Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O)([CH3:13])[CH3:12].P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl-].[NH4+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C.C(COC)OC.O>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([O:9][CH3:10])=[C:2]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH:11]([CH3:13])[CH3:12])[CH:7]=1
Reactant: COc1ccc(C)cc1Br
Reactant: CC(C)c1ccccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccc(C)cc1-c1ccccc1C(C)C
Yield: 118.7 %

Procedure:
A mixed solution of 1 mL of water and 4 mL of dimethoxyethane was added into a flask into which 2-bromo-4-methylanisole (600 mg, 2.98 mmol), 2-isopropylphenylboronic acid (734 mg, 4.47 mmol), palladium acetate (16 mg, 0.074 mmol), triphenylphosphine (72 mg, 0.27 mmol), and potassium phosphate (1.12 g, 5.28 mmol) were already added, and then refluxed at normal temperature for 6 hours. After cooling to normal temperature, an ammonium chloride aqueous solution (5 mL) and 10 mL of diethylether were added thereto to separate an organic layer and extract residues with diethylether. The separated organic layer was dried with magnesium sulfate and volatile materials were removed to produce 850 mg of grey 4-methyl-2-(2′-isopropylphenyl)anisole solid. The anisole thus produced was dissolved in 5 mL of methylene chloride without separate purification, 3 mL of boron tribromide (1 M methylene chloride solution) was dropped thereonto at −78° C., and a reaction was carried out while the temperature slowly increased to normal temperature. After the reaction, a mixed solution of water (5 mL) and diethylether (10 mL) was added to separate an organic layer and extract an aqueous solution layer using diethylether (5 mL×3), and the separated organic layer was dried. Residues from which volatile components were removed at reduced pressure were purified using a silica gel chromatography tube in a mixed solvent of hexane and methylene chloride to produce 633 mg of white 4-methyl-2,6-(2′-isopropylphenyl)phenol solid.
Reaction SMILES: [C:1]([C:3]1([NH:9][C:10](=[O:37])[C@@H:11]([NH:24][C@@H:25]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:26]([F:29])([F:28])[F:27])[CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:15])=[O:14])[CH2:8][CH2:7]S[CH2:5][CH2:4]1)#[N:2].OO[S:40]([O-:42])=[O:41].[K+]>CO>[C:1]([C:3]1([NH:9][C:10](=[O:37])[C@@H:11]([NH:24][C@@H:25]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[C:26]([F:29])([F:27])[F:28])[CH2:12][S:13]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)(=[O:15])=[O:14])[CH2:4][CH2:5][S:40](=[O:42])(=[O:41])[CH2:7][CH2:8]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccc(F)cc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CCSCC1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: CO
Product: N#CC1(NC(=O)[C@H](CS(=O)(=O)Cc2ccc(F)cc2)N[C@@H](c2ccc(F)cc2)C(F)(F)F)CCS(=O)(=O)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
N-(4-cyanotetrahydrothiopyran-4-yl)-3-(4-fluorophenylmethanesulfonyl)-2(R)-(2,2,2-trifluoro-1(S)-4-fluorophenylethylamino)propionamide (24 mg) was weighed into a 25 mL pear flask fitted with a stir bar and vented cap. Methanol (4.75 mL) was added and the reaction mixture was stirred at 50° C. to obtain a clear colorless solution. OXONE® (0.43 mL of a 0.30M aqueous solution) was added. A white precipitate formed. After 2 h, methanol was removed on a rotary evaporator and the residue was partitioned between 10 mL water and 10 mL dichloromethane. The organic phase was separated, washed with water and brine and dried over anhydrous MgSO4 and concentrated to give the title compound (16 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2](=[CH2:4])[CH3:3].O1CCOCC1.[Br:11][CH:12]([CH3:16])[C:13]([OH:15])=[O:14].S(=O)(=O)(O)O>ClCCl>[Br:11][CH:12]([CH3:16])[C:13]([O:15][C:2]([CH3:3])([CH3:1])[CH3:4])=[O:14]
