Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[N:20]=[C:21]([C:25]4[O:26][CH:27]=[CH:28][CH:29]=4)[O:22][C:23]=3[CH3:24])=[C:13]([O:30][CH3:31])[CH:12]=2)=[N:5][CH:6]=[CH:7][CH:8]=1)#N.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:53])C>CCCCCC>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1[C:21]1[O:22][C:23]([CH3:24])=[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][O:9][C:4]3[C:3]([CH:1]=[O:53])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:12][C:13]=2[O:30][CH3:31])[N:20]=1
Reactant: COc1cc(COc2ncccc2C#N)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: COc1cc(COc2ncccc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 16 %

Procedure:
To a mixture of 3-cyano-2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]pyridine (6.30 g) and anhydrous toluene (250 mL) was dropwise added a solution (0.95 M, 47 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1 hr. A saturated aqueous ammonium chloride solution (50 mL) was dropwise added to the reaction mixture at 0° C. and ethyl acetate was further added. Insoluble materials were filtered off and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give crystals (1.0 g, yield 16%) of 2-[4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]-3-methoxybenzyloxy]-3-pyridinecarbaldehyde from a fraction eluted with ethyl acetate-hexane (2:3, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [CH2:1]=[O:2].[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5]=1[CH:10]=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]1=[O:20].C(N(CC)CC)C>CN(C)C=O.O>[CH3:3][C:4]1[CH:8]=[C:7]([CH3:9])[NH:6][C:5]=1/[CH:10]=[C:11]1\[C:12](=[O:20])[N:13]([CH2:1][OH:2])[C:14]2[C:19]\1=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: C=O
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(/C=C2\C(=O)N(CO)c3ccccc32)[nH]1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
Aqueous formaldehyde (15.0 g of 38% solution, 190 mmol) was added to a stirred solution of 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (23.8 g, 100 mmol) and triethylamine (15.0 g, 150 mmol) in dimethylformamide (200 mL). After 1 h, the solution was diluted with water and the precipitate was filtered off, washed with water, and dried to give 26.4 g of the title compound, mp 196–200° C. HPLC Rt 5.71 min. 1H NMR (CDCl3) δ 2.34 (s, 6H), 3.14 (t, 1H), 5.44 (d, 2H), 5.98 (d, 1H), 7.08 (m, 2H), 7.18 (m, 1H), 7.36 (s, 1H), 7.48 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C16H16N2O2: C, 71.62; H, 6.01; N, 10.44. Found: C, 71.33; H, 6.09; N, 10.43. A sample was recrystallized from ethyl acetate; mp 200–202° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:10](OCC)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.[NH2-].[Na+].[Na]>O1CCCC1>[C:11]1([C:10](=[O:17])[CH2:2][C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:3])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)c1ccccc1
Reactant: CCOC(=O)c1ccccc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
A THF solution of acetophenone (6.2 g) is added to a tetrahydrofuran suspension of NaNH2 (4.0 g). The mixture is stirred at room temperature for ten minutes. Ethyl benzoate (15.5 g) is then added to the mixture. A gelatinous precipitate forms over the course of 24 hours. The mixture is added to an aqueous solution of HCl to neutralize the sodium amide and the sodium salt of the β-diketone. The mixture is then extracted with chloroform. The organic layer is stripped on a rotary evaporator. 1,3-diphenyl-1,3-propanedione is isolated from the residue by precipitating its copper salt. Decomposition of the complex with HCl yields the desired product in pure form. NMR analysis confirms the expected structure.
Reaction SMILES: C[N+]1([O-])CCOCC1.[Si:9]([O:16][C@@H:17]1[CH2:22][C@H:21]([OH:23])[CH2:20][CH2:19][C@H:18]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].[NH4+].[Cl-]>CC#N.