Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[F:2][CH:3]([F:14])[C:4]1[C:8]([C:9](F)=[O:10])=[C:7]([F:12])[N:6]([CH3:13])[N:5]=1.Cl.S1(=O)(=[O:21])CCCC1>>[F:12][C:7]1[N:6]([CH3:13])[N:5]=[C:4]([CH:3]([F:14])[F:2])[C:8]=1[C:9]([OH:21])=[O:10]
Reactant: Cn1nc(C(F)F)c(C(=O)F)c1F
Reactant: O=S1(=O)CCCC1
Agent: Cl
Agent: [Na]
Product: Cn1nc(C(F)F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 400 ml of a 1N sodium hydroxyde aqueous solution, was added dropwise 67.5 g of a solution (10% molar) of 3-(difluoromethyl)-5-fluoro-1-methyl-1H-pyrazole-4-carbonyl fluoride in tetrahydrothiophene 1,1-dioxide. The temperature was kept below 20° C. during the addition. After 2 hours of stirring at room temperature, the reaction mixture was carefully acidified to pH 2 with concentrated aqueous hydrochloric acid. The resulting white precipitate was filtered, washed with water, and dried to yield 6 g of 5-fluoro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carboxylic acid as a white solid.
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N+:51]([C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][NH:60][CH2:59][CH2:58]1)([O-:53])=[O:52]>CN(C=O)C.O>[N+:51]([C:54]1[CH:66]=[CH:65][CH:64]=[CH:63][C:55]=1[O:56][CH:57]1[CH2:62][CH2:61][N:60]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[NH:11][N:10]=2)=[O:13])[CH2:59][CH2:58]1)([O-:53])=[O:52]
Reactant: O=[N+]([O-])c1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2[N+](=O)[O-])CC1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 8 h
Yield: 37.1 %

Procedure:
To a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (0.15 g, 0.0006 mol) in DMF (3 mL) was added DIPEA (0.27 g, 0.0021 mol), HOBt (0.12 g, 0.0009 mol) and EDCI.HCl (0.17 g, 0.0009 mol) at ambient temperature. After 2 minutes 4-(2-nitro-phenoxy)-piperidine hydrochloride (0.19 g, 0.00073 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The product was extracted with ethyl acetate, and the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using neutral aluminium oxide (5% methanol in chloroform) to afford 0.1 g (44%) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[4-(2-nitro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 450.17 (M+1)+, 96.5%, 1H NMR (DMSO-d6): δ 8.1 (bs, 1H), 7.9 (m, 3H), 7.6 (m, 1H), 7.5 (m, 4H), 7.1 (m, 2H), 5.0 (m, 1H), 4.2 (m, 2H), 3.8 (m, 8H), 2.0 (m, 2H).
Reaction SMILES: B1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][CH:11]=2)OC(C)(C)C(C)(C)O1.I[C:24]1[CH:37]=[N:36][C:27]2[NH:28][C:29]3[CH:34]=[N:33][C:32]([Br:35])=[CH:31][C:30]=3[C:26]=2[CH:25]=1>C(=O)([O-])[O-].[Na+].[Na+].CC1CCCO1.C(OCC)(=O)C>[Br:35][C:32]1[N:33]=[CH:34][C:29]2[NH:28][C:27]3[N:36]=[CH:37][C:24]([C:10]4[CH:11]=[CH:12][C:13]([CH2:16][N:17]5[CH2:18][CH2:19][O:20][CH2:21][CH2:22]5)=[CH:14][CH:15]=4)=[CH:25][C:26]=3[C:30]=2[CH:31]=1
Reactant: Brc1cc2c(cn1)[nH]c1ncc(I)cc12
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC1CCCO1
Product: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCOCC4)cc3)cc12
Temperature: 85 °C
Yield: 30.2 %