Reactant: CC(Br)C(=O)O
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(Br)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
Isobutylene (2.4 g, 42.8 mmoles) was condensed into a pressure bottle at −15° C. Dioxane (6 mL) and 2-bromopropionic acid (3.5 mL, 38.9 mmoles) were added and the mixture was stirred for 5 min, warmed to −10° C., and concentrated sulfuric acid (250 μL) was added. The bottle was scaled, the reaction mixture was stirred overnight at room temperature, and the bottle was then opened and the contents poured into dichloromethane (50 mL). The solution was washed with 2096 potassium carbonate (50 mL), water (50 ml), dried over anhydrous magnesium sulfate and evaporated to give t-butyl bromopropionate (2.17 g, 27%). 1HMR (CDCl3, δ): 4.31 (1H, q, 7.1 Hz), 1.81 (3H, d, 7.1 Hz), 1.52 (9H, s).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[S:23]1[CH:27]=[N:26][N:25]=[C:24]1[CH:28]([OH:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].[O-]S([O-])(=S)=O.[Na+].[Na+].CO.C(Cl)Cl>C(Cl)Cl.CCOCC.C([O-])(O)=O.[Na+]>[S:23]1[CH:27]=[N:26][N:25]=[C:24]1[C:28](=[O:46])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH:36]=[CH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]
Reactant: CCCCCCCCC=CCCCCCCCC(O)c1nncs1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: CCCCCCCCC=CCCCCCCCC(=O)c1nncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
(141) A suspension of the Dess-Martin periodinane (1.2 equiv, 0.013 mmol, 14 mg) in anhydrous CH2Cl2(0.5 mL) was treated with a solution of 1-([1,3,4]thiadiazol-2-yl)octadec-9-en-1-ol (4 mg, 0.011 mmol) in anhydrous CH2Cl2 (0.5 mL) at rt under N2. After 10 h the suspension was diluted with Et2O (10 mL), and poured into a solution of Na2S2O3 (40 mg) in saturated aqueous NaHCO3 (3.4 mL). The mixture was stirred at rt for 1 h and the layers were separated. The ethereal layer was washed with saturated aqueous NaHCO3 (1×10 mL) and H2O (1×10 mL), dried (MgSO4), filtered and evaporated. Flash chromatography (SiO2, 1.5 cm×15 cm, 2% MeOH—CH2Cl2) afforded 1-([1,3,4]thiadiazol-2-yl)octadec-9-en-1-one (141) (3 mg, 0.008 mmol, 70% yield) as a dark yellow oil: MALDI-FTMS (DHB) m/z 351.2464 (C20H34N2OS+H+ requires 351.2470).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH:18]C(=O)OCC4C=CC=CC=4)[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1>CO.[Pd]>[F:30][C:2]([F:1])([F:29])[C:3]1[CH:4]=[C:5]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][CH:16]=[C:17]([NH2:18])[C:11]=3[N:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Nc1cccc2[nH]c(-c3cccc(C(F)(F)F)c3)nc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a stirred solution of benzyl 2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-4-ylcarbamate (12; 1.45 g, 3.5 mmol) in methanol (20 mL) was added 5% Pd/C (0.20 g). The reaction mixture was thoroughly purged with nitrogen and then stirred under 1 atm of hydrogen at room temperature for 18 h. The mixture was filtered through a pad of Celite and the filtrate was concentrated under reduced pressure to give 2-(3-(trifluoromethyl)phenyl)-1H-benzo[d]imidazol-4-amine 13 (0.90 g, 3.25 mmol, 93%) as a solid. MS (ESI) calcd for C14H10F3N3: 277.08; found: 278 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10].[OH-].[Na+]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc[n+]([O-])cc1F
