Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH2:9]([NH:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:10][CH2:11][CH3:12].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:9]([N:13]([CH2:14][CH2:15][CH2:16][CH3:17])[C:2]1[C:3]([CH3:8])=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: Cc1ccccc1Br
Reactant: CCCCNCCCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCCCN(CCCC)c1ccccc1C
Reaction time: 6 h
Yield: 82.5 %

Procedure:
The above general procedure was followed using 2-bromotoluene (171 mg, 1.00 mmol) and dibutylamine (129 mg, 1.00 mmol) with 2 mol % Pd(OAc)2 and 1.6 mol % tri-t-butylphosphine in 1.0 mL of toluene. After 6 hours, the reaction mixture was adsorbed onto silica gel and chromatographed with 2% ethyl acetate/hexanes to give 181 mg (83%) of N,N-dibutyl-o-toluidine. 1H NMR (500 MHz, CDCl3) δ 7.18 (t, J=7.8 Hz, 1H), 7.13 (d, J=7.8 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.97 (t, J=7.8 Hz, 1H), 2.91 (t, J=7.5 Hz, 4H), 2.30 (s, 3H), 1.41-1.37 (m, 4H), 1.27 (sept, J=7.3 Hz, 4H), 0.87 (t, J=7.3 Hz, 6H). 13C NMR (125 MHz, CDCl3) δ 150.7, 135.0, 130.9, 126.0, 123.1, 122.3, 53.9, 29.6, 20.5, 18.3, 14.0.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1)=O.B.C1COCC1>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@@H](c2ccc(F)cc2)C1
Agent: B
Solvent: C1CCOC1
Product: Fc1ccc([C@@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)cc1

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(S*)-3-(4-fluorophenyl)piperidin-1-yl]methanone (20 mg, 0.058 mmol) was treated with BH3THF according to the above general procedure. Flash chromatography gave the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:2]=1.Cl>C(O)C.[Pd]>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1ccncc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CC1CCNCC1

Procedure:
2.0 g of ethyl 4-pyridylacetate in 20 ml of ethanol are mixed with 400 mg of palladium black (20% by weight), adjusted to pH 2 with 1 N hydrochloric acid and hydrogenated under 3 bar at room temperature for 2 days. Solids are filtered off with suction through kieselguhr, and the solvent is removed from the filtrate under reduced pressure. The residue is taken up in 50 ml of ethyl acetate and 50 ml of water. The aqueous phase is adjusted to pH 13 with 1 N sodium hydroxide solution and extracted twice with 50 ml of ethyl acetate each time. The combined organic phases are dried over magnesium sulphate, and the solvent is removed under reduced pressure. 1.21 g (58% of theory) of the product are obtained.
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].Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: Brc1nccs1
Reactant: CC(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Oc1ccc(Oc2nccs2)cc1
Yield: 91.4 %

Procedure:
A mixture of Example 1A (15.5 g, 0.1 mol), 2-bromothiazole (18.2 g, 0.11 mol) and potassium carbonate (15.2 g, 0.11 mol) in dimethylsulfoxide was heated at 160° C. under nitrogen for six hours. After cooling and treating with water, the aqueous phase was extracted with dichloromethane. The organic layer was washed with brine, dried, and concentrated to give 27.5 g of the crude as a dark brown oil, which was purified on a silica gel (ethyl acetate/hexane 5-35%) to afford 21.5 g of the product as a brown oil (91% yield) 1H NMR (500 MHz, CDCl3) δ ppm 1.32-1.36 (m, 6H) 1.34 (none, 6H) 1.34 (none, 5 H) 4.45-4.57 (m, 1H) 6.76 (d, J=3.91 Hz, 1H) 6.87-6.93 (m, 2H) 7.15-7.20 (m, 2H) 7.21 (d, J=3.91 Hz, 1H). MS (ESI): m/z 236 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CN(C=O)C.[Pd]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([CH:6]=1)[NH2:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: Cc1ccc(C(C)(C)C)cc1N
Reaction time: 12 h

