Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][CH2:3][C:4](=N)OCC.[NH2:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][CH:16]=[CH:15][CH:14]=2>C(Cl)(Cl)Cl>[Cl:2][CH2:3][C:4]1[N:20]([CH:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:9]=1
Reactant: CCOC(=O)CC(C)Nc1c(N)cnc2ccccc12
Reactant: CCOC(=N)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(C)n1c(CCl)nc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 72 h
Yield: 97.7 %

Procedure:
Ethyl 2-chloroethanimidoate hydrochloride (10.8 g, 68.4 mmol) was added to a solution of ethyl 3-[(3-aminoquinolin-4-yl)amino]butanoate (9.41 g, 34.4 mmol) in chloroform (130 mL), and the reaction was stirred at room temperature for three days and then heated at reflux for two hours. An analysis by liquid chromatography/mass spectrometry (LC/MS) indicated the presence of starting material, and additional ethyl 2-chloroethanimidoate hydrochloride (2.7 g) was added. The reaction was heated at reflux for an additional 1.5 hours, allowed to cool to room temperature, diluted with chloroform (100 mL), washed sequentially with brine (2×150 mL) and deionized water (100 mL), dried over magnesium sulfate, filtered through a layer of CELITE filter agent, concentrated under reduced pressure, and further dried overnight under high vacuum to provide 11.15 g of ethyl 3-[2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate as a dark yellow solid.
Reaction SMILES: [BH4-].[Li+].C(OC(=O)[C:7]([CH:9]1[CH2:13][CH2:12][O:11][CH:10]1[O:14][CH3:15])=[O:8])C.Cl.C(N(CC)CC)C>C1COCC1>[O:14]1[CH:10]2[O:11][CH2:12][CH2:13][CH:9]2[CH:7]([OH:8])[CH2:15]1
Reactant: CCOC(=O)C(=O)C1CCOC1OC
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC1COC2OCCC12
Temperature: 67.5 °C
Reaction time: 2 h
Yield: 46.6 %

Procedure:
2 M Lithium borohydride solutions (24.7 ml) was added to the flask under nitrogen atmosphere. Ethyl-2-(2-methoxytetrahydrofuran-3-yl)-2-oxoacetate (5 g) was dissolved in THF (25 ml) and slowly added at 65-70° C. Reaction mass was then maintained at 65-70° C. for 10 hrs. Reaction mass was cooled to −10° C. and slowly added concentrated hydrochloric acid (16 ml) and stirred for 2 hrs at −5 to 0° C. Triethyl amine (14.6 ml) was added to the reaction mass. Reaction mass was concentrated under vacuum. Ethyl acetate (20 ml) was added and again concentrated to residue. Ethyl acetate (50 ml) was added to it and filtered the un-dissolved salts. Filtrate was concentrated to get residue of Hexahydrofuro[2,3-b]furan-3-ol (yield 1.5 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[C:9]([F:21])[CH:8]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([CH:8]=[C:9]([F:21])[CH:10]=1)[CH:24]=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CN(C)C=O
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cc(F)cc(OCc2ccccc2)c1
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Add n-butyl lithium (35 mL, 1.6M, 55.96 mmol) over 15 minutes to 1-bromo-3-fluoro-5-benzyloxy-benzene (14.30 g, 50.87 mmol) in tetrahydrofuran (300 mL) cooled in a dry ice/acetone bath, maintaining the internal temperature <−70°. Stir 30 minutes and add N,N-dimethylformamide (7.44 g, 101.74 mmol). Stir 30 minutes and remove cold bath. After 1 hour, quench with saturated aqueous ammonium chloride. Wash organic layer with water and saturated aqueous sodium chloride. Dry (sodium sulfate), filter and concentrate to an oil. Purify on 120 g silica gel eluting with 100:0 to 90:10 hexanes:ethyl acetate to give 3.75 g (32%) of the desired compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:51][C:52]1[CH:53]=[C:54]([CH:58]=[CH:59][CH:60]=1)[CH:55]([OH:57])[CH3:56]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:57][CH:55]([C:54]2[CH:58]=[CH:59][CH:60]=[C:52]([Cl:51])[CH:53]=2)[CH3:56])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(O)c1cccc(Cl)c1
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4cccc(Cl)c4)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 59.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (75 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (110 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 3-chloro-α-methylbenzyl alcohol (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (70 mg, yield 56%).
