Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11]I)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:15][NH2:16].[ClH:17]>C(O)C>[ClH:17].[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH2:10][CH2:11][NH:16][CH3:15])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(OCCCI)cc1
Agent: Cl
Solvent: CCO
Product: CNCCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-(4-Nitrophenoxy)-3-iodopropane (4.76 g, 15.50 mmol) was added portionwise to a stirring solution of methylamine (33%) in ethanol (100 mL) at 0° C. The mixture stirred at room temperature for 4 hours and was then concentrated. The residue was partitioned between ethyl acetate/10% aqueous K2CO3. The organic phase was dried, decolorized and concentrated to afford an oil which was treated with ethanolic HCl. Yield: 2.5 g of hydrochloride salt which was used without purification.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[OH-].[K+].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[C:12]([O:19][CH:20]([CH3:22])[CH3:21])[CH:11]=1>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH:20]([O:19][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[N+:16]([O-:18])=[O:17])[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])([CH3:22])[CH3:21]
Reactant: CN(C)CCO
Reactant: CC(C)Oc1cc(F)ccc1[N+](=O)[O-]
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [K+]
Product: CC(C)Oc1cc(OCCN(C)C)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
N,N-Dimethylethanolamine (1.6 g, 18 mmol) was added to a mixture of powdered KOH (1.0 g, 18 mmol) and Aliquat 336 (0.72 g, 1.8 mmol), and the resulting mixture was stirred for 5 minutes at 80° C. Then 4-fluoro-2-isopropoxy-1-nitrobenzene (3.0 g, 15 mmol) was added, and stirring proceeded at this temperature for 30 minutes. The mixture was cooled and partitioned between methylene chloride (100 mL) and dilute aqueous HCl (100 mL), and the organic layer was extracted with dilute aqueous HCl (2×100 mL). The combined aqueous phases were washed with methylene chloride (3×150 mL), basified (3N NaOH), and extracted with methylene chloride (3×100 mL). The combined organic extracts were washed with water (3×100 mL), dried (MgSO4), and evaporated, providing 2.2 g as a yellow oil, in 55% yield; 1H NMR (CDCl3) δ 1.40 (d, J=6.1 Hz, 6H), 2.34 (s, 6H), 2.74 (t, J=5.6 Hz, 2H), 4.10 (t, J=5.6 Hz, 2H), 4.61 (septet, J=6.1 Hz, 1H), 6.48 (dd, J=9.1 Hz, J=2.5 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 7.91 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH:1]12[O:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([O:10]CC)=[O:9].[OH-].[K+]>O.C(O)C>[CH:1]12[O:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1CC2C=CC1O2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1CC2C=CC1O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.0 g (17.8 mmol) of ethyl 7-oxabicyclo[2.2.1]hept-5-en-2-carboxylate are suspended in 10 ml of water and 20 ml of ethanol. The temperature is kept below 20° C. by cooling with ice, while 3.5 g (62.3 mmol) of potassium hydroxide are added. The mixture is stirred for 2 hours at ambient temperature, the ethanol is distilled off at a bath temperature of 30° C. and the aqueous solution is extracted with ethyl acetate. The aqueous phase is acidified to a pH of 6 while cooling with ice and shaken with dichloromethane, then the combined organic extracts are dried and evaporated down. 0.8 g (32% of theory) of the title compound are obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8]2.Cl[C:14]1[N:19]=[C:18]([O:20][CH3:21])[N:17]=[C:16]([O:22][CH3:23])[N:15]=1>>[CH3:23][O:22][C:16]1[N:17]=[C:18]([O:20][CH3:21])[N:19]=[C:14]([CH:8]2[C:7]3[C:11](=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][CH:6]=3)[NH:10][C:9]2=[O:12])[N:15]=1
Reactant: COc1cccc2c1NC(=O)C2
Reactant: COc1nc(Cl)nc(OC)n1
Product: COc1nc(OC)nc(C2C(=O)Nc3c(OC)cccc32)n1

Procedure:
7-Methoxy-1,3-dihydro-2H-indol-2-one (1.24 g) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.84 g) are reacted analogously to Example 1 Variant A. This gives the title compound as solid in an HPLC purity of 87% area (1.04 g, 43% of theory).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][S:7][CH2:8][CH:9]1[CH2:11][CH2:10]1)[C:3](O)=[O:4].[H][H]>[H-].[Al+3].[Li+].[H-].[H-].[H-]>[NH2:1][C@@H:2]([CH2:6][S:7][CH2:8][CH:9]1[CH2:11][CH2:10]1)[CH2:3][OH:4]
Reactant: [H][H]
Reactant: N[C@@H](CSCC1CC1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: N[C@H](CO)CSCC1CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To an ice water cooled solution of lithium aluminum hydride (200 mL of 1.0 M) was added solid 2(R)-amino-3-cyclopropylmethylsulfanylpropionic acid. The addition was done by tapping in portions through a funnel in such a manner as to control hydrogen gas evolution. The ice bath was removed, and the reaction mixture was heated at reflux for 16 h. The reaction mixture was removed from heat and cooled in an ice water bath. Diethyl ether (110 mL) was added, followed by dropwise addition of water (5 mL), 15% aqueous sodium hydroxide (5 mL), and water (15 mL). After stirring in the ice water bath for 1.5 h, the reaction mixture was filtered. The filtrate was dried over anhydrous sodium sulfate, and concentrated to give 2(R)-amino-3-cyclopropylmethylsulfanylpropan-1-ol (14.9 g).