Procedure:
4-tert-Butyl-2-nitrotoluene (200 mg, 1.1 mmol) was dissolved in DMF (10 mL). The catalyst (10% Pd/C, 5 mg) was added and the system was purged with argon then exposed to H2 (1 atm) for 12 h. The mixture was filtered over a pad of diatomaceous earth and the filtrate was diluted with water and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with brine and dried (MgSO4). Removal of the volatiles in vacuo provided the product 5-tert-butyl-2-methylaniline.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([N+:12]([O-])=O)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Ni]>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([NH2:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)cc1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1ccc(C(C)(C)C)cc1N
Temperature: 35 °C

Procedure:
A solution of (239 g, 1.2 mol) 4-tert-butyl-1-methyl-2-nitro-benzene (M. S. Carpenter, W. M. Easter, T. F. Wood, J. Org. Chem. (1951), 586) in MeOH (1.0 L) was treated with Raney nickel (25 g) in a Parr shaker. The apparatus was sealed under hydrogen pressure to 52 psi, heated to 35° C. for 15 hours, and cooled to room temperature. The apparatus was vented and the contents filtered. The filtrate was concentrated in vacuo and distilled, collecting the major fraction (75-85° C., 1.0 torr). 1H NMR (CDCl3) δ 1.26 (s, 9 H), 2.11 (s, 3 H), 3.54 (bs, 2 H), 6.69 (d, 1 H), 6.72 (dd, 1 H), 6.96 (d, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH2:9][CH:10](I)[Sn:11]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])=[CH:4][CH:3]=1.O1CCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:26])([CH3:25])[CH:9]=[CH:10][Sn:11]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:20][CH2:21][CH2:22][CH3:23])=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)C(I)CC(C)(C)c1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](C=CC(C)(C)c1ccc(F)cc1)(CCCC)CCCC
Yield: 88.2 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 17.2 grams (0.030 mole) of 3-(4-fluorophenyl)-3-methyl-1-iodo-1-tributylstannylbutane and 13.7 grams (0.090 mole) of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)in 100 mL of tetrahydrofuran is heated at reflux for about 18 hours. The reaction mixture is cooled and poured into about 500 mL of water. The mixture is then made acidic with aqueous 2N hydrochloric acid and extracted with three 200 mL portions of diethyl ether. The combined extracts are dried with magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel, using 5% methylene chloride in petroleum ether as the eluant. The product-containing fractions are combined and concentrated under reduced pressure, yielding 12.0 grams of 3-(4-fluorophenyl)-3-methyl-1-tributylstannyl-1-butene. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11].C(N(CC)CC)C.[N+](C1C=CC([O:39][C:40]([N:42]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH2:45][CH2:44][CH2:43]2)=O)=CC=1)([O-])=O>>[F:21][C:19]([F:22])([F:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[S:10]([NH:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][NH:2][C:40]([N:42]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45][CH2:44][CH2:43]1)=[O:39])(=[O:12])=[O:11]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCCc2ccccc21
Reactant: NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(NCCCCCCNS(=O)(=O)c1ccccc1C(F)(F)F)N1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.3 %