Temperature: 120 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a solution of 3-fluoropyridine N-oxide (3-2) (10.4 g, 90 mmol) in sulfuric acid (52 mL) stirring at 120° C. was added fuming nitric acid (21 mL) over 1 hour. After stirring at 120° C. for another 3 hours, the reaction mixture was cooled to ambient temperature and poured into 300 mL of ice. The pH of the solution was adjusted to pH 7 by addition of 20% sodium hydroxide, and extracted with chloroform. The organic layer was dried, filtered and concentrated. The residue was recrystallized from diethyl ether/hexane to give a pale yellow solid (7.5 g, 51%). 1H NMR (400 MHz, CDCl3): 8.05 (m, 2H), 8.22 (m, 1H)
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[S:18]1[CH:22]=[CH:21][C:20]2[CH:23]=[C:24]([CH:27]([OH:43])[CH2:28][O:29][CH2:30][CH2:31][O:32][S:33]([C:36]3[CH:41]=[CH:40][C:39]([CH3:42])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:25]=[CH:26][C:19]1=2.[O:44]1[CH:49]=[CH:48][CH2:47][CH2:46][CH2:45]1>C(Cl)Cl>[S:18]1[CH:22]=[CH:21][C:20]2[CH:23]=[C:24]([CH:27]([O:43][CH:45]3[CH2:46][CH2:47][CH2:48][CH2:49][O:44]3)[CH2:28][O:29][CH2:30][CH2:31][O:32][S:33]([C:36]3[CH:37]=[CH:38][C:39]([CH3:42])=[CH:40][CH:41]=3)(=[O:35])=[O:34])[CH:25]=[CH:26][C:19]1=2
Reactant: C1=COCCC1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(O)c2ccc3sccc3c2)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCC(OC2CCCCO2)c2ccc3sccc3c2)cc1
Reaction time: 0.5 h

Procedure:
0.97 g of pyridinium p-toluenesulfonate was added, at room temperature, to a solution of 7.6 g of 1-(benzo[b]thiophen-5-yl)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethanol and 3.5 ml of 3,4-dihydro-2H-pyran dissolved in 40 ml of methylene chloride. The mixture was stirred at the same temperature for 20 minutes and further at 40 for 30 minutes. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure to obtain 8.7 g of colorless, oily 1-(benzo[b]thiophen-5-yl)-1-(2-tetrahydropyranyloxy)-2-[2-(p-toluenesulfonyloxy)ethoxy]ethane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:15])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+].[C:21]([O:25][CH3:26])(=[O:24])[CH:22]=[CH2:23]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([F:15])[CH2:10][CH2:11][N:12]([CH2:23][CH2:22][C:21]([O:25][CH3:26])=[O:24])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: C=CC(=O)OC
Reactant: FC1(c2ccc(Cl)cc2)CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCN1CCC(F)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 94 %

Procedure:
To a solution of 3-[4-(4-chlorophenyl)-4-fluoropiperidine hydrochloride (280 mg, 1.12 mmol) in methanol (5 mL) was added sodium bicarbonate (500 mg, 5.94 mmol) followed by methyl acrylate (1 mL). The resulting mixture was stirred at room temperature for 14 hours then filtered and concentrated under reduced pressure. The residue was treated with ethyl acetate (10 mL) and the resulting suspension re-filtered and concentrated under reduced pressure. This afforded methyl 3-[4-(4-chlorophenyl)-4-fluoropiperidin-1-yl]propionate as a viscous yellow oil in 94% yield, which was used without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[F:30][C:31]1[CH:39]=[CH:38][C:34]([C:35](O)=[O:36])=[CH:33][CH:32]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:35](=[O:36])[C:34]3[CH:38]=[CH:39][C:31]([F:30])=[CH:32][CH:33]=3)[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C(O)c1ccc(F)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)c3ccc(F)cc3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 23 mg (0.17 mmol, 1.1 eq.) of 4-fluorobenzoic acid were reacted according to General Method 1. Yield: 53 mg (83% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13]C)=O)=[CH:4][CH:3]=1.[Cl-].[NH4+:16].N>CO>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH2:16])=[O:13])=[CH:4][CH:3]=1