Reaction SMILES: C([O:5][C:6](=[O:33])[CH:7]([N:10]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[N:12]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:11]1=[O:32])[CH2:8][CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[C:19]([C:16]1[CH:17]=[CH:18][C:13]2[N:12]([S:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)(=[O:23])=[O:22])[C:11](=[O:32])[N:10]([CH:7]([CH2:8][CH3:9])[C:6]([OH:33])=[O:5])[C:14]=2[CH:15]=1)#[N:20]
Reactant: CCC(C(=O)OC(C)(C)C)n1c(=O)n(S(=O)(=O)c2ccc(OC)cc2)c2ccc(C#N)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C(=O)O)n1c(=O)n(S(=O)(=O)c2ccc(OC)cc2)c2ccc(C#N)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
A stirred solution of 2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-butyric acid tert-butyl ester (34 mg, 0.07 mmol) in CH2Cl2 (1 mL) was treated with trifluoroacetic acid (1 mL). The reaction mixture was stirred at room temperature for 3 hours, concentrated in vacuo and co-evaporated the solvent with toluene (3×) to afford 2-[6-cyano-3-(4-methoxy-benzenesulfonyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]-butyric acid (29 mg, 99%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][C:11](O)=[O:12])[CH:6]=[CH:5][N:4]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[NH2:2][C:3]1[CH:8]=[C:7]([CH2:9][CH2:10][CH2:11][OH:12])[CH:6]=[CH:5][N:4]=1
Reactant: Nc1cc(CCC(=O)O)ccn1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1cc(CCCO)ccn1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A suspension of 3-(2-aminopyridin-4-yl)propanoic acid hydrochloride (0.73 g. 3.60 mmol, prepared according to WO94/14776 in THF (10 mL) was added over 45 min to lithium aluminum hydride (12 mL, 12 mmol, 1M in THF) at 0° C. The ice bath was removed and the reaction was allowed to stir at RT for 4.5 h. The reaction was cooled to 0° C. diluted with toluene (22 mL) and quenched by the sequential addition of H2O (0.86 mL) and NaF (1.54 g). The resulting suspension was stirred at 0° C. for 45 min. The reaction mixture was filtered and the precipitate was washed with additional 10% MeOH in CHCl3. The combined filtrates were concentrated under reduced pressure. Flash chromatography (10% MeOH/CHCl3, silica gel) gave 0.25 g of the desired material as a clear oil: MS(ES+) m/z 152.7 [M+H]+.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:56]=[CH:55][C:54]([O:57][Si](C(C)(C)C)(C)C)=[CH:53][CH:52]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:66])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:52]=[CH:53][C:54]([OH:57])=[CH:55][CH:56]=3)[CH:46]([OH:65])[CH2:45]2)[CH:7]([CH3:67])[CH:6]([OH:68])[CH2:5][C:4]1=[O:69])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc(O)cc4)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Yield: 64.5 %

Procedure:
To a stirred solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-tert-butyldimethylsilyloxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl]23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (41.9 mg) in CH2Cl2 (1.5 mL.) at 0° C. was added a solution of p-toluenesulfonic acid in methanol (1.5 mL. of a 10% w/v solution). The mixture was stirred 3H at 0° C. and then 3H at room temperature. The reaction mixture was quenched with saturated aqueous NaHCO3 and extracted 4× with CH2Cl2. The organic extracts were combined and dried over anhydrous Na2SO4. The mixture was filtered and concentrated in vacuo. The product was isolated by preparative TLC on silica gel (eluted with 2:1 hexanes/acetone) affording 23.9 mg of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-(4'"-hydroxyphenyloxy)-3"-hydroxycyclohexyl)-1'-methylvinyl] 23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone. (1H NMR and mass spectral analysis are consistent with the desired structure).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:18][CH3:19])=[C:6]([CH:8]2[C:14](=[O:15])[CH:13]3[CH2:16][CH:10]([CH2:11][CH2:12]3)[C:9]2=[O:17])[CH:7]=1.[CH3:20][C:21]1[CH:22]=[N:23][NH:24][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[CH2:18]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH:22]=[C:21]([CH3:20])[CH:25]=[N:24]2)=[CH:7][C:6]=1[CH:8]1[C:14](=[O:15])[CH:13]2[CH2:16][CH:10]([CH2:11][CH2:12]2)[C:9]1=[O:17])[CH3:19]