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Si:9]([O:16][C@@H:17]1[CH2:22][C@@H:21]([OH:23])[CH2:20][CH2:19][C@H:18]1[NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](O)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Tetrapropylammonium perruthenate (21 mg, 0.06 mmole) was added to a stirred suspension of N-methylmorpholine N-oxide (107 mg, 0.92 mmole), tert-butyl (1R,2R,4R)-2-(tert-butyldimethylsilyloxy)-4-hydroxycyclohexylcarbamate (39B) (210 mg, 0.61 mmole) and crushed 4 A° molecular sieves (500 mg) in dry CH3CN (5 mL). After 5 min, the solvent was removed and the residue was suspended in a 1:1 mixture of EtAc and hexane. This was applied onto a short column of silica gel and eluted with five column volumes of the EtAc/hexane mixture. Removal of the solvents left tert-butyl (1R,2R)-2-(tert-butyldimethylsilyloxy)-4-oxocyclohexylcarbamate (189 mg, 90%). This was dissolved in dry THF and the reaction cooled to −78° C. Lithium tri-sec-butylborohydride (1.1 mL, 1.1 mmole, 1.0 M in THF) was added dropwise and the reaction was left stirring for 1 hr after which it allowed to warm to 0° C. A saturated aq. solution of NH4Cl was carefully added and the reaction was extracted with a mixture of EtOAc/hexane=1/1. The organic extracts were washed with brine and dried (Na2SO4). Removal of the solvents followed by radial chromatography [silica gel, step gradient elution starting with mixture of hexane containing 0 to 30% EtOAc) afforded, in order of elution, the product (127 mg, 67%) as an oil: 1H NMR (CDCl3) 0.05 (s, 3H), 0.07 (s, 3H), 0.86 (m, 9H), 1.42 (s, 9H), 1.47 (m, 1H), 1.57 (m, 2H), 1.70 (m, 3H), 1.91 (m, 1H), 3.43 (s, 1H), 3.83 (m, 1H), 4.05 (d, 1H), 4.48 (d, 1H) and tert-butyl (1R,2R,4R)-2-(tert-butyldimethylsilyloxy)-4-hydroxycyclohexylcarbamate (9 mg, 5%).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[C:11]1([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:20]=[C:19]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]#[N:36])[CH:18]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[NH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:19]1[CH:18]=[C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:20]=1
Reactant: N#CCCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: NCCCCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
To a dry flask was added aluminum chloride (0.857 g, 6.42 mmol). The flask was cooled to less than 0° C. with an ice/ethanol bath. Ether (15 mL) was added, and the reaction was stirred for 5 min until the aluminum chloride dissolved. Lithium aluminum hydride (0.244 g, 6.42 mmol) was then added, and the reaction was heated to reflux. 6-[(4,6-Diphenyl-2-pyridinyl)oxy]-hexanenitrile (1.0 g, 2.92 mmol) was dissolved in ether (5 mL) and added dropwise to the refluxing solution. After addition was complete, the reaction was stirred overnight at room temperature. The reaction was then quenched with water. 6 N Aqueous sulfuric acid was added until a clear solution formed. This mixture was then extracted with ether (3×). The aqueous layer was then cooled in an ice bath and basified to pH 14 with 50% aq. NaOH. This was then extracted with ether (4×). The organic layer was then washed with saturated NaCl, dried over magnesium sulfate, and evaporated to give 0.7184 g (71%) of 1-amino-6-[(4,6-diphenyl-2-pyridinyl)oxy]-hexane as an oil. ESMS: Calcd. For C23H26N2O, 346.20; Found, 347.3 (M+H)+1
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9](=[O:22])[C:10]1C(=[CH:15][CH:16]=[CH:17][C:18]=1[N+:19]([O-:21])=[O:20])C(O)=O>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][C:9](=[O:22])[C:10]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][CH:16]=[CH:15][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1c(C(=O)O)cccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1c(C(=O)Cl)cccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Oxalyl chloride (5.4 mL, 62.4 mmol) was added to a suspension of 3-nitro-phthalic acid 2-methyl ester (11.7 g, 52.0 mmol, Step A) in 150 mL of anhydrous CH2Cl2 at RT. A few drops of DMF were added, then the mixture was heated to reflux for 2 h, and cooled to RT. The mixture was washed with NaHCO3 (aq), brine, dried over MgSO4, filtered, and condensed to give the titled compound as a white solid.
Reaction SMILES: OO.[OH:3][N:4]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH:7]([O:12][C:13](=[O:31])[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([OH:28])[C:22]([CH3:30])([CH3:29])[CH2:21]2)=[O:18])[CH2:6][C:5]1([CH3:33])[CH3:32].S([O-])([O-])=O.[Na+].[Na+].[C:40]([OH:44])([CH3:43])([CH3:42])[CH3:41]>>[OH:44][C:40]([CH3:43])([CH3:42])[CH2:41][O:28][N:23]1[C:22]([CH3:30])([CH3:29])[CH2:21][CH:20]([O:19][C:17](=[O:18])[CH2:16][CH2:15][CH2:14][C:13]([O:12][CH:7]2[CH2:8][C:9]([CH3:11])([CH3:10])[N:4]([O:3][CH2:41][C:40]([OH:44])([CH3:43])[CH3:42])[C:5]([CH3:33])([CH3:32])[CH2:6]2)=[O:31])[CH2:25][C:24]1([CH3:27])[CH3:26]
Reactant: CC1(C)CC(OC(=O)CCCC(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)CCCC(=O)OC2CC(C)(C)N(OCC(C)(C)O)C(C)(C)C2)CC1(C)C

