Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:20]1[C:28]2[CH:27]=[CH:26][C:25](C#N)=[C:24]3[CH2:31][CH:32]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[CH2:33][CH:22]([C:23]=23)[CH2:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Mg]Br.[NH4+].[Cl-].C1C[O:49][CH2:48][CH2:47]1>C(OCC)C>[C:48]([C:25]1[CH:26]=[CH:27][C:28]2[NH:20][CH2:21][C@H:22]3[CH2:33][C@@H:32]([N:34]([CH2:38][CH2:39][CH3:40])[CH2:35][CH2:36][CH3:37])[CH2:31][C:24]=1[C:23]=23)(=[O:49])[CH3:47]
Reactant: C1CCOC1
Reactant: CCCN(CCC)C1Cc2c(C#N)ccc3c2C(C1)CN3C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CCCN(CCC)[C@H]1Cc2c(C(C)=O)ccc3c2[C@@H](CN3)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2.4 g (4.6 mmol) (+)-1-trityl-6-cyano-4-(di-n-propylamino)-1,2,2a,3,4,5-hexahydrobenz[cd]indole in 100 mL of THF was treated with 25 mL of 2.0M methylmagnesium bromide in diethyl ether. The reaction mixture was refluxed for 16 hr. The reaction mixture was cooled and excess Grignard reagent was decomposed with addition of saturated NH4Cl solution. The reaction mixture was extracted with ethyl acetate. The organic solution was evaporated to an oil. The oil was dissolved in 25 mL of 5N HCl and the solution was stirred at room temperature for 30 min. The acidic solution was made alkaline with the addition of excess concentrated NH4OH solution. The basic mixture was extracted twice with ethyl acetate. The combined organic solution was washed once with saturated NaCl solution and dried over MgSO4. The ethyl acetate solution was evaporated to yield 1.4 g of an oil. Chromatography of this oil over silicia gel with ethyl acetate as eluent gave 1.2 g (87%) of product. Recrystallization from hexanes yielded 840 mg of the product (+) ketone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH2:8].[CH2:9]([O:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[CH2:9]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[O:1][C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]=2)=[CH:24][CH:25]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Nc1cnccc1O
Reactant: O=C(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: c1ccc(COc2ccc(-c3nc4cnccc4o3)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a cooled (0° C.) suspension of commercially available 4-hydroxy-3-amino-pyridine (14, 19.3 g, 175 mmol) in acetonitril (1500 ml) was added 4-benzyloxy-benzoic acid (24, Ra═Rb═H, 40 g, 175 mmol), triphenylphosphine (142.5 g, 543 mmol, 3.1 eq) and trichloroactonitril (54.5 ml, 543 mmol, 3.1 eq). The reaction mixture was allowed to reach room temperature and the mixture was stirred for 16 hrs at 80° C. The mixture was concentrated in vacuo and the residues was dissolved in DCM and washed with 2N NaOH (3×). The combined water layers were extracted with DCM and the organic layers dried (Na2SO4) to give crude 25 (Ra═Rb═H) as oil which was used in the next step without further purification.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:48])([CH3:47])[CH3:46])[C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][OH:40])=[CH:35][CH:34]=3)=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[NH2:68][C:69]1[N:73]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[N:72]=[C:71]([C:81]2[CH:86]=[CH:85][C:84](O)=[CH:83][CH:82]=2)[C:70]=1[C:88]#[N:89].C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C1COCC1>[NH2:68][C:69]1[N:73]([C:74]([O:76][C:77]([CH3:80])([CH3:79])[CH3:78])=[O:75])[N:72]=[C:71]([C:81]2[CH:86]=[CH:85][C:84]([O:40][CH2:39][C:36]3[CH:35]=[CH:34][C:33]([C:25]4[S:24][C:23]([N:20]5[CH2:19][CH2:18][C:17]6[C:22](=[C:13]([C:11](=[O:12])[N:10]([C:2]7[S:1][C:5]8[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=8[N:3]=7)[CH2:41][O:42][CH2:43][CH2:44][Si:45]([CH3:47])([CH3:46])[CH3:48])[CH:14]=[CH:15][CH:16]=6)[CH2:21]5)=[N:27][C:26]=4[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:38][CH:37]=3)=[CH:83][CH:82]=2)[C:70]=1[C:88]#[N:89]
Reactant: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Reactant: CC(C)(C)OC(=O)n1nc(-c2ccc(O)cc2)c(C#N)c1N
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(COc2ccc(-c3nn(C(=O)OC(C)(C)C)c(N)c3C#N)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 601 %

