Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[CH:13]([C:15]1[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=1)=[O:14].[Li]C1C=CC=CN=1>CCOCC>[OH:14][CH:13]([C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Agent: [Li]c1ccccn1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(O)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 0.42 h
Yield: 64.4 %

Procedure:
To a cooled solution (-78° C.) of 10.6 mL (0.11 mol) of 3-bromopyridine in 1.2 L of anhydrous Et2O was added dropwise 93.8 mL (0.15 mol) of 1.6M n-BuLi in hexanes over 1 h period. The turbid yellow solution was stirred at -78° C. for 25 min, and then 24.62 g (0.15 mol) of methyl 4-formylbenzoate in 300 mL of Et2O was cannulated to the lithiopyridine solution. The mixture was continually stirred at -78° C. for 2 h and at room temperature for 2 more h. The reaction was quenched with 400 mL of brine and 200 mL of H2O. The organic layer was separated and the aqueous layer was extracted with 3×1.0 L of CH2Cl2. To the combined organic layer was added 200 mL of MeOH to dissolve the product which precipitated out. This was then dried over MgSO4 and concentrated. The crude product was crystallized from MeOH to afford 17.24 g (64%) of a white solid: mp 151° C.; 1H NMR (CDCl3) δ8.62 (br s, 1H), 8.51 (br s, 1H), 8.02 (d, J=8.3 Hz, 2H), 7.70 (d, J=7.9 Hz, 1H), 7.45 (d, J=8.3 Hz, 2H), 7.30 (br s, 1H), 5.93 (s, 1H), 3.90 (s, 3H), 2.92 (br s, 1H); FDMS 244 (M+1). Anal. (C14H13NO3.0.16C2H4O) C, H, N.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([CH2:12]Br)[CH:3]=1.Cl.[CH3:15][O:16][C:17](=[O:23])[C@@H:18]([CH:20]([CH3:22])[CH3:21])[NH2:19].C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:10][CH:11]=1)[C:6](=[O:8])[N:19]([C@H:18]([CH:20]([CH3:22])[CH3:21])[C:17]([O:16][CH3:15])=[O:23])[CH2:12]2
Reactant: COC(=O)[C@H](N)C(C)C
Reactant: COC(=O)c1ccc(Br)cc1CBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H](C(C)C)N1Cc2cc(Br)ccc2C1=O

Procedure:
Methyl 4-bromo-2-(bromomethyl)benzoate (650 mg, 2.12 mmol) and D-valine methyl ester hydrochloride (527 mg, 3.15 mmol) was taken in toluene (6.5 mL) and to this reaction mixture, triethyl amine (428 mg, 4.24 mmol) was added and refluxed for about 16 h. After completion of the reaction, the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over anhydrous sodium sulfate and concentrated to obtain an oil, which was purified by column chromatography (silica gel, 30% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:31])[CH:20]=[CH:21]S(C2C=CC=CC=2)(=O)=O)=[CH:14][CH:13]=1.[OH-].[Na+]>CN(C=O)C>[CH3:11][C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19](=[O:31])[CH:20]=[CH:21][S:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:16][CH:17]=1
Reactant: Cc1ccc(NC(=O)C=CS(=O)(=O)c2ccccc2)cc1
Reactant: Cc1cccc(S)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C=CSc2cccc(C)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
To a solution of 3-methylthiophenol (0.85 g) in DMF (10 mL) was added 60% sodium hydride (81 mg) under a nitrogen atmosphere under ice-cooling. The mixture was stirred at room temperature for 30 minutes under a nitrogen atmosphere, and then was added dropwise to a solution of N-(4-methylphenyl)-3-(phenylsulfonyl)acrylamide (0.85 g) in DMF (10 mL) under ice-cooling. The mixture was stirred at room temperature for 2 hours, alkalinized by addition of a 1N aqueous sodium hydroxide solution, and then extracted with tert-butyl methyl ether (100 mL). The organic layer was washed with water and then a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain N-(4-methylphenyl)-3-(3-methylphenylthio)acrylamide (0.45 g) as a white crystal.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23](O)=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.N.O1CCOCC1.O[N:35]1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC>O.C1COCC1>[C:1]1([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]([CH2:21][CH2:22][C:23]([NH2:35])=[O:24])[C:13]2=[O:26])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: O
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: NC(=O)CCn1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Reaction time: 20 h
Yield: 76.5 %