Procedure:
Aqueous hydrogen peroxide is added to a mixture of bis(1-oxyl-2,2,6,6-tetramethylpieridin-4-yl)glutarate and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-50° C. Excess peroxide is decomposed with aqeuous sodium sulfite solution. The organic layer is concentrated and the crude product is purified by flash chromatography on silica gel to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][CH:10]=[C:6]2[N:5]=[C:4]([CH2:11][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH:3]=1.[CH:20]1([NH2:23])[CH2:22][CH2:21]1.C(N(CC)CC)C.C(#N)C>O>[CH:20]1([NH:23][C:2]2[N:7]3[N:8]=[CH:9][CH:10]=[C:6]3[N:5]=[C:4]([CH2:11][C:12]3[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=3)[C:15]#[N:16])[CH:3]=2)[CH2:22][CH2:21]1
Reactant: N#Cc1cccc(Cc2cc(Cl)n3nccc3n2)c1
Reactant: NC1CC1
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: N#Cc1cccc(Cc2cc(NC3CC3)n3nccc3n2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To the reaction flask, 3-((7-chloropyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile (400 mg, 1.5 mmol) was added along with cyclopropylamine (115 μL, 1.6 mmol), triethylamine (230 μL, 1.6 mmol), and acetonitrile (3 mL). The reaction was stirred at room temperature for 8 hours at 80° C. then cooled to room temperature, diluted with water, filtered and washed with water. The product, 3-((7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)benzonitrile, was collected as a solid in 83% yield after drying under vacuum overnight. LCMS (M+1=290)
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[C:6]([C:9]1[CH:39]=[CH:38][C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25](O)=O)=[CH:17][CH:16]=2)=[C:11]([CH3:40])[C:10]=1[OH:41])(=[O:8])[CH3:7].[OH-].[K+].Cl>CC(C)=O.O>[OH:41][C:10]1[C:11]([CH3:40])=[C:12]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]([C:22]3[CH:30]=[CH:29][CH:28]=[C:24]([C:25]4[NH:5][C:3]([SH:4])=[N:2][N:1]=4)[CH:23]=3)[O:31][CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)=[CH:17][CH:16]=2)[CH:38]=[CH:39][C:9]=1[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(C(=O)O)c3)cc2)c(C)c1O
Reactant: NNC(N)=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)c1ccc(OCc2ccc(C(OC3CCCCO3)c3cccc(-c4nnc(S)[nH]4)c3)cc2)c(C)c1O

Procedure:
Heat a solution of 3-[[4-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-phenyl]-(tetrahydro-pyran-2-yloxy)-methyl]-benzoic acid thiosemicarbazide (1.20 g, 2.04 mmol) and potassium hydroxide (0.228 g, 4.08 mmol) in acetone (5.0 mL) and water (5.0 mL) overnight. Acidify with 2N hydrochloric acid and extract with ethyl acetate (5×). Combine organic layers and wash with brine, dry, and concentrate to afford the title compound which was used without further purification (1.12 g, 2.04 mmol, 99%). MS (m/z): 544 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:4][CH:3]=1.[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:26]=1[C:27](Cl)=[O:28].NC1C=CC(N2C(=O)CC(=O)NC3C(CC)=CC=CC2=3)=CC=1>>[Cl:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:10]=3[NH:11][C:12](=[O:15])[CH2:13][N:14]=2)=[CH:6][CH:7]=1)=[O:28]
Reactant: COc1cccc(Cl)c1C(=O)Cl
Reactant: Nc1ccc(C2=NCC(=O)Nc3c2ccc2ccccc32)cc1
Agent: CCc1cccc2c1NC(=O)CC(=O)N2c1ccc(N)cc1
Product: COc1cccc(Cl)c1C(=O)Nc1ccc(C2=NCC(=O)Nc3c2ccc2ccccc32)cc1
Yield: 83.5 %

