Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[CH:9][C:8]=1[C:15](=[O:18])[CH2:16][CH3:17])(=O)=O.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:35]2[CH2:36][CH2:37][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:39][CH:40]=2)O1>C(O)C.C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:14][C:10]1[C:11]([CH3:13])=[CH:12][C:7]([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)=[C:8]([C:15](=[O:18])[CH2:16][CH3:17])[CH:9]=1
Reactant: CCC(=O)c1cc(C)c(C)cc1OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC(=O)c1cc(C)c(C)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 75 °C

Procedure:
A vigorously stirred solution of triflate 83 (10.5 g, 33.8 mmol), aqueous sodium carbonate (50.8 mL of a 2.0 M solution, 102 mmol), tert-butyl 4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)carboxylate (10.45 g, 33.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (3.91 g, 3.38 mmol) in ethanol/toluene (1:1, 100 mL) was degassed via three vacuum/nitrogen ingress cycles and heated to 75° C. for 30 min. The reaction mixture was poured into ice water and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried (MgSO4), filtered, and the filtrate concentrated in vacuo. Purification of the crude residue by flash chromatography on silica gel (gradient elution; 0%-25% EtOAc/hexanes as eluent) afforded 84 as a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)occ1OCc1ccccc1
Yield: 59.2 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (7-03) (26.0 g, 59.19%) was synthesized as a light brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (25.0 g, 108.2 mmol) and 2-chloro-benzenesulfonyl chloride (6-03) (27.2 g, 129.87 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [CH3:1][Mg]Br.[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2=[O:15])=[CH:7][CH:6]=1.[Cl-].[NH4+]>CCOCC.O1CCCC1>[Br:4][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][CH:11]([CH2:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)[C:12]2([OH:15])[CH3:1])=[CH:7][CH:6]=1
Reactant: O=C1c2cc(Br)ccc2CCC1Cc1cccnc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(O)c2cc(Br)ccc2CCC1Cc1cccnc1
Reaction time: 10 h

Procedure:
Methyl magnesium bromide (15 ml of a 3M solution in ether) was added dropwilse over 5 minutes to a stirred solution of 7-bromo-2-(3-pyridylmethyl)-1-tetralone (3.20 g) in dry tetrahydrofuran (50 ml). The resulting mixture was heated under reflux with stirring for 10 hours and then cooled. An excess of aqueous ammonium chloride solution was added and the mixture was extracted several times with ether. The combined ethereal extracts were dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel. Elution with chloroform gave 7-bromo-1-hydroxy-1-methyl-2-(3-pyridylmethyl)-1,2,3,4-tetrahydronaphthalene (2.87 g) as a mixture of isomers which was used directly in the next stage.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:24][CH:12]2[N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:14](=[O:16])[O:15][CH:11]2[CH2:10][CH2:9]1.[Br:25][C:26]1[N:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]>CCOC(C)=O>[Br:25][C:26]1[N:31]=[C:30]([C:32]([NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]2[CH2:24][CH:12]3[N:13]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[C:14](=[O:16])[O:15][CH:11]3[CH2:10][CH2:9]2)=[O:33])[CH:29]=[CH:28][C:27]=1[F:35]
Reactant: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3N)CC21
Reactant: O=C(O)c1ccc(F)c(Br)n1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)OC2CCC(c3ccncc3NC(=O)c3ccc(F)c(Br)n3)CC21

Procedure:
Following Method 9, tert-butyl 5-(3-aminopyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate and 6-bromo-5-fluoropicolinic acid were coupled and following addition of EtOAc and washing with H2O, NaCl(sat.) and drying over MgSO4, tert-butyl 5-(3-(6-bromo-5-fluoropicolinamido)pyridin-4-yl)-2-oxohexahydrobenzo[d]oxazole-3(2H)-carboxylate was obtained. LCMS (m/z): 537.1 (MH+); LCMS Rt=0.71 min.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[OH:11].[C:12](Cl)(Cl)=[S:13]>O.C(OCC)C>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]2[N:2]=[C:12]([SH:13])[O:11][C:4]=2[CH:5]=1
Reactant: COc1ccc(N)c(O)c1
Reactant: S=C(Cl)Cl
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: COc1ccc2nc(S)oc2c1

