Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=O)=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2].[F:21][C:22]1[C:27]([F:28])=[CH:26][CH:25]=[CH:24][C:23]=1[C:29]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:30]=1[CH2:31][C:32](=[O:38])[NH:33]2>>[CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:16]=[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[CH:37][C:29]=4[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]([F:28])[C:22]=4[F:21])[NH:33][C:32]3=[O:38])=[C:14]([CH3:15])[C:8]=2[C:7]1=[O:18])[CH3:2]
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: CCN(CC)CCN1CCc2[nH]c(C=O)c(C)c2C1=O
Product: CCN(CC)CCN1CCc2[nH]c(C=C3C(=O)Nc4cccc(-c5cccc(F)c5F)c43)c(C)c2C1=O
Yield: 22 %

Procedure:
The title compound was prepared under the same conditions as described in Example 1 with 5-(2-diethylamino-ethyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one (prepared according to WO2002055517) as starting materials to give 5-(2-diethylamino-ethyl)-2-[4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (20 mg, 22.0%) as a yellow solid.
Reaction SMILES: Cl.[NH:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[C:3]([NH2:5])=[NH:4].[C:15]([O:19][C:20](=[O:47])[CH2:21][C:22]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([OH:33])[CH:30]=[CH:29][C:28]=2[CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)[CH2:23]1)([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O.C(#N)C.CN1C(=O)CCC1>[C:15]([O:19][C:20](=[O:47])[CH2:21][C:22]1([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[O:26][N:25]=[C:24]([C:27]2[CH:32]=[C:31]([O:33][C:10](=[O:11])[C:9]3[CH:8]=[CH:7][C:6]([NH:2][C:3]([NH2:5])=[NH:4])=[CH:14][CH:13]=3)[CH:30]=[CH:29][C:28]=2[CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:23]1)([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(O)ccc2C2CCCCC2)=NO1
Reactant: N=C(N)Nc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CC1(C(=O)OC(C)(C)C)CC(c2cc(OC(=O)c3ccc(NC(=N)N)cc3)ccc2C2CCCCC2)=NO1
Reaction time: 120 h
Yield: 17.4 %

Procedure:
4-Carbamimidamidobenzoyl chloride hydrochloride (55.1 mg) was added to a mixture of tert-butyl 5-(2-tert-butoxy-2-oxoethyl)-3-(2-cyclohexyl-5-hydroxyphenyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (54.1 mg), pyridine (0.06 mL), and NMP (0.06 mL) at 50 C, and the obtained mixture was stirred at 50 C for 5 days. The reaction mixture was fractionated by HPLC (C18, mobile phase: water/acetonitrile (system containing 0.1% TFA)). To the obtained fraction, a saturated aqueous solution of sodium bicarbonate was added, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the title compound (12.7 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[CH:10]1([CH2:16][CH:17]=O)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:17]/[CH2:16][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=CCC1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C/N=C/CC1CCCCC1
Yield: 96.1 %

Procedure:
In a manner similar to the method described in Example 1a, glycine tert-butyl ester (1.3 g, 10 mmol) was reacted with 2-cyclohexylacetaldehyde (Betapharma) (1.3 g, 10 mmol) in CH2Cl2 at room temperature for 5 h to give [2-cyclohexyl-eth-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (2.3 g, 96%).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][S@@](C(C)(C)C)=O)[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].Cl>CO.O>[CH:1]([O:4][C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1ccc([C@H](C)N[S@](=O)C(C)(C)C)cn1
Agent: Cl
Solvent: O
Solvent: CO
Product: CC(C)Oc1ccc([C@H](C)N)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(R)-2-Methyl-propane-2-sulfinic acid [(S)-1-(6-isopropoxy-pyridin-3-yl)-ethyl]-amide (2.90 g, 10.2 mmol) was dissolved in methanol (48 mL). A mixture of 12.0 M HCl in water (4.25 mL) and water (4.25 mL) was added drop wise over 3 minutes. The mixture was stirred at room temperature overnight. The mixture was evaporated to dryness. The oily residue was subjected to flash chromatography (silica, EtOAc/EtOH/triethylamine 90:5:5) on a short column to give (S)-1-(6-isopropoxy-pyridin-3-yl)ethylamine IM24 (1.71 g, 93%) as a pale-yellow oil sufficiently pure for the next step. The overall yield from 1-(6-isopropoxy-pyridin-3-yl)-ethanone IM16 was 54%.
Reaction SMILES: [O:1]=[CH:2][C:3]([Cl:6])([Cl:5])[Cl:4].[P:7]([O-:12])([O:10][CH3:11])[O:8][CH3:9]>C1C=CC=CC=1>[CH3:9][O:8][P:7]([CH:2]([OH:1])[C:3]([Cl:6])([Cl:5])[Cl:4])(=[O:12])[O:10][CH3:11]
Reactant: COP([O-])OC
Reactant: O=CC(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COP(=O)(OC)C(O)C(Cl)(Cl)Cl