Procedure:
A degassed mixture of 4-(4-morpholinomethyl)phenylboronic acid pinacol ester (486 mg, 1.61 mmol), 3-iodo-6-bromo-9H-dipyrido[2,3-b;4′,3′-d]pyrrole (400 mg, 1.07 mmol), 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) (131 mg, 0.16 mmol) in 2N aqueous sodium carbonate solution (8 mL) and 2-methyltetrahyrdofuran (16 mL) was heated at 85° C. for 18 h. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (75 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 50 g column, Biotage, 0-15% methanol in DCM) to afford the title compound as an off-white solid (137 mg, 30%). 1H NMR (CDCl3, 300 MHz): 12.41 (s, 1H), 9.04 (d, J=2.3 Hz, 1H), 8.95 (d, J=2.3 Hz, 1H), 8.72 (d, J=1.0 Hz, 1H), 8.53 (s, 1H), 7.76 (d, J=8.0 Hz, 2H), 7.47 (d, J=8.0 Hz, 2H), 3.65-3.56 (m, 4H), 3.53 (s, 2H), 2.44-2.29 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](C=O)=[CH:5][C:6]2[CH2:7][CH:8]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[CH:9]3[CH:14]([C:15]=2[CH:16]=1)[CH2:13][CH2:12][CH2:11][CH2:10]3.[C:27]([C:32]1C=CC=C[C:33]=1P(=C)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28].C(OCC)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:27](=[O:28])[CH:32]=[CH:33][C:4]1[C:3]([O:2][CH3:1])=[CH:16][C:15]2[CH:14]3[CH:9]([CH2:10][CH2:11][CH2:12][CH2:13]3)[CH:8]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:31]
Reactant: COc1ccc(C2Cc3cc(C=O)c(OC)cc3C3CCCCC23)cc1
Reactant: C=P(c1ccccc1)(c1ccccc1)c1ccccc1C(=O)OCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1cc2c(cc1OC)C1CCCCC1C(c1ccc(OC)cc1)C2
Yield: 74.6 %

Procedure:
Combine 3-Methoxy-9-(4-methoxy-phenyl)-4b,5,6,7,8,8a,9,10-octahydro-phenanthrene-2-carbaldehyde (1.77 g, 5.13 mmol), carboethoxy-methylene triphenylphosphorane (03.19 g, 9.03 mmol) in toluene (53 ml) and reflux 15 hours. Remove solvent in vacuo, slurry with diethyl ether and chromatograph the residue from the concentrated filtrate on silica gel with 20% ethyl acetate/hexanes, then 25% ethyl acetate/hexanes to yield the titled compound (1.61 g, 76%). MS m/z 421(M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C[O:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24]Br)[CH:19]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([OH:26])=[O:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(COc2ccc(-c3ccc(Br)cc3)cc2)c1

Procedure:
3-(4′-Bromo-biphenyl-4-yloxymethyl)-benzoic acid was prepared using general procedure A from 4-bromo-4′-hydroxybiphenyl (available from TCI America, Portland, Oreg.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 91 mg. Mass spectrum (ES) MH+=383.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Cl[CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][CH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=1)=[O:6]
Reactant: ClCc1ccc2ccccc2n1
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCc2ccc3ccccc3n2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
A mixture of 3-hydroxybenzaldehyde (6.71 g), 2-(chloromethyl)quinoline (8.88 g) and potassium carbonate (8.28 g) in N,N-dimethylformamide (25 ml) was stirred at 60° C. for 3 hours. The mixture was allowed to cool and concentrated in vacuo. The residue was treated with water. The separated oil was extracted with ethyl acetate. The organic layer was washed with brine, dried, and evaporated to give an oil, which was crystallized from n-hexane to yield 2-[[3-(formyl)phenoxy]methyl]quinoline (12.5 g).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[NH:9][N:8]=1)=[O:6].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[CH3:3][O:4][C:5]([C:7]1[N:11]=[C:10]([Cl:12])[N:9]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[N:8]=1)=[O:6]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COC(=O)c1n[nH]c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)n(COCC[Si](C)(C)C)n1
Reaction time: 0.5 h
Yield: 57.6 %

