyrrolidine-1,2-dicarboxylate were obtained.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:10][C:11]1[C:12]([Cl:21])=[CH:13][C:14]([F:20])=C([CH:19]=1)C(O)=O)[CH:8]=[CH2:9]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:10][C:11]1[C:12]([Cl:21])=[CH:13][C:14]([F:20])=[C:1]([CH:19]=1)[C:2]([Cl:4])=[O:3])[CH:8]=[CH2:9]
Reactant: C=CCOc1cc(C(=O)O)c(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOc1cc(C(=O)Cl)c(F)cc1Cl

Procedure:
With ice-cooling, 1 drop of dimethylformamide and 49.2 g (0.38 mol) of oxalyl chloride were added in succession to a solution of 59.7 g (0.26 mol) of 5-allyloxy-4-chloro-2-fluorobenzoic acid in 0.5 1 of toluene. After the evolution of gas had ceased, the mixture was concentrated to about half its volume. In this form, the product solution was used for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:17][N:18]1[C:22]([C:23](Cl)=[O:24])=[CH:21][C:20]([CH3:26])=[N:19]1>O1CCCC1.O>[F:8][C:7]1[CH:6]=[CH:5][C:4]([OH:9])=[CH:3][C:2]=1[NH:1][C:23]([C:22]1[N:18]([CH3:17])[N:19]=[C:20]([CH3:26])[CH:21]=1)=[O:24]
Reactant: Nc1cc(O)ccc1F
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cc(O)ccc2F)n(C)n1
Yield: 100 %

Procedure:
To a solution of 3-amino-4-fluorophenol (5.05 g, 39.7 mmol) and triethylamine (5.77 mL, 41.7 mmol) in tetrahydrofuran (30 mL) was added dropwise with stirring under ice-cooling a solution of 1,3-dimethyl-1H-pyrazole-5-carbonyl chloride (6.61 g, 41.7 mmol) in tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with water and extracted with ethyl acetate (×3). The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was collected by filtration and washed with ethyl acetate-hexane to give the title compound (9.89 g, 99%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][CH2:12][OH:13].[OH-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][OH:13])=[CH:5][CH:4]=1
Reactant: OCCCl
Reactant: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(OCCO)cc1
Yield: 35.4 %

Procedure:
A mixture of 148.8 g (1.20 mole) of p-methoxyphenol, 170.0 g (2.11 mole) of 2-chloroethanol and 47.2 g (1.18 mole) of sodium hydroxide in 1.5 liter of absolute ethanol was heated at reflux for 22 hr. The solution was filtered, and the solvent was removed from the filtrate in vacuo. The residue was crystallized from methylene chloride-hexane to give 71.4 g (35%) of title compound as a white crystalline solid, mp 69°-71° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=CC3NC4CCN(CCN(CC)CC)C(=O)C=4C=3C)[C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:31].N1CCCCC1.[CH3:38][O:39][CH2:40][C:41](Cl)=[O:42]>O1CCCC1>[F:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:41](=[O:42])[CH2:40][O:39][CH3:38])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: COCC(=O)Cl
Reactant: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cc(N)c(F)cc43)c(C)c2C1=O
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COCC(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: -50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A stirred solution of d 6-amino-5-fluoro-1,3-dihydro-indol-2-one (2.028 g, 12.2 mmol) obtained from Example 7 in 30 ml of tetrahydrofuran was added with piperidine (1.3 ml). The mixture was cooled to −50° C. in an ethanol-dry ice bath and added with methoxyacetyl chloride (1.35 g, 12.5 mmol) in 20 ml of tetrahydrofuran dropwise. Upon the completion of the addition, the resulting mixture was stirred at the room temperature overnight until the precipitate was formed. The solid was filtered, washed with water and recrystallized from methanol to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-methoxy-acetamide (2.0 g, 69.2%) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([OH:9])[CH:8]=1)[CH3:2].[CH3:12][C:13]([Si:16]([CH3:22])([CH3:21])[O:17][CH2:18][CH2:19]Br)([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:10]=[O:11])=[C:7]([O:9][CH2:19][CH2:18][O:17][Si:16]([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:22])[CH3:21])[CH:8]=1)[CH3:2]
Reactant: CCc1ccc(C=O)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCc1ccc(C=O)c(OCCO[Si](C)(C)C(C)(C)C)c1

