Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[C:12]([O:13][CH3:14])=[CH:11][C:10]([CH3:15])=[C:9]([O:16][CH3:17])[C:8]=2[O:18][CH3:19])[N:6]=1.C(OC(C[N:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH:29]1[C:37](O)=[O:38])=O)(C)(C)C.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[CH3:19][O:18][C:8]1[C:9]([O:16][CH3:17])=[C:10]([CH3:15])[CH:11]=[C:12]([O:13][CH3:14])[C:7]=1[C:5]1[N:6]=[C:2]([NH:1][C:37]([C:29]2[NH:28][C:36]3[C:31]([CH:30]=2)=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:38])[S:3][CH:4]=1
Reactant: COc1cc(C)c(OC)c(OC)c1-c1csc(N)n1
Reactant: CC(C)(C)OC(=O)CN1c2ccccc2CC1C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C)c(OC)c(OC)c1-c1csc(NC(=O)c2cc3ccccc3[nH]2)n1
Reaction time: 48 h
Yield: 33.1 %

Procedure:
0.16 g of 2-amino-4-(2,3,6-trimethoxy-4-methylphenyl)thiazole is dissolved in 10 ml of DMF. 0.18 g of N-(tert-butyloxycarbonylmethyl)-2-indolinecarboxylic acid, 0.2 ml of triethylamine and 0.38 g of BOP are added, and the reaction mixture is left stirring for 48 hours. 100 ml of water are added, the resulting mixture is extracted with AcOEt, and the organic phase is separated after settling has taken place, dried over sodium sulphate and concentrated under vacuum. The residue is dissolved in 10 ml of CHCl3, 10 ml of TFA are then added and the reaction mixture is stirred at r.t. for 2 hours 30 minutes. It is concentrated under vacuum, adding three times 20 ml of benzene. The residue is dissolved in 20 ml of dimethoxyethane, 0.1 ml of triethylamine and 0.112 g of DDQ are then added and the reaction mixture is left overnight at room temperature. It is concentrated under vacuum, and the residue is taken up in AcOEt and washed successively with 1N NaOH solution, with KHSO4 solution and with sodium chloride solution; the organic phase is separated after settling has taken place, dried over sodium sulphate, filtered and concentrated under vacuum. The residue is chromatographed on silica gel, eluting with CHCl3 /AcOEt (50:50; v/v). The fractions of pure products are concentrated under vacuum, and the residue is solidified in pentane to yield 0.08 g of the expected product; m.p.=200° C.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][OH:16].Cl[C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1.O>CN(C)C=O.O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:18]1[CH:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][N:19]=1
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccnc(OCc2nc(-c3ccccc3)oc2C)c1
Reaction time: 0.25 h
Yield: 13.5 %

Procedure:
Sodium hydride-(60%, oily, 2.40 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (9.46 g) in N,N-dimethylformamide (50 ml) at 0° C., which was stirred for 15 minutes. A solution of methyl 2-chloro-4-pyridinecarboxylate (8.58 g) in tetrahydrofuran (50 ml) was added to the mixture. After being stirred at room temperature for 1 hour, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain methyl 2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridinecarboxylate (2190 mg, yield 14%) as colorless crystals from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio). This was recrystallized from ethyl acetate-hexane. Melting point: 106–107° C.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:14]3[CH2:19][CH2:18][O:17][CH:16]([CH2:20][NH:21]C=O)[CH2:15]3)[C:11]=2[F:13])[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[ClH:29].O>CO>[ClH:29].[NH2:21][CH2:20][CH:16]1[CH2:15][N:14]([C:10]2[C:11]([F:13])=[C:12]3[C:7]([C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=2[F:24])[CH2:19][CH2:18][O:17]1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CNC=O)C3)c(F)c21
Agent: Cl
Solvent: O
Solvent: CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCOC(CN)C3)c(F)c21

