Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3][CH:2]=1.C(O)(=O)CCCCCCCCCCCCCCCCC.[OH-].[K+]>O>[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[CH:1][CH:2]=[CH:3][CH:4]=1
Reactant: C1=CCCC=CCCC=CCC1
Agent: CCCCCCCCCCCCCCCCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: C1=CC=CCCCCCCC=C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 600 mL beaker was charged with 150 g deionized water, 100 g of 91% pure 1,5,9-cyclododecatriene and 5.0 g of stearic acid. The resulting mixture was heated to 75°-80° C. to melt stearic acid and was intensively mixed at this temperature using a high shear Tekmar agitator while adding sufficient 50% aq. KOH to raise the pH to 10.5-11.0. The emulsion was cooled to room temperature and allowed to stand overnight. (Note: density differences between bulk water and emulsified particles caused some separation overnight, but gentle mixing again gave a uniform emulsion). The final emulsion contained 39.2 percent 1,5,9-cyclododecatriene (I) by weight.
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[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].[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl.CN(C=O)C>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:35]([CH:32]6[CH2:34][CH2:33]6)(=[O:37])=[O:36])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[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]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
A round bottom flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.40 g, 0.92 mmol), TEA (0.51 mL, 3.7 mmol) in DCM (3 mL) and DMF (6 mL). Cyclopropanesulfonyl chloride (0.16 g, 1.1 mmol) was added drop-wise and the resulting suspension was stirred at ambient temperature for about 18 h. The solvent was removed under reduced pressure and DCM (10 mL) was added. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.27 g, 55%): LC/MS (Table 2, Method a) Rt=2.14 min; MS m/z 541 (M+H)+.
Reaction SMILES: [C:1]1(C)C=CC(S(O)(=O)=O)=CC=1.C[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH2:21]([OH:24])[CH2:22][OH:23]>O>[CH3:1][C:14]([O:23][CH2:22][CH2:21][OH:24])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: OCCO
Reactant: CC=Cc1ccccc1
Solvent: O
Product: CC(C)(OCCO)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 4 %

Procedure:
A catalytic amount of either p-toluene sulfonic acid .H2O or Bio-Rad SCX resin (analytical grade, 5.1 meq/g, AG 50W-X8) was added to -methylstyrene (0.5 mL, 3.85 mmol) and ethylene glycol (0.21 mL, 3.85 mmol), and the reaction was stirred at rt for 5 days. The reaction mixture was loaded directly onto a SPE cartridge (10 g silica) and eluted with the following 10 mL fractions: 10% EtOAc/hexanes (fractions 1,2), 30% EtOAc/hexanes (fractions 3,4), and 50% EtOAc/hexanes (fractions 5,6) to give the title compound (30.5 mg, 4%) for both conditions. The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH:11](B(O)O)=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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>[Cl:8][C:6]1[CH:7]=[C:2]([CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3](=[O:10])[N:4]([CH3:9])[N:5]=1
Reactant: Cn1nc(Cl)cc(Br)c1=O
Reactant: OB(O)C=Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cn1nc(Cl)cc(C=Cc2ccccc2)c1=O
Temperature: 85 °C
Yield: 67.9 %

