Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)CO.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1(O)[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:40][CH2:39][CH2:38][O:37]3)[CH2:34]2)[CH2:30]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>C1C=CC=CC=1>[CH2:16]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH2:36][C@@H:35]2[C@@H:31]([CH2:32][C:33]3([O:37][CH2:38][CH2:39][O:40]3)[CH2:34]2)[CH:30]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OC1(CCCCCOCc2ccccc2)C[C@@H]2CC3(C[C@@H]2C1)OCCO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: OCCO
Product: C1=C(CCCCCOCc2ccccc2)C[C@H]2CC3(C[C@@H]12)OCCO3
Reaction time: 3.5 h
Yield: 97.2 %

Procedure:
Ethylene glycol (0.05 ml) and 10 mg of p-toluenesulfonic acid were added to a solution of 209 mg of 3-(5-benzyloxypentyl)-7,7-ethylenedioxy-3-hydroxy-cis-bicyclo[3,3,0]octane (prepared as described in Preparation 9) in 2 ml of benzene, and the mixture was heated, with stirring, for 3.5 hours, whilst removing water as an azeotropic mixture. Upon completion of the reaction, the reaction mixture was neutralized with a 5% w/v aqueous solution of sodium bicarbonate. The reaction mixture was then washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off from the reaction mixture under reduced pressure, giving 193 mg of a residue. This residue was purified by silica gel column chromatography and 142 mg of the title compound were obtained as an oil from the fractions eluted with hexane containing 2-5% by volume of ethyl acetate. The product had the same properties as that of Preparation 4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][N:6]=[C:5]2[NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1.[C:20](O)(=[O:24])[CH2:21][C:22]#[CH:23].Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:19][C:15]1[CH:14]=[C:13]([NH:12][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20](=[O:24])[CH:21]=[C:22]=[CH2:23])[CH:3]=3)[N:8]=[CH:7][N:6]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Reactant: C#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: C=C=CC(=O)Nc1ccc2ncnc(Nc3cccc(Br)c3)c2c1
Yield: 64.8 %

Procedure:
To a solution of 6-amino-4-[(3-bromophenyl)amino]quinazoline (316 mg, 1.0 mmol), and 3-butynoic acid (173 mg, 2.06 mmol) in DMF (5 mL) stirred under nitrogen at 0° C. was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (384 mg, 2.0 mmol). After 1.5 hours the reaction was quenched with 0.1 M HCl solution (10 mL). The yellow precipitate was collected by Buchner filtration and washed with water followed by acetone. The solid was taken up into acetone with the addition of triethylamine. The formed solution was filtered through a 2-inch silica gel eluting with 50% acetone/CH2Cl2. The filtrate was collected and concentrated under reduced pressure to give the title compound as a yellow solid (247 mg, 56%), mp 268-270° C.
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25]OS(C)(=O)=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:13]([O:20][C:21](=[O:22])[NH:23][CH2:24][CH2:25][O:12][C:9]1[CH:8]=[CH:7][C:6]([C:4]2[N:3]=[CH:2][O:1][CH:5]=2)=[CH:11][CH:10]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Oc1ccc(-c2cocn2)cc1
Reactant: CS(=O)(=O)OCCNC(=O)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(NCCOc1ccc(-c2cocn2)cc1)OCc1ccccc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A stirred mixture of 290.0 g (1.80 mol) of 4-oxazol-4-yl-phenol (H. Jones, et al., J. Med. Chem., 21, 1110 (1978)), 737.7 g (2.70 mol) of methanesulfonic acid 2-benzyloxycarbonylamino-ethyl ester, and 746.0 g (5.40 mol) of potassium carbonate in 4.6 l of dry dimethylsulfoxide was heated to about 85° C. An additional 500 ml of dimethylsulfoxide was added and the viscous slurry was stirred at about 80° C. for about an additional two hours. The resulting mixture was cooled to about 50° C., poured into about 1 l of stirred ice water, slurried for about one hour, and then filtered. The wet filter cake was washed with water (2×1 l), and then partially dried by aspiration under vacuum for about two hours. The moist solid was charged into a round-bottomed flask, 6 l of methanol was added, and the mixture was then warmed to about 60° C. where 3 l of water was added. The heating source was removed, the mixture was stirred for about eighteen hours, and then filtered. The filter cake was washed with 2:1 methanol/water (v/v; 2×500 ml), and then dried under vacuum at about 40° C. for about eighteen hours. The title compound (389.5 g, 64% yield) was obtained as a beige powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:25])[CH2:11][N:10]([CH:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:9]2)=[C:4]([F:26])[CH:3]=1.C(=O)(O)[O-].[Na+].Cl[C:33]([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]>CC(C)=O.O>[C:33]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:25])[CH2:9][N:10]([CH:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:11]2)=[C:4]([F:26])[CH:3]=1)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(C2(O)CN(C(c3ccccc3)c3ccccc3)C2)c(F)c1)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 3-(4-amino-2-fluorophenyl)-3-hydroxy-1-(1,1-diphenylmethyl)azetidine (Example 81, Step 1, 5.10 g, 14.7 mmol) in acetone (75 mL) was added a solution of sodium bicarbonate (2.52 g, 30.0 mmol) in water (40 mL) to give a creamy suspension. Benzyl chloroformate (2.57 g, 15.1 mmol) was added and stirring continued overnight. The suspension was filtered and the acetone evaporated. The residue was partitioned between ethyl acetate (200 mL) and water (50 mL). The organic layer was washed with brine (50 mL), dried over magnesium sulfate, filtered and evaporated to leave an amber foam. Chromatography over silica gel (150 g, 40-60 μM) eluting with 1-2% methanol-methylene chloride gave the title compound as a cream foam. HRMS: meas. 483.2087, theory 483.2084.
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[Na+].[Na+].O=P(Cl)(Cl)[Cl:32]>>[Cl:32][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cccc(Nc2ncc(C#N)c(O)n2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cccc(Nc2ncc(C#N)c(Cl)n2)c1
Temperature: 25 °C