Procedure:
By using 5-(4-aminophenyl)-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one (40 mg, 0.13 mmol) obtained in Example 64, and 2-chloro-6-methoxybenzoyl chloride (0.2 mmol), the title compound (51 mg, yield 54%) was obtained in the same manner as that of Example 1, (4).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[CH:6]1[CH:15]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=3[CH:8]([C:9]3[C:14]2=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7]1.[O:22]1CCOCC1.[ClH:28]>>[ClH:28].[CH:20]1[C:21]2[CH:8]3[CH2:7][CH:6]([C:2]([O:1][CH2:5][CH2:4][NH2:3])=[O:22])[CH:15]([C:14]4[C:9]3=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: C1COCCO1
Reactant: c1ccc2c(c1)C1CC(C3=NCCO3)C2c2ccccc21
Agent: Cl
Product: NCCOC(=O)C1CC2c3ccccc3C1c1ccccc12
Reaction time: 2.5 h

Procedure:
A solution of 11-(2-oxazolin-2-yl)-9,10-dihydro-9,10-ethanoanthracene (4.122 g) in 1.074 N hydrochloric acid (13.9 ml) is allowed to stand at room temperature for 2.5 hours. The reaction mixture is mixed with dioxane to dissolve the precipitate formed and evaporated at room temperature under reduced pressure to remove the solvent. The residue is recrystallized from anhydrous ethanol-ether to give β-aminoethyl 9,10-dihydro-9,10-ethanoanthracene-11-carboxylate hydrochloride 1/2 hydrate (4.641 g) as crystals melting at 155° to 158° C. IR (Nujol), 3379, 1735 cm-1.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>C(OCC)(=O)C.CO>[Br:1][CH2:2][CH2:3][CH2:4][C:5]1[S:9][C:8]([C:10]([O:12][CH3:14])=[O:11])=[CH:7][CH:6]=1
Reactant: O=C(O)c1ccc(CCCBr)s1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CCCBr)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.1 %

Procedure:
To a solution consisting of 5-(3-bromopropyl) thiophene-2-carboxylic acid (from procedure above, 24 g, 78 mmol) in ethyl acetate (150 mL) and methanol (15 mL) at 0° C. was added TMS-diazomethane (50 mL, 100 mmol, 2 M) dropwise over one hour. The reaction mixture was then allowed to warm to room temperature and was stirred for 16 hours, The reaction mixture was concentrated under reduced pressure without workup. The residue was purified by silica gel chromatography. Elution with ethyl acetate-heptane (1:80 v/v) afforded the title compound as a white solid (4.95 g; 24% over two steps); TLC Rf 0.45 (solvent system: 15:85 v/v ethyl acetate-hexanes); MS (ESI+) m/z 263, 265 (isotopic bromines, each (M+H)+); 1HNMR (CDCl3) δ 7.5 (d, 1H), 6.7 (d, 1H), 3.75 (s, 3H), 3.3 (t, 2H), 2.9 (t, 2H), 2.1-2.0 (m, 2H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH3:18])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:5])C.[Li+].[OH-].O>C1COCC1.CO>[CH3:18][N:9]1[C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]1
Reactant: CCOC(=O)c1cnn(C)c1Oc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(C(=O)O)c1Oc1ccccc1

Procedure:
1-Methyl-5-phenoxy-1H-pyrazole-4-carboxylic acid ethyl ester (22.6 g; 91.4 mmol) is dissolved in THF/MeOH (1/1) and LiOH in water (7.67 g; 183 mmol) is added. After 16 hours at ambient temperature the reaction mixture is washed with EtOAc. The aqueous layer is acidified with 1 N HCl and extracted with EtOAc. The organic layer is dried and evaporated.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=[O:9])[S:5][C:6]=1[CH3:7].[CH3:11]O>OS(O)(=O)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[CH3:7]
Reactant: CO
Reactant: Cc1sc(C(=O)O)cc1Br
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Br)c(C)s1
Reaction time: 12 h
Yield: 94 %

Procedure:
A solution of 4-bromo-5-methyl-2-thiophenecarboxylic acid (3 g, 13.6 mmol) in MeOH (67 mL) and H2SO4 (3 mL) was stirred at 50° C. After 12 h, the solution was added to ice-H2O and the pH was adjusted to ˜11. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly yielding the title compound (3 g, 94%) as an orange solid: LCMS (ES) m/z 236 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:34]=[CH:33][C:11]([O:12][CH:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[CH:19][N:18]=3)[CH2:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[CH:7]=1.[OH-].[Na+].Cl>CO>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[N:5][N:6]([C:8]2[CH:9]=[CH:10][C:11]([O:12][CH:13]([C:17]3[CH:32]=[CH:31][C:20]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[CH:19][N:18]=3)[CH2:14][CH2:15][CH3:16])=[CH:33][CH:34]=2)[CH:7]=1
Reactant: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)OCC)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1)c1ccc(C(=O)NCCC(=O)O)cn1
Temperature: 25 °C
Yield: 99 %