Reaction SMILES: [N:1]1[N:2]([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[N:3]=[CH:4][CH:5]=1.[N:16]#[C:17][NH2:18].[N+:19]([O-:22])([OH:21])=[O:20].NC(N)=N>>[N+:19]([O-:22])([O-:21])=[O:20].[N:1]1[N:2]([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:17]([NH2:18])=[NH2+:16])=[CH:11][CH:10]=2)[N:3]=[CH:4][CH:5]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1ccc(OCCn2nccn2)cc1
Reactant: N#CN
Agent: N=C(N)N
Product: NC(=[NH2+])Nc1ccc(OCCn2nccn2)cc1
Product: O=[N+]([O-])[O-]

Procedure:
The title compound was prepared from 4-[2-(1,2,3-triazol-2-yl)ethoxy]aniline (8.85 g, 43.4 mmol), cyanamide (2.82 g, 73.78 mmol) and concentrated HNO3 (1.58 mL, 26.47 mmol) in a manner similar to the guanidine of Example 1 to give the desired material (7.95 g) as an off-white solid, m.p.>250°. δH (d6DMSO) 9.32 (1H, s), 7.80 (2H, s), 7.16-7.13 (6H, m), 7.00-6.97 (2H, m), 4.79 (2H, t, J 4.95 mmol) and 4.41 (2H, t, J 4.95 mmol).
Reaction SMILES: [OH:1][CH:2]([CH2:17][OH:18])[CH2:3][N:4]1[C:13]2[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=2[N:6]=[CH:5]1.[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26](O)=[O:27])=[CH:22][CH:21]=1.O>C1(C)C(C)=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:19][C:20]1[CH:30]=[CH:29][C:23]([O:24][CH2:25][C:26]([O:18][CH2:17][CH:2]([OH:1])[CH2:3][N:4]2[C:13]3[C:12](=[O:14])[N:10]([CH3:11])[C:9](=[O:15])[N:8]([CH3:16])[C:7]=3[N:6]=[CH:5]2)=[O:27])=[CH:22][CH:21]=1
Reactant: Cn1c(=O)c2c(ncn2CC(O)CO)n(C)c1=O
Reactant: O=C(O)COc1ccc(Cl)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: Cn1c(=O)c2c(ncn2CC(O)COC(=O)COc2ccc(Cl)cc2)n(C)c1=O
Yield: 79 %

Procedure:
27.0 g (0.1 mol) 7-(2,3-dihydroxypropyl)-theophylline and 18.6 g (0.1 mol) p-chlorophenoxyacetic acid were heated in 100 ml xylene for 8 hours in a water separator with the addition of 0.9 g p-toluenesulfonic acid. After cooling down, the xylene was decanted and the residue dissolved in hot isopropanol. After addition of a little water the monoester crystallized out slowly. The yield was 33.4 g (79% yield) of 1-(7-theophyllinyl)-2-hydroxy-3-propyl (p-chlorophenoxyacetate) with a melting point of 81°-83°C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=2)[CH:10]=1.[CH:29](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[N:8]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[C:11]([NH:19][CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[CH:29]1
Reactant: NC(=O)Cc1cnc(Nc2ccccc2N)cc1NCc1cc(F)cc(F)c1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: NC(=O)Cc1cnc(-n2cnc3ccccc32)cc1NCc1cc(F)cc(F)c1
Reaction time: 4 h
Yield: 94 %

Procedure:
9 mg of 6-[(2-aminophenyl)amino]-4-[(3,5-difluorobenzyl)amino]pyridine-3-carboxyamide (the compound of step 1 of Example 365) was suspended in 0.2 ml of methanol, to which 0.2 mL of trimethyl orthoformate and a catalytic amount of p-toluenesulfonic acid monohydrate were added at room temperature, and stirred at the same temperature for 4 hours. The solvent was evaporated, saturated sodium bicarbonate was added to the residue, extracted with chloroform, the extract was washed with water, and dried on anhydrous sodium sulfate. The solvent was evaporated to obtain 9 mg (yield 94%) of the title compound as a light brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:18])[C:14]=2[C:15]([OH:17])=O)[CH:6]=[CH:7][CH:8]=1)[CH3:2].FC1C=C(NC2C=NN(C)C=2C(O)=O)C=CC=1.ClC1C2C(CC)=CC=CC=2N=C2C=NN(C)C=12.ClC1C2C=CC(CC)=CC=2N=C2C=NN(C)C=12>C(O)(=O)C>[CH2:1]([C:3]1[C:4]2[C:15](=[O:17])[C:14]3[N:13]([CH3:18])[N:12]=[CH:11][C:10]=3[NH:9][C:5]=2[CH:6]=[CH:7][CH:8]=1)[CH3:2].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]2[C:15](=[O:17])[C:14]3[N:13]([CH3:18])[N:12]=[CH:11][C:10]=3[NH:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cccc(Nc2cnn(C)c2C(=O)O)c1