Procedure:
This compound was prepared in a manner analogous to that of Step (b) of Example 1, using 17.0 grams (0.113 mole) of 5-ethyl-2-formylphenol, 27.7 grams (0.116 mole) of 2-(1,1-dimethylethyldimethylsilyloxy)ethyl bromide, 19.2 grams (0.139 mole) of potassium carbonate, and a catalytic amount of 18-crown-6 in 200 mL of THF. The yield of the subject compound was 12.7 grams, following purification by column chromatography on silica gel. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[C:13]([F:15])[C:12]([CH2:16][S:17][C:18]2[N:19]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=3)[C:20]([C:23]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([O:33][CH3:34])[CH:27]=3)([CH3:25])[CH3:24])=[CH:21][N:22]=2)=[C:11]([F:42])[CH:10]=1)(=O)=O.[CH3:43][NH:44][CH3:45].C(NC(C)C)(C)C.CN(C=O)C>CCOC(C)=O>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([C:23]([C:20]2[N:19]([C:35]3[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=3)[C:18]([S:17][CH2:16][C:12]3[C:13]([F:15])=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:44]([CH3:45])[CH3:43])=[CH:10][C:11]=3[F:42])=[N:22][CH:21]=2)([CH3:25])[CH3:24])=[CH:27][C:28]=1[O:33][CH3:34]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCOS(C)(=O)=O)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCN(C)C)cc3F)n2-c2ccc(F)cc2)ccc1Cl
Temperature: 110 °C
Yield: 88 %

Procedure:
A mixture of 2-(4-((5-(2-(4-Chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)ethyl methanesulfonate (230 mg, 0.36 mmol, 1.0 eq), dimethylamine (7.2 mL, 14.4 mmol, 40.0 eq, 2.0 M in THF) and diisopropylamine (0.2 mL, 1.1 mmol, 3.0 eq) in anhyd DMF (3.5 mL) was heated at 110° C. for 16 h. The mixture was diluted with EtOAc, washed sequentially with brine, satd NaHCO3 and brine, dried over MgSO4 and concentrated to provide 2-(4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-3,5-difluorophenoxy)-N,N-dimethylethanamine (187 mg). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.72-6.65 (m, 2H), 6.48-6.40 (m, 2H), 6.34-6.25 (m, 4H), 3.98-3.92 (m, 4H), 3.68 (s, 3H), 2.68 (t, J=5.5 Hz, 2H), 2.28 (s, 3H), 1.41 (s, 6H); MS (EI) m/z 590 (MH+).
Reaction SMILES: [Bi]=[O:2].[C:3]([OH:6])(=O)[CH3:4].[C:7]([O:10][CH2:11][CH3:12])(=O)[CH3:8]>[Bi].C([O-])(=O)C.[Bi+3].C([O-])(=O)C.C([O-])(=O)C.C(Cl)(Cl)Cl>[CH3:8][CH:7]1[C:4](=[O:2])[C:3]([OH:6])=[C:11]([CH3:12])[O:10]1
Reactant: CC(=O)O
Reactant: CCOC(C)=O
Reactant: O=[Bi]
Agent: CC(=O)[O-]
Agent: [Bi+3]
Agent: [Bi]
Solvent: ClC(Cl)Cl
Product: CC1=C(O)C(=O)C(C)O1
Yield: 79 %

Procedure:
17.5 g of 2,5-dimethyl-3,4-dihydroxy-tetrahydrofuran-3-one of about 80% purity were heated, in a suspension of 40 g of bismuth oxide and 50 g of glacial acetic acid, for 25 minutes at 120° C. After the reaction mixture had cooled, it was diluted with 80 g of ethyl acetate, whereupon metallic bismuth and bismuth acetate precipitated. The filtrate was fractionated, giving, at 85°-101° C./0.3 mbar, 14.2 g of a distillate containing about 77% of (I). This corresponds to a yield of 79%. 2.5 g of this fraction were taken up in a mixture of 2.8 g of chloroform and 1.6 g of petroleum ether, from which, after cooling, pure (I) of solidification point 75°-76° C. crystallized.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)=[CH:17][CH:18]=2)[N:13]=1>O.CN(C)C=O.C(#N)C>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([C:16]2[N:15]=[C:14]3[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:5](=[O:7])[C:4]4[CH:8]=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)=[N:13]3)=[CH:18][CH:17]=2)=[CH:27][CH:26]=1
Reactant: Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1
Reactant: O=C(O)c1cccc(Br)c1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccc2ccc(-c3ccc(Cl)cc3)nc2n1)c1cccc(Br)c1
Temperature: 4 °C
Yield: 45.3 %

Procedure:
The procedure is analogous to that described in Example 11, but starting with 3-bromobenzoic acid (2.1 g), N,N'-carbonyldiimidazole (1.6 g) and 2-amino-7-(4-chlorophenyl)-1,8-naphthyridine (1.8 g). The product obtained by precipitation in water (2.2 g; m.p. 210° C.) is dissolved in a boiling mixture of dimethylformamide (20 cc) and acetonitrile (100 cc). After cooling for 4 hours at 4° C., the crystallized solid is separated by filtration, washed with acetonitrile (3×10 cc) and dried at 40° C. under reduced pressure (0.07 kPa). N-[7-(4-Chlorophenyl)1,8-naphthyridin-2-yl]-3-bromobenzamide (1.4 g), m.p. 220°-224° C., is obtained.