Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=2)[CH2:5][CH2:4]1)#N.COC1C=CC(OCC[N:29]2[CH2:37][CH2:36][CH:32](C(N)=O)[CH2:31][CH2:30]2)=CC=1.C(Cl)(Cl)[Cl:41]>>[ClH:41].[ClH:41].[OH:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][N:6]2[CH2:5][CH2:4][CH:3]([CH2:1][C:30]3[CH:31]=[CH:32][CH:36]=[CH:37][N:29]=3)[CH2:8][CH2:7]2)=[CH:17][CH:16]=1
Reactant: ClC(Cl)Cl
Reactant: COc1ccc(OCCN2CCC(C#N)CC2)cc1
Reactant: COc1ccc(OCCN2CCC(C(N)=O)CC2)cc1
Product: Cl
Product: Oc1ccc(OCCN2CCC(Cc3ccccn3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Cyano-1-(2-(4-methoxyphenoxy)ethyl)piperidine. To a stirred suspension of 1-(2-(4-methoxyphenoxy)ethyl)isonipecotamide (10.0 g, 35.9 mmol) in CHCl3 (80 mL) neat SOCl2 (30 mL) was added drop wise over 5 min. The resulting suspension was heated at reflux with stirring under N2 for 1 h. The reaction was allowed to cool to 25° C. and the volatile portion was removed to give a yellow syrup. The syrup was partitioned between CHCl3 and H2O (200 mL) each. The stirred yellow mixture was made basic by the addition of concd NH4OH (50 mL) to give a pink mixture. The layers were separated and the aqueous portion was extracted with CHCl3 (2×50 mL). The combined organic portion was washed with 10% NH4OH, H2O and brine (200 mL each), was filtered through cotton and the solvent was removed to give a red oil that partially solidified upon standing. The product was purified on silica gel (3.5×25 cm) with CHCl3 then 2% EtOH/98% CHCl3 elution to yield the title compound as an amber oil that solidified to a beige solid upon standing (6.8 g, 73%): mp 49-51° C.; 1H NMR (CDCl3) 1.78-2.03 (m, 4H), 2.40-2.54 (m, 2H), 2.58-2.84 (m, 5H), 3.76 (s, 3H), 4.03 (t, J=5.7 Hz, 2H), 6.83 (s, 4H).
Reaction SMILES: [CH2:1]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)[CH:2]=[CH2:3].[Br:12][CH2:13][CH2:14][CH2:15][NH:16][CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19]>C1C=CC=CC=1>[Br:12][CH2:13][CH2:14][CH2:15][N:16]([CH:17]([CH2:20][O:21][CH3:22])[CH:18]=[O:19])[C:10]([NH:9][C:7]1[S:8][C:4]([CH2:1][CH:2]=[CH2:3])=[N:5][N:6]=1)=[O:11]
Reactant: C=CCc1nnc(N=C=O)s1
Reactant: COCC(C=O)NCCCBr
Solvent: c1ccccc1
Product: C=CCc1nnc(NC(=O)N(CCCBr)C(C=O)COC)s1

Procedure:
5-Allyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-γ-bromopropylamino-3-methoxypropionaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated at reflux for a period of about 30 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. This residue is then recrystallized to yield the desired product 2-[1-γ-bromopropyl-3-(5-allyl-1,3,4-thiadiazol-2-yl)-ureido]-3-methoxypropionaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[C:8]([C:17]([OH:19])=O)=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([S:29]([NH2:32])(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN1C(=O)CCC1.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[C:8]([C:17]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([S:29](=[O:31])(=[O:30])[NH2:32])[CH:24]=3)=[O:19])=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:21]=1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Reactant: O=C(O)c1nc2ccccc2nc1Oc1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Solvent: CN1CCCC1=O
Product: NS(=O)(=O)c1cccc(NC(=O)c2nc3ccccc3nc2Oc2ccc(F)cc2)c1
Yield: 31.7 %