Reactant: COC(=O)CCCc1ccc(N)cc1
Reactant: [NH4+]
Agent: N
Agent: [Cl-]
Solvent: CO
Product: NC(=O)CCCc1ccc(N)cc1
Temperature: 100 °C
Reaction time: 20 h
Yield: 35.1 %

Procedure:
A 100-mL vial was charged with methyl 4-(4-aminophenyl)butanoate (2.07 g, 10.7 mmol), ammonium chloride (0.76 g, 14.2 mmol) in methanol (10 mL). To this mixture was added NH3 (10 mL, 7N in methanol, 70.0 mmol, 6.5 eq.). The vial was sealed and the resulting mixture was stirred at 100° C. for 20 h. After this time, the crude reaction solution was concentrated under reduced pressure. The residue was absorbed on silica (10 g) then purified by chromatography on silica using dichloromethane/methanol (10:0 to 9:1) as eluent to afford the title compound (0.67 g, 35%) as a white solid. MW=178.23. 1H NMR (DMSO-d6, 500 MHz) δ 7.20 (br s, 1H), 6.83-6.80 (m, 2H), 6.66 (br s, 1H), 6.49-6.46 (m, 2H), 2.37 (t, J=7.5 Hz, 2H), 2.01 (t, J=7.5 Hz, 2H), 1.68 (quin, J=7.5 Hz, 2H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:12])/[CH:7]=[CH:8]\[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.C(N(CC)CC)C.C(=O)=O.C(=O)(O)[O-].[Na+]>O.ClCCl>[C:1]([N:5]=[C:6]1[O:12][C:9](=[O:11])[CH:8]=[CH:7]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)NC(=O)/C=C\C(=O)O
Agent: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: O=C=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)N=C1C=CC(=O)O1
Temperature: -5 °C
Reaction time: 2.5 h
Yield: 89.8 %

Procedure:
In a round bottom flask with a nitrogen atmosphere and containing a mechanical stirrer, a thermometer, an addition funnel and a condenser, was combined 700 grams (4.0 moles) of (Z)-4-(tert-butylamino)-4-oxo-2-butenoic acid and 7,757 grams dichloromethane. The mixture was cooled to −5° C. and 439 grams (4.0 moles) ethyl chloroformate (commercially available from Aldrich Chemical, Milwaukee, Wis.) was added. The mixture was cooled to −10° C. and 409 grams (4.0 moles) triethylamine (commercially available from Aldrich Chemical, Milwaukee, Wis.) was added slowly at a rate such that the temperature remained below −7° C. Stirring was continued at −5° C. for 2.5 hours during which time the evolution of carbon dioxide was observed. The mixture was warmed to 11° C. and a premix of 272 grams of sodium bicarbonate dissolved in 3,640 grams of distilled water was added. The mixture was stirred for 10 minutes, allowed to phase separate, and the aqueous phase was removed. The organic phase was extracted three times, each time with 3 liters of distilled water. The organic phase was dried with 275 grams of sodium sulfate, filtered and the solvent was removed in vacuo at 30° C. The residue was purified by distillation (50° C., 0.05 millimeters of Hg) to give 550 grams of 5-(tert-butylimino)-2,5-dihydro-2-furanone. This material is hereinafter referred to as TBIMI (tert-butylisomaleimide). 13C NMR indicated the product to be >99% pure.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9](F)=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2].[F:16][C:17]([F:22])([F:21])[CH:18]([OH:20])[CH3:19]>>[CH2:1]([S:3]([C:6]1[CH:7]=[CH:8][C:9]([O:20][CH:18]([CH3:19])[C:17]([F:22])([F:21])[F:16])=[C:10]([CH:14]=1)[C:11]([OH:13])=[O:12])(=[O:5])=[O:4])[CH3:2]
