Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1.[C:9]1([CH3:20])[CH:14]=[CH:13][C:12]([S:15]([O:18]C)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[C:9]1([CH3:20])[CH:10]=[CH:11][C:12]([S:15]([O-:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH3:1][N+:2]1([CH3:9])[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CCC(O)CC1
Product: C[N+]1(C)CCC(O)CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 274.4 %

Procedure:
The procedures of Reference Example 1 were repeated using 1.16 g of 1-methyl-4-piperidinol and 1.18 g of methyl p-toluenesulfonate to give 2.62 g of the desired compound, m.p. 139°-140° C. (decomp.).
Reaction SMILES: [Br-].[CH2:2]([Zn+])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:10]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH:10]1([C:16]([CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: [Zn+]Cc1ccccc1
Reactant: O=C(Cl)C1CCCCC1
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 52 %

Procedure:
To a solution of 11 ml of 0.5 M solution of benzyl zinc bromide in anhydrous tetrahydrofuran were added at 0° C. 5 mg of bis-triphenylphospinepalladium dichloride and 0.66 ml of cyclohexanecarbonyl chloride. The mixture was stirred at r.t. for 1.5 h, quenched with a saturated solution of ammonium chloride and extracted with ethyl acetate. The collected organic layers were washed with water, dried (Na2SO4) and the solvent was evaporated under vacuum. The crude was purified by flash chromatography eluting with petroleum ether-EtOAc 95:5 to give 0.78 g (52%) of the title compound.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[C:13]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[CH3:14].[CH2:21]([O:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37]([CH:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[O:38])[CH:32]=[CH:33][CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.C(O)(=O)C>[C:17]([O:16][C:13](=[O:15])[CH2:14][C:37]([CH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1)([OH:38])[CH2:36][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:30]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(=O)OC(C)(C)C
Reactant: O=C(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)(CCc1cccc(OCc2ccccc2)c1)C1CCCC1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
Diisopropyl amine (9.56 mL, 68.2 mmol) was dissolved in freshly distilled THF (30 mL) and cooled to -15° C. with a dry ice/acetone bath. 1.6 M n-BuLi (42.7 mL, 68.2 mmol) in hexanes was then added dropwise over 20 minutes. The solution was then cooled to -40° C. and allowed to stir for 20 minutes. tert-Butyl acetate (9.2 mL, 68.2 mmol) was then dissolved in freshly distilled THF (20 mL) and added dropwise over 30 minutes to the -40° C. solution. This was allowed to stir for an additional 30 minutes at 40° C. after addition was complete. 3-(3-Benzyloxy-phenyl)-1 -cyclopentyl-propan-1 -one (10.51 g, 34.1 mmol) from Example YYYY was dissolved in freshly distilled THF (35 mL) and added rapidly to the -40° C. solution, such that the temperature did not exceed -40° C. Monitored reaction with TLC and shown to be complete in 5 minutes. Added glacial acetic acid dropwise (20 mL) to neutralize solution and allowed to warm to room temperature. The majority of THF was removed under reduced pressure and took up remaining organics in EtOAc. The organics were washed with brine, saturated sodium bicarbonate, and again with brine. The organics were dried over MgSO4 and the solvent removed under reduced pressure. The residue was flash chromatographed (15% EtOAc/85% hexane, silica gel) to yield the title compound as a viscous oil. 1H NMR (CDCl3) δ 1.47 (s, 9 H), 1.47-1.69 (br m, 8 H), 1.83 (m, 2 H), 2.08 (m, 1 H), 2.46 (d of ABX q, 1 H), 2.49 (d of ABX q, 1 H), 2.63 (m, 2 H), 3.78 (br s, 1 H), 5.05 (s, 2 H), 6.82 (br m, 3 H), 7.26 (t, 1 H), 7.32-7.46 (br m, 5 H).
Reaction SMILES: [NH2:1]C(O)C.[CH2:5]([CH2:9][C:10](=O)[CH3:11])[C:6]([CH3:8])=O.[C:13]([OH:16])(=O)[CH3:14].C1(C)C=CC=CC=1>C(OCC)(=O)C.O>[CH3:8][C:6]1[N:1]([CH2:14][CH2:13][OH:16])[C:10]([CH3:11])=[CH:9][CH:5]=1
Reactant: CC(=O)O
Reactant: CC(N)O
Reactant: CC(=O)CCC(C)=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1ccc(C)n1CCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
30.5 g (0.5 mol) of aminoethanol, 57 g (0.5 mol) of acetonylaceton and 0.35 g (5 mmol, a catalytic amount) of acetic acid were added to 300 ml of toluene, and then, the mixture was refluxed for 3 hours using a Dean-stark trap. The reaction mixture was cooled to room temperature, 200 ml of water and 100 ml of ethyl acetate were added thereto, and was stirred for 30 minutes. The organic phase was separated and filtered through a silica gel pad, and the filtrate was distilled under a reduced pressure to obtain 66 g of the titled compound in the form of a pale orange oil (yield: 95%).
Reaction SMILES: CN(C)[C:3](=[O:10])[CH2:4][C:5]([CH3:9])([CH3:8])[CH:6]=[CH2:7].[C:12]([Cl:16])(Cl)(Cl)[Cl:13].C([O:21]OC(C)(C)C)(C)(C)C>O>[Cl:13][C:12]([Cl:16])=[CH:7][CH:6]1[O:21][C:3](=[O:10])[CH2:4][C:5]1([CH3:9])[CH3:8]
Reactant: C=CC(C)(C)CC(=O)N(C)C
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: ClC(Cl)(Cl)Cl
Solvent: O
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Yield: 380 %