Agent: CCc1ccc2c(Cl)c3c(cnn3C)nc2c1
Agent: CCc1cccc2nc3cnn(C)c3c(Cl)c12
Agent: Cn1ncc(Nc2cccc(F)c2)c1C(=O)O
Solvent: CC(=O)O
Product: CCc1ccc2c(=O)c3c(cnn3C)[nH]c2c1
Product: CCc1cccc2[nH]c3cnn(C)c3c(=O)c12
Temperature: 25 °C
Yield: 41 %
Yield: 56 %

Procedure:
4-[(3-Ethylphenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid (EXAMPLE 8 and 9, step 1) was treated according to the procedure of step 2 in EXAMPLE 3 instead of 4-[(3-fluorophenyl)amino]-1-methyl-1H-pyrazole-5-carboxylic acid. The obtained inseparable mixture of 9-chloro-8-ethyl-1-methyl-1H-pyrazolo[4,3-b]quinoline and 9-chloro-6-ethyl-1-methyl-1H-pyrazolo[4,3-b]quinoline (200 mg, 0.81 mmol) in 50% aqueous acetic acid (8 ml) was refluxed for 8 h. After cooling to room temperature, the mixture was concentrated and chromatographed on a column of silica gel with ethyl acetate/hexane (1:2) to afford 75 mg (41%) of 8-ethyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one as a solid and 103 mg (56%) of 6-ethyl-1-methyl-1,4-dihydro-9H-pyrazolo[4,3-b]quinolin-9-one as a solid.
Reaction SMILES: C([O:8][C:9]1[C:18]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][C:10]=1[Cl:23])C1C=CC=CC=1>CO.C(Cl)Cl.CC(O)=O.[Pd]>[Cl:23][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:19][CH:20]([CH3:22])[CH3:21])[C:9]=1[OH:8])[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1cc(Cl)c(OCc2ccccc2)c(OC(C)C)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1cc(Cl)c(O)c(OC(C)C)c1
Yield: 92.6 %

Procedure:
Methyl 4-(benzyloxy)-3-chloro-5-isopropoxybenzoate (2) (3.00 g, 8.96 mmol) was dissolved in a mixture of MeOH (100 mL), DCM (10 mL) and AcOH (0.1 mL) and the solution was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 25° C. under H2 (full H2 mode). The solvents were removed in vacuo to afford methyl 3-chloro-4-hydroxy-5-isopropoxybenzoate (3) (2.03 g, 89%): m/z 245 [M+H]+ (ES+), 243 [M−H](ES−).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:16][CH:17]=1)[C:8]1[S:9][C:10]([C:12](=[O:14])[CH3:13])=[CH:11][C:7]=1[CH:6]=[CH:5]2.OC1C([O:26][S:27]([C:30]2[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=2)(=[O:29])=[O:28])=C(I)C=CC=1.C(O)C>C(#N)C>[CH3:34][C:33]1[CH:32]=[CH:31][C:30]([S:27]([O:29][CH2:13][C:12]([C:10]2[S:9][C:8]3[C:15]4[C:4]([CH:5]=[CH:6][C:7]=3[CH:11]=2)=[CH:3][C:2]([Br:1])=[CH:17][CH:16]=4)=[O:14])(=[O:28])=[O:26])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Reactant: CC(=O)c1cc2ccc3cc(Br)ccc3c2s1
Solvent: CCO
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)OCC(=O)c2cc3ccc4cc(Br)ccc4c3s2)cc1
Yield: 81.5 %

Procedure:
To a solution of 1-(7-bromonaphtho[1,2-b]thiophen-2-yl)ethanone (11c) (1.26 g, 4.13 mmol) in 15 ml of acetonitrile at 75° C., hydroxytosyloxyiodobenzene (2.59 g, 6.61 mmol) was added and the mixture was refluxed for 8 hr. The volume of acetonitrile was reduced under vacuum and ethanol was added to it. The orange solid obtained was filtered and washed with ether to obtain the desired compound (11d) (1.6 g, 82%).