Procedure:
To a solution of 4-hydroxy-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile in POCl3 was added DMF 0.5 ml. The solution was refluxed for 3 h. The reaction mixture was cooled to room temperature and poured into ice-water. The solution was adjusted to pH=8-9 by aqueous sodium carbonate solution and extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo to afford 4-chloro-2-(3-methoxyphenylamino)pyrimidine-5-carbonitrile.
Reaction SMILES: C([N:3](CC)CC)C.[C:8]1(C)[C:9]([C:14](Cl)=[O:15])=[CH:10][CH:11]=[CH:12][CH:13]=1.C(OCC)(=O)C>C(Cl)Cl>[C:14]([NH2:3])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:8]=1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: NC(=O)c1ccccc1
Yield: 337.5 %

Procedure:
To a solution of 391 mg (1 mmol) of 2R-hydroxy-3-[(2-methylpropyl)(4-aminophenyl)sulfonyl]amino-1S-(phenylmethyl)propylamine in 3 mL of anhydrous methylene chloride, was added 0.42 mL (3 mmol) of triethylamine, then at room temperature, 0.12 mL (0.9 mmol) of ortho-toluoyl chloride was added. After 15 hours at room temp ethyl acetate was added, washed with 5% critic acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 420 mg of crude material. This was chromatgraphed on 40 g of silica gel using 50% ethyl acetate/hexane to afford 368 mg of pure benzamide, N-[2R-hydroxy-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl) amino]-1S-(phenylmethyl)propyl]-2-methyl, m/e=516 (M+Li).
Reaction SMILES: [CH2:1]1[O:13][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[NH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21]>C(O)C>[CH2:20]([NH:21][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][NH:14][CH2:1][CH:2]([OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC1CO1
Reactant: NCCCCCCN
Solvent: CCO
Product: CCCCCCCCCCC(O)CNCCCCCCNCC(O)CCCCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-dodecene oxide (50 g.) and hexamethylenediamine (15.8 g.) and recrystallization of the resulting product from ethanol gave N,N'-(1,6-hexylene)-bis[2-hydroxydodecylamine] (I: R= CH3 (CH2)9, R' = H, X= (CH2)6, Z= H) (35 g., m.p. 123.6°-128.0° C.).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].O[CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17]>Cl.CO>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:13][NH:14][C:15](=[O:18])[CH2:16][Cl:17])=[C:7]([OH:11])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=C(CCl)NCO
Reactant: CC(=O)Nc1cccc(O)c1
Agent: Cl
Solvent: CO
Product: CC(=O)Nc1ccc(CNC(=O)CCl)c(O)c1
Yield: 20 %