Procedure:
In another process, Pesticide Manufacturing and Toxic Materials Control Encyclopedia, edited by Marshall Sittig, Noyes Data Corporation, Park Ridge, N.J. 1980, 75 grams of chloral are dropped into 60 grams of dimethyl phosphite at an initial temperature of 25° C. The temperature slowly rises to 50° C. and is kept at 50° C. to 60° C. by external cooling. After cooling the oil is dissolved in benzene, and the benzene solution is washed with a sodium bicarbonate solution and dried with anhydrous sodium sulfate. After the solvent has been distilled off, an oil is left which is almost completely solidified. After washing with an icy mixture of ether and petroleum ether, the trichloro-α-hydroxyethyl phosphonic dimethyl ester is obtained in the form of colorless needles with a melting point of about 81° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[C-:19]#[N:20].[Na+]>CC(C)=O.C(O)C.O>[C:19]([CH2:2][C:3]1[C:11]2[O:10][CH:9]=[C:8]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1)#[N:20]
Reactant: [C-]#N
Reactant: Fc1ccc(-c2coc3c(CCl)cccc23)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCO
Solvent: O
Product: N#CCc1cccc2c(-c3ccc(F)cc3)coc12

Procedure:
To a solution of 7-chloromethyl-3-(4-fluorophenyl)benzofuran (130.3 g., 0.50 mole) in acetone (750 ml.) and ethanol (500 ml.) is added a solution of sodium cyanide (39.5 g., 0.50 mole) in water 150 ml.). The mixture is heated to its reflux for 5 hours. The mixture is then evaporated in vacuo to concentrate it. The residue is dissolved in dichloromethane, then washed thoroughly with water, dried and concentrated by evaporation in vacuo. The oily residue is recrystallized twice from cyclohexane, then deposited on 70 g. of a magnesium silicate material used for elution chromatography and chromatographed on 400 g. of the silicate type column. Elution with hexane, benzene-hexane (1:4), (1:1) and (3:2), followed by benzene gives the desired product, 7-cyanomethyl-3-(4-fluorophenyl)benzofuran, in the benzene fractions.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:15](Br)=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[Cl-].[NH4+].[C:34](=O)(O)[O-:35].[Na+]>C1COCC1.CN(C=O)C.CCCCCC>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:15]([CH:34]=[O:35])=[CH:16][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)n1COCC[Si](C)(C)C
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(C=O)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1.08 h
Yield: 45 %