Procedure:
To a solution of N-(6-Aminohexyl)-2-trifluoromethylbenzene sulfonamide Hydrochloride (0.1 g, 0.27 mmol) dimethyl formamide (3 mL) and triethylamine (0.1 g, 1 mmol) was added 3,4-Dihydro-2H-quinoline-1-carboxylic acid 4-nitrophenyl ester (0.09 g, 0.3 mmol) and the reaction mixture was stirred at room temperature for 4 h. Solvent was evaporated and purification by preparative TLC afford the titled compound as an oil (0.08 g, 61%).
Reaction SMILES: [ClH:1].CC([N:6]([CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]3[C:24]([CH3:25])=[CH:23][NH:22][C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)C(=O)[O-])(C)C>O1CCOCC1>[ClH:1].[CH3:25][C:24]1[C:17]2[C:16]([N:13]3[CH2:14][CH2:15][CH:10]([NH2:6])[CH2:11][CH2:12]3)=[N:21][CH:20]=[N:19][C:18]=2[NH:22][CH:23]=1
Reactant: Cc1c[nH]c2ncnc(N3CCC(N(C(=O)[O-])C(C)(C)C)CC3)c12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c[nH]c2ncnc(N3CCC(N)CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4M HCl in dioxane (10 mL) was added to 1,1-dimethylethyl[1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-4-piperidinyl]carbamate D10 (1.39 g) and the mixture stirred at room temperature for 1.5 hour. The white precipitate was filtered off, washed with dioxane and then Et2O before it was dried in a vacuum oven to give D11 (1.149 g) as a white solid, 1H NMR (d6-DMSO) δ 12.60 (1H, brs), 8.36 (1H, s), 8.34 (2H, m), 7.35 (1H, s), 4.20 (3H, m), 3.40 (2H, dt), 2.37 (3H, s), 2.10 (2H, m), 1.80 (2H, m), MS(ES+) 232 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C@H:5]([OH:10])[CH2:6][CH2:7][CH2:8][CH:9]=1.[Cl:11][C:12]([Cl:16])([Cl:15])[C:13]#[N:14]>C(OCC)C>[Cl:11][C:12]([Cl:16])([Cl:15])[C:13](=[NH:14])[O:10][C@@H:5]1[CH2:6][CH2:7][CH2:8][CH:9]=[C:4]1[Cl:3]
Reactant: O[C@@H]1CCCC=C1Cl
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Product: N=C(O[C@@H]1CCCC=C1Cl)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
Combine sodium hydride (0.50 g, 60% in oil, 12 mmol) and diethyl ether (50 mL) and cool to 0° C. Add over 15 minutes a solution of (R)-2-chloro-cyclohex-2-enylalcohol (23.0 g, 160 mmol) in diethyl ether (40 mL). Stir until gas evolution ceases. Add a solution of trichloroacetonitrile (20 mL, 200 mmol) in diethyl ether (30 mL). Stir at 0° C. for 30 minutes and then warm to ambient temperature over 1.5 hours. Evaporate the reaction mixture in vacuo to give the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Br:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:2]([O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1cccc(OCc2ccccc2)c1
Yield: 26.6 %

Procedure:
To a stirred solution of bromomethylbenzene (24.39 g, 143 mmol), 3-bromophenol (24.92 g, 144 mmol) in acetone (20 ml) was added potassium carbonate (59.72 g, 430 mmol). The suspension was refluxed overnight and then evaporated. To the residue was added H2O (100 ml) and extracted with EtOAc (3×80 ml). The combined EtOAc extracts were back washed with Na2CO3 and then dried over MgSO4, filtered and evaporated to get an off-white solid, which was purified via flash column chromatography (10% CH2Cl2 in hexane) to give 1-benzyloxy-3-bromo-benzene as a white solid (10 g, 67%): 1HNMR (DMSO-d6) 7.46-7.00 (m, 9H, Ar), 5.12 (s, 2H, CH2). The product was carried over to the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19].C([O-])(O)=O.[Na+]>ClCCl.CN(C1C=CN=CC=1)C>[F:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])=[N:3][CH:4]=1
Reactant: Nc1ccc(F)cn1
Reactant: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1ccc(F)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 76.6 %

Procedure:
To a 0° C. solution of 2-amino-5-fluoropyridine (1.00 g, 8.92 mmol) and triethylamine (1.35 g, 13.4 mmol) in dichloromethane (30 mL) was added trimethylacetyl chloride (1.29 g, 10.7 mmol) and DMAP (0.11 g, 0.89 mmol). The solution was allowed to warm to room temperature. After 4 h, saturated aqueous NaHCO3 was added, the layers separated and the aqueous phase backwashed with DCM. The combined organics were dried over magnesium sulfate, filtered and concentrated and the residue purified by silica gel chromatography (5%→40% EtOAc/hexanes) to give the title compound (1.34 g). MS 197.3 (M+1).
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CO>C1COCC1>[CH:1]1([C:7]2[C:15]3[C:10](=[CH:11][C:12]([C:16]([OH:18])=[O:17])=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(C3=CCCCC3)c[nH]c2c1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.9 %

Procedure:
3-Cyclohexenyl-1H-indole-6-carboxylic acid (38 g) was added to a Parr bottle, followed by methanol (100 mL) and THF (100 mL). The bottle was flushed with argon and 10% palladium on carbon (1.2 g) was added. The flask was then evacuated and subsequently refilled with H2 to a pressure of 55 psi, and the resultant mixture was shaken for 18 hours at RT. The catalyst was then removed by filtration through celite. Concentration of the filtrate provided the desired product as a pale purple solid (30.6 g, 79%). ESI-MS m/z 244 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][NH2:6].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCCC1>[C:18]([NH:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=1[O:2][CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccccc1CN
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1CNC(=O)c1ccccc1
Temperature: 16 °C
Yield: 87.1 %