Procedure:
A solution of 3-acetamidophenol (1.5 g, 10 mmol) and N-(hydroxymethyl)-2-chloroacetamide (1.2 g, 10 mmol) was stirred in 50 ml of 20% HCl in methanol at room temperature for 2 days. After removal of solvent, the desired product was isolated in 20% yield (0.51 g, 2 mmol) by chromatography (silica gel, eluted with ethyl acetate and hexane, 40/60).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH3:28])[C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[C:19](=[C:20]([O:25]C)[N:21]=[CH:22][CH:23]=3)[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1.Cl.O1CCOCC1>>[CH:1]1([CH2:4][N:5]([CH3:28])[C:6]2[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][C:7]=2[C:16]2[C:24]3[CH:23]=[CH:22][NH:21][C:20](=[O:25])[C:19]=3[N:18]([CH3:27])[CH:17]=2)[CH2:3][CH2:2]1
Reactant: COc1nccc2c(-c3cc(S(C)(=O)=O)ccc3N(C)CC3CC3)cn(C)c12
Agent: Cl
Solvent: C1COCCO1
Product: CN(CC1CC1)c1ccc(S(C)(=O)=O)cc1-c1cn(C)c2c(=O)[nH]ccc12
Temperature: 70 °C
Yield: 58.8 %

Procedure:
The product from Example 45A (0.12 g, 0.30 mmol) and 4 M hydrogen chloride in dioxane (5 mL, 20.00 mmol) were combined and heated at 70° C. for 24 hours, cooled and concentrated. Purification by reverse phase chromatography (C18, CH3CN/water (0.1% TFA), 10-100%) afforded the title compound (0.068 g, 45%) as the TFA salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 10.91 (d, J=5.09 Hz, 1H) 7.70 (dd, J=8.48, 2.37 Hz, 1H) 7.61 (d, J=2.37 Hz, 1H) 7.54-7.56 (m, 1H) 7.21 (d, J=8.48 Hz, 1H) 6.84 (dd, J=7.12, 5.76 Hz, 1H) 6.31 (d, J=5.76 Hz, 1H) 4.11 (s, 3H) 3.15 (s, 3H) 2.77 (s, 3H) 2.74 (d, J=6.78 Hz, 2H) 0.64-0.78 (m, 1H) 0.28-0.37 (m, 2H) −0.11-−0.05 (m, 2H). MS (ESI+) m/z 386 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([SH:10])=[S:9])([CH3:4])([CH3:3])[CH3:2].[CH3:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH2:21]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([S:10][C:20]([CH3:21])([CH3:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[S:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C(=S)S)cc(C(C)(C)C)c1O
Reactant: C=C(C)c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(C(=S)SC(C)(C)c2ccccc2)cc(C(C)(C)C)c1O