Procedure:
To a suspension of NaH (60% dispersion, 53.9 mg, 1.34 mmol) in DMF (5 mL) at 0° C., a solution of 5-chloro-1H-[1,2,4]-triazole-3-carboxylic acid methyl ester (Bull. Pharm. Sci., 20(1): 47-61, (1997), 218 mg, 1.35 mmol) in DMF (10 mL) was added dropwise. The resulting suspension was stirred at the same temperature for 30 min and then treated with SEMCl (0.24 mL, 1.4 mmol). The resulting solution was stirred at RT for 30 min and poured onto ice. The mixture was extracted with ether (3×20 mL) and the ether layers were combined, dried (Na2SO4) and concentrated in vacuo. The residue obtained was chromatographed on silica (10% EtOAc/hexane) to obtain the title compound (227 mg, 58%). Mass spectrum (ESI, m/z): Calcd. for C10H18ClN3O3Si, 292.0 and 294.0 (M+H). found 291.5 and 293.6.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[C:17](C(OC)=O)([F:19])[F:18]>CN(C=O)C.O>[F:18][CH:17]([F:19])[O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: COC(=O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(OC(F)F)cc1
Temperature: 95 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a solution of 4-hydroxybenzonitrile (4.76 g, 40 mmol) in 150 mL of DMF was added 5.52 g (40 mmol) of K2CO3. The mixture was heated at 95° C. and 5.27 mL (50 mmol) of CICF2CO2Me was added slowly over 10 minutes. The reaction was stirred at 95 ° C. for 15 minutes and a 1.5 mL portions of ClCF2CO2Me were added until no changes were observed by TLC. The reaction was stirred overnight at room temperature diluted with water (300 mL) and extracted with Et2O. The combined organic layers were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (30% ethyl acetate/hexane) to afford the corresponding nitrile as a white solid (3.0 g, 44%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[C:15]([CH3:19])[CH:14]=[CH:13][C:12]=3[NH:11][C:10](=[O:20])[C:9]=2[CH:8]=[N:7]1)[CH3:2].CI.[C:24]([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[C:15]([CH3:19])[CH:14]=[CH:13][C:12]=3[N:11]([CH3:24])[C:10](=[O:20])[C:9]=2[CH:8]=[N:7]1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)Cn1ncc2c(=O)[nH]c3ccc(C)cc3c21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)Cn1ncc2c(=O)n(C)c3ccc(C)cc3c21
Yield: 80 %

Procedure:
(8-Methyl-4-oxo-4,5-dihydro-pyrazolo[4,3-c]quinolin-1-yl)-acetic acid ethyl ester m (285 mg, 1 mmol), methyl iodide (142 mg, 1 mmol) and Cs2CO3 (650 mg, 2 mmol) were combined in dry DMF (4 mL) and the resultant mixture was heated at 40° C. for 8 h. The reaction mixture was cooled, diluted with water and extracted with ethyl acetate (2×20 mL) and the combined organic extract was dried over Na2SO4, and concentrated in vacuo. The crude residue was purified by column chromatography to provide the desired compound n (80% yield): LC MS (Method B): 300 (M+1).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH2:5][CH2:4][N:3]=1.Cl[CH2:17][C:18](=O)[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(=O)([O-])O.[Na+]>C(O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]1[CH:1]=[C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[CH2:5][CH2:4][N:3]2[CH:17]=1
Reactant: COC(=O)CC(=O)CCl
Reactant: COc1cc2c(cc1OC)C(C)=NCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)Cc1cc2n(c1)CCc1cc(OC)c(OC)cc1-2
Yield: 56.4 %

Procedure:
10.3 g (50.0 mmol) of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline, 8.3 g (55.0 mmol) of methyl 4-chloroacetoacetate and 12.6 g (150 mmol) of sodium hydrogen carbonate in 100 ml of ethanol are heated at reflux for 5 hours. After evaporation to dryness, the residue is taken up in 250 ml of dichloromethane and washed twice with 100 ml of water each time. After drying the organic phase over magnesium sulphate and then concentrating, the residue (15.5 g) is chromatographed on 500 g of silica (eluant: dichloromethane) to yield 8.5 g of the expected product (theory: 15.1 g).
Reaction SMILES: [CH:1]1([CH2:13][CH2:14][C:15]([O:17]C)=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:19].[Na+].[OH2:21]>CO>[CH:1]1([CH2:13][CH2:14][C:15]([C:14]2[C:15](=[O:17])[O:19][CH2:1][C:13]=2[OH:21])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: [OH-]
Reactant: COC(=O)CCC1CCCCCCCCCCC1
Reactant: O
Agent: [Na+]
Solvent: CO
Product: O=C(CCC1CCCCCCCCCCC1)C1=C(O)COC1=O
Temperature: 55 °C