Procedure:
A mixture of compound 34D (0.14 g, 0.2 mmol), PPh3 (0.079 g, 0.3 mmol), and compound 31F (0.066 g, 0.022 mmol) was dissolved in THF (3 mL). The solution was cooled to 0° C. To this solution was added DBAD. The reaction mixture was stirred at rt for 2 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel eluting with 2:1/hexanes:EtOAc to afford 0.13 g of the title compound as a mixture of two inseparable isomers. MS (ESI(+)): m/z 982 (M+NH4—H2O).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]=[O:11])[S:7][CH:6]=1)=[O:4].[CH2:12]([Mg]Cl)[C:13]([CH3:16])([CH3:15])[CH3:14].O>CCOCC>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([CH:10]([OH:11])[CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[S:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C[Mg]Cl
Reactant: COC(=O)c1csc(C=O)c1
Solvent: CCOCC
Solvent: O
Product: COC(=O)c1csc(C(O)CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
A solution of 5-formyl-thiophene-3-carboxylic acid methyl ester (0.504 g, 2.96 mmol) in Et2O (30 mL) at 0° C. is treated with neopentyl magnesium chloride (7.1 mL, 0.5 M in Et2O, 3.6 mmol) and stirred for 15 min. Solution warmed to rt and additional Et2O (10 mL) added. The reaction mixture is stirred overnight at rt. after which it is poured into H2O (30 mL) and extracted with EtOAc (3×50 mL). Combined extracts washed with brine, dried over MgSO4, filtered, and concentrated. The residue is loaded onto silica gel and eluted using hexanes with an ethyl acetate gradient from 0% to 50%. The resulting mixture is then loaded onto C18 and eluted using H2O and a MeCN gradient from 15% to 100% giving (±)-5-(1-hydroxy-3,3-dimethyl-butyl)-thiophene-3-carboxylic acid methyl ester (0.316 g, 44%) as a light yellow syrup.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH:6]2[O:8][CH:5]2[CH2:4]1)[CH3:2].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[OH:16].Cl>Cl.C(Cl)Cl>[ClH:9].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][C@@H:6]1[CH2:7][N:3]([CH2:1][CH3:2])[CH2:4][C@H:5]1[OH:8]
Reactant: Oc1ccccc1Cl
Reactant: CCN1CC2OC2C1
Agent: Cl
Solvent: ClCCl
Product: CCN1C[C@@H](O)[C@H](Oc2ccccc2Cl)C1

Procedure:
A mixture of 17.0 g. (0.15 mole) of 1-ethyl-3,4-epoxypyrrolidine, 20.5 g. (0.16 mole) of a o-chlorophenol and 3 drops concentrated hydrochloric acid was heated on a steam both overnight. The oil was dissolved in methylene chloride and washed with three 50-ml. portions of 5% sodium hydroxide and one 50-ml. portion of water. The methylene chloride solution was dried over anhydrous sodium sulfate, concentrated and chromatographed on silica gel to give 8.9 g. (25%) of an oil as residue. The oil was converted to the hydrochloride and recrystallized from ethyl acetateacetonitrile to yield white powder, m.p. 108°-110° C.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][NH2:27].N1CCCN2CCCCCC=12.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:27][CH2:26][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[O:17][CH3:16])[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(I)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
A solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (50 g, 157 mmol), (2,4-dimethoxyphenyl)methanamine (60 g, 359 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (47.9 g, 314 mmol) in acetonitrile (500 mL) was treated with ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (100 g, 192 mmol) and stirred for 6 hours at room temperature under nitrogen. The resulting suspension was filtered to remove precipitate and the filtrate was evaporated. The residue was purified on a silica cartridge (1500 g) (applied in minimum DCM) eluted with 0-80% cyclohexane-EtOAc (12 column volumes). Product-containing fractions were part evaporated to give a heavy suspension that was filtered and the solid air-dried to give the title compound (37.5 g, 80 mmol) as a white powder.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]3[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]4[O:32][C:31]([CH3:34])([CH3:33])[CH:30](O)[C:29]=4[C:36]=3[CH3:37])[CH2:21][CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>>[CH2:1]([NH:8][CH:30]1[C:29]2[C:36]([CH3:37])=[C:25]([N:22]3[CH2:21][CH2:20][CH:19]([C:13]4[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([O:10][CH3:9])[CH:12]=4)[CH2:24][CH2:23]3)[C:26]([CH3:39])=[C:27]([CH3:38])[C:28]=2[O:32][C:31]1([CH3:34])[CH3:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1OC
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)C(NCc3ccccc3)C(C)(C)O4)CC2)cc1OC
Yield: 80 %