Procedure:
A solution of 16.25 g (0.0575 mol) 3,5-di-t-butyl-4-hydroxydithiobenzoic acid and 13.6 g (0.115 mol α-methylstyrene in 50 ml toluene was heated at reflux for 2 hours. The reaction mixture was evaporated under reduced pressure to give an oil. The oil was chromatographed on silica gel (hexane eluant) to give the product, m.p. 100°-104° C. Elemental analysis of the product is tabulated in Table I.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])[CH:7]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([N+:30]([O-])=O)[CH:25]=2)[C:3]=1[C:4]#[N:5]>[Pd].C(OCC)(=O)C>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:18])[CH3:19])[CH:7]=[C:6]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=2)[C:3]=1[C:4]#[N:5]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc([N+](=O)[O-])c2)c(C#N)c(N)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccccc1-c1cc(-c2cccc(N)c2)c(C#N)c(N)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 2-amino-6-(2-{[tert-butyl(dimethyl)-silyl]oxy}phenyl)-4-(3-nitrophenyl)nicotinonitrile (3.2 g, 7.2 mmol), 10% Pd—C (0.25 g) and ethyl acetate (1 L) was stirred at room temperature for 12 hrs. under a hydrogen atmosphere (2.5 atm). The reaction mixture was filtered on Celite Pad and the filtration was concentrated under reduced pressure to give starting compound 2, which was used for the next step without further purification (2.6 g, yield 87%).
Reaction SMILES: Cl.[CH:2]12[NH:9][CH:6]([CH2:7][CH2:8]1)[CH2:5][CH:4]([OH:10])[CH2:3]2.C(=O)([O-])[O-].[Na+].[Na+].Br[CH2:18][CH2:19][OH:20]>C(O)C>[OH:20][CH2:19][CH2:18][N:9]1[CH:6]2[CH2:7][CH2:8][CH:2]1[CH2:3][CH:4]([OH:10])[CH2:5]2
Reactant: OC1CC2CCC(C1)N2
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: OCCN1C2CCC1CC(O)C2
Temperature: 25 °C

Procedure:
8-Aza-bicyclo[3.2.1]octan-3-ol hydrochloride (5.1 g, 31.45 mmol)) and sodium carbonate (13.3 g, 125.8 mmol) are suspended in 150 ml of ethanol at room temperature. 2-Bromo-ethanol (4.4 ml, 62.9 mmol) is added dropwise within 20 minutes and the reaction mixture is refluxed for 15 hours. After cooling to room temperature the reaction mixture is evaporated under reduced pressure. The mixture is stirred with 200 ml of DCM and filtered. The clear filtrate is dried over anhydrous sodium sulfate, filtered, evaporated under reduced pressure and dried at high vacuum.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10]([C:11]([OH:31])=[C:12]([C:26]([O:28]CC)=O)[C:13](=[O:25])[N:14]3[CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])=[N:9][CH:8]=2)=[CH:4][CH:3]=1.[CH:34]1([NH2:37])[CH2:36][CH2:35]1>CCO>[CH:34]1([NH:37][C:26]([C:12]2[C:13](=[O:25])[N:14]([CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][C:20]3=[O:24])[C:15]3[C:10]([C:11]=2[OH:31])=[N:9][CH:8]=[C:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:33][CH:32]=2)[CH:16]=3)=[O:28])[CH2:36][CH2:35]1
Reactant: NC1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Solvent: CCO
Product: O=C(NC1CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCC2=O)c1=O
Temperature: 120 °C

Procedure:
A mixture of ethyl 7-(4-fluorobenzyl)-4-hydroxy-2-oxo-1-[2-(2-oxopyrrolidin-1-yl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (47 mg, 104 μmol) and cyclopropylamine (0.1 mL, 1.44 mmol) in EtOH (3 mL) was heated at 120° C. in a microwave for 20 min. The mixture was concentrated in vacuo, triturated with EtOH and the product was collected by filtration as a white solid: 1H NMR (CDCl3) δ 10.06 (1H, d, J=3 Hz), 8.57 (1H, d, J=1.2 Hz), 8.08 (1H, s), 7.25 (2H, dd, J=8.5, 5.5 Hz), 7.00 (2H, t, J=8.5 Hz), 4.32 (2H, q, J=7 Hz), 4.14 (2H, s), 3.49 (2H, t, J=7.4 Hz), 3.41 (2H, t, J=7 Hz), 2.95 (1H, m), 2.32 (2H, t, J=8 Hz), 1.97 (2H, m), 0.90 (2H, m), 0.69 (2H, m); HRMS calcd for C25H25FN4O4+H+: 465.1938. Found: 465.1932.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14](=[O:30])[C:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[CH:28]=O)([CH2:18][CH3:19])[CH2:16][CH3:17].N1CCCC1>CO>[CH3:12][O:13][C:14](=[O:30])[C:15]([O:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1/[CH:28]=[C:6]1\[C:7](=[O:11])[NH:8][C:9]2[C:5]\1=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)([CH2:16][CH3:17])[CH2:18][CH3:19]
Reactant: O=C1Cc2ccc(Cl)cc2N1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C=O)C(=O)OC
Solvent: CO
Solvent: C1CCNC1
Product: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)Nc2cc(Cl)ccc21)C(=O)OC
Temperature: 70 °C
Yield: 77.9 %