Procedure:
(+/−)-Ethyl 3-(6-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl) nicotinamido)propanoate (45 mg, 0.089 mmol) was dissolved in methanol (2 mL). 1 M NaOH (2 mL) was added with stirring at room temperature. After stirring for 6 hours, 1M HCl (2 mL) was added. The pH was adjusted to approximately 4, using 1M HCl and 1M NaOH. The resulting cloudy solution was extracted with ethyl acetate (2×15 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated to give (+/−)-3-(6-(1-(4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenoxy)butyl)nicotinamido)propanoic acid (42 mg, 100%) as a foamy solid. 1H NMR (400 MHz, CDCl3, δ): 9.23 (d, J=1.6 Hz, 1H), 8.38 (dd, J=8.2, 2.1 Hz, 1H), 7.99 (s, 1H), 7.85-7.80 (m, 2H), 7.55 (d, 1H), 7.49-7.42 (m, 2H), 6.92-6.85 (m, 2H), 5.31 (dd, J=7.7, 4.8 Hz, 1H), 3.83-3.76 (m, 2H), 2.75-2.69 (m, 2H), 2.09-1.85 (m, 2H), 1.60-1.39 (m, 2H), 0.96 (t, J=7.3 Hz, 3H). MS (M+1): 477.3.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:15][CH2:14][CH:13]([C:16]([OH:18])=[O:17])[NH:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.[CH:28]([N:30]([CH2:39][C@@H:40]([CH2:44][CH2:45][CH2:46][CH3:47])[C:41](F)=[O:42])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:29]>CN(C=O)C.C(OCC)(=O)C>[CH:28]([N:30]([CH2:39][C@@H:40]([CH2:44][CH2:45][CH2:46][CH3:47])[C:41]([N:12]1[C@H:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15][N:11]1[C:9]([O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10])=[O:42])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:29]
Reactant: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)F
Reactant: O=C(O)C1CCN(C(=O)OCc2ccccc2)N1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](CN(C=O)OCc1ccccc1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.4 %

Procedure:
To a solution of 1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid 91.52 g, 6.1 mmol) and DIPEA (3.15 g, 24.4 mmol) in DMF (8 mL) was added (2R)-2-({formyl[(phenylmethyl)oxy]amino}methyl)hexanoyl fluoride (10) (1.7 g, 6.1 mmol) in DMF. The reaction mixture was stirred at rt overnight and LC/MS indicated completion of the reaction. The mixture was diluted with ethyl acetate (20 mL), and washed with 5% aqueous citric acid, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:1) followed by DCM/MeOH (200:1) to provide the title compound (0.48 g, 32%). LCMS: (M+H)+: 512.0. 1H NMR (300 MHz, CDCl3) δ ppm 0.79 (t, J=6.0 Hz, 3H), 1.10 (m, 4H), 1.40 (m, 1H), 1.57 (m, 1H), 1.77 (m, 1H), 2.17 (m, 1H), 2.97 (m, 2H), 3.25-3.69 (m, 1H), 4.13 (m, 3H), 4.56-4.93 (m, 2H), 5.12 (s, 2H), 7.34 (m, 10H), 7.74 (s, 0.3H), 8.36 (s, 0.6H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:4]
Reactant: Brc1ccccc1
Reactant: COC(=O)c1sc(C2=CCCCC2)cc1N
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1sc(C2=CCCCC2)cc1Nc1ccccc1
Yield: 75.4 %

Procedure:
To a solution of 5-cyclohex-1-enyl-3-amino-thiophene-2-carboxylic acid methyl ester (111 mg, 0.47 mmol) and bromobenzene (54 μL, 0.51 mmol) in dry dioxane (3 mL) were added cesium carbonate (459 mg, 1.41 mmol) and Pd2 dba3 (43 mg, 0.047 mmol), and the mixtue was deoxygenated by bubbling nitrogen through solution for 10 min. Then BINAP (47 mg, 0.075 mmol) was added to the mixture, and it was refluxed under nitrogen overnight. The mixture was diluted with CH2Cl2 and filtered through celite washing with CH2Cl2. Filtrate was concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 2-30% EtOAc in hexanes to give 111 mg (76%) of 5-cyclohex-1-enyl-3-phenylamino-thiophene-2-carboxylic acid methyl ester.