Reaction SMILES: O.Cl.CS[C:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]=1)([CH3:9])[C:6]([OH:8])=[O:7]>[Zn].C(OCC)C>[O:16]([C:12]1[CH:11]=[C:10]([CH:5]([CH3:9])[C:6]([OH:8])=[O:7])[CH:15]=[CH:14][CH:13]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CSC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Agent: Cl
Agent: [Zn]
Solvent: O
Solvent: CCOCC
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 100.3 %

Procedure:
Water (1.5 ml) and 1.5 ml of conc. hydrochloric acid were added to 432 mg of α-methylthio-α-(m-phenoxyphenyl)propionic acid, and then 300 mg of zinc powder was added. With stirring, the mixture was heated under reflux for 2.5 hours. Water (10 ml) and 30 ml of diethyl ether were added to the reaction mixture. The insoluble matter was separated by filtration. The filtrate was extracted three times with 30 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure to afford 364 mg of α-(m-phenoxyphenyl)propionic acid as an oil.
Reaction SMILES: [F:1][C:2]1[C:11]([CH:12]=O)=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([O:14][CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][C@@H:26]([CH2:29]S(C2N(C3C=CC=CC=3)N=NN=2)(=O)=O)[O:25][CH2:24]1)([CH3:19])([CH3:18])[CH3:17].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O>COCCOC.CC(=O)OCC>[C:16]([O:20][C:21](=[O:44])[NH:22][C@@H:23]1[CH2:28][CH2:27][C@@H:26](/[CH:29]=[CH:12]/[C:11]2[C:2]([F:1])=[CH:3][CH:4]=[C:5]3[C:10]=2[N:9]=[C:8]([O:14][CH3:15])[CH:7]=[CH:6]3)[O:25][CH2:24]1)([CH3:19])([CH3:17])[CH3:18]
Reactant: COc1ccc2ccc(F)c(C=O)c2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](CS(=O)(=O)c2nnnn2-c2ccccc2)OC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2ccc(F)c(/C=C/[C@@H]3CC[C@@H](NC(=O)OC(C)(C)C)CO3)c2n1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 7-fluoro-2-methoxy-quinoline-8-carbaldehyde (5 g, 24.36 mmol; prepared according to WO 2008/126024) and (3R,6S)-[6-(1-phenyl-1H-tetrazole-5-sulfonylmethyl)-tetrahydro-pyran-3-yl]-carbamic acid tert-butyl ester (10.32 g, 24.36 mmol, prepared according to WO 2006/032466) in DME (104 mL) was cooled to −60° C. A solution of LiHMDS (1M in THF, 42 mL) was added drop wise over 30 min. The reaction was stirred 1 hour at this temperature before warming slowly to rt. Water (80 mL) and EA (80 mL) were added. The two layers were decanted and the aq. layer was extracted twice with EA (2×100 mL). The combined org. layers were washed with brine (100 mL), dried over MgSO4 and concentrated to dryness. The residue (10.5 g) was carried on without further purification. The analytical data were obtained by trituration of a small portion of the crude in diethyl ether.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]2[CH2:24][C:23]3[C:18](=[CH:19]C=C(C=C)[CH:22]=3)[CH2:17]2)=[O:15])=[CH:9][CH:8]=1)=[O:6])[CH2:2][CH3:3].C[N+]1([O-])CC[O:31]CC1.[O:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>CC(O)C.[Os](=O)(=O)(=O)=O>[OH:31][CH:38]([C:37]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:36]=1)[CH2:24][N:16]([C:14]([NH:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]([NH:4][CH2:1][CH2:2][CH3:3])=[O:6])=[CH:8][CH:9]=1)=[O:15])[CH2:17]2)[CH2:39][OH:35]
Reactant: C=Cc1ccc2c(c1)CN(C(=O)Nc1ccc(C(=O)NCCC)cc1)C2
Reactant: C[N+]1([O-])CCOCC1
Reactant: C1CCOC1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)O