Procedure:
2-amino-5-methoxyphenol hydrochloride (6 g) in 80 ml of water was stirred at room temperature while thiophosgene (3.92 g) was added dropwise as a solution in 30 ml of diethyl ether at a rate such that the resultant exotherm was controlled.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[CH:5]=[C:4]([N+:11]([O-])=O)[CH:3]=1.B.C1COCC1.C(O)(=O)C>C1COCC1.[Fe]>[NH2:11][C:4]1[CH:3]=[C:2]([Br:1])[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=1
Reactant: O=C(O)c1cc([N+](=O)[O-])cc(Br)n1
Agent: [Fe]
Agent: B
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1cc(Br)nc(CO)c1
Yield: 33.9 %

Procedure:
A solution of 6-bromo-4-nitro-pyridine-2-carboxylic acid (6.60 g, 29.1 mmol) in THF (150 ml) was treated with borane/THF (87 ml of a 1M solution). The mixture was refluxed for 6 hr, then powdered iron (16.3 g, 291 mmol) was added, followed by acetic acid ( 150 ml). Reflux was maintained for 6 hr, the mixture was filtered, evaporated and partitioned (AcOEt/aqueous NaHCO3-solution). The organic phase was dried (Na2SO4), concentrated and chromatographed (SiO2 with CH2Cl/MeOH=93/7) to provide 2.0 g (34%) of the title compound as a white solid material. Mp. 144-145° C. (AcOEt), MS: m/e=202 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[C:35]([O:37][CH2:38][CH3:39])=[O:36].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]([C:19]4[C:20]([F:33])=[C:21]([N:26]([S:27]([CH2:30][CH2:31][CH3:32])(=[O:28])=[O:29])[C:35](=[O:36])[O:37][CH2:38][CH3:39])[CH:22]=[CH:23][C:24]=4[F:25])=[O:18])=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Reactant: CCOC(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)N(C(=O)OCC)c1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4ccc(Cl)cc4)cc23)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52.1 %

Procedure:
To a suspension of N-(3-(5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)-propane-1-sulfonamide (0.2 g, 0.41 mmol) in dioxane (15 mL) were added ethyl chloroformate (EtOCOCl, 44 mg, 0.41 mmol) and triethylamine (0.14 g, 1.38 mmol). The reaction was stirred at rt for 1.5 h, then concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/EtOAc (v/v)=4/1) to afford the title compound as a white solid (0.12 g, 50%). The title compound was characterized by LC-MS and 1H NMR as shown below:
Reaction SMILES: [CH3:1][C:2]([CH3:21])=[CH:3][CH2:4][C@@H:5]([OH:20])[C:6]1[C:16](=[O:17])[C:15]2[C:14]([OH:18])=[CH:13][CH:12]=[C:11]([OH:19])[C:10]=2[C:8](=[O:9])[CH:7]=1.C1(N=C=NC2CCCCC2)CCCCC1.[C:37](O)(=[O:39])[CH3:38].CCCCCC>CN(C)C1C=CN=CC=1.ClCCl>[C:37]([O:20][CH:5]([C:6]1[C:16](=[O:17])[C:15]2[C:10]([C:8](=[O:9])[CH:7]=1)=[C:11]([OH:19])[CH:12]=[CH:13][C:14]=2[OH:18])[CH2:4][CH:3]=[C:2]([CH3:21])[CH3:1])(=[O:39])[CH3:38]
Reactant: CC(=O)O
Reactant: CC(C)=CC[C@@H](O)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=O)OC(CC=C(C)C)C1=CC(=O)c2c(O)ccc(O)c2C1=O
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
288 mg (1 mmole) of shikonin, 226 mg (1.1 mmole) of dicyclohexylcarbodiimide and 30 mg (0.25 mmole) of 4-dimethylaminopyridine were dissolved in 3 ml of dry dichloromethane. To the resulting solution was added 60 mg (1 mmole) of acetic acid at 0° C. under nitrogen gas, and the mixture was stirred for 30 minutes and then at room temperature for further 3 hours. 20 ml of n-hexane was added to the reaction solution. The mixture was filtered to remove the insoluble materials. The filtrate was dried and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (n-hexane: ethylacetate=20:1-5:1) to obtain 247 mg (Yield: 75%) of the title compound having the following structure as a red precipitate.
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.N1C=CC=CC=1.[OH:31][NH2:32]>C(Cl)Cl>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][N:4]1[C:8]2[N:9]=[C:10]([C:13]#[N:14])[N:11]=[CH:12][C:7]=2[CH:6]=[C:5]1[CH2:15][N:16]1[CH2:21][CH2:20][C:19](=[N:32][OH:31])[CH2:18][CH2:17]1
Reactant: CC(C)(C)Cn1c(CN2CCC(=O)CC2)cc2cnc(C#N)nc21
Reactant: NO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)Cn1c(CN2CCC(=NO)CC2)cc2cnc(C#N)nc21
Reaction time: 24 h
Yield: 97.9 %

