Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]([CH2:25][C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1)([CH2:18][C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)[C:5]([NH:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:6].C[Mg]Br.C1(C)C=CC=CC=1.O1CCCC1>O1CCCC1>[C:8]12([N:7]3[C:5](=[O:6])[C:4]([CH2:25][C:26]4[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=4)([CH2:18][C:19]4[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=4)[C:3]3=[O:2])[CH2:9][CH:10]3[CH2:16][CH:14]([CH2:13][CH:12]([CH2:11]3)[CH2:17]1)[CH2:15]2
Reactant: COC(=O)C(Cc1ccncc1)(Cc1ccncc1)C(=O)NC12CC3CC(CC(C3)C1)C2
Agent: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1N(C23CC4CC(CC(C4)C2)C3)C(=O)C1(Cc1ccncc1)Cc1ccncc1
Temperature: 50 °C
Yield: 21.7 %

Procedure:
To a solution of N-adamantan-1-yl-2,2-bis-pyridin4-ylmethyl-malonamic acid methyl ester (100 mg, 0.23 mmol) in anhydrous tetrahydrofuran (1.5 ml), a 1.4M solution of methyl magnesium bromide in toluene/ tetrahydrofuran (Aldrich Chemical Co., 330 μl, 0.46 mmol of methyl magnesium bromide) and cuprous bromide (1.6 mg) was added. The reaction was heated at 50° C. for 6 hours and then quenched by addition to 15 ml of ice water containing 200 μl of concentrated sulfuric acid. The pH of the mixture was then adjusted to 8.0 with aqueous sodium bicarbonate. Two 15 ml methylene chloride extractions were combined, dried (anhydrous sodium sulfate), and concentrated in vacuo to an oil (104 mg). Flash chromatography of the entire sample (silica gel, 40 micron mesh; elution with methanol/methylene chloride=4:96 in volume) afforded the title compound (20 mg) as an oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH:12]2[CH2:17][CH2:16][CH:15]3[CH2:18][CH:13]2[C:14]3([CH3:20])[CH3:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:21]([OH:25])[CH2:22][C:23]#[CH:24]>CN(C=O)C.CCN(C(C)C)C(C)C>[CH3:19][C:14]1([CH3:20])[CH:13]2[CH2:18][CH:15]1[CH2:16][CH2:17][CH:12]2[NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([C:24]#[C:23][CH2:22][CH2:21][OH:25])=[CH:3][CH:4]=1)(=[O:10])=[O:9]
Reactant: C#CCCO
Reactant: CC1(C)C2CCC(NS(=O)(=O)c3ccc(Br)cc3)C1C2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)C2CCC(NS(=O)(=O)c3ccc(C#CCCO)cc3)C1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
A solution of the product of Step A (0.37 g, 0.5 mmol) and but-3-yn-1-ol (0.12 ml, excess) in a mixture of DMF (5 ml) and DIPEA (0.5 ml) was degassed with N2 and Cl2Pd(PPh3)2 (0.07 g) was added, followed by catalytic amount of CuI and the mixture was stirred for 16 h at room temperature. The reaction was quenched with saturated NH4Cl solution and diluted with H2O followed by the extraction with EtOAc (100 ml). The organic layer was separated, dried over MgSO4, filtered and the filtrate was evaporated to dryness and the residue was purified by FCC (SiO2, hexane/EtOAc) to give the product (0.11 g, 60%), as creamy paste. 1H-NMR (CDCl3) 7.66 (d, 2H, J=8.43 Hz); 7.51 (d, 2H, J=8.43 Hz); 3.81 (b, 2H); 3.01-2.86 (m, 2H); 2.71-2.67 (m, 4H); 2.50-2.10 (m, 2H); 1.94-1.82 (m, 5H); 1.52-1.48 (m, 1H); 1.18 (s, 3H); 1.02 (s, 3H).
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:25]1[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26]1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:30][C:27]1[CH:28]=[CH:29][O:25][CH:26]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=Cc1ccoc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC(Br)=Cc1ccoc1
Temperature: 25 °C
Yield: 55.4 %