Procedure:
2-[5-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (3.804 g, 8.52 mmol) was dissolved in THF (42 mL) and cooled to −78° C. n-BuLi (3.4 mL of a 2.5 M hexane solution, 8.52 mmol) was added dropwise over 3 min. After 65 min, DMF (4 mL) was added and the reaction mixture was warmed to RT. After stirring at RT for 75 min, a saturated aqueous solution of ammonium chloride (50 mL) was added and the entire content of the flask was poured into saturated aqueous sodium bicarbonate. The aqueous phase was extracted 3 times with diethyl ether. The combined organic layers were dried over magnesium sulfate, concentrated and purified by silica column chromatography (30% to 70% EtOAc/hexanes) to provide 2-[5-Formyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.50 g, 45%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH:6]1[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7]1.[O:13]=[C:14]([NH:29][CH2:30][C:31](=O)[NH:32][C@@H:33]1[CH2:37]CNC1)[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CC(O)=O.C(Cl)Cl.CCOC(C)=O>[O:13]=[C:14]([NH:29][C@@H:30]1[CH2:37][CH2:33][N:32]([CH:9]2[CH2:10][CH2:11][CH:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH2:7][CH2:8]2)[CH2:31]1)[CH2:15][NH:16][C:17](=[O:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1
Reactant: O=C1CCC(c2nccs2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC(=O)N[C@@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCN(C2CCC(c3nccs3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
To a mixture of 4-(1,3-thiazol-2-yl)cyclohexanone (0.069 g, 0.38 mmol) and N-[2-oxo-2-({2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}amino)ethyl]-3-(trifluoromethyl)benzamide (0.10 g, 0.32 mmol) in 2% AcOH/CH2Cl2 (10 mL) was added NaB(OAc)3H (0.134 g, 0.634 mmol). After being stirred overnight at room temperature under N2, the reaction mixture was diluted with EtOAc and washed with saturated Na2CO3. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were dried (MgSO4), concentrated and flash chromatographed [EtOAc to MeOH/EtOAc (1:9) then to 5% MeOH/EtOAc/Et3N (1:9:0.5)] to give 0.129 g of the title compound in 85% yield. MS (EI) calcd: (M+H)+=480.2. Found: 480.3.
Reaction SMILES: C1(/C=[CH:8]/[C:9]2[CH:14]=[N:13][C:12]3=[N:15][S:16][N:17]=[C:11]3[CH:10]=2)C=CC=CC=1.C[N+]1([O-])CC[O:22]CC1.O.I([O-])(=O)(=O)=O.[Na+]>[Os](=O)(=O)(=O)=O.O.CC(C)=O>[N:17]1[S:16][N:15]=[C:12]2[C:11]=1[CH:10]=[C:9]([CH:8]=[O:22])[CH:14]=[N:13]2
Reactant: C[N+]1([O-])CCOCC1
Reactant: C(=C/c1cnc2nsnc2c1)\c1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=Cc1cnc2nsnc2c1
Reaction time: 20 h

Procedure:
To 6-[(E)-2-phenylethenyl][1,2,5]thiadiazolo[3,4-b]pyridine (0.88 g, 3.68 mmol) was added acetone (30 ml), N-methyl-morpholine-N-oxide, 50 wt. % in water (1.525 ml, 7.35 mmol) and then osmium tetroxide in water (0.225 ml, 0.037 mmol). The reaction was then stirred for 20 hours. To the pale brown solution was added sodium periodate (3.15 g, 14.71 mmol) and stirring continued for 45 mins. The solvent was reduced by rotary evaporation and the remainder partitioned between chloroform and water. The aqueous was further extracted with chloroform and the combined organic extracts passed through a hydrophobic frit and concentrated to give brown/black solid (0.6 g). A portion of this material (0.575 g) was purified by chromatography on silica eluting with 20% EtOAc in cyclohexane to a pale yellow solid (160 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([C:16](Cl)=[O:17])=[N:6][N:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:8]=1)[CH3:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][C:35]=1[F:41]>N1C=CC=CC=1.CCOC(C)=O>[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][C:30]=1[O:31][CH3:32])[N:27]=[CH:26][CH:25]=[C:24]2[O:33][C:34]1[CH:40]=[CH:39][C:37]([NH:38][C:16]([C:5]2[C:4]([O:3][CH2:1][CH3:2])=[CH:8][N:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[N:6]=2)=[O:17])=[CH:36][C:35]=1[F:41]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOc1cn(-c2ccc(F)cc2)nc1C(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(F)c1
Reaction time: 8 h
Yield: 51.6 %