Procedure:
A solution of 3-(4-fluorophenoxy)quinoxaline-2-carboxylic acid (28.42 mg, 0.1 mmol), 3-aminobenzenesulfonamide (20.7 mg, 0.12 mmol), HATU (38.0 mg, 0.10 mmol) and N-methylmorpholine (21.99 μL, 0.20 mmol) in NMP (0.5 mL) and DMSO (0.1 mL) was stirred at 25° C. for 16 hours. The reaction was filtered and purified by reverse phase HPLC using a gradient of 1-99% ACN in Water and HCl as a modifier. 3-(4-Fluorophenoxy)-N-(3-sulfamoylphenyl)quinoxaline-2-carboxamide (1) (13.9 mg, 32%) was obtained as a white solid. ESI-MS m/z calc. 438.08, found 439.5 (M+1)+; Retention time: 1.49 minutes (3 minutes run).
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.[NH2:12][C@:13]1([C:21]2[C:29]3[O:28][C:27]([F:31])([F:30])[O:26][C:25]=3[CH:24]=[CH:23][CH:22]=2)[C@H:18]([CH2:19]O)[CH2:17][CH2:16][O:15][CH2:14]1>ClCCl>[F:30][C:27]1([F:31])[O:26][C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C@@:13]34[N:12]=[C:10]([NH2:9])[S:11][CH2:19][C@@H:18]3[CH2:17][CH2:16][O:15][CH2:14]4)[C:29]=2[O:28]1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: N[C@@]1(c2cccc3c2OC(F)(F)O3)COCC[C@H]1CO
Solvent: ClCCl
Product: NC1=N[C@@]2(c3cccc4c3OC(F)(F)O4)COCC[C@H]2CS1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzoyl isothiocyanate (372 μl) was added to a solution of (±)-[(3S*,4R*)-3-amino-3-(2,2-difluorobenzo[1,3]dioxol-4-yl)tetrahydropyran-4-yl]methanol (661 mg) in dichloromethane (9.53 ml). The mixture was stirred at room temperature for three hours, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography. The resulting intermediate was dissolved in methanol (20 ml). Concentrated hydrochloric acid (five drops) was added and the mixture was heated under reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was dissolved in methanol (20 ml) and DBU (700 μl) was added, followed by heating under reflux for five hours. The reaction solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was purified by NH-silica gel column chromatography to obtain the title compound (350 mg). 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43-1.48 (m, 1H), 2.08-2.19 (m, 1H), 2.64 (dd, J=2.8, 12.4 Hz, 1H), 2.74-2.80 (m, 1H), 2.98 (dd, J=4.4, 12.4 Hz, 1H), 3.69 (ddd, J=2.4, 11.6, 12.8 Hz, 1H), 3.79 (d, 11.2 Hz, 1H), 3.93 (d, J=10.8 Hz, 1H), 4.10 (dd, J=5.2, 11.2 Hz, 1H) 6.99 (dd, J=2.0, 7.2 Hz, 1H), 7.03-7.09 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.COCCOC.C([O-])([O-])=O.[K+].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOC(C)=O>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][N:31]1[CH:35]=[C:34]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([CH2:11][C:12]4[CH:13]=[C:14]5[C:19](=[CH:20][CH:21]=4)[N:18]=[CH:17][CH:16]=[CH:15]5)=[CH:9][N:10]=3)[N:7]=2)[CH:33]=[N:32]1
Reactant: Clc1ccc2ncc(Cc3ccc4ncccc4c3)n2n1
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: c1cnc2ccc(Cc3cnc4ccc(-c5cnn(CCOC6CCCCO6)c5)nn34)cc2c1
Temperature: 90 °C
Reaction time: 5.5 h
Yield: 80 %

Procedure:
6-(6-Chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-quinoline (Example 14, 500 mg, 1.679 mmol) was introduced in a microwave reactor together with 1-[2-(tetrahydro-pyran-2-yloxy)ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 171.4, 812 mg, 2.52 mmol) and DME (10 mL). The solution was degassed with argon before adding Pd(PPh3)2Cl2 (36 mg, 0.051 mmol) and 2 M K2CO3 (2.267 mL, 4.53 mmol). The mixture was stirred at 90° C. for 5.5 h. The RM was taken up with EtOAc and washed with NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford a first batch of the desired product as a brownish oil (80% pure). 10% of the residue was dissolved in DCM and purified by flash chromatography (DCM/MeOH=100:0→93.5:6.5) to afford the title compound as a brownish oil (tR 2.30 min (8), MH+=455.1).
Reaction SMILES: FF.[CH2:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1O)[CH:4]=[CH2:5].[OH-:13].[K+].[Br:15][C:16](Br)([F:18])[F:17]>CN(C)C=O>[Br:15][C:16]([F:18])([F:17])[O:13][CH:5]=[CH:4][CH2:3][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: [OH-]
Reactant: FC(F)(Br)Br
Reactant: C=CCc1ccccc1O
Agent: FF
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(Br)OC=CCc1ccccc1
Yield: 9 %