Procedure:
A solution of 500 mg of 1-ethyl-6,8-difluoro-7-[2-(formylaminomethyl)morpholino]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1 ml of concentrated hydrochloric acid, 2 ml of water and 10 ml of methanol is refluxed for 1.5 hours. The reaction mixture is concentrated under reduced pressure. The obtained crystals are washed with acetone, collected by filtration and recrystallized from dimethylformamide to give 7-[2-(aminomethyl)morpholino]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride, melting at 276°-278° C. with decomposition.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:37])[C@H:10]([C:22]1[O:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:29][CH:28]=2)=[N:24][N:23]=1)[NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[C:14]([Cl:20])[C:13]=1[CH3:21])(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:20][C:14]1[C:13]([CH3:21])=[C:12]([NH:11][C@@H:10]([C:22]2[O:26][C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34](=[O:36])[CH3:35])=[CH:31][CH:32]=3)=[N:24][N:23]=2)[C@@H:9]([OH:8])[CH3:37])[CH:17]=[CH:16][C:15]=1[C:18]#[N:19]
Reactant: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O[Si](C)(C)C(C)(C)C)o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(-c2nnc([C@H](Nc3ccc(C#N)c(Cl)c3C)[C@H](C)O)o2)cc1
Temperature: 11 °C
Yield: 88.1 %

Procedure:
To a pre-cooled (−55° C.) solution of N-(4-(5-((1R,2S)-2-(tert-butyl dimethylsilyloxy)-1-(3-chloro-4-cyano-2-methylphenylamino)propyl)-1,3,4-oxadiazol-2-yl)phenyl)acetamide (216 mg, 0.40 mmol) in THF (20 mL) was added TBAF (0.48 mL, 0.48 mmol, 1 M solution in THF) over 5 minutes. Upon complete addition the reaction mixture was allowed to warm to 11° C. over 3 h and quenched with sat. aq. NH4Cl (15 mL). The resulting mixture was partitioned between H2O (25 mL) and EtOAc (40 mL). The aqueous layer was extracted with EtOAc (50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to provide a colourless oil, which was purified by flash chromatography over silica gel (50-100% EtOAc in hexanes) to provided the title compound as a colourless solid (150 mg, 88%): 1H NMR (400 MHz, d6-acetone, δ in ppm) 9.49 (s 1H), 7.90 (dm, J=9.0 Hz, 2H), 7.80 (dm, J=9.0 Hz, 2H), 7.47 (d, J=8.8 Hz, 1H), 6.85 (d, J=8.6 Hz, 1H), 5.66 (d, J=8.4 Hz, 1H), 5.07 (dd, J=3.7, 8.4 Hz, 1H), 4.84 (br s, 1H), 4.61 (dq, J=3.5, 5.9 Hz, 1H), 2.39 (s, 3H), 2.12 (s, 3H), 1.40 (d, J=6.3 Hz, 3H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]([CH2:30][C:31]([NH:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)=[O:32])[CH3:29].[OH-].[Na+]>CN(C=O)C.CO>[CH3:29][N:28]([CH2:30][C:31]([NH:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:16](=[C:6]2\[C:5](=[O:26])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=3)/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:39][CH:40]=1)=[O:32])[CH3:27]
Reactant: CN(C)CC(=O)Nc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CN(C)C=O
Product: CN(C)CC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-dimethylaminomethylcarbonylamino-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][CH:12]([NH:15][C:16](=[O:22])OC(C)(C)C)[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl[CH2:32][CH2:33][CH2:34]C(Cl)=O.[OH-].[Na+]>C(#N)C.O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]3[CH2:34][CH2:33][CH2:32][C:16]3=[O:22])[CH2:11]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)CCCCl
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Nc1ccc(N2CC[C@@H](N3CCCC3=O)C2)cc1
Reaction time: 2 h