Procedure:
A mixture of 4-bromo-6-chloro-2-methylpyridazin-3(2H)-one (8 g, 35.8 mmol, Preparation #28), styrylboronic acid (6.62 g, 44.8 mmol, Combiblocks), bis(triphenylphosphine)palladium(II) chloride (2.51 g, 3.58 mmol, Hindustan Platiniums) and potassium phosphate (11.40 g, 53.7 mmol, Aldrich) in aqueous dioxane (75%: 100 mL) was heated to about 85° C. for 6 h. The reaction mixture was cooled to RT and then concentrated on the rotovapor to 25 mL. The oily residue obtained was partitioned between EtOAc (100 mL) and water (50 mL). The layers were separated and then the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic layers were dried over sodium sulphate and evaporated under reduced pressure. The residue obtained was purified by silica gel column chromatography by eluting with 10-20% ETOAc in hexane. The relevant fractions containing the product were combined and evaporated under reduced pressure to afford 6-chloro-2-methyl-4-styrylpyridazin-3(2H)-one 6 g (67.9%) as yellow solid. 1H NMR (400 MHz, CDCl3) δ 7.878-7.838 (d, J=17 Hz, 1H), 7.620-7.560 (m, 2H) 7.412-7.344 (m, 3H) 7.279 (s, 1H) 7.177-7.136 (d, J=16 Hz, 1H) 3.809 (s, 3H); MS m/z: 247.1 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)=[O:16])[CH2:10][CH2:9]2)=[CH:5][CH:4]=1)#[N:2].[OH-].[Li+].Cl>CO.C1COCC1.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([NH:14][C:15]([C:17]3[CH:18]=[CH:19][C:20]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=3)=[O:16])[CH2:12][CH2:13]2)=[CH:27][CH:28]=1)#[N:2]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(Cc3ccc(C#N)cc3)CC2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1ccc(CN2CCC(NC(=O)c3ccc(C(=O)O)cc3)CC2)cc1
Reaction time: 8 h
Yield: 83 %

Procedure:
Methyl 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoate (900 mg, 2.38 mmol) and lithium hydroxide (600 mg, 14.28 mmol) was added to MeOH/THF/H2O (2/1/1, 20 mL), and the mixture was stirred overnight, then acidified with 2M hydrochloric acid (10 mL) to pH 5. A white solid separated, and was collected by filtration and washed with water. The combined filtrate and washings were acidified by adding further 2M hydrochloric acid to pH 1 and the solution was extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried with magnesium sulphate and evaporated to give 4-(1-(4-cyanobenzyl)piperidin-4-ylcarbamoyl)benzoic acid (0.718 g, 83%). LCMS (m/z): 364 (MH+).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:14][CH2:15][O:16][C:17]([F:20])([F:19])[F:18])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:23][CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([C:7]1[N:6]([CH2:14][CH2:15][O:16][C:17]([F:20])([F:19])[F:18])[C:5]2[CH:21]=[CH:22][C:2]([S:23][CH:24]3[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]3)=[CH:3][C:4]=2[N:8]=1)[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CC(S)C1
Reactant: CC(C)(C)Cc1nc2cc(Br)ccc2n1CCOC(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)Cc1nc2cc(SC3CN(C(=O)OC(C)(C)C)C3)ccc2n1CCOC(F)(F)F
Temperature: 160 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
A mixture of 5-bromo-2-neopentyl-1-(2-(trifluoromethoxy)ethyl)-1H-benzo[d]imidazole (STEP A, 265 mg, 0.700 mmol), tert-butyl 3-mercaptoazetidine-1-carboxylate (STEP D of Example 1, 189 mg, 0.999 mmol), Xantphos (20.2 mg, 0.0350 mmol), tris(dibenzylideneacetone)dipalladium (16.0 mg, 0.0175 mmol) and N,N-diisopropylethylamine (245 microL, 1.40 mmol) in 1,4-dioxane (4 mL) was stirred at 160° C. for 1 h under microwave. The mixture was diluted with ethyl acetate and filtered through a celite. The filtrate was concentrated in vacuo and the residue was purified by silica gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (278 mg, 81%).
Reaction SMILES: [CH2:1]([O:8][CH:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]=[C:10]1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17](N(C(C)C)CC)(C)C>CO.C(#N)C.CCCCCC>[CH2:1]([O:8][C:9]1[C:10]([CH3:16])=[N:11][CH:12]=[CH:13][C:14]=1[O:15][CH3:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC1=NC=CC(=O)C1OCc1ccccc1
Solvent: CCCCCC
Solvent: CO
Solvent: CC#N
Product: COc1ccnc(C)c1OCc1ccccc1
Reaction time: 8 h
Yield: 75.5 %