Reactant: Cc1cn[nH]c1
Reactant: CCc1ccc(Br)cc1C1C(=O)C2CCC(C2)C1=O
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: CCc1ccc(-n2cc(C)cn2)cc1C1C(=O)C2CCC(C2)C1=O
Temperature: 160 °C

Procedure:
3-(5-Bromo-2-ethylphenyl)bicyclo[3.2.1]octane-2,4-dione (100 mg, 0.31 mmol), 4-methylpyrazole (38 mg, 0.46 mmol), potassium phosphate (264 mg, 1.24 mmol), L-proline (36 mg, 0.31 mmol) and copper (I) iodide (60 mg, 0.31 mmol) are combined in a microwave vial, suspended in DMSO and heated under microwave irradiation at 160° C. for 45 minutes. The mixture is filtered and purified by preparative reverse-phase HPLC to give 3-[2-ethyl-5-(4-methylpyrazol-1-yl)phenyl]bicyclo-[3.2.1]octane-2,4-dione.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:23])=[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2=[O:12])=[CH:4][CH:3]=1.[CH2:24](O)[CH2:25][CH2:26][CH3:27].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH2:24]([O:23][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[C:9](=[O:12])[N:8]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:7]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:25][CH2:26][CH3:27]
Reactant: CCOC(=O)c1c(O)c2ccc(F)cc2c(=O)n1CC(C)(C)C
Reactant: CCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCOc1c(C(=O)OCC)n(CC(C)(C)C)c(=O)c2cc(F)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of ethyl 7-fluoro-4-hydroxy-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (5.12 g, 31.9%) (from Example 1(1), 3.21 g, 10 mmol), 1-butanol (1.4 ml, 15 mmol) and tributylphosphine (5.0 ml, 20 mmol) in tetrahydrofuran (30 ml) was added 1,1′-(azodicarbonyl)dipiperidine (5.05. g, 20 mmol) and the mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated, under reduced pressure and the residue was purified by silica gel column chromatography to give ethyl 4-butoxy-7-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (3.55 g, 94.2%) as an oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[C:20]2[S:21][C:22]([C:24]3[C:29]([F:30])=[CH:28][N:27]=[C:26]([NH:31][CH2:32][CH2:33][N:34]4[CH:38]=[CH:37][N:36]=[N:35]4)[N:25]=3)=[CH:23][C:19]=2[CH:18]=[CH:17][CH:16]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:34]1([CH2:33][CH2:32][NH:31][C:26]2[N:25]=[C:24]([C:22]3[S:21][C:20]4[C:15]([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[CH2:8][NH2:7])=[CH:16][CH:17]=[CH:18][C:19]=4[CH:23]=3)[C:29]([F:30])=[CH:28][N:27]=2)[CH:38]=[CH:37][N:36]=[N:35]1
Reactant: CC(C)(C)OC(=O)NCc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccccc1-c1cccc2cc(-c3nc(NCCn4ccnn4)ncc3F)sc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.3 %

Procedure:
Combine (2-{2-[5-fluoro-2-(2-[1,2,3]triazol-1-yl-ethylamino)-pyrimidin-4-yl]-benzo[b]thiophen-7-yl}-benzyl)-carbamic acid tert-butyl ester (100 mg, 0.18 mmol) and dry TFA acid (2.0 mL) in dry DCM (2.2 mL). Stir the solution at RT for 1 h. Remove the solvent. Add DCM, wash with saturated sodium bicarbonate solution, water, and aqueous saturated sodium chloride. Separate the organic layer and dry over magnesium sulfate. Filter and concentrate in vacuo. Purify the residue by column chromatography [0.1% to 2% 2 M ammonia in methanol/DCM] to give the title compound (78 mg, 96%). MS (ES) m/z 446 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.S(Cl)(Cl)=O.[CH3:16][N:17]([CH3:25])[CH:18]=[CH:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)CC)C>C1(C)C=CC=CC=1.C1COCC1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([C:19](=[CH:18][N:17]([CH3:25])[CH3:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:9]