Procedure:
To a stirred and cooled (0° C.) solution of carbon tetrabromide (34.5 g, 104.1 mmol) in CH2Cl2 (70 mL) was added triphenylphosphine (54.6 g, 208.1 mmol) in five equal portions over a period of 5 nm. The resulting dark red solution was stirred for a further 10 min, and a solution of 3-furaldehyde (9) (5 g, 52.0 mmol) in CH2Cl2 (25 mL) was added slowly. The resulting black solution was allowed to warm to r.t. After 5.5 h the mixture was poured into ice-cold pentane and stirred vigourously. The mixture was filtered and the collected solid washed extensively with diethyl ether-ethyl acetate mixture. The combined solutions were washed with saturated aqueous Na2S2O3 (×1), water (×1), 1 M aqueous NaOH, saturated brine (×1), dried (MgSO4), filtered and concentrated. The residue was partially purified by silicagel chromatography (SGC) with hexane as eluent. Appropriate fractions were combined, concentrated and purified by vacuum distillation (150° C./0.5 mm Hg) to afford the dibromo-furan 10 (7.26 g, 55%) as a yellow oil. 1H NMR (400 MHz; CDCl3) δ 6.79 (m, 1H), 7.27 (m, 1H), 7.41 (m, 1H) and 7.83 (m, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:27]>CO>[ClH:27].[ClH:27].[N:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:26]=[C:17]([CH2:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCc2cnc3ccccc3c2)CC1
Agent: Cl
Solvent: CO
Product: c1ccc2ncc(CCCC3CCNCC3)cc2c1

Procedure:
A solution of 1-(t-butoxycarbonyl)-4-(3-(quinolin-3-yl)propyl)piperidine from Step A (240 mg, 0.68 mmol) in 1M HCl solution (8 mL) in methanol was stirred at rt for 48 h. The solution was concentrated and the residue crystallized from ethyl acetate to afford the title compound (182 mg),
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:4]1([CH3:10])[CH:5]=[CH:6][CH:7]=[C:8]([O:9][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[CH:3]=1
Reactant: Cc1cccc(O)c1
Reactant: COc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: COc1ccc(Oc2cccc(C)c2)cc1
Temperature: 170 °C
Reaction time: 2 h