Procedure:
3-Benzyloxy-2-methyl-4-pyridone (21.5 g, 0.10 mol) was suspended in methanol-acetonitrile (1:9 v/v, 400 ml). Diisopropylethylamine (18.1 g, 0.14 mol) was added to the suspension. The mixture was then stirred. A 2.0 M solution (70 ml) of tetramethylsilyldiazomethane in n-hexane was added dropwise to the mixture, and a reaction was allowed to proceed at room temperature overnight. The reaction solution was concentrated under the reduced pressure. The concentrate was applied to column chromatography on silica gel (Wako Gel C-200, n-hexane-ethyl acetate) to give 17.3 g (yield 76%) of 3-benzyloxy-4-methoxy-2-methylpyridine.
Reaction SMILES: [Cl:1][CH:2]([Cl:7])[C:3]([CH2:5]Cl)=O.[C:8]([NH2:11])(=[S:10])[CH3:9].[Br:12]Br>CC(C)=O.C(O)(=O)C>[Br:12][C:5]1[S:10][C:8]([CH3:9])=[N:11][C:3]=1[CH:2]([Cl:7])[Cl:1]
Reactant: O=C(CCl)C(Cl)Cl
Reactant: BrBr
Reactant: CC(N)=S
Solvent: CC(=O)O
Solvent: CC(C)=O
Product: Cc1nc(C(Cl)Cl)c(Br)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1,1,3-trichloroacetone (30.0 g, 185.85 mmol) in acetone (80.0 mL) was added thioacetamide (18.15 g, 241.60 mmol) and stirred at room temperature overnight. The mixture was then concentrated and re-dissolved in concentrated HCl (30.0 mL) and stirred initially at room temperature for 1 h followed by heating to 55° C. for 70 h. The system was cooled to room temperature, poured into ice water, extracted with EtOAc, dried over sodium sulfate and concentrated. The crude reaction mixture was purified using normal phase conditions (0%→20% EtOAc: hexanes) to afford a pale yellow solid. To this solid (13.9 g, 76.0 mmol) in acetic acid (109 mL) was added bromine (5.90 mL, 115 mmol) and the system was stirred at room temperature overnight. The mixture was poured into ice water, extracted with EtOAc, dried over sodium sulfate and concentrated. The crude reaction mixture was purified using normal phase conditions (5% EtOAc:hexanes) to afford the title compound (2-4) as a bone powder. ESI+ MS: 261.9 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:7]([C:12]([O:14][CH3:15])=[O:13])=[C:8]([OH:11])[C:9]=1[OH:10])=[O:4].N1C=CC=C1.[CH2:28]([C:30]([CH2:35][CH3:36])([CH2:33]O)[CH2:31]O)[CH3:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:7]([C:12]([O:14][CH3:15])=[O:13])=[C:8]2[C:9]=1[O:10][CH2:33][C:30]([CH2:35][CH3:36])([CH2:28][CH3:29])[CH2:31][O:11]2)=[O:4]
Reactant: CCC(CC)(CO)CO
Reactant: COC(=O)c1c(O)c(O)c(C(=O)OC)n1Cc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: c1cc[nH]c1
Product: CCC1(CC)COc2c(c(C(=O)OC)n(Cc3ccccc3)c2C(=O)OC)OC1