Procedure:
To a mixture of o-methoxybenzylamine (20.0 g, 0.146 mol), tetrahydrofuran (124 mL) and triethylamine (15.6 g, 0.154 mol) was added dropwise benzoyl chloride (20.5 g, 0.146 mol) at −9-0° C., and the dropping funnel was washed with THF (10 mL). Under a nitrogen atmosphere, the reaction mixture was gradually warmed to about 16° C. During warming, THF (total 51 ml) was appropriately added to stir the content. The reaction was confirmed by TLC (eluent: hexane/ethyl acetate (1:1)). The reaction mixture was stirred at about 16° C. for 10 hr, and cooled to 5° C. Water (44 ml) was added thereto, and the mixture was extracted three times with ethyl acetate (120 mL, 40 mL, 40 mL). The combined organic layers were washed successively with 10% hydrochloric acid (40 mL), saturated aqueous sodium hydrogen carbonate solution (40 mL), water (40 mL) and saturated brine (44 mL), and dried over magnesium sulfate (20 g), and the solvent was evaporated under reduced pressure at 40° C. or lower. Ethyl acetate was added to the residue (content 74 g), and the solid was dissolved with heating to 60° C. The solution was gradually cooled to 6° C., the precipitated crystals were collected by filtration, washed with cold ethyl acetate (10 mL), and dried under reduced pressure at 40° C. or lower to give N-benzoyl-2-methoxybenzylamine (30.7 g, 87.1%) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[CH:12]=[C:11]([CH2:13][OH:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1.CCO>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]3[CH:12]=[C:11]([CH:13]=[O:14])[N:10]=[C:8]3[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)sc1nc(CO)cn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: COc1ccc2c(c1)sc1nc(C=O)cn12
Yield: 75 %

Procedure:
5.0 g (0.0225 mole) of the product of Step A and 10 g (0.115 mole) of manganese dioxide were stirred under reflux in 500 ml of chloroform for 2 hours. The mixture was filtered hot through celite and evaporated under reduced pressure to obtain 3.92 g (79% yield) of 7-methoxy-imidazo[2,1-b]benzothiazole-2-carboxaldehyde as colorless crystals melting at 214° to 215° C. (EtOH).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][CH2:7][CH2:8][CH2:9][OH:10]>C(Cl)Cl>[CH3:1][S:2]([O:10][CH2:9][CH2:8][CH2:7][F:6])(=[O:4])=[O:3]
Reactant: OCCCF
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OCCCF
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
A solution of methanesulfonyl chloride (1.714 ml, 22.00 mmol) in DCM (5 ml) was added dropwise to a stirred cold (0° C.) solution of 3-fluoropropan-1-ol (1.562 g, 20 mmol) and TEA (3.35 ml, 24.00 mmol) in DCM (20 ml). The mixture was stirred at 0-5° C. for ˜2 h and washed with water, satd. NaHCO3, water, brine and dried (MgSO4). Evaporation of DCM gave 3-fluoropropyl methanesulfonate as a colorless oil (2.92 g, 93.6%). Neat potassium thioacetate (2.74 g, 24.00 mmol) was added to a stirred solution of 3-fluoropropyl methanesulfonate (2.9 g) in DMSO (20 ml) and the mixture stirred overnight. Product was extracted with ether (2×25 ml), washed with water, brine and dried (MgSO4). Evaporation of ether gave S-3-fluoropropyl ethanethioate as a light brown oil. Chlorine gas was bubbled into cold (−10° C.) stirred two-phase solution of S-3-fluoropropyl ethanethioate (1.0 g, 7.34 mmol) in DCM (5 ml) and Water (5.00 ml) until green color appeared in aqueous phase and maintained for 1-2 h. Layers separated and aq. layer re-extracted with DCM (2×10 ml). Combined DCM extracts were washed with 10% NaHSO3 solution, water, brine and dried (MgSO4). Evaporation of DCM gave the intermediate, 3-fluoropropane-1-sulfonyl chloride as a light brown oil (405 mg, 34%) which was treated with an. NH3 solution (10 ml, 0.5M in dioxane) and stirred for 30-45 min. Precipitated NH4Cl was filtered off and the filtrate was evaporated to dryness to afford 3-fluoropropane-1-sulfonamide as a light brown oil (265 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([CH:8]([Br:10])[Br:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C=CC=CC=1.[Br:20]Br.[OH-].[Na+]>O>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([Br:20])([Br:9])[Br:10])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: BrBr
Reactant: O=[N+]([O-])c1ccc(C(Br)Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(C(Br)(Br)Br)cc1
Temperature: 50 °C
Reaction time: 10 h
Yield: 85 %