Procedure:
21.8 g of sodium hydride (55% in oil) are placed in 100 ml of absolute pyridine and treated dropwise during 1 hour with 54.1 g of m-cresol in 200 ml of pyridine. After completion of the reaction, 1.2 g of cuprous chloride are added and subsequently 93.5 g of 4-bromoanisole are added dropwise during 1 hour at reflux temperature. After refluxing for 4 hours, the pyridine is distilled off, the mixture being heated at the end up to 170° C. (internal temperature). After 2 hours, 350 ml of water are added dropwise with ice-cooling, followed by 500 ml of diethyl ether and a further 150 ml of water. The mixture is filtered with suction over Celite and the phases are separated. The organic phase is washed in sequence with 200 ml of 2N hydrochloric acid, three times with 100 ml of 2N sodium hydroxide each time, with 200 ml of water and with 200 ml of saturated sodium chloride solution. After drying over sodium sulfate and evaporation, there is obtained a brown-red oil which is filtered over a five-fold amount of silica gel with n-hexane/diethyl ether and then distilled to yield pure p-(m-tolyloxy)anisole; b.p. 106°-108° C./0.04 Torr; nD20 =1.5738.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:10]2=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][C:22]3[N:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH:14]=[C:9]2[CH:8]=[CH:7]1)(C)(C)C.Cl.C([O-])(O)=O.[Na+].C(OCC)(=O)C>CO>[N:27]1[CH:26]=[CH:25][CH:24]=[N:23][C:22]=1[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:13]1[CH:14]=[C:9]2[CH:8]=[CH:7][NH:6][C:10]2=[N:11][CH:12]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3ccccc3Oc3ncccn3)cnc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: c1cnc(Oc2ccccc2-c2cnc3[nH]ccc3c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
A mixture of 40 prepared above (120 mg, approx. 0.24 mmol), MeOH (1.1 mL) and 10% aq. HCl (2.4 mL) were stirred at room temperature for 1 h then poured onto saturated aq. NaHCO3/ethyl acetate. The aqueous phase was extracted with more ethyl acetate and the combined organic extracts dried (MgSO4) and concentrated to give pure product 41 (40.8 mg, 44% over 3 steps from 26); 1H NMR (400 MHz, CDCl3) δ 6.40 (dd, J=3.4, 1.6 Hz, 1H), 6.76 (t, J=4.8 Hz, 1H), 7.21 (m, 2H), 7.32 (dt, J=7.8 Hz, 1.8 Hz, 1H), 7.39 (dt, J=7.8, 1.8 Hz, 1H), 7.46 (dd, J=7.5, 1.8 Hz, 1H), 8.04 (d, J=2.0 Hz, 1H), 8.30 (d, J=4.8 Hz, 2H), 8.37 (d, J=2.0 Hz, 1H), 10.26 (bs, NH).
Reaction SMILES: Cl.[F:2][CH2:3][C@@H:4]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH2:18][F:19])(=[O:17])=[O:16])=[CH:11][CH:10]=2)[O:7]C(C)(C)[N:5]1C(OC(C)(C)C)=O>CO>[NH2:5][C@H:4]([CH2:3][F:2])[C@@H:8]([C:9]1[CH:10]=[CH:11][C:12]([S:15]([CH2:18][F:19])(=[O:17])=[O:16])=[CH:13][CH:14]=1)[OH:7]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(S(=O)(=O)CF)cc2)OC1(C)C
Agent: Cl
Solvent: CO
Product: N[C@H](CF)[C@H](O)c1ccc(S(=O)(=O)CF)cc1
Temperature: 40 °C
Yield: 96.8 %

Procedure:
A solution of 6N HCl (30 ml, 5.5 eq) was added to a solution of 16 (12.0 g) in 200 ml of MeOH at room temperature, and the reaction mixture was warmed up to 40° C. overnight. Methanol was removed in vacuo. The reaction mixture was washed with diethyl ether (50 ml×2). The aqueous solution was neutralized with 2N NaOH and extracted with ethyl acetate (100 ml×3). The organic layer was washed with brine, dried over sodium sulfate, and concentrated to provide the pure desired product (7.6 g).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].[CH3:19][O:20][C:21]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][C:22]=1[C:23]([O:25][CH3:26])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC>[C:8]([O:7][C:6]([NH:5][CH2:4][C:3]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:2]=1[C:28]1[CH:29]=[CH:30][C:21]([O:20][CH3:19])=[C:22]([CH:27]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:12])([CH3:11])([CH3:10])[CH3:9]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)ccc1OC
Reactant: COc1ccc(Br)c(CNC(=O)OC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccc(OC)cc2CNC(=O)OC(C)(C)C)ccc1OC
Temperature: 80 °C
Yield: 112.5 %

Procedure:
570 mg of t-butyl N-(2-bromo-5-methoxybenzyl)carbamate, 440 mg of methyl 2-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, 86 mg of dichlorobistriphenyl phosphinoferrocene palladium and 1.0 g of potassium carbonate were dissolved in 15 ml of dimethoxyethane, and the mixture was heated at 80° C. for 24 hours in a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was evaporated. The residue was purified by silica gel column, to give 680 mg of the title compound in the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: Br[CH2:2][CH2:3][OH:4].[F:5][C:6]([F:37])([F:36])[C:7]1[CH:8]=[C:9]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C@H:13]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=[O:11]>C(#N)C>[F:37][C:6]([F:5])([F:36])[C:7]1[CH:8]=[C:9]([CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:2][CH2:3][OH:4])[CH2:14][C@H:13]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)=[O:11]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCNC[C@H]1Cc1ccc(C(F)(F)F)cc1
Reactant: OCCBr
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCO)C[C@H]1Cc1ccc(C(F)(F)F)cc1
Temperature: 70 °C
Reaction time: 19 h
Yield: 85 %

