Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[N+:6]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11]Br)([O-:8])=[O:7].C(=O)(O)[O-].[Na+].[CH2:22]([O:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[N:31]=[C:32]([CH3:34])[NH:33][C:29]=2[CH:28]=1)=[O:26])[CH3:23]>O.C(OCC)(=O)C>[CH2:22]([O:24][C:25]([C:27]1[CH:36]=[CH:35][C:30]2[N:31]([CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N+:6]([O-:8])=[O:7])[C:32]([CH3:34])=[N:33][C:29]=2[CH:28]=1)=[O:26])[CH3:23]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: CCOC(=O)c1ccc2nc(C)[nH]c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)nc(C)n2Cc1ccccc1[N+](=O)[O-]
Temperature: 60 °C

Procedure:
N,N-dimethylformamide (15 ml), 2-nitrobenzyl bromide (1.59 g) and sodium bicarbonate (1.23 g) are added to 5-ethoxycarbonyl-2-methylbenzimidazole (1.00 g) and the solution is heated for one hour at 60° C. After adding ethyl acetate (70 ml) and water (70 ml) and separating the solution, the organic layer is washed with water three times and extraction is performed on the aqueous layer using ethyl acetate three times. By concentrating the obtained organic layer under reduced pressure, a mixture of 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole and 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole is obtained. Purification using medium pressure silica gel column chromatography (eluate: hexane/etlhyl acetate=1/4˜0/100) produced 6-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (83) (0.614 g) and 5-ethoxycarbonyl-2-methyl-1-(2-nitrobenzyl)benzimidazole (84) (0.259 g). 1H-NMR CDCl3, δ): 1.38 (3H, t, J=7.2 Hz), 2.56 (3H, s), 4.37 (2H, q, J=7.1 Hz), 5.84 (2H, s), 6.41 (1H, d, J=6.8 Hz), 7.44-7.53 (2H, m), 7.78 (1H, d, J=8.6 Hz), 7.88 (1H, s), 8.02 (1H, dd, J=8.3 and 1.5 Hz), 8.30 (1H, dd, J=7.9 and 1.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>ClCCl>[F:1][CH:2]1[C:7]([F:8])([C:19](=[O:21])[CH3:20])[CH:6]=[CH:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:3]1
Reactant: Fc1ccc(-c2ccccc2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)C1(F)C=CC(c2ccccc2)=CC1F
Temperature: 20 °C
Reaction time: 10 h
Yield: 106.3 %

Procedure:
To one liter of dichloromethane were added 191 g of 3,4-difluorobiphenyl and 160 g of aluminum chloride, and maintaining the temperature to about 20° C., 86 g of acetyl chloride was gradually added dropwise under stirring. After completion of the dropwise addition, stirring was continued for 10 hours, and then 100 ml of hydrochloric acid was added to the mixture and the mixture was stirred well and washed. The mixture was further washed with water and the solvent was removed under reduced pressure. The residue was purified by distillation under reduced pressure (164° C./1 mmHg) to obtain 250 g of 3,4-difluoro-4-acetylbiphenyl.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH:16]2[CH2:20][O:19][C:18]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])([CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])[S:17]2)=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2].[OH-].[Li+]>>[C:1]([C:4]1[CH:36]=[CH:35][C:7]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][S:14][CH2:15][CH:16]2[CH2:20][O:19][C:18]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[S:17]2)=[C:6]([CH2:37][CH2:38][CH3:39])[C:5]=1[OH:40])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCCCSCC2COC(CCC(=O)OCC)(CCC(=O)OCC)S2)ccc(C(C)=O)c1O
Agent: [Li+]
Agent: [OH-]
Product: CCCc1c(OCCCCCSCC2COC(CCC(=O)O)(CCC(=O)O)S2)ccc(C(C)=O)c1O