Procedure:
To the THF (1.0 mL) suspension of 3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionic acid (50 mg, 0.14 mmol) at room temperature are added ammonia 0.5 M solution in dioxane (1.4 mL, 0.72 mmol) and 1-hydroxybenzotriazole (94 mg, 0.7 mmol). Then N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (118 mg, 0.61 mmol) is added in small portions. The reaction mixture is stirred for 20 hr and then water (5 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The organic layers are combined, dried over MgSO4 and concentrated to give crude product. Purification by preparative TLC using 5% MeOH in CH2Cl2 affords 37 mg (74%) of 3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-propionamide. LCMS (ESMS): m/z 346.12 (M+H+).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[CH3:11][C:12](OC(C)=O)=[O:13].C([O-])(O)=O.[Na+]>CC(O)=O>[O:10]1[C:9]2[CH:8]=[CH:7][C:5]([NH:6][C:12](=[O:13])[CH3:11])=[CH:4][C:3]=2[O:2][CH2:1]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 3,4-(Methylenedioxy)aniline (8 g, 58.3 mmol) in AcOH (120 ml) was added Ac2O (48 mL). The mixture was stirred for overnight. After reaction, the mixture was poured into saturated NaHCO3 solution, and then filtered. The filtrate was extracted with ethyl acetate to give N-(benzo[d][1,3]dioxol-5-yl)acetamide (10 g, 95%). LCMS: 180 [M+1]+; 1H NMR (DMSO-d6) δ 2.0 (s, 3H), 5.96 (s, 2H), 6.82 (d, 1H, J=8.1 Hz), 6.91 (d, 1H, J=2.1 Hz), 7.30 (d, 1H, J=1.8 Hz), 9.84 (s, 1H).
Reaction SMILES: [CH2:1]([N:3](S(F)(F)F)[CH2:4][CH3:5])[CH3:2].[C:10]([C:12]1[NH:16][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])=[N:14][C:13]=1[C:29]([OH:31])=O)#[N:11].[F-].[K+].C(NCC)C>COCCOCCOC.ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:29]([C:13]1[N:14]=[C:15]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:25])([F:27])[F:26])=[CH:19][C:18]=2[Cl:28])[NH:16][C:12]=1[C:10]#[N:11])=[O:31])[CH3:2]
Reactant: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(=O)O
Reactant: CCN(CC)S(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: COCCOCCOC
Solvent: CCNCC
Product: CCN(CC)C(=O)c1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethylaminosulphur trifluoride (1.5 ml) was added dropwise to a stirred suspension of 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxylic acid (1.4 g, 0.004 mol) in 2-methoxyethyl ether (11 ml) whilst maintaining the temperature at about 0° C. Potassium fluoride (0.67 g, 0.0115 mol) was added and the mixture was stirred at 0° C. for 0.5 hours, and added slowly to a solution of diethylamine (8.8 g, 12.5 ml, 0.12 mol) in dichloromethane (75 ml) whilst maintaining the temperature in the range 0°-5° C. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 0.5 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluting with a mixture of ethyl acetate and dichloromethane (1:2) to give N,N-diethyl 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxamide (0.26 g) m.p. 195°-197° C. as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7](C(C3C=CC=CC=3)C)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[CH3:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c1Oc1ccccc1N2C(C)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cccc2c1Oc1ccccc1N2