Procedure:
2-Bromoethanol (310 mg) was added to a solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-[4-(trifluoromethyl)-benzyl]piperazine (1 g) in acetonitrile (10 ml). The reaction mixture was stirred at 70° C. for 19 hours. The mixture was filtered, and the residue on filter was washed with dichloromethane twice. The filtrate and combined washings were concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with methanol in dichloromethane (2% then 5%) to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-4-(2-hydroxyethyl)-2-[4-(trifluoromethyl)benzyl]piperazine (927 mg) as an amorphous powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:27])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>C(OCC)(=O)C>[ClH:28].[CH3:26][S:23]([O:22][C:18]1[CH:17]=[C:16]([CH2:15][C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)=[O:27])[CH:21]=[CH:20][CH:19]=1)(=[O:24])=[O:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc(OS(C)(=O)=O)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Oc1cccc(CC(=O)N2CCNCC2)c1
Reaction time: 0.25 h

Procedure:
Through a solution of the product from Step B (2.07 g, 5.22 mmol) in 75 mL of ethyl acetate at 0° C. was bubbled anhydrous HCl gas for 5 minutes. After 15 minutes, the reaction was concentrated in vacuo to produce the titled product as a white foam.
Reaction SMILES: O.[NH2:2][NH2:3].[O:4]=[C:5]1[CH2:9][CH2:8][C@H:7]([CH2:10][C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[N:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22].[NH4+].[Cl-]>C1COCC1>[C:24]([O:23][C:21]([NH:6][C@@H:7]([CH2:10][C:11]1[CH:12]=[N:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=1)[CH2:8][CH2:9][C:5]([NH:2][NH2:3])=[O:4])=[O:22])([CH3:25])([CH3:27])[CH3:26]
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1Cc1ccc(C(F)(F)F)nc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)NN)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
Hydrazine monohydrate (0.93 mL, 18.6 mmol) was added to a solution of (R)-tert-butyl 2-oxo-5-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyrrolidine-1-carboxylate (1.6 g, 4.65 mmol) in THF (23 mL), and the mixture was stirred at room temperature for 1 hour. Saturated aqueous NH4Cl (20 mL) was added and the mixture was extracted with EtOAc (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting off-white solid was purified by recrystallization from EtOAc to provide (R)-4-(tert-butoxycarbonylamino)-5-(6-(trifluoromethyl)pyridin-3-yl)pentanehydrazide (1.40 g, 80%) as a white solid. LCMS (API-ES) m/z: 399.1 (M+Na+).
Reaction SMILES: Cl.N1C=CC=CC=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]=2[CH:28]=1>O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][CH2:14][C:13]=2[CH:28]=1
Reactant: COc1ccc2c3c(ccc2c1)-c1ccc(Br)cc1CO3
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: Oc1ccc2c3c(ccc2c1)-c1ccc(Br)cc1CO3
Temperature: 190 °C
Reaction time: 4 h
Yield: 56.1 %