Procedure:
To a solution of 100 mg (0.30 mmoles) of 7-(2,2-dimethyl-propyl)-6-(4-oxo-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile and 0.047 ml (0.75 mmoles) of pyridine in 5 ml of CH2Cl2, 52 mg (0.75 mmoles) of hydroxyl amine is added at ambient temperature. After being stirred for 24 hours, the reaction mixture is quenched with H2O and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 100 mg of desired 7-(2,2-dimethyl-propyl)-6-(4-hydroxyimino-piperidin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 98% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)cc2)nc2cccnc21)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stream of nitrogen gas was bubbled through a stirred suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.96 g, 0.0208 mole), 1,1'-carbonyldiimidazole (3.37 g, 0.0208 mole), and anhydrous tetrahydrofuran (100 ml) at room temperature for 3 hrs. To the resulting solution was added dropwise a solution of morpholine (1.81 g, 0.0208 mole) in tetrahydrofuran (10 ml). The reaction mixture was stirred overnight at room temperature. The tetrahydrofuran was evaporated and the crystalline residue suspended in water and filtered, giving 5.35 g (72%). Recrystallization from 95% ethanol gave 4.9 g of white flakes, mp 213°-216° C.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[N:11]=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C:9]1[N:10]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[N:11]=[C:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2)[C:32]([NH:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=[O:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(-n2nc3ccccc3c2NCc2ccccc2)cc1
Reactant: O=C=NC1CCCCC1
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)N(Cc1ccccc1)c1c2ccccc2nn1-c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described in example 1.2, benzyl-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-amine was reacted with cyclohexylisocyanate ([3173-53-3]) in toluene for 48 h under reflux conditions to give the title compound as yellow solid. MS: m/e=459.4 [M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][OH:11])[CH:3]=1.CC1(C)C(C)(C)OB([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)O1.ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[N+:26]([C:23]1[CH:24]=[CH:25][C:20]([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([CH2:10][OH:11])[CH:3]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: OCc1ccc(Br)cc1CO
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(-c2ccc(CO)c(CO)c2)cc1
Temperature: 80 °C