Procedure:
A mixture of 40 g (0.26 mole) of 3,3-dimethylpent-4-enoic aicd N,N-dimethylamide, 231 g (1.5 moles) of carbon tetrachloride and 7 g (0.05 mole) of di-tert.-butyl peroxide is stirred for 6 hours at 140° C. in a stainless steel autoclave. 180 g (1.17 mole) of carbon tetrachloride are then distilled from the reaction mixture under reduced pressure, and the residue is stirred with 200 g of water for 1 hour at 80°-90° C. Extraction with methylene chloride, and subsequent distillation of the methylene chloride solution, gives 39 g (0.19 mole) of 5-(2,2-dichlorovinyl)-4,4-dimethyltetrahydrofuran-2-one, of boiling point 101° C./0.27 mbar.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19](Cl)(=[O:21])=[O:20])=[C:10]2[O:15]C(=O)C)(=[O:3])[CH3:2].C(Cl)(Cl)Cl.C(=O)([O-])[O-].[NH4+:31].[NH4+].Cl>O>[C:1]([NH:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9]([S:19]([NH2:31])(=[O:21])=[O:20])=[C:10]2[OH:15])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c(OC(C)=O)c(S(=O)(=O)Cl)ccc12
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1cccc2c(O)c(S(N)(=O)=O)ccc12

Procedure:
The 5-acetamido-1-hydroxynaphthalene-2-sulfonamide was prepared by dissolving 10.8 g. of 5-acetamido-1-acetoxynaphthalene-2-sulfonyl chloride in 10 ml. dry chloroform and heating on the steam bath with 25.0 g. anhydrous ammonium carbonate for 2.5 hours. The yellow-brown solid was dissolved by heating with 50 ml. water on the steam bath for 4 hours. Acidification with dilute hydrochloric acid to pH5 caused the sulfonamide to precipitate. It was filtered off, washed and dried, yielding 5.61 g. (63%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1.[CH3:12]OS(OC)(=O)=O.[H-].[Na+]>CN(C=O)C>[CH3:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[CH:10]=[O:11])[CH:3]=[CH:2]1
Reactant: COS(=O)(=O)OC
Reactant: O=Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2cccc(C=O)c21
Temperature: 25 °C

Procedure:
A solution of 1H-indole-7-carbaldehyde (500 mg, 3.444 mmol) and dimethylsulfate (478 mg, 3.789 mmol) in DMF (3 ml) was cannulated into a suspension of NaH (99 mg, 95% in mineral oil, 4.133 mmol) in DMF (2 ml) at 0° C. The reaction was stirred and allowed to warmed up to room temperature for 1 hour. The reaction was quenched with water and the product was extracted with EtOAC (×2). The organic layers were combined and washed with water, and brine, and dried (MgSO4) and the solution was concentrated to produce a light pink solid, which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:22])(=[O:3])[CH3:2].[N+](=[CH2:30])=[N-].N(CNC(N)=O)=O.[OH-].[K+]>C(O)(=O)C.C(OCC)C>[C:1]([O:4][C@@H:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])/[CH:6]=[CH:7]/[C@@H:8]1[C@@H:12]([CH2:13]/[CH:14]=[CH:15]\[CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:30])=[O:20])[CH:11]=[CH:10][CH:9]1[OH:22])(=[O:3])[CH3:2]
Reactant: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)O)OC(C)=O
Reactant: C=[N+]=[N-]
Agent: NC(=O)NCN=O
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCCC[C@@H](/C=C/[C@H]1C(O)C=C[C@@H]1C/C=C\CCCC(=O)OC)OC(C)=O