Procedure:
A solution of 100 parts of p-nitrobenzal bromide in 500 parts of toluene is added to a solution of 80 parts of bromine plus 160 parts of 50% sodium hydroxide in a 1,000 parts of water at 50° C. The mixture is stirred mechanically at 50° C for 10 hours. The toluene layer is separated; the water layer is extracted with 500 parts of toluene. The combined toluene layers are dried and evaporated to give 110 parts (85% yield) of p-nitrobenzotribromide, m.p. 74°-81° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: O=Cc1ccc(-c2ccc(Cl)cc2)cc1
Yield: 94 %

Procedure:
A mixture of 4-chlorobenzeneboronic acid (19.4 g, 1 equiv), 4-bromobenzaldehyde (22.9 g, 1 equiv), palladium(II) acetate (1.4 g, 0.05 equiv), aqueous sodium carbonate (30.3 g in 144 ml solution, 2 equiv) and dimethoxyethane (500 ml) was stirred at reflux under argon for 2.5 h, then evaporated to low volume and diluted with dichloromethane. Workup continued as in (a) above to give identical material (25.2 g, 94%). 1H-NMR (CDCl3) δ 10.05 (1H, s), 7.96 (2H, d), 7.73 (2H, d), 7.57 (2H, d), 7.46 (2H, d); MS (AP+) found (M+1)=217, C13H9ClO requires 216.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)CCCOc1cccc(Br)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCCOc1cccc(Br)c1
Temperature: 50 °C

Procedure:
Ethyl 4-(3-bromophenoxyl)butanoate was taken up in 100 mL THF and 50 mL water and treated with lithium hydroxide LiOH (hydrate, 4.9 g). The whole was heated at 50° C. for 2 days. The mixture was cooled to room temperature and acidified to pH 1 with 2N HCl. The aqueous was extracted with ethylacetate. The combined organics were washed with brine and dried over sodium sulfate to give crude 4-(3-Bromophenoxy)butanoic acid as a sticky solid. 1H NMR (DMSO-d6, 500 MHz) 7.24 (m, 1H), 7.13 (m, 1H), 7.11 (m, 1H), 6.95 (m, 1H), 3.99 (m, 2H), 2.37 (m, 2H), 1.94 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:33])([F:32])[F:31])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([C:26]([F:29])([F:28])[F:27])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH:55]1[CH2:59][C:58](=[O:60])[NH:57][CH2:56]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:30]([F:31])([F:32])[F:33])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:55]4[CH2:59][C:58](=[O:60])[NH:57][CH2:56]4)=[O:22])=[C:19]([C:26]([F:27])([F:28])[F:29])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(C(F)(F)F)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: O=C1CNCN1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C1CN(C(=O)c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2C(F)(F)F)CN1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 50-mL round bottom flask, was placed 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)benzoic acid (50 mg, 0.10 mmol, 1.00 equiv), N,N-dimethylformamide (2 mL), EDCI (38 mg, 0.20 mmol, 2.00 equiv), HOBt (27 mg, 0.20 mmol, 2.02 equiv), TEA (50 mg, 0.49 mmol, 5.00 equiv), imidazolidin-4-one (17 mg, 0.20 mmol, 2.00 equiv). The resulting solution was stirred for 30 min at 25° C. The resulting solution was allowed to react, with stirring, for an additional 5 h at 25° C. The reaction was then quenched by the addition of 10 ml of water. The resulting solution was extracted with 2×10 ml of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×10 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a TLC plate with PE/EA (1/1). This resulted in 50 mg (79%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-4,5-dihydro-1,2-oxazol-3-yl]-2-(trifluoromethyl)phenyl)carbonyl]imidazolidin-4-one as yellow oil.