Procedure:
The compound of example 669 (7 g, 32.25 mmol), 4,4,5,5-tetramethyl-2-(4-nitrophenyl)-1,3,2-dioxaborolane (9.63 g, 38.70 mmol) and [1,1-Bis(diphenylphosphino)-ferrocine]dichloropalladium(II), complex with dichloromethane (789 mg, 0.967 mmol) were taken in dry DMF under Argon atmosphere. Degassed 2M solution of sodium carbonate (8.54 g, 80.62 mmol) was added and the reaction mixture was heated to 80° C. for 3 h. The reaction mixture was cooled and the solvent was removed by distillation. The residue was taken in water and the aqueous mixture was extracted with ethyl acetate. The crude material obtained was purified using column chromatography (silicagel, 30% dichloromethane in petroleum ether) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[C:14]([NH2:16])[CH:13]=[N:12]2)[O:6]CCO1.[CH3:17][C:18]1[O:19][C:20]([C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[C:21]([C:23](O)=[O:24])[N:22]=1>>[O:6]=[C:2]([CH3:1])[CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH:15]=[C:14]([NH:16][C:23]([C:21]2[N:22]=[C:18]([CH3:17])[O:19][C:20]=2[C:26]2[CH:27]=[C:28]([CH3:32])[CH:29]=[CH:30][CH:31]=2)=[O:24])[CH:13]=[N:12]1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Reactant: CC1(CCCCn2cc(N)cn2)OCCO1
Product: CC(=O)CCCCn1cc(NC(=O)c2nc(C)oc2-c2cccc(C)c2)cn1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-butyl]-1H-pyrazol-4-ylamine and 2-methyl-5-m-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][C:5](=[O:26])[CH2:6][C:7]([CH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)(O)[CH2:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[S:18][CH3:19].COC(=O)CC(=O)CC(C1CCCC1)(O)CCC#CC1C=C(C)C(O)=CC=1C>>[CH:21]1([C:7]2([CH2:8][CH2:9][C:10]#[C:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18][CH3:19])[O:27][C:3](=[O:2])[CH2:4][C:5](=[O:26])[CH2:6]2)[CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: COC(=O)CC(=O)CC(O)(CCC#Cc1ccccc1SC)C1CCCC1
Agent: COC(=O)CC(=O)CC(O)(CCC#Cc1cc(C)c(O)cc1C)C1CCCC1
Product: CSc1ccccc1C#CCCC1(C2CCCC2)CC(=O)CC(=O)O1

Procedure:
The desired product was prepared analogously to example F(1), substituting 5-cyclopentyl-5-hydroxy-9-(2-methylsulfanyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester (43 mg, 0.11 mmol) from Step 2 below in place of 5-cyclopentyl-5-hydroxy-9-(4-hydroxy-2,5-dimethyl-phenyl)-3-oxo-non-8-ynoic acid methyl ester. Yield: 38 mg, 97%.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:26][NH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:32][CH2:31]1>C(Cl)Cl>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([CH2:26][NH:27][CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([O:36][C:37](=[O:51])[NH:38][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH2:32][CH2:31]2)=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CNCCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: O=Cc1ccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.6 %

Procedure:
To a three-necked 1-L flask was added 4-carboxybenzaldehyde (4.77 g, 31.8 mmol), EDC (6.64 g, 34.7 mmol), HOBT (1.91 g, 31.8 mmol), and DCM (200 mL). When the mixture was homogenous, a solution of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (10 g, 31.8 mmol; prepared as described in Preparation 9) in DCM (100 mL) was added slowly. The reaction mixture was stirred at room temperature for 16 hours and then washed with water (1×100 mL), 1N HCl (5×60 mL), 1N NaOH (1×100 mL) brine (1×50 mL), dried over sodium sulfate, filtered and concentrated to afford 12.6 g of the title compound (92% yield; 85% purity based on HPLC). MS m/z: [M+H+] calcd for C29H31N3O4, 486.2; found, 486.4. Rf=3.12 min (10-70 ACN:H2O, reverse phase HPLC).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[CH3:11][NH2:12]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH:12][CH3:11])=[O:6]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CN
Product: CNC(=O)c1cccc(O)c1
Yield: 91.5 %