Procedure:
The title compound was prepared according to the procedure of Example 3 using the ester produced in Example 4 (1.0 g, 0.0016 mol) and aqueous lithium hydroxide solution (2 M, 3.0 ml). Following the workup procedure of Example 3, 0.99 g (96%) of the product was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10].[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[Sn](CCCC)(CCCC)CCCC)[CH3:31]>O1CCOCC1.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]>[CH2:30]([N:32]([CH2:49][CH3:50])[CH2:33]/[CH:34]=[CH:35]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([C:17]3[CH:29]=[CH:28][O:27][C:18]=3[CH:19]=[N:20]2)=[CH:15][CH:14]=1)(=[O:11])=[O:10])[CH3:31]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1ncc1occc12
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(ncc3occc32)c1C(=O)OC
Temperature: 100 °C
Yield: 15.9 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino)-furo[2,3-c]quinoline-6-carboxylate (Intermediate 9, 0.165 g), N,N-diethyl-N-((Z)-1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.3 g), tri-tert-butylphosphinium tetrafluoroborate (0.01 g), tris-(dibenzylideneacetone)dipalladium (0.019 g) in dioxane (6 mL) was degassed then heated at 100° C. for 75 minutes. After cooling, the mixture was evaporated to approximately half volume then partitioned between ethyl acetate and water. The organic layer was washed with water, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM, with a gradient of 0-14% to give methyl 7-[2((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-furo[2,3-c]quinoline-6-carboxylate (0.028 g) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:29]([OH:32])CO)[CH:25]=5)[C:19]=4[N:20]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+].C(OCC)(=O)C>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:29]=[O:32])[CH:25]=5)[C:19]=4[N:20]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCC(O)c1ccc2c(ccc3oc(CCC4(c5ccc(F)cc5)CCCCC4)nc32)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc2c(ccc3oc(CCC4(c5ccc(F)cc5)CCCCC4)nc32)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)naphtho[1,2-d]oxazol-7-yl)ethane-1,2-diol (Preparation 42D, 0.051 g, 0.117 mmol) in methanol (1 mL) at 0° C. was added a solution of sodium periodate (0.038 g, 0.176 mmol) in water (1.000 mL) dropwise and the mixture was stirred for 30 mins at the same temp. Next, about 5 mL of ethyl acetate was added and the mixture was stirred for an addition 1 hr at 0-10° C. The mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, and evaporated to give the desired 2-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)naphtho[1,2-d]oxazole-7-carbaldehyde as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (1H, s), 8.51 (1H, d, J=8.58 Hz), 8.44 (1H, s), 8.09 (1H, dd, J=8.58, 1.32 Hz), 7.89 (1H, d, J=9.02 Hz), 7.68 (1H, d, J=9.02 Hz), 7.35 (2H, dd, J=9.02, 5.28 Hz), 7.02 (2H, t, J=8.69 Hz), 2.66-2.72 (2H, m), 2.15-2.22 (2H, m), 1.17-1.92 (10H, m).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH2:12][C:13]([OH:15])=[O:14])=[N:4][NH:3]1.[OH-].[Na+].[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>CO>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][N:3]2[N:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]2=[O:1])=[CH:21][CH:20]=1
Reactant: O=C(O)Cc1n[nH]c(=O)c2ccccc12
Reactant: BrCc1ccc(Br)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cc1nn(Cc2ccc(Br)cc2)c(=O)c2ccccc12
Yield: 16.4 %