Reactant: O=C(O)c1cc(Br)cnc1F
Reactant: CCOC(=O)C=CN(C)C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)C(=CN(C)C)C(=O)c1cc(Br)cnc1F
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
To a solution of 5-bromo-2-fluoronicotinic acid (3 g, 13.64 mmol) in toluene (30 mL) was added thionyl chloride (5 mL, 68.18 mmol, 5 equiv.) followed by DMF (0.5 mL). This was stirred at 110° C. for 2 h then concentrated in vacuo. The residue was resuspended in THF (15 mL) and added dropwise to a solution of ethyl 3-(dimethylamino)acrylate (2 mL, 13.64 mmol) and triethylamine (2.85 mL, 20.45 mmol) in THF (15 mL). The reaction was stirred at 70° C. for 18 h, cooled down to room temperature, and quenched with water. The reaction was partitioned between water (70 mL) and ethyl acetate (70 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (2×70 mL). The combined organic layers were washed with 1 N HCl (100 mL) and brine (100 mL), dried over sodium sulftate, and concentrated. The concentrate was purified via silica gel chromotography to provide ethyl 2-(5-bromo-2-fluoronicotinoyl)-3-(dimethylamino)acrylate as an orange solid (3.64 g, 77%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11]([NH2:14])(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.C[Al](C)C.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:35][C:36](=O)[O:37]C)[N:29]=1>C(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([NH:35][C:36]([NH:14][S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:12])=[O:13])=[O:37])[N:29]=1
Reactant: NS(=O)(=O)c1cccc2cccnc12
Reactant: COC(=O)Nc1nc(C)cc(OC)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3cccnc23)n1
Reaction time: 0.75 h
Yield: 47.8 %

Procedure:
To a stirred mixture of 8-quinolinesulfonamide (4.2 g) in 100 ml methylene chloride is added a 2 M toluene solution of trimethylaluminum (15 ml). The resulting solution is stirred under N2 for 45 min. Solid methyl (4-methoxy-6-methylpyrimidin-2-yl)carbamate (4.0 g) is added and the mixture is heated at reflux for 60 hrs. The reaction is quenched sequentially with acetic acid (2 ml) 6 N HCl (5 ml) and water (25 ml). The organic solution is retained, dried with MgSO4, filtered, and is concentrated in vacuo to a crude solid. Washing with methyl acetate afforded 3.6 g of a pale yellow powder m.p. 181°-185° C. The infrared spectrum showed characteristic absorption bands at 3100 and 1700 cm-1.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][OH:33])(=[O:24])=[O:23])([O-:15])=[O:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:58]1[C:62](=[O:63])[C:61]2=[CH:64][CH:65]=[CH:66][CH:67]=[C:60]2[C:59]1=[O:68]>O1CCCC1>[N+:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([O:25][C:26]1[CH:27]=[C:28]([CH:34]=[C:35]([CH3:37])[CH:36]=1)[O:29][CH2:30][CH2:31][CH2:32][O:33][N:58]1[C:59](=[O:68])[C:60]2=[CH:67][CH:66]=[CH:65][CH:64]=[C:61]2[C:62]1=[O:63])(=[O:24])=[O:23])([O-:15])=[O:14]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCCCON2C(=O)c3ccccc3C2=O)cc(OS(=O)(=O)c2ccccc2[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.3 %

Procedure:
Diethyl azodicarboxylate (910 μL, 5.78 mmol) was slowly added to a solution of 3-[3-(2-nitrophenylsulfonyloxy)-5-methylphenoxy]propanol (1.77 g, 4.82 mmol), as prepared in the preceding step, triphenylphosphine (1.52 g, 5.80 mmol), and N-hydroxyphthalimide (864 mg, 530 mmol) in tetrahydrofuran (10 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and the product purified by flash chromatography (dichloromethane) to give 2.33 g (95%) of the title compound as an oil. 1H-NMR (300 MHz, CDCl3) δ7.98 (dd, 1H, J=7, 1 Hz), 7.67-7.88 (m, 7H), 6.67 (s, 1H), 6.64 (m, 1H), 6.55 (t, 1H, J=2 Hz), 4.36 (t, 2H, J=6 Hz), 4.12 (t, 2H, J=6 Hz), 2.28 (s, 3H), 2.18 (pentet, 2H, J=6 Hz). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid) calcd. for C24H20N2O9S: 535.1 (M+Na). Found 535.0.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[F:35][C@@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][C:5]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:38]4[CH2:39][CH2:40][C@@H:36]([F:35])[CH2:37]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:4][CH2:3]1