Procedure:
tert-Butyl [1-(4-Nitrophenyl)pyrrolidin-3-yl]carbamate was treated by method G. The crude product (1.4 g) was dissolved in acetonitrile (20 ml) and mixed with trisodium phosphate (0.67 g) and 4-chlorobutyryl chloride (1.1 g). After 2 hours, sodium hydroxide (0.6 g) in water (10 ml) was added and the mixture was vigorously stirred. After 12 hours, the same amount of sodium hydroxide solution was again added, and the mixture was stirred for a further 24 hours. The concentrated reaction solution was partitioned between water and-ethyl acetate, and the organic phase was dried and concentrated. The residue was hydrogenated by method B. This resulted in the product with the molecular weight of 245.33 (C14H19N3O); MS (ESI): 246 (M+H+).
Reaction SMILES: [CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH:8](Br)[C:7]1=O)=[O:5])[CH3:2].[F:16][CH2:17][CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:1]([N:3]([CH2:14][CH3:15])[C:4]([CH:6]1[C:7]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([F:26])[CH:24]=3)[N:19]([CH2:18][CH2:17][F:16])[C:8]=2[CH2:9][CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)C1CCCC(Br)C1=O
Reactant: FCCNc1ccc(F)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCN(CC)C(=O)C1CCCc2c1c1cc(F)ccc1n2CCF
Temperature: 50 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
A mixture of 3-bromo-2-oxo-cyclohexanecarboxylic acid diethylamide (35; prepared according to Example 7(c)) (336 mg, 1.2 mmol) and (2-fluoro-ethyl)-(4-fluoro-phenyl)-amine (38) (383 mg, 2.4 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (2 mL) and dry zinc chloride (491 mg, 3.6 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (20 mL) and washed with 2 N HCl (10 mL), water (2×10 mL) and aqueous potassium carbonate solution (2×5 mL) then dried and concentrated in vacuo. The crude material was triturated with diethyl ether to afford 40 mg (10%) of 6-fluoro-9-(2-fluoro-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid diethylamide (non-radioactive imaging agent 9) as white solid. The structure was confirmed by 1H NMR (300 MHz, CDCl3) δH 1.13 (3H, t, J=9 Hz, N(CH2CH3)2), 1.30 (3H, t, J=9 Hz, N(CH2CH3)2), 1.55-2.14 (4H, m, 2- and 3-CH2), 2.78-2.86 (2H, m, 1-CH2), 3.36-3.67 (4H, m, N(CH2CH3)2), 4.00-4.10 (1H, m, 4-CH), 4.30 (2H, dm, J=21 Hz, NCH2CH2F), 4.60 (2H, dm, J=41 Hz, NCH2CH2F), 6.75-6.95 (2H, m, NCCHCHCFCH), and 7.05-7.15 (1H, m, NCCHCHCFCH.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].[N:11]#[C:12]Br.CC(C)=O.C(N(CC)CC)C>O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:12]#[N:11])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2]
Reactant: C=C(C)c1ccc(O)cc1
Reactant: N#CBr
Solvent: O
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: C=C(C)c1ccc(OC#N)cc1
Temperature: -5 °C
Yield: 86.8 %