Procedure:
Using benzylamine and 5-(4-(3,4-dimethoxyphenyl)piperidino)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 19, the title compound was synthesized in the same manner as in Example 57. Yield 80%. Amorphous state powder.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[OH-].[Na+].[C:13](Cl)(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].S(=O)(=O)(O)O>O.CC(C)=O>[C:13]([NH:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6])(=[O:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: NC(=O)CC[C@H](N)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@@H](CCC(N)=O)C(=O)O

Procedure:
108 g of L-glutamine was dissolved in 343 g of water and 102 g of aqueous 27% sodium hydroxide solution, and cooled to 10° C. 138 g of acetone was added to it, and 152 g of lauroyl chloride and 108 g of aqueous 27% sodium hydroxide solution were dropwise added thereto. The acylation liquid was diluted with 300 g of water, then neutralized with 35 g of 75% sulfuric acid and filtered to obtain a white powdery substance, N-lauroyl-L-glutamine. 72.4 g of thionyl chloride was dropwise added to 424 g of isopropyl alcohol, then 100 g of N-lauroyl-L-glutamine was added thereto and reacted at room temperature for 8.5 hours. The reaction liquid was added to 2.0 L of water to precipitate the intended product, and this was taken out by filtration to obtain a crude product. This was recrystallized repeatedly three times with acetone to obtain 59.1 g of N-lauroyl-L-glutamine isopropyl ester.
Reaction SMILES: [CH2:1]([CH:3]1[C:9](=[O:10])[NH:8][C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4]1)[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:2].[CH3:22][C:23](C)([O-])C.[K+].BrCC>O1CCCC1>[CH2:22]([N:8]1[C:7]2=[C:11]3[C:16](=[N:17][C:18]4=[CH:19][CH:20]=[CH:21][C:5](=[C:6]24)[O:4][CH:3]([CH2:1][CH3:2])[C:9]1=[O:10])[CH2:15][CH2:14][CH2:13][CH2:12]3)[CH3:23]
Reactant: CC(C)(C)[O-]
Reactant: CCC1Oc2cccc3nc4c(c(c23)NC1=O)CCCC4
Agent: [K+]
Solvent: CCBr
Solvent: C1CCOC1
Product: CCC1Oc2cccc3nc4c(c(c23)N(CC)C1=O)CCCC4
Reaction time: 0.33 h
Yield: 80.4 %