Product: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(C(O)CO)cc3C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A suspension of N-[4-(propylcarbamoyl)phenyl]-5-vinyl-1,3-dihydro-2H-isoindole-2-carboxamid (0.03 g, 0.086 mmol) in tetrahydrofuran (1 ml) and 2-propanol (0.3 ml) was treated with osmium tetroxide (2.5% wt. % solution in 2-methyl-2-propanol) (0.108 ml, 8.59 μmol). The reaction mixture was treated with N-methylmorpholine-N-oxide (0.030 g, 0.258 mmol). The reaction mixture was allowed to stir at room temperature overnight, quenched with aqueous sodium sulfite solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. Flash chromatography provided the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.55 (s, 1H), 8.25 (t, J=5.7 Hz, 1H), 7.74-7.78 (m, 2H), 7.63-7.68 (m, 2H), 7.27-7.33 (m, 3H), 5.24 (d, J=4.2 Hz, 1H), 4.75-4.77 (bs, 4H), 4.70 (t, J=5.8 Hz, 1H), 4.53-4.59 (m, 1H), 3.43 (t, J=5.8 Hz, 2H), 3.16-3.23 (m, 2H), 1.42-1.63 (m, 2H), 0.89 (t, J=7.4 Hz, 3H); MS (ESI(+)) m/e 384 (M+H)+.
Reaction SMILES: CS(N)(=O)=O.[N:6]1([S:10]([NH2:13])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1.C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:41]1([C:44]2[C:45]([O:54][CH:55]3[CH2:60][CH2:59][CH2:58][C:57]([CH3:62])([CH3:61])[CH2:56]3)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[CH2:43][CH2:42]1>>[N:6]1([S:10]([NH:13][C:49](=[O:50])[C:48]2[CH:52]=[C:44]([CH:41]3[CH2:42][CH2:43]3)[C:45]([O:54][CH:55]3[CH2:60][CH2:59][CH2:58][C:57]([CH3:62])([CH3:61])[CH2:56]3)=[CH:46][C:47]=2[F:53])(=[O:12])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: CC1(C)CCCC(Oc2cc(F)c(C(=O)O)cc2C2CC2)C1
Reactant: NS(=O)(=O)N1CCC1
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: CC1(C)CCCC(Oc2cc(F)c(C(=O)NS(=O)(=O)N3CCC3)cc2C2CC2)C1

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methane sulfonamide with azetidine-1-sulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((3,3-dimethylcyclohexyl)oxy)-2-fluorobenzoic acid, the title compound was obtained as a white solid (0.035 g, 15%): 1H NMR (300 MHz, DMSO-d6) δ11.58 (s, 1H), 7.11 (d, J=8.5 Hz, 1H), 7.03 (d, J=13.3 Hz, 1H), 4.67-4.58 (m, 1H), 4.04 (t, J=7.7 Hz, 4H), 2.21-2.11 (m, 2H), 2.06-1.96 (m, 2H), 1.76-1.70 (m, 1H), 1.65-1.53 (m, 2H), 1.38-1.14 (m, 4H), 0.98 (s, 3H), 0.97 (s, 3H), 0.90-0.84 (m, 2H), 0.69-0.64 (m, 2H); MS (ES+) m/z 425.1 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH:6]([NH2:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:15]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH3:2])=[O:16])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: COC(=O)CC(N)c1ccc(OC)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid methyl ester hydrochloride (1.50 g, 6.1 mmol) and sodium carbonate (90.65 g, 6.1 mmol) in 40 mL of water was added N-carboethoxyphthalimide (1.34 g, 6.1 mmol) in 12 mL of acetonitrile. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partially concentrated and this mixture was stirred for 72 hours. The resulting slurry was filtered and the solid was washed with copious amount of water. The solid was dried in vacuo (30° C., <1 mm) to afford 1.70 g (50%) of methyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder. mp 65°-66° C.; 1H NMR (DMSO-d6, 250 MHz) δ 7.83-7.91 (m, 4H), 6.88-7.3 (m, 4H), 5-80 (dd, 1H, J=7.5, 2.5), 3.72 (S, 3H), 3.54 (3, 3H), 3.2-3.6 (m, 2H); 13C NMR (DMSO-d6) δ 170.7, 167.5, 158.7, 134.6, 131.0, 130.5, 128.3, 123.2, 113.9, 55.0, 51.5, 49.4, 35.4. Anal. Calcd for C19H17NO5 : C, 67.25; H, 5.05; N, 4.13; Found: C, 66.96; H, 5.00; N, 4.11.