Procedure:
A 201.26 gram (1.50 mole) portion of p-isopropenyl phenol, 166.84 grams (1.575 mole) of cyanogen bromide and 900 milliliters of acetone were added to a reactor and maintained under a nitrogen atmosphere with stirring. The p-isopropenyl phenol used herein was of in excess of 99 percent purity. The stirred solution was cooled to -5° C. then 151.79 grams (1.50 mole) of triethylamine was added to the reactor over a twenty minute (1200 s) period and so as to maintain the reaction temperature at -5° to 0° C. After completion of the triethylamine addition, the reactor was maintained at -3° to 5° C. for an additional thirty-two minutes (1820 s), followed by addition of the reactor contents to 1 gallon of chilled deionized water. After five minutes (300 s) the water and product mixture was multiply extracted with three 400 milliliter volumes of methylene chloride. The combined methylene chloride extract was washed with 500 milliliters of 5 percent aqueous hydrochloric acid followed by washing with 800 milliliters of deionized water then drying over anhydrous sodium sulfate. The dry methylene chloride extract was filtered and solvent removed by rotary evaporation under vacuum. p-Isopropenylphenyl cyanate (207.24 grams) was recovered in 86.8 percent yield as a transparent, light amber colored liquid. Infrared spectrophotometric analysis of a film sample of the product confirmed the product structure (disappearance of phenolic hydroxyl group, appearance of --C≡N group). Gas chromatographic-mass spectroscopic analysis of the produuct confirmed the structure of p-isopropenylphenyl cyanate (parent ion m/e=159) with essentially no other compounds being present.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:23])=[O:22])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1Cl.C(=O)([O-])[O-].[Cs+].[Cs+].[OH:37][CH2:38][CH:39]1[CH2:41][CH2:40]1>CC(O)C.CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N:11]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([NH:24][C:25]4[CH:29]=[CH:28][O:27][N:26]=4)(=[O:22])=[O:23])=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]2=[O:30])[C:5]([O:9][CH3:10])=[N:6][C:7]=1[O:37][CH2:38][CH:39]1[CH2:41][CH2:40]1
Reactant: OCC1CC1
Reactant: COc1nc(Cl)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CC(C)O
Product: COc1nc(OCC2CC2)c(Cl)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 90 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
A 5-mL vial was sequentially charged with 1-(5,6-dichloro-2-methoxypyridin-3-yl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (300 mg, 0.642 mmol), cesium carbonate (154 μl, 1.926 mmol), dimethyl sulfoxide (2.1 mL), and (hydroxymethyl)cyclopropane (130 μL, 1.605 mmol). The vial was sealed with a PTFE lined cap and heated to 90° C. After 16 h, the brown reaction mixture was allowed to cool to RT, then diluted with IPA (3 mL) and filtered through a pad of celite. The pad was rinsed with IPA (2×5 mL) and the filtrate was concentrated under reduced pressure to furnish a brown oil, which was dissolved in DMSO (2 mL) filtered through a 0.2 micron filter and purified by reverse-phase HPLC (Waters XBridge Prep Shield RP18 10 μm OBD 19×100 mm) gradient, 20 to 75% MeCN in water (containing 0.1% trifluoroacetic acid as an additive), flow rate 40 mL/min to afford 1-(5-chloro-6-(cyclopropylmethoxy)-2-methoxy-3-pyridinyl)-N-3-isoxazolyl-2-oxo-1,2-dihydro-6-quinolinesulfonamide (180 mg, 0.358 mmol, 55.7% yield) as a tan amorphous solid. 1H NMR (500 MHz, DMSO-d6) δ=11.65 (br. s., 1H) 8.72 (s, 1 H) 8.36 (s, 1 H) 8.21 (d, J=9.67 Hz, 1 H) 8.04 (s, 1 H) 7.85 (dd, J=8.95, 1.75 Hz, 1 H) 7.00 (d, J=9.02 Hz, 1 H) 6.79 (d, J=9.67 Hz, 1 H) 6.45 (d, J=1.10 Hz, 1 H) 4.23-4.40 (m, 2 H) 3.78 (s, 3 H) 1.30-1.43 (m, 1 H) 0.62 (d, J=7.66 Hz, 2 H) 0.41 (br. s., 2 H). m/z (ESI) 503.3 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].IC.[CH3:34][Si](C)(C)[N-][Si](C)(C)C.[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([C:28](=[O:30])[CH3:29])[CH2:26][CH3:27])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:34])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C(C)c1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(C)=O)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
{2′-[(Acetyl-ethyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid ethyl ester (0.143 g, 0.33 mmol) and iodomethane (0.02 mL, 0.36 mmol) were combined in THF (1.5 mL) and cooled to −78° C. Sodium hexamethyldisilazide (1M in THF; 0.36 mL, 0.36 mmol) was added, and the mixture was stirred for 1 hour at −78° C. Once no starting material was seen by analytical LCMS, the mixture was quenched with aqueous 1N HCl and diluted with CH2Cl2. The aqueous layer was separated and extracted with CH2Cl2, and the combined organic layers were washed with H2O, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (0-100% EtOAc in hexanes) to give the title compound.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([OH:12])=[O:11].[CH3:17]O>>[Br:6][C:7]1[C:8]([CH3:16])=[C:9]([CH:13]=[CH:14][CH:15]=1)[C:10]([O:12][CH3:17])=[O:11]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1C
Yield: 95 %