Reactant: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: F[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1(O)CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@@H](F)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-1-hydroxy-cyclohexylmethyl)-amide, DIPEA and (R)-3-fluoro-pyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 5.43-5.56 (1H), 4.56 (s, 1H), 3.89 (m, 2H), 3.70 (m, 1H), 3.55 (m, 1H), 3.26 (m, 2H), 2.44 (m, 2H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 442 [M+H]
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1.[C:23]([O:38][CH3:39])(=[O:37])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O-:36])=O>C(Cl)Cl>[C:23]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:36])([O:38][CH3:39])=[O:37]
Reactant: CNc1ccccc1OCc1ccccc1
Reactant: COC(=O)CCCCCCCCCCC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CCCCCCCCCCC(=O)N(C)c1ccccc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a stirred ice-cold solution of (27) (0.21 g., 1.0 mM) in dried methylene chloride (10 mL) containing anhydrous pyridine (0.3 mL) is added (7) (0.27 g., 1.03 mM), dissolved in 5 methylene chloride (5 mL), dropwise over 1 minute (some methylene chloride used as a rinse). After stirring cold for 30 minutes, the mixture is allowed to stir at ambient temperature for completion of the reaction. The reaction mixture is washed 1× with 1N HCL, dried (Na2SO4) and filtered. Flash chromatography (silica gel, 20% ethyl acetate/hexane as eluant) of the residue obtained gives the title compound (28) (0.33 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:23])[CH:20]=[C:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4ccccc4F)c3O2)cc1
Yield: 93.5 %

Procedure:
Treatment of (±)-(7-bromo-5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.00 g, 4.98 mmol) with 2-fluorophenyl boronic acid (1.05 g, 7.48 mmol), dichlorobis(tri-o-tolylphosphine)palladium(II) (0.196 g, 0.249 mmol), and potassium carbonate (1.72 g, 12.46 mmol) generally according to the procedure described for Intermediate 37 gave 1.94 g (94%) of (±)-[5-fluoro-7-(2-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a yellow oil. Rf=0.38 (silica, ethyl acetate:hexanes 3:17); Anal. calcd. for C22H18F2O4S: C, 63.45; H, 4.36. Found: C, 63.13; H, 4.19.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([O:23]CC)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].CO>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:15])[CH:11]=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc(C(=O)N2CCCC2)cc(-c2ccc(C)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of ethyl 4′-methyl-5-(pyrrolidine-1-carbonyl)biphenyl-3-carboxylate (3.94 g, 11.7 mmol), lithium hydroxide (0.65 g, 27.1 mmol), MeOH (250 mL), and water (40 mL) was stirred at rt for 20 hr. LC-MS indicated completion of the reaction. The solvent was removed in vacuo and the residue was treated with water and acidified with 1N aq. HCl to pH=2-3. The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic layers were washed with water, brine, dried and concentrated to yield the product as a white solid. LC-MS: 310.4 [M+1]+; 1H NMR (400 MHz, DMSO-d6): 13.29 (s, 1H), 8.21 (t, 1H, J=1.6 Hz), 7.99 (t, 1H, J=1.6 Hz), 7.98 (t, 1H, J=1.5 Hz), 7.64 (d, 2H, J=8.2 Hz), 7.31 (d, 2H, J=7.9 Hz), 3.50 (t, 2H, J=6.7 Hz), 3.43 (t, 2H, J=6.5 Hz), 2.36 (s, 3H), 1.98-1.78 (m, 4H).