Procedure:
4-methyl-N-(α-phenylethyl)phenoxazine in 30 ml of ethyl acetate and 130 ml of ethanol was hydrogenated at atmospheric pressure (585 mm Hg) in the presence of 1.5 g of 10% palladium-charcoal as catalyst, until the calculated amount of hydrogen was consumed (16 hours). The catalyst was then separated by filtration through celite and the solvent removed under reduced pressure. Chromatography of the solid residue (1 g) on 100 g of silica gel in a column, using hexane-ethyl acetate (80:20) as the eluting solvent produced 4-methylphenoxazine, a white solid, which was recrystallized from pentane, mp: 91° C.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH2:23])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C1COCC1>[C:1]1([NH:7][C:8]([C:10]2[C:18]3[C:17]4[CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=[CH:22][C:16]=4[O:15][C:14]=3[C:13]([O:24][CH3:25])=[CH:12][CH:11]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(N)cc12
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2ccccc2)c2c1oc1ccc(NC(C)=O)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N1-phenyl-4-methoxy-8-amino-dibenzo[b,d]furan-1-carboxamide (69 mg, 0.207 mmol) (step 2) was treated with acetyl chloride (1.1 eq.) in THF (10 ml) containing pyridine (1.1 eq) at 0° C. and allowed to warm to room temperature. The reaction was stirred at room temperature for 2 h. THF was evaporated and the residue was washed ethanol to obtain 40 mg of N1-phenyl-4-methoxy-8-acetamido-dibenzo[b,d]furan-1-carboxamide as white solid; mp: 252° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][C:10]=2[Cl:32])[CH:5]=[CH:4][N:3]=1.CCN(CC)CC.[C:40](Cl)(=O)[O:41]C1C=CC=CC=1.[NH:50]1[CH2:55][CH2:54][O:53][CH2:52][CH2:51]1>C1COCC1>[Cl:32][C:10]1[CH:11]=[C:12]([NH:15][C:16]([C:18]2[C:19](=[O:31])[N:20]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:21]([CH3:24])[C:22]=2[CH3:23])=[O:17])[CH:13]=[CH:14][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:40]([N:50]2[CH2:55][CH2:54][O:53][CH2:52][CH2:51]2)=[O:41])[CH:7]=1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Reactant: O=C(Cl)Oc1ccccc1
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)N4CCOCC4)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a suspension of N-(4-((2-aminopyridin-4-yl)oxy)-3-chlorophenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (135 mg, 0.3 mmol) in THF (3 mL) was added Et3N (0.080 mL, 0.6 mmol), followed by adding phenyl carbonochloridate (0.075 mL, 0.6 mmol) dropwise. The reaction mixture was stirred at rt for 2 hours, then morpholine (0.250 mL, 3.0 mmol) was added. The reaction mixture was stirred at rt for 22 hours, quenched with saturated NH4Cl aqueous (20 mL) and CH2Cl2 (20 mL). The resulted mixture was stirred at rt for 10 minutes, and extracted with CH2Cl2 (20 mL×3). The combined organic phases were washed with brine (20 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=6/1) to give the title compound as a beige solid (43 mg, 25.4%).
Reaction SMILES: Cl[C:2]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl>C(Cl)Cl>[C:2]([O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(=O)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 50 °C
Yield: 67.3 %