Procedure:
According to the Journal of Fluorine Chemistry, 20, 765 (1982), o-allylphenol is dissolved in dimethylformamide, an equimolar amount of potassium hydroxide and a catalytic amount of 18-crownether-6 are added and then 2 moles of dibromodifluoromethane per mole of o-allylphenol is added. The mixture is reacted to obtain the corresponding o-(bromodifluoromethoxy)allylbenzene in a 9% yield.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.O1CCCC1.O1CCCC1.[Br-].[CH2:19]([Zn+])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>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.O>[CH2:19]([C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: [Zn+]Cc1ccccc1
Reactant: Brc1csc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: Brc1csc(Cc2ccccc2)n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
A flask containing 267 mg of tetrakis(triphenylphosphine)palladium and 1.00 g of 2,4-dibromothiazole was subjected to nitrogen substitution. To this flask, 9 ml of dry tetrahydrofuran and 9.9 ml of a 0.5 M benzylzinc bromide tetrahydrofuran solution were added. The obtained mixture was stirred at 70° C. for 6 hours. Thereafter, the reaction solution was cooled to a room temperature, and 30 ml of water was then added thereto, followed by extraction with 30 ml of ethyl acetate twice. The organic layer was washed with 30 ml of water twice and then with 30 ml of a saturated brine once. The resultant was dried over magnesium sulfate. The magnesium sulfate was filtrated, and the organic layer was then concentrated. The residue was then purified by column chromatography (Wako Gel C-200; hexane:ethyl acetate=14:1), so as to obtain 0.36 g of 2-benzyl-4-bromothiazole.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])[C:4](=O)[C:3]=1[C:22]#[N:23].[OH2:24].[NH2:25][NH2:26].O>C(O)C>[NH2:23][C:22]1[C:3]2[C:4](=[O:24])[N:5]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH3:20])[CH:6]=[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]=2[NH:26][N:25]=1
Reactant: O
Reactant: NN
Reactant: Cc1ccccc1-n1cc(-c2ccccc2)c(Cl)c(C#N)c1=O
Solvent: CCO
Product: Cc1ccccc1-n1cc(-c2ccccc2)c2[nH]nc(N)c2c1=O
Temperature: 70 °C
Yield: 26.6 %

Procedure:
To a solution of 4-chloro-1-(2-methylphenyl)-2-oxo-5-phenyl-1,2-dihydropyridine-3-carbonitrile obtained in Step B (255 mg) in ethanol (1.6 mL) was added hydrazine monohydrate (59.7 mg) at room temperature. The reaction mixture was heated at 70° C. for 2 hr, and cooled to room temperature, water was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by thin layer silica gel chromatography (methanol/dichloromethane) to give the title compound (67.0 mg).
Reaction SMILES: [CH2:1]([N:4]1[C:12](=[O:13])[C:11]2[N:10]=[C:9]([CH:14]([CH3:27])[CH2:15][C:16]3[CH:21]=[CH:20][C:19]([S:22][CH2:23][C:24]([OH:26])=O)=[CH:18][CH:17]=3)[NH:8][C:7]=2[N:6]([CH2:28][CH2:29][CH3:30])[C:5]1=[O:31])[CH2:2][CH3:3].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[CH2:52]([NH2:55])[CH2:53][NH2:54]>CN(C)C=O.CO.C(Cl)(Cl)Cl>[NH2:54][CH2:53][CH2:52][NH:55][C:24](=[O:26])[CH2:23][S:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][CH:14]([C:9]2[NH:8][C:7]3[N:6]([CH2:28][CH2:29][CH3:30])[C:5](=[O:31])[N:4]([CH2:1][CH2:2][CH3:3])[C:12](=[O:13])[C:11]=3[N:10]=2)[CH3:27])=[CH:17][CH:18]=1
Reactant: NCCN
Reactant: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)O)cc3)[nH]c2n(CCC)c1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2nc(C(C)Cc3ccc(SCC(=O)NCCN)cc3)[nH]c2n(CCC)c1=O
Reaction time: 1 h