Procedure:
to a solution of 8 parts of (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oic acid in 175 parts of diethyl ether is added an ethereal solution of diazomethane prepared from 30 parts of N-nitrosomethylurea, 90 parts of aqueous 40% potassium hydroxide, and 210 parts of diethyl ether as described in Org. Syn., 15, 4 (1935). The resultant mixture is allowed to stand at 5° for 30 minutes, whereupon 2 parts of acetic acid is introduced and the mixture thus obtained extracted with diethyl ether. The extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual red oil is taken up in benzene; and the benzene solution is chromatographed on silica gel, using benzene and mixtures thereof with increasing amounts of ethyl acetate as developing solvents. From an eluate comprising 30% ethyl acetate in benzene, on evaporation of solvent, methyl (5Z,13E,15S)-15-acetyloxy-11ξ-hydroxyprosta-5,9,13-trien-1-oate is obtained as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([O:22][C:2]1[N:7]=[C:6]([NH:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][CH:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: CNc1nc(Cl)ccc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNc1nc(OCc2ccccc2)ccc1[N+](=O)[O-]

Procedure:
A procedure similar to that described in Preparation 88 was repeated, except that 7.00 g of 6-chloro-2-methylamino-3-nitropyridine (prepared as described in Preparation 66), 1.79 g of sodium hydride (as a 55% by weight dispersion in mineral oil), 4.3 ml of benzyl alcohol and 150 ml of dimethylformamide were used. After working up the product as described in Preparation 86, the resulting crude product was crystallized by trituration with isopropanol, to give 9.02 g of the title compound, melting at 149° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([SH:13])=[N:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH:14]1([C:20](O)=O)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.Cl.[CH2:24](N=C=NCCCN(C)C)C.[OH-].[Na+].Cl.CI>O1CCOCC1.O>[CH:14]1([C:20]2[NH:1][C:2]3[C:3]([S:13][CH3:24])=[N:4][C:5](=[O:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=3[N:8]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)C1CCCCC1
Reactant: CCCn1c(N)c(N)c(S)nc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CI
Solvent: O
Product: CCCn1c(=O)nc(SC)c2[nH]c(C3CCCCC3)nc21
Reaction time: 8 h
Yield: 77 %