Procedure:
In the present method, 1-Benzyl-3,4-dihydroxy-1H-pyrrole-2,5-dicarboxylic acid dimethyl ester, the pyrrole derivative labeled A4 in FIG. 4 (hereinafter referred to as compound A4) is first synthesized from commercially available chemicals according to prior art techniques (see A. Merz, R. Schropp, E. Dotterl, “3,4-Dialkoxypyrroles and 2,3,7,8,12,13,17,18-Octaalkoxyporphyrins”, Synthesis, 7, pp. 795-800, (1995)). Then, a solution of compound A4, 2,2-diethyl-1,3-propanediol (labeled B4 in FIG. 4), triphenylphosphine (PPh3; labeled C4 in FIG. 4), and diethyl azodicarboxylate (DEAD; labeled D4 in FIG. 4) is refluxed in tetrahydrofuran (THF) for about 10-20 hours (preferably under an inert atmosphere). The reaction mixture is then quenched using a small amount of water, mixed with silica gel, and evaporated to dryness. The resulting material is loaded into a silica gel column and eluded by hexane and dichloromethane (1:1 volume ratio) to yield 2-Benzyl-6,6-diethyl-6,7-dihydro-2H,5H-4,8-dioxa-2-aza-azulene-1,3-dicarboxylic acid dimethyl ester, the pyrrole derivative labeled E4 in FIG. 4 (hereinafter referred to as compound E4).
Reaction SMILES: [Cl:1][C:2]1([N:8]=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C1CCC=CC=1>C(O)C.C(Cl)(Cl)(Cl)Cl>[ClH:1].[CH:5]12[CH2:6][CH2:7][CH:2]([CH:3]=[CH:4]1)[NH:8][O:9]2
Reactant: O=NC1(Cl)CCCCC1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: C1=CCCC=C1
Product: C1=CC2CCC1NO2
Product: Cl
Reaction time: 144 h
Yield: 73.8 %

Procedure:
To a solution of 6.1 g of 1-chloro-1-nitrosocyclohexane in 135 ml of ethanol and 260 ml of carbon tetrachloride, cooled to -20° C. in an acetone-dry ice bath, was slowly added 33.6 ml of 1,3-cyclohexadiene. The mixture was stored at -20° C. for 6 days and the solid collected, giving 4.5 g of 2-oxa-3-azabicyclo[2.2.2]oct-5-ene, hydrochloride.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH:7]=[CH:6]2.[H-].[Na+].CN(C=[O:22])C.[CH2:23]1[CH2:27][O:26][CH2:25][CH2:24]1>C1COCC1>[O:13]=[C:8]1[CH:7]=[CH:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[N:9]1[CH2:24][C:25]([O:26][CH2:27][CH3:23])=[O:22]
Reactant: C1CCOC1
Reactant: CN(C)C=O
Reactant: O=c1ccc2cc(C(F)(F)F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cn1c(=O)ccc2cc(C(F)(F)F)ccc21
Temperature: 25 °C

Procedure:
To a stirring mixture of the above crude 6-(trifluoromethyl)quinolin-2(1H)-one in DMF/THF (0.5 M, 1:1) at rt was added NaH portionwise (1.2 g, 30.88 mmol) over 15 min. The reaction mixture was stirred at rt for additional 20 min before a solution of bromo methyl acetate (4.73 g, 30.88 mmol) in THF was added. The resulting mixture was stirred at rt until the starting material was consumed. The mixture was slowly quenched with brine and extracted with EtOAc. The crude product mixture was purified by column chromatography (3.6 g, 82% in two steps). Retention time (min)=2.042, method [1], MS (ESI) 286.1 (M+H).
Reaction SMILES: [ClH:1].Cl.[C:3]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[NH:8][C:9](=[O:24])[CH2:10][N:11]1[CH2:16][CH2:15][N:14](CC2C=CC=CC=2)[CH2:13][CH2:12]1)(=[O:5])[NH2:4].O>[C].[Pd].CO>[ClH:1].[ClH:1].[C:3]([C:6]1[CH:28]=[CH:27][CH:26]=[CH:25][C:7]=1[NH:8][C:9](=[O:24])[CH2:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)(=[O:5])[NH2:4]
Reactant: NC(=O)c1ccccc1NC(=O)CN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: NC(=O)c1ccccc1NC(=O)CN1CCNCC1