Procedure:
To a solution of 7.6 g (30 mmol) of methyl 3-cyclododecylpropanoate in 100 ml of methanol is added 2.4 g of sodium hydroxide. The mixture is heated to 55° C. and is maintained for 4 hours. The reaction mixture is diluted with water and is extracted with hexane. The aqueous phase is acidified with 1N hydrochloric acid and is extracted (2 times) with ethyl ether. The combined ethereal extracts are washed with 1N hydrochloric acid and are dried over magnesium sulfate. Filtration and evaporation gives 7.48 g of crude title compound. Recrystallization of a portion of the product from hexane gives 1.81 g of the title compound: m.p. 72°-74° C.; IR (KBr) 1715 cm-1 ; NMR (CDCl3) δ 1.34 (m, 23H), 1.57 (q, 2H, J=8 Hz), 2.36 (t, 2H, J=8 Hz). Anal. Calc'd. for C15H28O2 : C, 74.95;H, 11.74; Found: C, 74.90;H, 11.20.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(N(CC)C(C)C)(C)C.[OH:38][CH2:39][C:40]1([C:43](O)=[O:44])[CH2:42][CH2:41]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O.O>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:39]([C:40]6([CH2:43][OH:44])[CH2:42][CH2:41]6)=[O:38])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Reactant: O=C(O)C1(CO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1)C1(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-amine tris-hydrochloride (230 mg, 0.50 mmol) in N,N-dimethylformamide (4 mL) were added N,N-diisopropylethylamine (0.7 mL, 4.0 mmol), 1-hydroxymethyl-cyclopropanecarboxylic acid (70 mg, 0.6 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (190 mg, 0.6 mmol). The resulting mixture was stirred at rt overnight. The mixture was diluted with water (30 mL), and the precipitate was collected by filtration and dried in vacuum, giving the title compound as brown solid. LC-MS (ES, Pos.): 447 [MH+]. 1H NMR (DMSO-d6, 400 MHz): δ=0.74 (s, 2H), 0.77 (s, 2H), 2.51 (m, 2H), 3.50 (d, J=5.9 Hz, 2H), 3.85 (m, 2H), 4.20 (m, 2H), 4.90 (br s, 1H), 6.44 (s, 1H), 6.84 (s, 1H), 7.88 (dd, J=8.9 Hz, 2.1 Hz, 1H), 8.04 (d, J=8.9 Hz, 1H), 8.34 (s, 1H), 8.92 (d, J=2.1 Hz, 1H), 9.24 (s, 1H), 9.62 (s, 1H), 12.02 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li].C[Si](N[Si](C)(C)C)(C)C.[C:28]1(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.O>O1CCCC1>[C:16]([CH:15]([C:12]1[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)[C:28]1([OH:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)#[N:17]
Reactant: N#CCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCCCC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: N#CC(c1ccc(OCc2ccccc2)cc1)C1(O)CCCCC1
Temperature: -78 °C
Yield: 69.5 %

Procedure:
p-Benzyloxyphenyl acetonitrile (50 g) was added to dry tetrahydrofuran (250 ml) and cooled to −78° C. Lithium HMDS (20.8 g) in tetrahydrofuran (60 ml) was added slowly to the reaction mixture at −70° C. followed by dropwise addition of cyclohexanone (26.6 g. 0.27 mol) and maintaining the temperature at −60° C. for 2 h. The reaction temperature was allowed to rise to 0° C., charged with water (300 ml) and the organic layer was separated. The aqueous layer was then extracted with ethylacetate. The two organic layers were combined, washed with DM water and dried using Na2SO4. The solvent was evaporated under reduced pressure to give 50 g (70.0%) of 1-[cyano(p-benzyloxyphenyl)methyl]-cyclohexanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([CH3:19])[CH:13]=2)[CH:3]=1.[NH2:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24]>>[ClH:1].[CH3:19][C:14]1[CH:13]=[C:12]([C:4]2[CH:3]=[C:2]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[CH:16][C:15]=1[CH3:18]
Reactant: Cc1ccc(-c2cc(Cl)c3ccccc3n2)cc1C
Reactant: NCC(O)CO
Product: Cc1ccc(-c2cc(NCC(O)CO)c3ccccc3n2)cc1C
Product: Cl

Procedure:
The title compound, m.p. 248° C. and MS: m/e=322 (M+), was prepared 4-chloro-2-(3,4-dimethyl-phenyl)-quinoline and (RS)-3-amino-1,2-propandiol.
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][O:14][C:15]1[CH:19]=[C:18]([CH2:20][OH:21])[O:17][N:16]=1.O[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][C:30]([O:32][CH3:33])=[O:31].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:19]=[C:18]([CH2:20][O:21][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH2:29][C:30]([O:32][CH3:33])=[O:31])[O:17][N:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CO)on1
Reactant: COC(=O)Cc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)Cc1ccccc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Reaction time: 15 h