Procedure:
A mixture of 3-hydroxybenzoic acid (1.3 g, 9.4 mmol) and a ethanolic methylamine solution (33%, 1.5 ml, 12.1 mmol) were stirred at 60° C. for 48 h, then the solvent was evaporated in vacuo, and the residue redissolved in a small volume of ethanol. The product precipitated from the solution by the addition of ethyl acetate. The precipitate was collected by filtration and dried to give the subtitled compound (1.3 g, 91%).
Reaction SMILES: [F:1][C:2]1[CH:36]=[C:35]([N+:37]([O-])=O)[CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=3)[S:13][C:6]=12.[NH4+].[Cl-]>[Fe].CCO.O>[NH2:37][C:35]1[CH:34]=[CH:33][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][O:31][CH3:32])[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:15]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:36]=1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
A solution of 125 (443 mg, 0.80 mmol) and NH4Cl (37 mg, 0.68 mmol) in 2:1 mixture of EtOH/water (10.5 mL) was treated with iron powder (380 mg, 6.79 mmol) and stirred at reflux for 1 hour. The reaction mixture was then filtered through a celite pad and concentrated to afford title compound 126 that was used without further purification (440 mg, 100% yield). MS (m/z): 525.2 (M+H).
Reaction SMILES: C[Li].C([O:5][CH2:6][CH3:7])C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21]C(N(OC)C)=O)=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.O>O1CCCC1>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C:6](=[O:5])[CH3:7])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CCOCC
Reactant: CON(C)C(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Cc1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
A solution of methyllithium in diethyl ether (40 mL, 44 mmol) was diluted with tetrahydrofuran (120 mL), and a solution of 2-(4′-bromobiphenyl-4-yl)-N-methoxy-N-methylacetamide (12 g, 37 mmol) in tetrahydrofuran (50 mL) was added at −78° C., followed by stirring at the same temperature for 30 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.50 (hexane/ethyl acetate=4/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (7.6 g, 26 mmol) as a white solid (yield 71%).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].C([O-])(=O)C.[Na+].C(O)C.Cl.[NH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1>O>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[N:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]([OH:30])=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1O
Reactant: Nc1ccc(O)c2ccccc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Oc1ccccc1C=Nc1ccc(O)c2ccccc12
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 82.5 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 5.50 grams (0.045 moles) of salicylaldehyde, 4.10 grams (0.050 moles) of sodium acetate and 40 milliliters of ethanol. The resulting mixture was then heated to a temperature of 50° C. and a solution consisting of 7.83 grams (0.040 moles) of 4-amino-1-naphthol hydrochloride in 20 milliliters of water was added thereto. The resulting reaction mixture was stirred for 15 minutes at a temperature of 50° C. and then cooled to room temperature forming a precipitate. The precipitate was removed from the reaction mixture by filtration, washed with water and dried over magnesium sulfate to give 8.68 grams (0.033 moles) of 4-(2-hydroxybenzylideneamino)-1-naphthol in the form of reddish-brown crystals having a melting point of 153.5°-157° C.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]1=2.O.[N+]([O-])([O-])=[O:15].[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(O)(=O)C>[O:15]=[C:12]1[C:2]2[S:1][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=2[CH2:9][CH2:10][CH2:11]1
Reactant: O=C(O)c1cc2c(s1)CCCC2
Reactant: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cc2c(s1)C(=O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 4,5,6,7-tetrahydrobenzo[b]thiophene-2-carboxylic acid (3.00 g, 16.5 mmol), acetic acid (40 mL) and water (40 mL). A solution of ammonium cerium(IV) nitrate (36.1 g, 65.9 mmol) in acetic acid (40 mL) was added dropwise, and the reaction was stirred at room temperature for 1 h. After this time, the reaction mixture was poured into water (200 mL) and extracted with methylene chloride (3×200 mL). The organic extracts were combined, dried over sodium sulfate, filtered and the solvent removed under reduced pressure to afford 16 in 72% yield (2.35 g) as a yellow solid: mp 174-175° C.; 1H NMR (500 MHz, DMSO-d6) δ 13.60 (bs, 1H), 7.68 (s, 1H), 2.86 (t, 2H, J=6.0 Hz), 2.59 (t, 2H, J=6.0 Hz), 2.08 (quintet, 2H, J=6.0 Hz).