Reaction SMILES: [C:1]1(=[O:18])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([CH2:11][F:12])=[O:10])[C:4](=[O:13])[C:3]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:2]12.[BH4-].[Na+].Cl>O1CCCC1.CO>[F:12][CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][CH2:6][N:5]1[C:1](=[O:18])[C:2]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:3]2[C:4]1=[O:13]
Reactant: O=C(CF)CCCN1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1CCCC(O)CF
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
To a solution of 550 mg (2.2 mmole) of fluoromethyl 3-phthalimidopropyl ketone in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol cooled to -20° C. is added a solution of 0.8 mmole of sodium borohydride in a mixture of 5 ml of tetrahydrofuran and 5 ml of methanol precooled to -20° C. The reaction mixture is stirred for 15 minutes at -20° C. and then neutralized with 2 M HCl to a pH of 1. The solvents are evaporated under reduced pressure and the residue is partitioned between water and chloroform. The organic phase is washed with brine, dried over magnesium sulfate and concentrated to give a residue which is recrystallized from tetrahydrofurandiethylether to afford 1-fluoro-5-phthalimido-2-pentanol, m.p. 85° C. A mixture of 264 mg (1.05 mmole) of 1-fluoro-5-phthalimido-2-pentanol, 170 mg (1.05 mmole) of the phthalimide, 302 mg (1.05 mmole) of triphenylphosphine and 201 mg (1.15 mmole) of diethylazodicarboxylate in 8 ml of tetrahydrofuran is stirred under nitrogen for 2 hours at 25° C. The solvent is evaporated under reduced pressure and the residue taken up in benzene. The insoluble material is discarded and the residue obtained after concentration of the filtrate is recrystallized from tetrahydrofuran-diethylether to give 1-fluoromethyl-1,4-butanediyl-bis-phthalimide, m.p. 112° C. A suspension of 3.1 g of 1-fluoromethyl-1,4-butanediyl-bis-phthalimide in 140 ml of concentrated HCl is heated at a reflux temperature for 3 days. The phthalic acid which precipitates on cooling to 4° C. is filtered off. The filrate is concentrated to about 20 ml and cooled to 4° C. The remaining phthalic acid which separates is filtered off and the filtrate is concentrated under reduced pressure. The residue is treated with 40 ml of boiling isopropyl alcohol 3 times and then recrystallized from absolute ethanol to give 1-fluoromethyl-1,4-butanediamine dihydrochloride, m.p. 154° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[O:16]([C:23]1[CH:28]=[CH:27][C:26]([CH2:29]O)=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][C:26]1[CH:27]=[CH:28][C:23]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)CCc1ccc(O)c(F)c1
Reactant: OCc1ccc(Oc2ccccc2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CCc1ccc(OCc2ccc(Oc3ccccc3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
To a solution of ice-cooled ethyl 3-(3-fluoro-4-hydroxyphenyl)propanoate (0.19 g, 0.88 mmol), (4-phenoxyphenyl)methanol (0.12 g, 0.58 mmol) and triphenylphosphine (0.23 g, 0.88 mmol) in tetrahydrofuran (5 mL) was added dropwise diethyl azodicarboxylate (a 40% solution in toluene, 0.40 mL, 0.88 mmol), and the mixture was stirred at room temperature for 4 hours. To the reaction solution was added water, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=8:2) to give the title compound (0.16 g, yield 71%) as an oily matter.