Procedure:
Pyridine hydrochloride (4.4 g, 37.8 mmol) was heated to 190° C. 8-bromo-2-methoxy-6H-dibenzo[c,h]chromene (1.29 g, 3.8 mmol) was added and the reaction was stirred at 190° C. After four hours, the reaction was cooled to room temperature and diluted with water. A precipitate formed which was collected by filtration and purified by flash column chromatography to yield 8-bromo-6H-dibenzo[c,h]-chromen-2-ol (697 mg, 56%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:47]=[CH:46][CH:45]=[CH:44][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[C:20]([NH:25][C:26]3[CH:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH:30]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[Cl:24][C:23]1[C:18]([CH2:17][CH2:16][C:15]2[CH:44]=[CH:45][CH:46]=[CH:47][C:14]=2[C:11]2([C:8]([NH2:9])=[O:10])[CH2:13][CH2:12]2)=[N:19][C:20]([NH:25][C:26]2[CH:27]=[N:28][N:29]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[CH:30]=2)=[N:21][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Nc3ncc(Cl)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3cnn(C4CCNCC4)c3)ncc2Cl)CC1
Reaction time: 16 h
Yield: 21 %

Procedure:
TFA (1 mL) was added to a solution of tert-butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-chloropyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A20 (0.021 g, 0.037 mmol) in DCM (5 mL) and the mixture was stirred for 16 hours. The volatiles were removed in vacuo and the resultant residue loaded onto a SCX cartridge (5 g). The cartridge was washed with MeOH (100 mL) and then with 5% NH4OH in MeOH (100 mL). The basic fractions were combined, the solvent was removed in vacuo and the resultant residue purified by prep-LCMS to give the title compound 17 as a yellow solid (3.6 mg, 21%). LCMS-B: rt 4.711 min; m/z 466.2 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=1
Reactant: C1CNCCN1
Reactant: FC(F)(F)c1cc(Cl)cc(Cl)c1
Product: FC(F)(F)c1cc(Cl)cc(N2CCNCC2)c1
Yield: 52.1 %

Procedure:
Beginning with 3,5-dichlorobenzotrifluoride (500 mg, 2.32 mmol) and piperazine (1 g, 11.6 mmol), 320 mg of the title compound was recovered by the procedure described in Example 1.
Reaction SMILES: [S:1]([C:11]1[C:24]2[C:23](=[O:25])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:26])[C:15]=2[C:14](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[NH:37]([C:14]1[C:15]2[C:16](=[O:26])[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23](=[O:25])[C:24]=2[C:11]([S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:3])=[O:2])=[CH:12][CH:13]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)c2ccc(S(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Product: Cc1ccc(S(=O)(=O)c2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Yield: 79 %

Procedure:
1-(anilino)-4-tosylanthraquinone was prepared by reaction of 1,4-ditosylanthraquinone with aniline. The isolated and purified reaction product has the structure illustrated below (where "Ts" is ##STR12## The yield was 79% and the m.p. 185°-186° C. Mass spec m/e 469 (M+), 314 (M-C7H7SO2), 155 (C7H7SO2), 91 (C7H7); H-NMR (CD2Cl2)δ11.50 (br s, 1H), 8.26-8.12 (m, 2H), 8.02-7.84 (m, 2H), 7.79-7.62 (m, 4H), 7.54-7.13 (m, 7H), 2.31 (s, 3H); IR (Nujol) 1355 cm-1 (asymmetric SO2 stretch), 1184 cm-1 (symmetrical SO2 stretch), 945 cm-1, 872, 840, 822, 810, 800, 788, 755 (S--O--C stretch); UV/VIS max (Xylenes) 500 nm (ε7000).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([O:24]CC)=[O:23].[OH-].[Na+].Cl>C(O)C>[CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1sc(N2CCN(CCOc3ccccc3)C2=O)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N2CCN(CCOc3ccccc3)C2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 99 %