Procedure:
Concentrated sulfuric acid (1 mL) was added to a solution of 3-bromo-2-methylbenzoic acid (27.9 mmol) in MeOH (60 mL) at rt. The reaction mixture was allowed to stir at reflux overnight and then concentrated to ˜half volume. The solution was diluted with diethyl ether and washed with saturated NaHCO3 and brine. The organic solution was dried over Na2SO4, filtered and concentrated to give methyl 3-bromo-2-methylbenzoate (27 mmol, 95%) as an oil which was used without further purification.
Reaction SMILES: S(=O)(=O)(O)O.O.[OH:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[O:7]=[C:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([OH:16])=[O:15])[CH2:9]1
Reactant: O=C(O)C1CCCC(O)C1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCCC(C(=O)O)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.2 %

Procedure:
The Jones oxidation reagent was prepared from sulfuric acid (30 mL), CrO3 (8.1 g) and H2O (30 mL) in an ice/water bath. A solution of 3-hydroxycyclohexane-1-carboxylic acid (11 g, 76.3 mmol, 1.00 equiv) in acetone (150 mL) was added slowly the prepared Jones reagent at 0° C. in 30 min. After addition, the resulting solution was stirred for 2 h at room temperature and the solids were filtered out. The resulting solution was extracted with DCM (3×100 mL). The combined organic layers were washed with brine and dried over sodium sulfate and concentrated under vacuum to give the desired 3-oxocyclohexane-1-carboxylic acid (8.7 g, crude) as a yellow oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)(O)[CH2:7]1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>ClCCCl.CCO>[CH2:1]([NH:3][C:4]([CH:6]1[CH2:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:13]([F:23])[CH:12]=2)[CH2:9]1)=[O:5])[CH3:2]
Reactant: CCNC(=O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CCNC(=O)C1CC(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: 80 °C
Yield: 24.7 %