Procedure:
Acid chloride D4 (0.17 mmol, 1.0 eq.) was dissolved in dry pyridine (1.5 mL) at 0° C. and A2 (34 mg, 0.11 mmol, 0.65 eq.) was added. The reaction was allowed to reach RT overnight. The mixture was diluted with EtOAc and washed twice with aq. KOH-solution (0.5N), twice with aq. sat. NH4Cl-solution, and finally once with brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (DCM/MeOH=100:0 to 10:1) to yield the desired product D5 (31 mg, 52% over 2 steps) as a white solid. 1H NMR (400 MHz, d6-DMSO, 300K) δ 1.38 (t, J=7.0 Hz, 3H), 3.94 (s, 6H), 4.09 (q, J=7.0 Hz, 2H), 6.48 (d, J=5.3 Hz, 1H), 7.43 (m, 4H), 7.53 (s, 1H), 7.70 (d, J=9.4 Hz, 1H), 8.01 (m, 3H), 8.47 (m, 2H), 10.17 (s, 1H). MS (ES) C29H24F2N4O5 requires: 546. Found: 547 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[C:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[CH:15]=2)[O:10][CH2:9]1.[H][H]>CCO.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:27])[F:28])=[CH:21][CH:20]=3)[CH:15]=2)[O:10][CH2:9]1
Reactant: [H][H]
Reactant: O=C1C(=Cc2ccccn2)COc2ccc(-c3ccc(OC(F)(F)F)cc3)cc21
Agent: [Pd]
Solvent: CCO
Product: O=C1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2OCC1Cc1ccccn1

Procedure:
A solution of 150 mg 3-(pyridin-2-ylmethylene)-6-(4-(trifluoromethoxy)phenyl)chroman-4-one (0.38 mmol) in 20 mL EtOH with catalytic Pd/C was stirred under 1 atm of hydrogen gas for 16 h. The reaction was filtered through celite and the filtrate concentrated. The filtrate was purified on silica gel column eluting with EA:Hex. 85 mg of an off-white solid was collected. m/z=400.
Reaction SMILES: [N:1]1([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C=O.[CH:20](O)=O>O>[CH3:20][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][N:9]=2)[CH2:2][CH2:3]1
Reactant: O=CO
Reactant: COC(=O)c1ccc(N2CCCNCC2)nc1
Agent: C=O
Solvent: O
Product: COC(=O)c1ccc(N2CCCN(C)CC2)nc1
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 1.50 g of methyl 6-homopiperazinylnicotinate (compound 13), 0.68 g of 35% formaldehyde and 1.2 g of formic acid was stirred at 70°-80° C. for 2 hours. The resulting mixture was poured into 120 ml of water and extracted with ethyl acetate. The extract was washed twice with water and once with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate and concentrated. Purification of the concentrate by column chromatography (silica gel; ethyl acetate : methanol=1:2) gave 1.35 g of methyl 6-(4-methyl-1-homopiperazinyl)nicotinate (yield 85%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][N:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[CH:11][C:10]2=[O:23])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:24][CH2:25][C:26](O)=[O:27].CN(C(O[N:37]1N=NC2C=[CH:41][CH:42]=[CH:43][C:38]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1.C(N(CC)CC)C>CN(C)C=O>[CH3:1][C:2]1[C:3]([NH:24][CH2:25][C:26](=[O:27])[N:37]2[CH2:38][CH2:43][CH2:42][CH2:41]2)=[CH:4][CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:11][C:10]1=[O:23]
Reactant: Cc1c(Cn2ccc(OCCc3cccs3)cc2=O)cccc1NCC(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCNC1
Product: Cc1c(Cn2ccc(OCCc3cccs3)cc2=O)cccc1NCC(=O)N1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of {2-Methyl-3-[2-oxo-4-(2-thiophen-2-yl-ethoxy)-2H-pyridin-1-ylmethyl]-phenylamino}-acetic acid (50 mg, 0.13 mmol), TBTU (60 mg, 0.19 mmol), pyrrolidine (0.02 ml, 0.25 mmol) and triethylamine (0.09 ml, 0.63 mmol) was dissolved in N,N-dimethylformamide (0.5 ml) and stirred at room temperature. After 1 hour, the resulting solution was evaporated, extracted with dichloromethane (20 ml) and subjected to silica gel column chromatography (ethyl acetate/MeOH, 20:1) to obtain the titled compound (41 mg, 71%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:10][C:5]2=[CH:4][CH:3]=1.C1C(=O)N([Br:27])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br-]>C(Cl)(Cl)(Cl)Cl>[Br:27][CH2:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2oc(-c3cccc([N+](=O)[O-])c3)nc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cccc(-c2nc3nc(CBr)ccc3o2)c1
Reaction time: 4 h