Procedure:
To a solution of 3-ethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one (4.98 g) in dry tetrahydrofuran (150 ml) was added potassium t-butoxide (2.26 g). The mixture was stirred for 20 mins, bromoethane (5.0 ml) was added, and the reaction mixture was refluxed overnight. The reaction mixture was concentrated, diluted with sodium bicarbonate solution (250 ml), and extracted twice with ethyl acetate (250 ml). The extracts were dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated, and the residue was triturated first with pentane and then diethyl ether to give 4.40 g (80.3%) of 1,3-diethyl-1,3,9,10,11,12-hexahydro-2H-quino[4,3,2-ef][1,4]benzoxazepin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29](C)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH3:33]>>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:14](=[O:15])[C:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:33])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2-c2ccc(F)cc2)cc1
Reactant: N
Product: NS(=O)(=O)c1ccc(-c2cnn(-c3ccc(F)c(F)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to Example 384 substituting 2-(3,4-difluorophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 182) in place of 2-benzyl-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (yield: 950 mg, 54%). mp 177–181° C. 1H NMR (300 MHz, DMSO-d6) δ 7.15 (t, 2H), 7.29 (m, 2H), 7.43 (s, 1H), 7.45 (bs, 2H), 7.59 (m, 2H), 7.76 (d, J=9 Hz, 2H), 7.85 (m, 1H), 8.27 (s, 1H). MS (DCI/NH3) m/z 458 (M+H)+, 475 (M+NH4)+. Anal. calc. for C22H14F3N3O3S: C, 57.77; H, 3.08; N, 9.19. Found, C, 57.22; H, 3.28; N, 8.99.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:28][CH2:27][C:26]([CH2:32][CH3:33])([C:29]([OH:31])=[O:30])[CH2:25][CH2:24]2)[CH:16]=[CH:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[C:34]1(C2(C(O)=O)CCNCC2)[CH:39]=CC=[CH:36][CH:35]=1.C(C1CCC(OC2C=C3C(=CC=2)C=C(C=O)C=C3)CC1)(C)(C)C.C(O)(=O)C.CO.C([BH3-])#N.[Na+]>>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH:18]=[C:17]([CH2:22][N:23]2[CH2:24][CH2:25][C:26]([C:32]4[CH:36]=[CH:35][CH:34]=[CH:39][CH:33]=4)([C:29]([OH:31])=[O:30])[CH2:27][CH2:28]2)[CH:16]=[CH:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC1(C(=O)O)CCN(Cc2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3c2)CC1
Reactant: O=C(O)C1(c2ccccc2)CCNCC1
Agent: CC(C)(C)C1CCC(Oc2ccc3cc(C=O)ccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)C1CCC(Oc2ccc3cc(CN4CCC(C(=O)O)(c5ccccc5)CC4)ccc3c2)CC1
Yield: 5 %

Procedure:
The compound was prepared in a manner similar as to that described for 1-[6-(4-tert-Butyl-cyclohexyloxy)-naphthalen-2-ylmethyl]-4-ethyl-piperidine-4-carboxylic acid using 4-Phenyl-piperidine-4-carboxylic acid (0.198 g, 0.967 mmol), 6-(4-tert-Butyl-cyclohexyloxy)-naphthalene-2-carbaldehyde (0.250 g, 0.805 mmol), acetic acid (0.16 mL, 2.8 mmol), Methanol (1.6 mL, 4.0E1 mmol) and sodium cyanoborohydride (75.314 mg, 1.1985 mmol) to give 21 mg of the title compound as a white solid (5%). ESI-LCMS (500 M+H). 1H NMR (DMSO-d6, 400 MHz): Shift (ppm) 7.80-7.98 (m, 3H), 7.16-7.63 (m, 8H), 4.51 (br. s., 3H), 3.45-3.64 (m, 2H), 2.96-3.18 (m, 2H), 2.68 (m, 2H), 2.13-2.31 (m, 2H), 1.74-2.09 (m, 4H), 1.00-1.53 (m, 5H), 0.89 (s, 9H)
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].I[CH3:27].[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N(C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.44 mmol) of Compound 27 obtained in Example 27 was dissolved in 30 ml of dimethylformamide under argon atmosphere and the solution was cooled on ice. 0.27 ml of iodomethane and 63 mg of sodium hydride (60% oil dispersion) were added, the mixture was stirred at the same temperature for 1 hour and the temperature was raised to room temperature to stir for additional 2 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was distilled off and the tan residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2) to give 2-[4-(N-acetyl-N-methylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [CH2:1](Cl)/[CH:2]=[CH:3]\[OH:4].C[OH:7].[OH-].[CH3:9][N+:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CN(C)C=O.C(O)(=O)C=CC1C=CC=CC=1.C1C=CC=CC=1>[C:3]([O-:4])(=[O:7])[CH:2]=[CH:1][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:9][N+:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CO
Reactant: O/C=C\CCl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C(O)C=Cc1ccccc1
Agent: [OH-]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: O=C([O-])C=Cc1ccccc1