Procedure:
To the mixture of 6-chlorooxindole (8.3 g, 49.7 mmol) and 2-(4-chloro-2-formyl-phenoxy)-2-ethyl-butyric acid methyl ester (13 g, 45.8 mmol) in methanol (200 mL) was added pyrrolidine (4.1 mL, 49.7 mmol) dropwise. The mixture was then heated at 70° C. for 2 h. After cooled to room temperature, the mixture was filtered and the precipitate was collected, dried to give the title compound as a yellow solid (15.5 g).
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:14]2[C:9](=[CH:10][C:11]([Br:16])=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7](=[O:17])[C:6]1=[O:18])([OH:3])=[O:2].[N+:19]([O-])([O-:21])=[O:20].[K+]>OS(O)(=O)=O>[C:1]([CH2:4][N:5]1[C:14]2[C:9](=[C:10]([N+:19]([O-:21])=[O:20])[C:11]([Br:16])=[C:12]([Br:15])[CH:13]=2)[NH:8][C:7](=[O:17])[C:6]1=[O:18])([OH:3])=[O:2]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)Cn1c(=O)c(=O)[nH]c2cc(Br)c(Br)cc21
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C(O)Cn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Br)c(Br)cc21
Temperature: 28 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
To a stirred solution of 1-carboxymethyl-6,7-dibromo-1,4-dihydroquinoxaline-2,3-dione (100 mg, 0.264 mmol) in concentrated H2SO4 (1.5 mL) at 5°-10° C., KNO3 (28 mg, 0.28 mmol) was added in one portion. The resulting dark green solution was stirred at 5°-10° C. for 30 min and at 28° C. overnight. The yellow colored suspension thus obtained was poured into ice-water (15 g) and the resulting shining yellow solid was filtered and dried under vacuum to obtain 53 mg (47%, pure by 1H NMR) 1-carboxymethyl-6,7-dibromo-5-nitro-1,4-dihydro-2,3-quinoxalinedione as a shining yellow powder; M.p. 260°-264° C. 1H NMR: δ4.91 (s, 1H), 7.98 (s, 1H). IR (KBr, cm-1): 1701, 1543, 1391, 1244. HRMS calcd for C10H5Br2N3O6 (M+) m/z 420.8546, found m/z 420.8559.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.[CH2:17]([OH:20])[C:18]#[CH:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:19]#[C:18][CH2:17][OH:20])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 86.6 %