Procedure:
50 Grams of o-carbamoyl-α-(4-benzyl-1-piperazinyl)acetanilide dihydrochloride, 4 g of 10%-palladium carbon, 70 ml of water and 300 ml of methanol were mixed together and the mixture was subjected to catalytic reduction at a room temperature. Then the catalyst was removed from the mother liquor, and the mother liquor was concentrated to dryness. The residue obtained was crystallized by adding acetone, and recrystallized from water-acetone to obtain 35.2 g of o-carbamoyl-α-(1-piperazinyl)acetanilide dihydrochloride. Colorless cotton fiber-like crystals. Melting point: 239.5°-242° C. (decomposed).
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=1[O:29]CC1C=CC=CC=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].O1CCCC1.C(O)C>[C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[OH:29])(=[O:18])=[O:19])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1O

Procedure:
(S)-3-(2-Benzyloxy-4-nitro-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester (150 mg, 0.28 mmol) was hydrogenated with 10% Pd/C (50 mg) in 1:1 tetrahydrofuran/ethanol (10 mL) at room temperature under 50 psi hydrogen in a Parr shaker for 3 h. The reaction mixture was filtered over a celite pad, the catalyst was washed with ethanol, the organics were combined and the solvent was removed under reduced pressure to give (S)-3-(4-amino-2-hydroxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 100 mg, 85%. RP-HPLC (10 to 90% acetonitrile in 0.1 N aqueous ammonium acetate over 10 min at 2 mL/min using a Waters Symmetry C18 150×4.6 mm column) 8.3 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[CH3:10][C:11]1([CH3:21])[CH2:16][O:15][CH:14]([CH2:17][CH2:18][CH:19]=[O:20])[O:13][CH2:12]1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]([OH:20])[CH2:18][CH2:17][CH:14]2[O:15][CH2:16][C:11]([CH3:10])([CH3:21])[CH2:12][O:13]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CC1(C)COC(CCC=O)OC1
Solvent: C1CCOC1
Product: CC1(C)COC(CCC(O)c2ccc(F)cc2)OC1
Temperature: -70 °C
Reaction time: 2 h
Yield: 87.6 %

Procedure:
4-Fluorophenyl magnesium bromide (8.7 ml, 2M solution in ether, 17.44 mmol) was added to a solution of 5,5-dimethyl-1,3-dioxane-2-propanal (2 g, 11.62 mmol) (Step 2) in THF (50 ml) at −70° C. After stirring at −70° C. for 2 hr, the reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with water and extracted with ethyl acetate. The organic fractions were combined and washed successively with water and brine. After drying (MgSO4), filtration and concentration, the crude compound (3.5 g) was chromatographed to give α-(4-fluorophenyl)-5,5-dimethyl-1,3-dioxane-2-propanol (2.73 g) as a white solid: mp (DSC) 84° C. Anal Calc'd. for C15H21FO3: C, 67.14; H, 7.89. Found: C, 67.18; H, 7.98.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:17](C(C)C)CC)(C)C.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>ClCCl>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[C:23]([NH2:17])=[O:30])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(Cl)c1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: O
Solvent: ClCCl
Product: NC(=O)c1ccccc1N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
To a mixture of 4-benzylpiperidine (0.263 g, 1.5 mM) and diisopropylethyl-amine (0.53 mL, 3.0 mM) in 10 mL dichloromethane at room temperature was added benzoyl chloride (0.281 g, 2.0 mM) and the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was poured into water and extracted with ethyl acetate (2×25 mL). The combined organic extract was washed with 1 N HCl, water and brine. The extract was dried over Na2SO4 and evaporated. The residue was chromatographed on a column of silica gel with ethyl acetate-hexane (10 to 50%, gradient). Evaporation of the desired fractions gave 0.402 g (96%) of the title compound as an oil. 1H NMR (CDCl3) δ 7.10-7.40 (m, 10H), 4.60-4.70 (m, 1H), 3.70-3.80 (m, 1H), 2.80-2.90 (m, 1H), 2.70-2.80 (m, 1H), 2.60 (d, 2H), 1.70-1.80 (m, 1H), 1.50-1.70 (m, 2H), 1.20-1.40 (m, 2H). MS (ESI) m/e 279 (M+)
Reaction SMILES: ClCCl.B(F)(F)F.C(Cl)(Cl)Cl.C[O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3=[N:30][N:31]=[C:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:22]3[N:21]=2)=[CH:16][CH:15]=1>O>[C:33]1([C:32]2[N:22]3[N:21]=[C:20]([C:17]4[CH:16]=[CH:15][C:14]([OH:13])=[CH:19][CH:18]=4)[C:29]4[C:24]([C:23]3=[N:30][N:31]=2)=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COc1ccc(-c2nn3c(-c4ccccc4)nnc3c3ccccc23)cc1
Agent: FB(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1ccc(-c2nn3c(-c4ccccc4)nnc3c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 136.6 %