Procedure:
To Example 12, 3-(3-Fluoro-4-pyrrolidin-1-ylmethyl-phenyl)-3-hydroxy-cyclobutanecarboxylic acid ethylamide (17 g, 53.1 mmol) in 200 mL of DCE at rt was added TFA (80.7 mL, 1.1 mol) and then the reaction was heated to 80° C. (oil bath). After 15 h the reaction was concentrated to approximately 45 g and used without further purification. The crude TFA salt from the above reaction was diluted with EtOH (500 mL), placed in a Parr bottle, purged with N2, and then 10% Pd/carbon (2.5 g, 14 wt %) was added. The resulting reaction mixture was hydrogenated with H2 (45 psi) at rt. After 1.5 h the reaction was purged with N2, then filtered through Celite™ and concentrated under reduced pressure. The resulting oil was diluted with EtOAc and then slowly quenched with a saturated solution of sodium bicarbonate. The layers were separated and the aqueous layer was back extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification of this material was accomplished by re-crystallization. Crude title compound was taken up in a minimal amount of warm EtOAc and allowed to cool to approximately 0° C. (refrigerator). The solid was filtered, dried under reduced pressure to give the title compound (4 g, 24% yield) as a white solid: Rf=0.21 (10% MeOH/CH2Cl2); LRMS m/z Calcd for C18H25FN2O, 304.4, found, 305.3, 1H NMR (300 MHz, CDCl3): δ 7.30 (apt t, J=7.9 Hz, 1H), 6.98 (dd, J=7.9, 1.6 Hz, 1H), 6.92 (dd, J=12.0, 1.6 Hz, 1H), 5.36 (bs, 1H), 3.67 (s, 2H), 3.42-3.26 (m, 3H), 2.94-2.85 (m, 1H), 2.57-2.50 (m, 6H), 2.42-2.33 (m, 2H), 1.82-1.74 (m, 4H), 1.14 (t, J=7.5 Hz, 3H); structure confirmed by x-ray crystallography and was determined to be cis.
Reaction SMILES: [CH3:1][C@@:2]1([O:30]C(=O)C)[C@H:6]([O:7]C(=O)C)[C@@H:5]([CH2:11][O:12]C(=O)C)[O:4][C@H:3]1[N:16]1[CH:29]=[C:20]2[CH:21]=[CH:22][C:23]3[C:24](=[S:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=32)=[N:17]1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[CH3:1][C@@:2]1([OH:30])[C@H:6]([OH:7])[C@@H:5]([CH2:11][OH:12])[O:4][C@H:3]1[N:16]1[CH:29]=[C:20]2[CH:21]=[CH:22][C:23]3[C:24](=[S:28])[NH:25][N:26]=[CH:27][C:18]([C:19]=32)=[N:17]1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc3ccc4c(=S)[nH]ncc(n2)c34)[C@](C)(OC(C)=O)[C@@H]1OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc2ccc3c(=S)[nH]ncc(n1)c23
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 22.7 %

Procedure:
To a suspension of compound 23.1 (180 mg, 0.38 mmol) in 4 mL ethanol was added 0.22 mL of 1N sodium hydroxide solution in water. The mixture was stirred at room temperature for 1.5 hr. after which time the pH was brought to 6 with acetic acid and the solvent evaporated. The residue was purified on silica gel column (10:1 CH2Cl2:MeOH) to afford 30 mg of product 23.2. 1H NMR (DMSO-d6) δ 10.49 (s, 1H), 8.52 (s, 1H), 7.50 (s, 1H), 7.00 (d, J 12 Hz, 1H), 6.08 (s, 1H), 5.65 (d, J 12 Hz, 1H), 5.18 (m, 3H), 3.82 (m, 3H), 3.68 (m, 1H), 0.73 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([OH:18])[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:2].[CH:19]([N:22]1[CH2:27][CH2:26][CH:25](O)[CH2:24][CH2:23]1)([CH3:21])[CH3:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:17]=[C:16]([O:18][CH:25]3[CH2:26][CH2:27][N:22]([CH:19]([CH3:21])[CH3:20])[CH2:23][CH2:24]3)[CH:15]=[CH:14][C:9]=2[C:10]=1[CH:11]([CH3:13])[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cc(O)ccc2c1C(C)C
Reactant: CC(C)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2cc(OC3CCN(C(C)C)CC3)ccc2c1C(C)C
Reaction time: 1 h
Yield: 119.7 %

Procedure:
The above prepared 6-hydroxy-3-isopropyl-benzofuran-2-carboxylic acid ethyl ester (0.400 g, 1.61 mmol) was dissolved in 8 mL of THF and treated successively at 0° C. with 1-isopropyl-piperidin-4-ol (0.461 g, 2 eq.), triphenylphosphine (0.845 g, 2 eq.) and DIAD (0.630 mL, 2 eq.), and the mixture then kept at ambient temperature for another 1 h. Pouring onto crashed ice, twofold extraction with AcOEt, washing with water, drying over sodium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, NEt3/AcOEt=5/95), yielded 0.720 g of the title compound as light yellow oil, contaminated with tiny amounts of reduced DIAD.