Procedure:
Dissolve 2-[4-[2-(2,3,6,9-tetrahydro-1,3-dipropyl-2,6-dioxo-1H-purin-8-yl)propyl]phenylthio]acetic acid (785 mg, 1.87 mmol) in dimethylformamide (20 mL) and treat with N-hydroxysuccinimide (215 mg, 1.87 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (751 mg, 3.92 mmol). Stir for 1 hour and add to a stirring solution of ethylenediamine (20 mL of a 10% solution in methanol). Stir for 1 hour and dilute with chloroform (600 mL). Separate the organic phase, wash with 5% sodium carbonate (200 mL), then brine (300 mL). Dry (MgSO4) and evaporate the solvent in vacuo. Purify by radial chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1>[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8])=[O:24])([CH3:19])[CH3:18])#[N:16]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(O)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(O)cc1NC(=O)c1cccc(C(C)(C)C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a two-layer solution of 3-amino-4-methylphenol (3.25 g, 26.4 mmol) in tetrahydrofuran (20 mL)/1N aqueous sodium hydrogencarbonate solution (39 mL) was added a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride synthesized above in tetrahydrofuran (20 mL), and the mixture was stirred at room temperature for 3 hr. The aqueous layer was separated, and extracted with ethyl acetate (100 mL). The combined organic layer was washed with 5% aqueous sodium hydrogencarbonate solution (50 mL) and saturated brine (50 mL), successively, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate (45 mL)/hexane (45 mL) to give the title compound (5.95 g, 77%) as a colorless powder.
Reaction SMILES: C(O[CH:5]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C:9]2[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]([CH3:25])[CH3:24])[C:8]=2[NH:7][C:6]1=[O:26])(=O)C.[I-].[Na+].[K].[C:30]1(=[O:40])[NH:34][C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12>CN(C)C=O>[C:30]1(=[O:40])[N:34]([CH:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[F:18])[C:9]3[CH:19]=[CH:20][CH:21]=[C:22]([CH:23]([CH3:25])[CH3:24])[C:8]=3[NH:7][C:6]2=[O:26])[C:33](=[O:35])[C:32]2=[CH:36][CH:37]=[CH:38][CH:39]=[C:31]12
Reactant: CC(=O)OC1N=C(c2ccccc2F)c2cccc(C(C)C)c2NC1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc2c1NC(=O)C(N1C(=O)c3ccccc3C1=O)N=C2c1ccccc1F
Temperature: 90 °C
Reaction time: 1.3 h
Yield: 90.6 %

Procedure:
A mixture of (3RS)-3-acetoxy-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (2.73 g), sodium iodide (11.5 g) and phthalimide potassium salt (2.14 g) in N,N-dimethylformamide (18 ml) was stirred at 90° C. for 1.3 hours. The hot reaction mixture was poured into an ice with stirring to afford precipitates, which were collected by filtration, washed with water and air dried at room temperature to afford (3RS)-3-phthalimido-5-(2-fluorophenyl)-9-isopropyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (3.08 g, 90.6%) as a crystalline powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[S:24]([CH3:23])(=[O:26])=[O:25]
Reactant: Cc1ccc(NCc2cccnc2)c(C)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1ccc(N(Cc2cccnc2)S(C)(=O)=O)c(C)c1

Procedure:
A 4.2 g. portion of 3-(2,4-dimethylphenylaminomethyl)pyridine was dissolved in 20 ml. of dichloromethane and 4.1 g. of potassium carbonate and 2.5 ml. of methanesulfonyl chloride were added. The mixture was stirred over the week-end under reflux, and was then extracted with 20 ml. of aqueous sodium bicarbonate. The organic phase was dried and evaporated under vacuum. The residue was dissolved in diethyl ether and the solution was separated from insolubles and evaporated under vacuum. The oil was dissolved in chloroform and chromatographed over silica gel, eluting with chloroform:ethyl acetate to obtain 2.5 g. of the desired product, m.p. 62°-65°.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].[CH2:30](Br)[CH:31]=[CH2:32]>>[CH2:32]([O:28][C:5]1[CH:6]=[C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:1])[F:29])[CH:31]=[CH2:30]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: C=CCBr
Product: C=CCOc1cc(-c2nc(CNC(=O)c3ccccc3OCC)co2)ccc1OC(F)F

Procedure:
Using the compound obtained in Example 347 and allyl bromide, white powdery N-[2-(3-allyloxy-4-difluoromethoxy phenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH2:18])[CH:13]=2)=[N:9][N:8]=1.C(N(CC)CC)C.[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][S:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:37](=[O:38])[CH2:36][CH2:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:13]=2)=[N:9][N:8]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCc1ccccc1)Nc1cc(-c2nnc(SCc3cccc(F)c3)o2)ccn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 39.6 %