Procedure:
1.5 ml (1.5 mmol) of a dichloromethane solution of 1 M boron trifluoride was added to a chloroform solution (4 ml) of 305 mg of the obtained 6-(4-methoxyphenyl)-3-phenyl-[1,2,4]triazolo[3,4-a]phthalazine, and stirred overnight at room temperature. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 400 mg of a crude product of 4-(3-phenyl-[1,2,4]triazolo[3,4-a]phthalazin-6-yl)-phenol.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[CH2:19]O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Br:21]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:21][CH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:18])([F:17])[F:16])[CH:13]=[CH:14][C:9]=1[C:3]1([O:2][CH3:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1(c2ccc(C(F)(F)F)cc2CO)CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC1(c2ccc(C(F)(F)F)cc2CBr)CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78.8 %

Procedure:
To a solution of (2-(1-methoxycyclohexyl)-5-(trifluoromethyl)phenyl)methanol (27 mg; 0.094 mmol) in methylene chloride (1 mL) was added N-bromosuccinimide (28 mg; 0.157 mmol) followed by triphenylphosphine (40 mg; 0.152 mmol). The reaction was stirred at room temperature for 4 hours. The reaction was directly loaded onto silica and purified over 4 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-40% ethyl acetate in heptane) to give 26 mg (79%) of a gum. MS-GC (El): Calc: 351.2, Found; 352 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 7.81 (d, J=1.66 Hz, 1H), 7.48 (td, J=8.30, 1.66 Hz, 1H), 7.39 (d, J=8.30 Hz, 1H), 5.12 (s, 2H), 3.00 (s, 3H), 2.25 (d, J=12.45 Hz, 2H), 1.84-1.71 (m, 3H), 1.65 (m, 4H), 1.27(m, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:15]Br)=[C:4]([NH:8][C:9](=O)[C:10]([F:13])([F:12])[F:11])[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[CH:15]=[C:9]([C:10]([F:13])([F:12])[F:11])[NH:8]2
Reactant: O=C(Nc1cccc(Br)c1CBr)C(F)(F)F
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: FC(F)(F)c1cc2c(Br)cccc2[nH]1
Temperature: 60 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
A solution of N-(3-bromo-2-bromomethyl-phenyl)-2,2,2-trifluoro-acetamide (2.9 g) in toluene (40 mL) was treated with triphenylphosphine (2.3 g, 8.7 mmol). The solution was stirred at 60° C. for 2 h, then cooled to 0° C. The beige solid that precipitated was collected by filtration, washed with diethyl ether, then dissolved in DMF (60 mL), and heated to reflux under nitrogen for 16 h. The reaction mixture was evaporated to dryness, then partitioned between EtOAc and a sat, sodium carbonate solution. The organic layer was isolated, dried (MgSO4), and purified by column chromatography to give the title compound as a yellow solid (1.55 g, 84%).