Procedure:
Phosphorus pentasulfide (27.1 g, 122 mmol, 1.5 equivalents) was suspended in pyridine (150 mL) and the mixture was heated to 100° C. To the suspension was gradually added 5,6-diamino-1-propyluracil (15.0 g, 81.3 mmol), which was obtained by the method described in Journal of Medicinal Chemistry (J. Med. Chem.), 32 (6), p. 1231, 1989, with heating and stirring, and then the mixture was stirred for 7 hours. After the reaction solution was cooled on ice, the deposited solid was separated by filtration using a filtration aid and washed with pyridine. The filtrate was concentrated, to the residue was added water (90 mL), and the mixture was stirred under reflux with heating for about 40 minutes until intense foaming ceased. The reaction mixture was cooled on ice and then further stirred overnight at room temperature. The deposited yellowish green ocher solid was collected by filtration, sufficiently washed with water and dried under reduced pressure to obtain 5,6-diamino-1,2-dihydro-4-mercapto-2-oxo-1-propylpyrimidine (Compound B4, 11.3 g, 69%). Compound B4 (10.0 g, 50.0 mmol) was suspended in 1,4-dioxane (200 mL) and water (100 mL), to the suspension were added cyclohexanecarboxylic acid (8.06 mL, 65.0 mmol, 1.3 equivalents) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.3 g, 85.0 mmol, 1.7 equivalents) at room temperature, and then the mixture was stirred overnight. To the reaction mixture was added 2 mol/L aqueous sodium hydroxide (100 mL), and the mixture was stirred with heating for 2.5 hours. The reaction mixture was cooled on an ice bath, adjusted to pH 6 with 4 mol/L hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 0.5 mol/L aqueous sodium hydroxide (150 mL), and to the solution was added methyl iodide (4.70 mL, 75.0 mmol, 1.5 equivalents) and the mixture was stirred overnight at room temperature. The reaction mixture was cooled on an ice bath, adjusted to pH 6.5 with 4 mol/L aqueous hydrochloric acid and extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 96:4) to obtain the title compound (11.8 g, 78%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH2:4][CH2:3]1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Tert-butyl(trans)-4-aminocyclohexylcarbamate (1.500 g) and triethylamine (2.93 mL, 2.125 g) were added to dichloromethane and stirred until the tert-butyl(trans)-4-aminocyclohexylcarbamate had dissolved completely. Acetyl chloride (0.577 g) was added slowly, and the solution was stirred at room temperature for 16 hours. The solvent was removed, and the residue taken up in ethyl acetate, washed with pH 4 buffer, washed with brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was concentrated under vacuum.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[F:19]>C1(C)C=CC=CC=1.C(O)C.O>[Cl:11][C:4]1[CH:3]=[C:2]([C:15]2[CH:16]=[CH:17][C:18]([F:19])=[C:13]([Cl:12])[CH:14]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1ccc(F)c(Cl)c1
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(-c2cc(Cl)c3c(n2)CCC3)cc1Cl
Yield: 64 %

Procedure:
Following General Procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol) in toluene/ethanol/water (6 mL:3 mL:1 mL) was reacted with (3-chloro-4-fluorophenyl)boronic acid (0.362 g, 2.07 mmol) to afford the title compound (0.289 g, 96%) as a white solid. MW=282.14. 1H NMR (CD3OD, 300 MHz) δ 8.15-8.07 (m, 1H), 7.94-7.86 (m, 1H), 7.66 (s, 1H), 7.33 (t, J=8.8 Hz, 1H), 3.12 (t, J=7.6 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 282 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Clc1cc(Cl)cc(OCc2ccccc2)c1
Temperature: 45 °C

Procedure:
To a stirred mixture of 3,5-dichlorophenol (3.00 g, 18.4 mmol) and Cs2CO3 (12.0 g, 36.8 mmol) in dry, degassed DMF (150 mL) was added benzyl bromide (3.46 g, 20.2 mmol) dropwise. The reaction mixture was heated to 45° C. for 18 hours, then the solvent was removed under reduced pressure. The residue was partitioned between saturated aqueous NaHCO3 (75 mL) and CH2Cl2 (100 mL). The aqueous layer was extracted further with CH2Cl2 (25 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane—2% EtOAc to yield the desired product as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[C:3]#[CH:4].Br[C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:18](=[O:24])[NH:19]2>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.CN(C=O)C.CCN(CC)CC>[OH:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[C:3]#[C:4][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1/[C:17](=[CH:25]/[C:26]1[NH:27][CH:28]=[CH:29][C:30]=1[O:31][CH3:32])/[C:18](=[O:24])[NH:19]2
Reactant: C#CC(O)c1ccc(OC)c(O)c1
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C(O)C#Cc2cccc3c2/C(=C/c2[nH]ccc2OC)C(=O)N3)cc1O

Procedure:
Using Method D above, 3-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propyne (105 mg, 0.59 mmol) (from Example 34 above) was coupled to (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (122 mg, 0.38 mmol) (Starting Material 1) using (Ph3P)2PdCl2 (34 mg) (Aldrich) and CuI (15 mg) (Aldrich) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 70° C. for 18 h, yielding rac-(Z)-1,3-dihydro-4-[3-hydroxy-3-(3-hydroxy-4-methoxyphenyl)-1-propynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 101 mg, 64%).
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)[CH2:10][C@@H:9]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7]>CO.[Pd]>[F:41][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)[CH2:10][CH:9]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](N2CCN(Cc3ccccc3)CC2)C[C@@H]1Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Yield: 98.4 %