Reactant: CC(O)C(F)(F)F
Reactant: CCS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Product: CCS(=O)(=O)c1ccc(OC(C)C(F)(F)F)c(C(=O)O)c1

Procedure:
Prepared in analogy to Example A14(c) from 5-ethanesulfonyl-2-fluoro-benzoic acid and rac-1,1,1-trifluoro-propan-2-ol. MS (m/e): 325.1 ([M−H]−, 100%)
Reaction SMILES: Br[C:2]1[C:7]2[CH:8]=[CH:9][O:10][C:6]=2[C:5]([Br:11])=[CH:4][N:3]=1.C(O[Na])=O>CN(C=O)C.O.CCOC(C)=O.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>[Br:11][C:5]1[C:6]2[O:10][CH:9]=[CH:8][C:7]=2[CH:2]=[N:3][CH:4]=1
Reactant: Brc1ncc(Br)c2occc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=CO[Na]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Brc1cncc2ccoc12
Temperature: 100 °C
Yield: 77 %

Procedure:
A suspension of 4,7-dibromofuro[3,2-c]pyridine (3.50 g, 12.6 mmol), HCO2Na (2.59 g, 38.1 mmol) and Pd(PPh3)4 (360 mg, 0.32 mmol) in dry DMF (35 mL) was heated at 100° C. (bath temperature) under Ar for 9 h. LC-MS showed the reaction was almost complete. The mixture was diluted with water (50 mL) and EtOAc (200 mL). Layers were separated and the organic phase was washed with water (3×40 mL), brine (40 mL), and dried over Na2SO4. The solvent was removed and residue was purified by silica gel chromatography eluting with Hexanes-EtOAc (80:20→70:30) to provide the title compound as an off-white solid (1.92 g, 77%). 1H NMR (CDCl3, 400 MHz): δ=6.98 (d, J=2.3 Hz, 1H), 7.79 (d, J=2.3 Hz, 1H), 8.62 (s, 1H), 8.89 (s, 1H).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:18])([F:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][CH:6]=1)C.C([O-])([O-])=O.[K+].[K+].Cl>>[CH2:15]([O:14][C:12](=[O:13])[C:11]([C:8]1[CH:9]=[CH:10][C:5]([C:4]([OH:19])=[O:3])=[CH:6][CH:7]=1)([F:17])[F:18])[CH3:16]
Reactant: CCOC(=O)c1ccc(C(F)(F)C(=O)OCC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(F)(F)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
According to the above-described scheme, 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoic acid ethyl ester (Compound 2d; 108.9 mg, 0.4 mmol) and 1N K2CO3 solution (1.5 mL) were put into an eggplant flask, and the mixture was stirred at room temperature for 26 hours. After the reaction, the reaction mixture was neutralized with 5% HCl solution, extracted with ethyl acetate and washed with water, and an organic layer was dried with anhydrous sodium sulfate. Ethyl acetate was distilled away under reduced pressure, and by carrying out purification by silica gel column chromatography, 4-(2-ethoxy-1,1-difluoro-2-oxoethyl)benzoic acid (Compound 4d) was obtained with a yield of 86%.
Reaction SMILES: C[O:2][C:3]([CH2:5][C:6]1([CH:12]([C:17](OC)=[O:18])[C:13](OC)=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)C.[OH-].[Na+]>O1CCCC1.O>[OH:2][CH2:3][CH2:5][C:6]1([CH:12]([CH2:13][OH:14])[CH2:17][OH:18])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)CC1(C(C(=O)OC)C(=O)OC)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCC1(C(CO)CO)CCCCC1
Yield: 57.8 %

Procedure:
To a solution of dimethyl 2-(1-methoxycarbonylmethylcyclohexyl)malonate (490 mg) in tetrahydrofuran (15 mL) was added lithium aluminum hydride (195 mg) under ice cooling. The solution was stirred under reflux for 1 hour, and then, cooled on ice. Diethyl ether was added to the solution, followed by addition of water (0.2 mL) and a 15% aqueous sodium hydroxide solution (0.2 mL). After stirring the solution at room temperature for 15 minutes, water (0.6 mL) was added thereto, and it was stirred at room temperature for additional 30 minutes. The solution was dried over anhydrous magnesium sulfate, and then, concentrated under reduced pressure. The resulting residue was purified by chromatography (silica gel, chloroform:methanol=85:15) to give the title compound (200 mg).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:7]=[C:8]([CH:27]=[CH:28][C:29]=1[NH2:30])[C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[CH:14][CH:13]=1)=[O:10].[OH:31][C:32]1[CH:39]=[CH:38][C:37]([C:40]2[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][C:33]=1[CH:34]=O.CO>ClCCl>[CH3:26][N:23]1[CH2:24][CH2:25][N:20]([CH2:19][CH2:18][C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:9]([C:8]3[CH:27]=[CH:28][C:29]4[N:30]=[C:34]([C:33]5[CH:36]=[C:37]([C:40]6[C:41]([O:46][CH3:47])=[N:42][CH:43]=[CH:44][CH:45]=6)[CH:38]=[CH:39][C:32]=5[OH:31])[NH:5][C:6]=4[CH:7]=3)=[O:10])=[CH:17][CH:16]=2)[CH2:21][CH2:22]1
Reactant: COc1ncccc1-c1ccc(O)c(C=O)c1
Reactant: CN1CCN(CCc2ccc(NC(=O)c3ccc(N)c(N)c3)cc2)CC1
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ncccc1-c1ccc(O)c(-c2nc3ccc(C(=O)Nc4ccc(CCN5CCN(C)CC5)cc4)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
To a suspension of silica gel (6.0 g) in dichloromethane (20 mL) was added SOCl2 (1.5 mL) and the mixture was stirred at the room temperature for 1 h (gas was released from the reaction mixture). 3,4-Diamino-N-{4-[2-(4-methyl-piperazin-1-yl)-ethyl]-phenyl}-benzamide (707.0 mg, 2.0 mmol) and 2-hydroxy-5-(2-methoxy-pyridin-3-yl)-benzaldehyde (458.5 mg, 2.0 mmol) were added, and the resulting mixture was stirred at the room temperature for 4 h. After methanol (10 mL) was added, the reaction mixture was stirred at room temperature for another 1 h and was evaporated under reduced pressure. The residue on silica gel was purified by chromatography (250:10:1 CH2Cl2/MeOH/28% aqueous NH4OH) to afford the title compound (528 mg, 47%). 1H NMR (MeOH-d4) δ 2.25 (s, 3H), 2.35-2.71 (12H), 3.94 (s, 3H), 6.96 (m, 1H), 7.00 (d, J=9 Hz, 1H), 7.11 (d, J=9 Hz, 2H), 7.50-7.60 (4H), 7.66 (d, J=9 Hz, 1H), 7.79 (d, J=9 Hz, 1H), 8.06 (d, J=7 Hz, 1H), 8.10 (s, 1H), 8.14 (s, 1H). ESI-MS m/z 563 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10](I)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7].[Si:16]([O:23][C:24]1[CH:25]=[C:26]([NH2:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[C:10]([NH:32][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:25]=2)[CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cccc(I)c1C(=O)OC
Reactant: COc1ccc(N)cc1O[Si](C)(C)C(C)(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(Nc2ccc(OC)c(O[Si](C)(C)C(C)(C)C)c2)c1C(=O)OC
Yield: 71 %

Procedure:
A mixture of 3-iodophthalic acid dimethyl ester (1.0 g, 3.1 mmol), 3-(tert-butyldimethylsilanyloxy)-4-methoxyphenylamine (0.79 g, 3.1 mmol), Pd2(dba)3 (0.13 g, 0.14 mmol), rac-BINAP (0.058 g, 0.093 mmol), and cesium carbonate (1.4 g, 4.3 mmol), in 6 mL toluene was heated to reflux under nitrogen for 24 hours. The reaction mixture was cooled, diluted with CH2Cl2 (10 mL), and filtered through Celite, and the filter was washed with additional CH2Cl2 (30 mL). The filtrate was evaporated, and the residue was chromatographed using a hexanes-ethyl acetate gradient, eluting 1.0 g of the product at 90:10 hexanes-ethyl acetate, in 71% yield: 1H NMR (CDCl3) δ 0.16 (s, 6H), 0.98 (s, 9H), 3.81 (s, 3H), 3.87 (s, 3H), 3.88 (s, 3H), 6.69-6.75 (m, 2H), 6.82 (d, J=8.2 Hz, 1H), 6.95 (dd, J=7.3 Hz, J=1.1 Hz, 1H), 7.12 (dd, J=7.0 Hz, J=1.1 Hz, 1H), 7.24 (t, J=7.8 Hz, 1H), 8.04 (s, 1H).