Procedure:
A 500 mL three-necked round bottom flask was charged with 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (14.0 g, 50 mmol; Intermediate 1) and triethylamine (300 mL). The flask was degassed with 3 cycles of vacuum/N2, followed by the addition of Pd(PPh3)2Cl2 (3.5 g, 5 mmol) and CuI (0.95 g, 5 mmol) under N2 atmosphere. The flask was again degassed with 3 cycles of vacuum/N2. Prop-2-yn-1-ol (8.4 g, 150 mmol) was added via syringe and the reaction mixture was stirred at 80° C. for 16 hours. Upon completion, the solvent was evaporated. The residue was diluted with dichloromethane (400 mL), washed with water (3×200 mL) and brine (200 mL), dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was further purified on silica gel column (1:100-1:20 EtOAc/petroleum ether) affording the title compound (11.1 g). 1H NMR (400 MHz, DMSO-d6): δ 8.13 (s, 1H), 7.90 (s, 1H), 7.75 (d, 1H), 7.44 (d, 1H), 5.86 (dd, 1H), 5.33 (t, 1H), 4.33 (d, 2H), 3.89-3.86 (m, 1H), 3.79-3.73 (m, 1H), 2.45-2.35 (m, 1H), 2.05-1.95 (m, 2H), 1.80-1.70 (m, 1H), 1.60-1.56 (m, 2H); LCMS: 257 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][C@@H:10]([C:13]1[CH:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][C:14]=1[CH3:22])[CH2:11][F:12])C1C=CC=CC=1>[Pd].CO>[F:12][CH2:11][C@H:10]([C:13]1[CH:18]=[CH:17][C:16]([B:19]([OH:21])[OH:20])=[CH:15][C:14]=1[CH3:22])[CH2:9][OH:8]
Reactant: Cc1cc(B(O)O)ccc1[C@@H](CF)COCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(B(O)O)ccc1[C@H](CO)CF
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To 24C (0.2 g, 0.662 mmol) was added Pd/C (0.070 g, 0.662 mmol) and MeOH (10 mL) under N2. The reaction was flush with N2 and degassed (3×). Then H2 balloon was introduced and system was degassed and flush with H2 (3×) before letting it stir at rt overnight. The mixture was filtered and washed with MeOH (3×). The filtrate was evaporated and dried under vacuo to give 24D (0.1 g, 0.472 mmol, 71.3% yield). 1H NMR (400 MHz, MeOD) δ ppm 7.36-7.46 (m, 2H) 7.23 (d, J=7.83 Hz, 1H) 4.68-4.78 (m, 1H) 4.56-4.67 (m, 1H) 3.66-3.93 (m, 2H) 3.37-3.53 (m, 1H) 2.31-2.46 (m, 3H); 19F NMR (376 MHz, MeOD) δ ppm −229.52-−222.26 (m, 1F).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH2:14][OH:15])=[C:4]([F:16])[CH:3]=1
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cnccc1-c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (3 g, 12.73 mmol) in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL) cooled to 0° C. was added NaBH4 (0.722 g, 19.10 mmol) and the solution stirred for 30 min. The reaction was quenched by addition of water (10 mL). The solution was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (1×15 mL) and brine (1×15 mL), dried with sodium sulfate and concentrated under reduced pressure to yield (4-(4-chloro-2-fluorophenyl)pyridin-3-yl)methanol that was used without further purification in the next step. LCMS (ESI) m/e 238 [(M+H)+, calcd for C12H10ClFNO 238.0].
Reaction SMILES: [CH2:1]([C:5]1[C:14]([CH2:15][NH:16]C(=O)OC(C)(C)C)=[C:13]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:31][CH2:32][C:33]([NH:35][CH3:36])=[O:34])[CH:11]=2)[N:6]=1)[CH:2]([CH3:4])[CH3:3].[ClH:37]>C(OCC)(=O)C>[ClH:37].[ClH:37].[NH2:16][CH2:15][C:14]1[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[N:6][C:7]2[C:12]([C:13]=1[C:24]1[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=1)=[CH:11][C:10]([O:31][CH2:32][C:33]([NH:35][CH3:36])=[O:34])=[CH:9][CH:8]=2
Reactant: CNC(=O)COc1ccc2nc(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c3ccc(C)cc3)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: CNC(=O)COc1ccc2nc(CC(C)C)c(CN)c(-c3ccc(C)cc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of tert-butyl {[2-isobutyl-6-[2-(methylamino)-2-oxoethoxy]-4-(4-methylphenyl)quinolin-3-yl]methyl}carbamate (0.26 g, 0.53 mmol) in ethyl acetate (5 ml) was added 4N solution of hydrogen chloride in ethyl acetate (2 ml), and the mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure and crystallized from diisopropyl ether to give the title compound (0.20 g, yield 79%) as pale-yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([O-:18])=[O:17])[CH:10]=3)[CH:8]=2)[CH2:3][CH2:2]1>Cl>[CH:1]1([C:4]2[N:5]=[CH:6][N:7]([C:9]3[C:14]([F:15])=[CH:13][N:12]=[C:11]([C:16]([OH:18])=[O:17])[CH:10]=3)[CH:8]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Agent: Cl
Product: O=C(O)c1cc(-n2cnc(C3CC3)c2)c(F)cn1
Temperature: 100 °C

Procedure:
4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropicolinate (640 mg, 2.11 mmol) was dissolved in 1N HCl (5 mL) and the reaction was heated to 100° C. overnight. The solvent was removed, CH3CN was added and the solvent removed to afford 4-(4-cyclopropyl-1H-imidazol-1-yl)-5-fluoropicolinic acid which was used directly in subsequent reactions (assuming 100% conversion).