Procedure:
To a solution of (chloromethanetriyl)tribenzene (9.8 g, 35.2 mmol) in DCM (500 ml), ethyl 2-hydroxyacetate (4.33 ml, 45.7 mmol) and Py (3.70 ml, 45.7 mmol) were added at RT. The reaction was heated at 50° C. for 9 hours. HCl 2N was added to the mixture, and the organic phase was separated, dried over Na2SO4 and evaporated under vacuum. The resulting white solid was triturated in Hexane. Ethyl 2-(trityloxy)acetate was obtained (8.2 g, 23.67 mmol, 67.3% yield) and used in the following step without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33]Br)([CH3:4])([CH3:3])[CH3:2].[F:36][C:37]([F:46])([F:45])[C:38]1[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][C:10]=1[CH2:33][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:37]([F:36])([F:45])[F:46])=[CH:39][CH:40]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1ccc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1COc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
A 50 mL round bottomed flask was charged with 3-[2-bromomethyl-4-(tert-butyldiphenylsilanyloxy)phenyl]propionic acid tert-butyl ester (1.0 g, 1.81 mmol), anhydrous DMF (10 mL), and then 4-trifluoromethylphenol (0.44 g, 2.7 mmol) and cesium carbonate (0.88 g, 2.7 mmol). The reaction mixture was stirred at ambient temperature under a nitrogen atmosphere for 18 h and concentrated. The residue was diluted with EtOAc (100 mL). The organic layer was washed with brine (2×), dried (Na2SO4), and concentrated to a yellow oil. The crude residue was purified using radial (EtOAc:hexanes 15:85 to 50:50) to give a yellow oil (0.66 g, 58%). MS (ES) m/e 635 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][CH:6]=1.C([Mg]Br)C.[C:11](Cl)(=[O:14])[CH2:12][CH3:13]>>[CH3:1][C:2]1[N:3]=[C:4]([C:11](=[O:14])[CH2:12][CH3:13])[S:5][CH:6]=1
Reactant: CCC(=O)Cl
Reactant: Cc1cscn1
Agent: CC[Mg]Br
Product: CCC(=O)c1nc(C)cs1

Procedure:
b. 4-Methyl-2-propionyl-thiazole was prepared according to the method described in Bull. 20, 702 (1953) by reacting 4-methyl-thiazole with ethyl-magnesium bromide and acylating the obtained Grignard intermediate with propionyl chloride. The product has a b.p. of 83°-88° C./9 mm. Hg.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][C:6]=1Br.O.CC(O)=O>CC(C)=O.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[O:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)c(Br)o1
Agent: [Zn]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Br)co1
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
A 500 mL three-necked round-bottom flask fitted with an overhead mechanical stirrer and reflux condenser was charged with 4,5-dibromo-furan-2-carboxylic acid (57.0 g, 211 mmol), H2O (168 mL), and HOAc (42 mL). The third neck of the flask was stoppered and the suspension was heated to reflux with a temperature controlled heating mantle held at 125-130° C. Zn dust (24.9 g, 381 mmol) (previously ground in a mortar and pestle to break up lumps) was added portionwise over 50 minutes. Subsequent portions are added after most of the previously added portion has disappeared. After the first portions of the Zn were added, all of the 4,5-dibromofuran-2-carboxylic acid dissolves to give a pale brown solution. Twenty-five minutes after the conclusion of the zinc addition a thick grey-white slurry had formed. HPLC analysis of the reaction slurry at this time indicated complete consumption of the starting 4,5-dibromofuran-2-carboxylic acid and conversion to the desired product. After 35 minutes, heating was discontinued, and the slurry was allowed to cool to ambient temperature. After cooling to ambient temperature the reaction slurry was diluted with cold H2O (175 mL), cooled in an ice bath, and then filtered. The white and grey solids were rinsed with cold H2O, and dried on the filter for 3 hours. The product/Zn mixture was then pumped down under high vacuum with gentle heating to afford white-grey flakes. A portion of the resulting solids (37.3 g) was dissolved in warm acetone (1.8 L, solubility about 20 g/L). The resulting solution was filtered to remove residual zinc dust, and then concentrated under reduced pressure to afford 4-bromo-furan-2-carboxylic acid as a white powder. This material was carried on to the acid chloride formation without purification. 1H-NMR (400 MHz, DMSO-d6): δ 7.96 (1H, d, J=0.8 Hz), 7.04 (1H, d, J=0.8 Hz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[F:15][C:14]([F:17])([F:16])[C:12]1[CH:11]=[C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:30]3[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=3)[CH:7]=2)[N:13]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(Cl)c3)n2)cc1
Reactant: OB(O)c1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3ccnc(-c4cccnc4)c3)n2)cc1