Procedure:
In a typical run, 400 mg of 5-methyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine (1.57 mmol) was suspended in 50 mL of CCl4 along with 280 mg (1.57 mmol) of NBS and 20 mg of benzoyl peroxide. The reaction mixture was stirred under reflux for 4 hours. LC/MS showed about 50% conversion to the desired bromide. After another 2 hours of reflux, no additional change was observed. Another 1 eq of NBS was added and reflux was continued for another 4 hours. LC/MS showed complete conversion. The reaction mixture was concentrated and the resulting crude product was purified by chromatography (Isco, gradient elution, CH2Cl2 to 9:1 CH2Cl2/MeOH) to afford essentially quantitative yield of 5-bromomethyl-2-(3-nitro-phenyl)-oxazolo[4,5-b]pyridine.
Reaction SMILES: CC1C2COC(=O)C=2C=CC=1[C@@H:12]1[CH2:14][O:13]1.Br[C:16]1[CH:25]=[CH:24][C:19]2[C:20](=[O:23])[O:21][CH2:22][C:18]=2[C:17]=1[C:26]([F:29])([F:28])[F:27]>>[O:13]1[CH2:14][CH:12]1[C:16]1[CH:25]=[CH:24][C:19]2[C:20](=[O:23])[O:21][CH2:22][C:18]=2[C:17]=1[C:26]([F:29])([F:28])[F:27]
Reactant: O=C1OCc2c1ccc(Br)c2C(F)(F)F
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Product: O=C1OCc2c1ccc(C1CO1)c2C(F)(F)F

Procedure:
5-(Oxiran-2-yl)-4-(trifluoromethyl)-2-benzofuran-1 (3H)-one was prepared in an analogous fashion to that described for the synthesis of 4-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (INTERMEDIATE 2) starting from 5-bromo-4-(trifluoromethyl)-2-benzofuran-1(3H)-one.
Reaction SMILES: [CH2:1]1[O:3][C@H:2]1[CH2:4][OH:5].[C:6]([NH2:10])([CH3:9])([CH3:8])[CH3:7]>O>[C:6]([NH:10][CH2:1][C@H:2]([OH:3])[CH2:4][OH:5])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)N
Reactant: OC[C@H]1CO1
Solvent: O
Product: CC(C)(C)NC[C@H](O)CO
Temperature: 25 °C
Yield: 78 %

Procedure:
(S)-Glycidol was added dropwise, with stirring, to a mixture of 54.7 g of tert-butylamine and 25 mL of water, heated at reflux. The resulting mixture was heated at reflux for 12 h, and was thereafter allowed to cool to room temperature. The mixture was concentrated in vacuo and was treated with ether to effect crystallization. 28.6 g (78%) of crystalline product was thus obtained: 1H NMR (CDCl3) δ1.0 (s, C(CH3)3), 2.4-2.6 (m), 3.3-4.2 (m); 13C NMR (CDCl3) δ28.6 (3 CH3), 45.2 (CH2NH), 50.2 (C(CH3)3), 65.5 (CH2OH), 70.6 (CHOH).
Reaction SMILES: [CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[N:17]=[CH:16][C:15]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[C:28]([F:33])[CH:27]=3)(C3C=CC(O)=C(F)C=3)[S:14]2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:36](I)[CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]>C(O)CCC>[CH2:1]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[S:14][C:15]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[C:28]([F:33])[CH:27]=3)=[CH:16][N:17]=2)=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCI
Reactant: CCCCCCc1ccc(C2N=CC(c3ccc(O)c(F)c3)(c3ccc(O)c(F)c3)S2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: CCCCCCOc1ccc(-c2cnc(-c3ccc(CCCCCC)cc3)s2)cc1F
Yield: 89.5 %