Procedure:
A mixture of compound 16 (8.4 g) in methanol (250 ml) was hydrogenated at 50° C. with palladium on activated carbon (10%) (2 g) as a catalyst. After uptake of H2, the catalyst was filtered off and the filtrate was evaporated, yielding 7 g (100%) of (±)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-(1-piperazinyl)piperidine (compound 15).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:20])[N:4]=1.I([O-])(=O)(=O)=[O:22].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:20][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:3]([CH:2]=[O:22])=[N:4]2
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Fc1cccc(-c2nc3c(Cl)cccc3nc2CBr)c1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1nc2cccc(Cl)c2nc1-c1cccc(F)c1
Temperature: 150 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(bromomethyl)-5-chloro-3-(3-fluorophenyl)quinoxaline (Prepared in Example 95, 0.8089 g, 2.301 mmol) and sodium metaperiodate (0.9842 g, 4.601 mmol) in DMF (15.34 mL, 2.301 mmol) was heated at 150° C. with stirring. After 5 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with sat'd Na2S2O3 (50 mL×1) and brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 20 min as eluent to give 5-chloro-3-(3-fluorophenyl)quinoxaline-2-carbaldehyde as a solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.18 (1 H, s), 8.31 (1 H, dd, J=8.2, 1.2 Hz), 8.25 (1 H, dd, J=7.4, 1.2 Hz), 7.99 (1 H, dd, J=8.4, 7.6 Hz), 7.56-7.70 (3 H, m), 7.38-7.46 (1 H, m); LC-MS (ESI) m/z 287.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[O:8][C:7]([C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=[C:31]=[N:32][CH2:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37].CN1CCCNCC1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:37][N:36]1[CH2:35][CH2:34][CH2:33][N:32]([C:13]([C:12]2[CH:11]=[CH:10][C:9]([C:7]3[O:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:17][CH:16]=2)=[O:15])[CH2:31][CH2:38]1
Reactant: CC(=O)c1ccc(-c2ccc(C(=O)O)cc2)o1
Reactant: CCN=C=NCCCN(C)C
Agent: CN1CCCNCC1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCCN(C)CC3)cc2)o1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 113 %

Procedure:
To a solution of 4-(5-acetylfuran-2-yl)benzoic acid (500 g, 2.17 mmol) and HOBt (587 mg, 4.35 mol) in DMF (5 mL) was added EDCI (835 mg, 4.35 mmol). The reaction was stirred at rt for 10 min and then 1-methylhomopiperazine (1.08 mL, 8.69 mol) was added, followed by DIEA (1.52 mL, 8.69 mmol). The reaction mixture was stirred at rt for 3 h and diluted with H2O (20 mL). The mixture was extracted with DCM (3×25 mL), washed with water (2×25 mL) then brine (25 mL), dried over Na2SO4 and concentrated to give brown oil (800 mg). LCMS (ES): m/z 442 [M+1]+.
Reaction SMILES: B(F)(F)F.[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][C:25](=[O:28])[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1.C(Cl)Cl.[CH2:32](O)[CH2:33][OH:34]>>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]3[CH2:27][CH2:26][C:25]4([O:34][CH2:33][CH2:32][O:28]4)[CH2:24][CH2:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(C3CCC(=O)CC3)cc2)cc1
Reactant: OCCO
Agent: FB(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ccc(C3CCC4(CC3)OCCO4)cc2)cc1
Reaction time: 0.67 h
Yield: 96 %

Procedure:
Boron trifluoride diethyletherate (3.3 mL, 26.0 mmol) was added dropwise via a syringe to a stirred solution of 4-(4-oxocyclohexyl)phenyl 4-methylbenzenesulphonate (2.49 g, 7.23 mmol) in dry DCM/ethylene glycol (15 mL/14.11 mL) cooled with an isopropanol/ice bath and stirred for 40 minutes. The mixture was poured onto water (50 mL) and extracted with DCM (2×100 mL). The organic phase was washed with 10% sodium hydrogen carbonate solution (100 mL) then dried and concentrated by evaporation to give the title compound (2.685 g, 96%) as a solid; 1H NMR δ 1.54-1.66 (4H, m), 1.68-1.75 (4H, m), 2.43 (3H, s), 2.54-2.60 (1H, m), 3.86-3.89 (4H, s), 6.91-6.95 (2H, m), 7.21-7.25 (2H, m), 7.46-7.48 (2H, m), 7.73-7.75 (2H, m); MS m/e M+Na+ 411.