Procedure:
To a mixture of 3-(5 methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethanol (0.859 g), methyl 2-(2-hydroxyphenyl)acetate (0.499 g), triphenylphosphine (0.944 g) and tetrahydrofuran (15 mL) was dropwise added a solution (40%, 1.74 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography to give methyl 2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]phenyl]acetate as an oil from a fraction eluted with ethyl acetate-hexane (1:2, v/v). This oil was dissolved in methanol-tetrahydrofuran (1:1, 20 mL) and a 1N aqueous sodium hydroxide solution (10 mL) was added. The mixture was stirred at room temperature for 15 hrs. The reaction mixture was poured into water, 1N hydrochloric acid (10 mL) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals of 2-[2-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazoly]methoxylphenyl]acetic acid. Recrystallization from ethanol-hexane gave colorless needle crystals (0.651 g, 52%). melting point: 152-153° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[F:7])=[O:5].[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:25]([CH3:30])([CH3:29])[O:26]2)=[CH:21][C:20]=1[C:37](=O)[CH3:38])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:28]=[C:27]2[C:22]([C:23]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:24][C:25]([CH3:29])([CH3:30])[O:26]2)=[CH:21][C:20]=1/[C:37](/[CH3:38])=[C:6](/[F:7])\[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH3:17]
Reactant: CCOc1cc2c(cc1C(C)=O)C(c1ccccc1)=CC(C)(C)O2
Reactant: CCOC(=O)C(F)P(=O)(OCC)OCC
Product: CCOC(=O)/C(F)=C(/C)c1cc2c(cc1OCC)OC(C)(C)C=C2c1ccccc1

Procedure:
Following General Procedure K, triethyl-2-fluoro-2-phosphonoacetate (0.42 mL, 1.70 mmol) and 1-(7-ethoxy-2,2-dimethyl-4-phenyl-2H-chromen-6-yl)-ethanone (Compound 66, 183 mg, 0.57 mmol) were reacted to give the title compound as a colorless oil after purification by flash chromatography (silica gel, 1:9 ethyl acetate/hexane).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[C:10]([NH2:15])[CH:11]=[CH:12][CH:13]=2)[N:8]=[CH:7][N:6]=1.[Cl:18][C:19]1[C:24]([C:25](O)=[O:26])=[C:23]([F:28])[C:22]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])=[CH:21][CH:20]=1.S(Cl)(Cl)=O.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[C:24]([C:25]([NH:15][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]3[C:9]=2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][CH2:3][C:2]([F:1])([F:16])[F:17])=[O:26])=[C:23]([F:28])[C:22]([CH2:29][NH:30][C:31](=[O:35])[CH:32]([CH3:33])[CH3:34])=[CH:21][CH:20]=1
Reactant: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Reactant: Nc1cccc2c(NCC(F)(F)F)ncnc12
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(NCC(F)(F)F)ncnc23)c1F
Yield: 12.5 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(2,2,2-trifluoroethyl)quinazoline-4,8-diamine (Intermediate-65, 70 mg, 0.29 mmol), 6-chloro-2-fluoro-3-(isobutyramidomethyl)benzoic acid (Intermediate-60, 118 mg, 0.43 mmol), thionyl chloride (1 mL), and DIPEA (148 mg, 1.15 mmol) in THF (2 mL) to afford 18 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.57 (s, 1H), 8.93 (t, 1H), 8.76-8.73 (d, J=7.2 Hz, 1H), 8.61 (s, 1H), 8.38 (t, 1H), 8.12-8.09 (d, J=9.3 Hz, 1H), 7.66-7.61 (t, J=7.8 Hz, 1H), 7.40-7.38 (m, 2H), 4.47 (m, 2H), 4.32 (d, J=4.8 Hz, 2H), 2.42 (m, 1H), 1.05-1.03 (d, J=6.9 Hz, 6H); MS [M+H]+: 498.31.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[C:11]([CH2:22][CH2:23][CH2:24][CH3:25])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:22]([C:11]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:23][CH2:24][CH3:25].[CH2:22]([C:11]([O:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[F:1])([CH2:17][OH:18])[CH2:12][OH:13])[CH2:23][CH2:24][CH3:25]
Reactant: OCc1ccccc1F
Reactant: CCCCC(Br)(C(=O)OCC)C(=O)OCC
Product: CCCCC(CO)(CO)OCc1ccccc1F
Product: CCCCC(OCc1ccccc1F)(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl 2-butyl-2-(2-fluorobenzyloxy)malonate was prepared by reaction of 2-fluorobenzyl alcohol with diethyl 2-bromo-2-butylmalonate and the crude ester was reduced, without purification, with lithium aluminum hydride, all according to the method of Example 31, part A, to give 2-butyl-2-(2-fluorobenzyloxy)-1,3-propanediol, b.p. 140°-150°/0.01 mm, nD25 1.5555, m.p. 66°-67°.