Procedure:
A mixture of ethyl 3-methyl-5-(2-oxo-3-(2-phenoxyethyl)imidazolidin-1-yl)thiophene-2-carboxylate (0.09 g, 0.24 mmol) and 1 N aqueous sodium hydroxide solution (1.5 mL, 1.5 mmol) in ethanol (3 mL) was stirred at reflux for 1 h, and then cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH ˜2. The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as a colorless solid in 99% yield (0.08 g): 1H NMR (300 MHz, DMSO-d6) δ 12.33 (br s, 1H), 7.29 (dd, J=8.8, 7.2 Hz, 2H), 6.99-6.93 (m, 3H), 6.28 (s, 1H), 4.13 (t, J=5.3 Hz, 2H), 3.87-3.79 (m, 2H), 3.72-3.64 (m, 2H), 3.58 (t, J=5.3 Hz, 2H), 2.39 (s, 3H); MS (ES+) m/z 347.3 (M+1).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:25]=[CH:24][C:9]3[CH:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][CH:21]([OH:23])[CH3:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>C1COCC1>[CH3:33][S:34]([O:23][CH:21]([CH3:22])[CH2:20][O:19][C@H:16]1[CH2:17][CH2:18][C@H:13]([C:11]2[O:12][C:8]3[CH:7]=[C:6]([O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[CH:25]=[CH:24][C:9]=3[CH:10]=2)[CH2:14][CH2:15]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(CO[C@H]1CC[C@H](c2cc3ccc(OCC4CC4)cc3o2)CC1)OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 1-({trans-4-[6-(cyclopropylmethoxy)-1-benzofuran-2-yl]cyclohexyl}oxy)propan-2-ol (555 mg), triethylamine (0.34 mL) and methanesulfonyl chloride (0.19 mL) in THF (5 mL) was stirred at room temperature for 1 hr and extracted with ethyl acetate and water. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (624 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42](Cl)=[O:43])=[CH:40][CH:39]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:36][O:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([O:1][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]3[O:24][CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)=[CH:7][CH:6]=2)=[O:43])=[CH:40][CH:39]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)OCCOc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3OCc3ccc4ccccc4c3)cc2)cc1
Temperature: 0 °C
Yield: 54.1 %

Procedure:
A solution of 150 mg (0.314 mmol) of tert-butyl (3RS,4RS)-4-[4-(2-hydroxy-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, 3.7 mg (0.031 mmol, 0.1 eq.) of 4-dimethylaminopyridine, 65.9 mg (0.375 mmol, 1.2 eq.) of 4-methoxy-benzoyl chloride and 51.7 μl of triethylamine in 10 ml of methylene chloride was stirred at room temperature for 15 hours. This reaction solution was poured into 50 ml of an ice/water mixture and extracted three times with ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The crude product (208 mg) was separated on silica gel using a 95:5 mixture of hexane and acetone as the eluent. There were obtained 104 mg (51% of theory) of tert-butyl (3RS,4RS)-4-[4-[2-(4-methoxy-benzoyloxy)-ethoxy]-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 612 (M+H)+.
Reaction SMILES: [CH3:1][Mg]Br.[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]=[O:15].[Cl-].[NH4+]>O1CCCC1>[N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH:14]([OH:15])[CH3:1]
Reactant: O=Cc1ccc2ccccc2n1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(O)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methylmagnesium bromide (17.6 mL of 1.4 M in toluene, 24.7 mmol) was added at <10° C. to a solution of quinoline-2-carboxaldehyde (3.0 g, 19 mmol) in anhydrous tetrahydrofuran (50 mL). The mixture was stirred at RT for 1 h and poured into saturated aqueous ammonium chloride (100 mL), and the resulting mixture was extracted with ethyl acetate (3×150 mL). The extracts were dried, concentrated, and the residue chromatographed on silica eluted with 30% and 40% ethyl acetate-hexanes giving a yellow solid. Yield 2.46 g, 75%. 1H NMR (CDCl3, 400 mHz) δ 8.15 (d, 1H, J=8.7 Hz), 8.07 (d, 1H, J=8.7 Hz), 7.81 (dd, 1H, J=1, 8 Hz), 7.71 (ddd, 1H, J=1, 7, 8.5 Hz), 7.51 (ddd, 1H, J=1, 7, 8.3 Hz), 7.33 (d, 1H, J=8.3 Hz), 5.07-4.99 (m, 2H), 1.56 (d, 3H, J=6.2 Hz).