Procedure:
A 6.5 g amount of polyepichlorohydrin was dissolved in 227 ml of dimethylformamide while heated under a nitrogen atmosphere. In addition, 13.6 g of cinnamic acid was dissolved in 177 ml of benzene and then 38.3 g of a 40% methanol solution of trimethylbenzyl ammonium hydroxide was admixed with the solution. Trimethylbenzyl ammonium cinnamate was isolated when the benzene solvent was evaporated in addition to the methanol and the water formed by the neutralization reaction. The product obtained was admixed with the solution of polyepichlorohydrin and the mixture was reacted at 80° C for 6.5 hours. The reaction mixture was mixed with methanol and 12 g of a rubber-like white polymer was obtained. Infrared spectrum analysis and elemental analysis of the product indicated that the polymer was a photosensitive resin having units 1 and 2 wherein the ratio of 1 to 2 was 71% to 29%. ##STR6##
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:39][C:40]1[N:41]([CH3:46])[CH2:42][C:43](=[O:45])[N:44]=1.C(N(CC)CC)C>C1COCC1>[CH3:46][N:41]1[CH2:42][C:43](=[O:45])[N:44]=[C:40]1[NH:39][C:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])=[O:38])=[C:18]([CH2:26][CH2:27][CH3:28])[CH:19]=1)=[O:24]
Reactant: CN1CC(=O)N=C1N
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCc1cc(C(=O)NC2=NC(=O)CN2C)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Yield: 60.5 %

Procedure:
To a solution of 200 mg (0.370 mmol) of N-(4-isopropylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (from Step D) in 1 mL of dry THF was added 90 mg (0.556 mmol) of 1,1-carbonyldiimidazole. The solution was stirred at reflux under N2 for 2 hours. The cooled solution was evaporated to dryness. The residue was dissolved in 1 mL of acetonitrile and treated with 63 mg (0.556 mmol) of 2-amino-4,5-dihydro-1-methyl-1H-imidazol-4-one (creatinine) and 129 μL (93.7 mg; 0.925 mmol) of triethylamine. The mixture was stirred at reflux overnight. The cooled reaction mixture was quenched by addition of 1N HCl and extracted twice with EtOAc. The combined organic extracts were dried over MgSO4, and filtered. The filtrate was concentrated, and the residue was flash chromatographed (silica gel, 27×3.5 cm; elution with 500 mL of 99:1:1 CHCl3 -MeOH-concentrated NH4OH followed by 1 L of 85:15:1 CHCl3 -MeOH-concentrated NH4OH) to give 142 mg (60%) of the title compound as a yellow solid, mp 137°-139 ° C.; homogeneous by TLC in 85:15:1 CHCl3 -MeOH-concentrated NH4OH. ESI mass spectrum m/e 635 (M+H)+.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[Mg].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>O1CCCC1>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]([OH:12])[CH2:3][CH:2]=[CH2:1])=[CH:9][CH:8]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: C=CCCl
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 108.6 %

Procedure:
Allyl chloride (97.88 g, 1.28 mol) in dry tetrahydrofuran (500 ml) was added to a suspension of magnesium turnings (60.08 g, 2.47 mol) in dry tetrahydrofuran (50 ml) at such a rate as to maintain steady reflux. The mixture was then heated under reflux for a further hour. 4-Chloro-benzaldehyde (120 g, 854 mmol) in dry tetrahydrofuran (600 ml) was then added dropwise and the mixture refluxed for a further 2 hours. After being cooled to room temperature the mixture was poured into ice/water, carefully acidified with 1M sulphuric acid and extracted with ether. The combined extracts were washed with brine, dried and evaporated in vacuo to give crude 4-(4-chlorophenyl)but-1-en-4-ol (169.4 g approximately 92% pure) which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](O)=[O:25])=[CH:18][CH:17]=1.S(Cl)(Cl)=O.[C:31]([NH2:34])(=[O:33])[CH3:32]>CO>[C:31]([NH:34][C:24](=[O:25])[CH2:23][CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:6][C:2]=2[CH3:1])=[CH:21][CH:20]=1)(=[O:33])[CH3:32]
Reactant: CC(N)=O
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCC(=O)O)cc1
Solvent: CO
Solvent: O=S(Cl)Cl
Product: CC(=O)NC(=O)CCc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 100 °C
Yield: 32.3 %

Procedure:
To 3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (1.50 g, 4.27 mmol) obtained in Example 17 was added thionyl chloride (2.0 ml), and the mixture was stirred under heating for 1 hr at 100° C. Excess thionyl chloride was evaporated under reduced pressure and acetamide (504 mg, 8.54 mmol) was added to the obtained residue. The mixture was stirred under heating for 1 hr at 120° C. Methanol (5 ml) was added, and the reaction mixture was stirred for 10 min and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (developing solvent; n-hexane:ethyl acetate=1:1) to give the title compound (541 mg, yield 32%) as a white solid.