Procedure:
To a solution of 4-[5-[(3-fluorobenzyl)thio]-1,3,4-oxadiazol-2-yl]pyridin-2-amine (360 mg, 1.19 mmol) and triethylamine (290 mg, 2.86 mmol) in tetrahydrofuran (30 mL) was added 3-phenylpropionyl chloride (482 mg, 2.86 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=95/5-0/100) and recrystallized from hexane/ethyl acetate to give the title compound (205 mg, yield 40%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23](Br)=[CH:24][N:25]=1)[C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([Mg]Cl)(C)C.[CH2:36]([Sn:40](Cl)([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:41][CH2:42][CH2:43][CH3:44])[CH2:37][CH2:38][CH3:39]>O1CCCC1>[C:1]([O:5][C:6](=[O:30])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:20]1[C:21]2[N:22]([CH:27]=[CH:28][N:29]=2)[C:23]([Sn:40]([CH2:41][CH2:42][CH2:43][CH3:44])([CH2:45][CH2:46][CH2:47][CH3:48])[CH2:36][CH2:37][CH2:38][CH3:39])=[CH:24][N:25]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N(c1ccc(N2CCOCC2)cc1)c1ncc(Br)n2ccnc12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cnc(N(C(=O)OC(C)(C)C)c2ccc(N3CCOCC3)cc2)c2nccn12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 63.8 %

Procedure:
To a cooled (−78° C.) solution of (5-bromo-imidazo[1,2-a]pyrazin-8-yl)-(4-morpholin-4-yl-phenyl)-carbamic acid tert-butyl ester (2.55 g, 5.38 mmol) in tetrahydrofuran (20 mL) is added isopropylmagnesium chloride (0.829 g, 8.06 mmol). After stirring for 5 min tributyltin chloride (2.97 g, 9.14 mmol) is added and the reaction is stirred at −78° C. for 10 min before being allowed to warm to room temperature. After stirring at room temperature for 30 min, the mixture is concentrated. The residue is purified by silica gel flash column chromatography eluting with 5:1 petroleum ether-ethyl acetate followed by 1:1 petroleum ether-ethyl acetate to afford the product as yellow solid (2.35 g, 64%).
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH3:16])([CH3:15])[CH2:5][O:6][C:7]1[C:8]([NH2:14])=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.[H-].[Na+]>CS(C)=O.O>[Br:13][C:11]1[CH:10]=[N:9][C:8]2[NH:14][C:3](=[O:2])[C:4]([CH3:16])([CH3:15])[CH2:5][O:6][C:7]=2[CH:12]=1
Reactant: COC(=O)C(C)(C)COc1cc(Br)cnc1N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)COc2cc(Br)cnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.3 %

Procedure:
To a solution of 3-(2-amino-5-bromo-pyridin-3-yloxy)-2,2-dimethylpropionic acid methyl ester (880 mg, 2.90 mmol) in DMSO (40 mL) was added NaH (60% in oil, 139-mg, 3.48 mmol), and the mixture was stirred overnight at room temperature. The mixture was diluted with water (100 mL), and further stirred for 15 min. The resulting precipitate was collected by filtration to give the title compound (600 mg, 76%) as a white solid: 1H NMR (300 MHz, CDCl3) δ8.34 (br s, 1H), 8.11 (d, J=1.8 Hz, 1H), 7.46 (d, J=1.8 Hz, 1H), 4.01 (s, 2H), 1.32 (s, 6H); ESI M Sm/e 271 (M+H)+.
Reaction SMILES: P(Br)(Br)(Br)(Br)Br.[Br:7]Br.P(Br)(Br)Br.[C:13]1([CH2:19][CH2:20][CH2:21][CH:22](O)[CH3:23])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Cl-]>C(Cl)Cl.O>[Br:7][CH:22]([CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:23]
Reactant: CC(O)CCCc1ccccc1
Reactant: BrBr
Agent: BrP(Br)(Br)(Br)Br
Agent: BrP(Br)Br
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: CC(Br)CCCc1ccccc1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To phosphorus pentabromide, prepared by addition of bromine (9.0 g.) in methylene chloride (10 ml.) to phosphorous tribromide (15.0 g.) in methylene chloride (15 ml.) at 0° C., is added 5-phenyl-2-pentanol (8.2 g.) in metnhylene chloride at 0° C. The mixture is stirred for 2.5 hours at 0° C. and is then allowed to warm to room temperature. Water (50 ml.) is added, the mixture stirred for 1 hour and the methylene chloride layer separated. The extraction is repeated and the combined extracts washed with water, saturated sodium bicarbonate solution, brine and then dried over magnesium sulfate. Concentration of the dried extracts gives 12.4 g. of title product as a light yellow oil.