Procedure:
The title compound was prepared from 2-(2-chloro-pyridin-4-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.6) (0.202 g, 0.5 mmol) and commercially available 3-pyridineboronic acid (0.08 g, 0.65 mmol) according to the general procedure VI. Obtained as a white solid (0.013 g, 6%). MS (ISP) 447.0 [(M+H)+]; mp 247° C.
Reaction SMILES: [O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24]C(=O)C/C=C/C)[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.[F:31][C:32]([F:39])([F:38])[CH:33]([OH:37])[C:34](O)=[O:35]>>[O:1]1[C:9]2[CH:8]=[CH:7][N:6]=[C:5]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:34](=[O:35])[CH:33]([OH:37])[C:32]([F:39])([F:38])[F:31])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: C/C=C/CC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Reactant: O=C(O)C(O)C(F)(F)F
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C(O)C(F)(F)F

Procedure:
The title compound, light yellow solid (80 mg, 70%), MS (ISP) m/z=457.4 [(M+H)+], mp 204° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(6-methyl-2,3-dihydro-furo[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexylamine trihydrochloride (intermediate E) (110 mg, 0.25 mmol) and (RS)-3,3,3-trifluoro-2-hydroxypropanoic acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([OH:21])=[O:1]
Reactant: C1COCCO1
Reactant: O=C1Cc2cccc(OCc3ccccc3)c2N1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1c(CC(=O)O)cccc1OCc1ccccc1

Procedure:
A mixture of 2-oxo-7-benzyloxyindoline (2.15 g.), sodium hydroxide (0.84 g.), dioxane (20 ml.) and water (20 ml.) was refluxed under heating for 72 hours with stirring. After cooling, the reaction mixture was evaporated under reduced pressure. The residue was dissolved in water and the solution was washed with ethyl acetate. Diethyl ether was added to the solution and adjusted to pH 4 to 5 with 5% sulfuric acid. The diethyl ether layer was separated, washed with water, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was crystallized with a mixture of ethyl acetate and n-hexane to give 2-(2-amino-3-benzyloxyphenyl)acetic acid (2.2 g.).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]=[C:21]=[O:22]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:21]([NH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([F:12])([F:23])[F:24])=[O:22]
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1C(F)(F)F
Yield: 52.7 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-trifluoromethylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (154 mg, 1.0 mmol) and 2-trifluoromethylphenylisocyanate (1.0 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (180 mg, 52%). EI-MS m/z 342(M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].O=[C:11]([CH2:17][CH3:18])[CH2:12][C:13]([O:15][CH3:16])=[O:14].C1(C)C=CC=CC=1>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]([CH2:17][CH3:18])=[CH:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CCC(=O)CC(=O)OC
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(=CC(=O)OC)Nc1cc(Cl)cc(Cl)c1
Reaction time: 1 h
Yield: 64.9 %

Procedure:
In a 300 mL-flask were placed 3,5-dichloroaniline (25.0 g, 154 mmol), methyl 3-oxopentanoate (22.1 g, 170 mmol) and toluene (160 mL). To this solution was added p-toluenesulphonic acid monohydrate (0.59 g, 3.1 mmol), and the resulting mixture was heated in a bath kept at 100° C. under a reduced pressure of 21 kPa for 3 hours, while the water generated was taken out of the reaction system by using a Dean-Stark trap under reflux. p-Toluenesulphonic acid monohydrate (0.59 g, 3.1 mmol) was then added, and reflux was continued for 1 hour. The heating was then discontinued, nitrogen leaked in, and the reaction mixture cooled. After distillation of the solvent under reduced pressure, the residue was distilled under reduced pressure to give 27.4 g of the title compound. The yield was 64.8%.