Procedure:
1,2-Dihydro-1-oxophthalazin-4-ylacetic acid (2.0 g.) was added to a solution of sodium hydroxide (0.9 g.) in methanol (50 ml.). A clear solution was obtained on slight warming, which was treated with 4-bromobenzyl bromide (2.6 g.). The mixture was then heated under reflux for 3 hours and then evaporated. The residue was treated with water (60 ml.) and the solution obtained was extracted with ether (3×60 ml.). The aqueous phase was then acidified to pH 2 with concentrated hydrochloric acid and the acid mixture extracted with ethyl acetate (150 ml.). The extracts were washed with water (50 ml.), dried (MgSO4) and evaporated. The solid obtained was recrystallised from a 1:4 v/v mixture of ethyl acetate and petrol (60-80) to give 2-(4-bromobenzyl)-1,2-dihydro-1-oxophthalazin-4-ylacetic acid (0.6 g.), m.p. 179°-181° C.
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH2:12][CH:13]=[CH2:14])=[C:9]([O:15][CH3:16])[CH:8]=[CH:7][C:6]=1[C:17](=[O:27])[CH2:18][C:19]1[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=1[Cl:26])C=C.C([O-])([O-])=O.[K+].[K+]>CO.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>[CH2:12]([O:11][C:10]1[C:5]([OH:4])=[C:6]([C:17](=[O:27])[CH2:18][C:19]2[C:24]([Cl:25])=[CH:23][N:22]=[CH:21][C:20]=2[Cl:26])[CH:7]=[CH:8][C:9]=1[O:15][CH3:16])[CH:13]=[CH2:14]
Reactant: C=CCOc1c(OC)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1OCC=C
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: [K+]
Solvent: CO
Product: C=CCOc1c(OC)ccc(C(=O)Cc2c(Cl)cncc2Cl)c1O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(2,3-Bis-allyloxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethanone from example 6 (3.9 g, 9.55 mmol) was dissolved in MeOH (96 mL) and cooled to 0° C. under argon. Pd(PPh3)4 (110 mg, 0.0955 mmol) was added followed by K2CO3 (1.3 g, 9.55 mmol). The cooling bath was removed and the reaction mixture was stirred for 3 hours and then evaporated in vacuo. The crude was redissolved in EtOAc (100 mL) and washed twice with NH4Cl (sat, 50 mL). The organic phase was dried over Na2SO4 and evaporated in vacuo and purified by flash chromatography using a gradient of toluene and 2% EtOAc as eluent. 1-(3-Allyloxy-2-hydroxy-4-methoxy-phenyl)-2-(3,5-dichloro-pyridin-4-yl)-ethanone was obtained as a white solid. 1H NMR (CDCl3) δ=11.90 (1H, s), 8.53 (2H, s), 7.68 (1H, d), 6.58 (1H, d), 6.10 (1H, m), 5.26 (2H, m), 4.66 (2H, s), 4.59 (2H, d), 3.96 (3H, s). Yield 2.2 g (64%)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[N:19]=[CH:18][C:17]([NH:20][C:21]([C:23]3[CH:24]=[N:25][N:26]([C:29]4[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=4)[C:27]=3[CH3:28])=[O:22])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[OH-].[Na+]>ClCCl>[CH3:28][C:27]1[N:26]([C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][N:30]=2)[N:25]=[CH:24][C:23]=1[C:21]([NH:20][C:17]1[CH:18]=[N:19][C:14]([C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)=[CH:15][CH:16]=1)=[O:22]
Reactant: Cc1c(C(=O)Nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(C3=CCNCC3)nc2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 62.9 %

Procedure:
To N-[6-(1-tert-butyloxycarbonyl-1,2,3,6-tetrahydropyridin-4-yl)pyridin-3-yl]-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (3.53 g) were added dichloromethane (70 ml) and trifluoroacetic acid (14 ml), and stirred at room temperature for 4.5 hours. To the reaction solution was added 4 N aqueous solution of sodium hydroxide under ice-cooling, and the precipitated solid was purified with basic silica gel chromatography (chloroform/methanol) to give the titled compound (1.8 g) as a yellow solid. MS (ESI) m/z: 429 (M+H)+.
Reaction SMILES: [CH2:1]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[K+].I[CH3:19].[Cl-].[NH4+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH3:19])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCc1c[nH]c2ccccc12
Reactant: CI
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCc1cn(C)c2ccccc12
Reaction time: 0.5 h

Procedure:
To a solution of 3-hexyl-1H-Indole in DMSO was added KOH at RT and was stirred for 30 minutes. Iodomethane was added to the above mixture and stirred for 3 hours. The reaction was treated with saturated ammonium chloride and ethyl acetate. The product was purified by column chromatography.
Reaction SMILES: [Br:1]Br.[CH:3]([C:5]1([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH3:21])[CH:10]=[CH:9][CH:8]=[CH:7][CH2:6]1)=[O:4].S([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH:3]([C:5]1([C:11]2[CH:20]=[C:19]([Br:1])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]=2[CH3:21])[CH:6]=[CH:7][CH:8]=[CH:9][CH2:10]1)=[O:4]
Reactant: Cc1c(C2(C=O)C=CC=CC2)ccc2ccccc12
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1c(C2(C=O)C=CC=CC2)cc(Br)c2ccccc12
Reaction time: 3 h