Procedure:
In a 30 ml-round-bottomed flask, 1.07 g (3.01 mM) of 2-(4-hexylphenyl)-5-(3-fluoro-4-hydroxyphenyl)-5-(3-fluoro-4-hydroxyphenyl)thiazole prepared in Synthesis Example 7, 0.23 g (3.48 mM) of potassium hydroxide and 5 ml of butanol were placed and heated to provide a solution. To the solution, 0.74 g (3.49 mM) of hexyl iodide was gradually added under heat stirring, followed by stirring for 5 hours at about 90° C. After the reaction, the solvent in the reaction mixture was distilled off under reduced pressure and water was added to the residue to precipitate a crystal. The crystal was recovered by filtration and washed with water. The resultant crystal was purified by silica gel column chromatography (eluent: toluene) and recrystallized from a mixture solvent (toluene-methanol) to obtain 0.90 g of 2-(4-hexylphenyl)-5-(3-fluoro-4-hexyloxyphenyl)thiazole (Yield: 68.0%). ##STR51##
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([C:11]([O:13]C)=O)=[N:5][CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][NH2:22])=[CH:19][CH:18]=1>O1CCCC1.C(OCC)(=O)C.O>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][N:5]=[C:4]2[C:11](=[O:13])[N:22]([CH2:21][C:20]3[CH:23]=[CH:24][C:17]([O:16][CH3:15])=[CH:18][CH:19]=3)[CH2:2][C:3]=12
Reactant: COC(=O)c1nccc(OC)c1CBr
Reactant: COc1ccc(CN)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2Cc3c(OC)ccnc3C2=O)cc1

Procedure:
Treat a solution of methyl 3-(bromomethyl)-4-methoxypicolinate (1.0 mmol, 1 eq) in tetrahydrofuran with 4-methoxybenzylamine (2.0 mmol, 2 eq) and stir the reaction for 16 h. After completion dilute the mixture with ethyl acetate and water and separate the layers. Wash the organic layer with 1 M hydrochloric acid and water. Concentrate the organic layer to give crude. Purify the crude by silica gel column chromatography to afford 4-methoxy-6-(4-methoxybenzyl)-5,6-dihydro-7H-pyrrolo[3,4-b]pyridin-7-one (2).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]1[CH2:12][CH:11]=[C:10](B2OC(C)(C)C(C)(C)O2)[CH2:9][CH2:8]1.Br[C:23]1[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=1.[Cl-].[NH4+]>COCCOC.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.C(OCC)(=O)C>[O:7]1[CH2:12][CH:11]=[C:10]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([F:29])[CH:24]=2)[CH2:9][CH2:8]1
Reactant: Fc1cc(Br)ccn1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Fc1cc(C2=CCOCC2)ccn1
Temperature: 80 °C
Yield: 88 %

Procedure:
A mixture of tetrakis(triphenylphosphine)palladium(0) (0.20 g, 0.17 mmol), aqueous sodium carbonate (2N aqueous, 8.52 mL, 17.05 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.43 g, 6.82 mmol), and 4-bromo-2-fluoropyridine (1.0 g, 5.68 mmol) in 1,2-dimethoxyethane (25 mL) was placed under argon atmosphere using 3 evacuation/backfill cycles. The mixture was then heated to 80° C. for 16 h then cooled to RT. Ethyl acetate and saturated aqueous ammonium chloride were added and the layers of the resulting biphasic mixture were separated. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 4-(3,6-dihydro-2H-pyran-4-yl)-2-fluoropyridine (0.90 g, 5.0 mmol, 89% yield) as a light yellow solid.