Procedure:
A mixture of 19.5 ml (380 mmol) of bromine and 300 ml of dichloromethane is added dropwise with exclusion of light to a solution, cooled to 0° C., of 86.2 g (350 mmol) of 2-(1-formylphenyl)-1-naphthylmethane in 1500 ml of dichloromethane. After stirring for a further 3 h, 1000 ml of 5% sodium sulfite solution are added, the mixture is stirred briefly, the organic phase is separated off, washed three times with 500 ml of water and evaporated in vacuo, and the residue is taken up in a little acetone. After standing for 24 h, the crystals are filtered off with suction, washed with acetone:n-hexane (1:1) and dried in vacuo. Yield: 90.7 g (279 mmol), 79.7%, purity about 98% (NMR).
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:14])[CH3:13])[C:3]#[CH:4]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CCCCCC>[CH3:1][C:2]([OH:16])([CH2:5][CH2:6][CH:7]=[C:8]([CH3:15])[CH2:9][CH2:10][CH2:11][CH:12]([CH3:13])[CH3:14])[CH:3]=[CH2:4]
Reactant: C#CC(C)(O)CCC=C(C)CCCC(C)C
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCCCCC
Product: C=CC(C)(O)CCC=C(C)CCCC(C)C
Yield: 99.1 %

Procedure:
An autoclave having an internal volume of 3 liters was charged with 630 g of the 3,7,11-trimethyl-6-dodecen -1-yn-3-ol thus obtained, 270 g of hexane and 0.22 g of a Lindlar catalyst (supported on calcium carbonate) to carry out the hydrogenation for 4 hours under hydrogen pressure of 5 to 8 kg/cm2 (gauge pressure) at a temperature of 25 to 43° C. Thereafter, the catalyst was filtered off, and the resultant filtrate was concentrated with a rotary evaporator to give 630 g of crude 3,7,11-trimethyl-1,6-dodecadien-3-ol. Analysis by gas chromatography (column: DC-550, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 160° C.; and column: PEG-20M, available from Gasukuro Kogyo Inc.; column length: 3 m; column temperature: 190° C.) revealed that the conversion of 3,7,11-trimethyl-6-dodecen-1-yn-3-ol was 95.5%, and the selectivity to 3,7,11-trimethyl -1,6-dodecadien-3-ol was 94.6%.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[OH:15][C@@H:16]1[CH2:41][CH2:40][CH:39]=[CH:38][C:37]2=[CH:42][C:33](=[CH:34][CH:35]=[CH:36]2)[C@@H:32]([CH3:43])[NH:31][C:30](=[O:44])[C@H:29]2[NH:45][N:25]([CH2:26][CH2:27][CH2:28]2)[C:24](=[O:46])[C@H:23]([CH3:47])[NH:22][C:21](=[O:48])[C@H:20]([CH:49]([CH3:51])[CH3:50])[NH:19][C:18](=[O:52])[C@@H:17]1[CH3:53].FC(F)(F)S(O[CH2:60][C:61]([F:64])([F:63])[F:62])(=O)=O>O1CCCC1.CN(C)C=O>[CH:49]([C@@H:20]1[NH:19][C:18](=[O:52])[C@H:17]([CH3:53])[C@H:16]([O:15][CH2:60][C:61]([F:64])([F:63])[F:62])[CH2:41][CH2:40][CH:39]=[CH:38][C:37]2=[CH:42][C:33](=[CH:34][CH:35]=[CH:36]2)[C@@H:32]([CH3:43])[NH:31][C:30](=[O:44])[C@H:29]2[NH:45][N:25]([CH2:26][CH2:27][CH2:28]2)[C:24](=[O:46])[C@H:23]([CH3:47])[NH:22][C:21]1=[O:48])([CH3:51])[CH3:50]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](O)CCC=Cc2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Agent: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](O)CC/C=C/c2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Agent: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](OCC(F)(F)F)CC/C=C/c2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H]1NC(=O)[C@H](C)[C@H](OCC(F)(F)F)CCC=Cc2cccc(c2)[C@@H](C)NC(=O)[C@@H]2CCCN(N2)C(=O)[C@H](C)NC1=O
Temperature: 0 °C

Procedure:
A solution of hexamethyldisilazane (235 μL, 1.13 mmol) in anhydrous tetrahydrofuran (4 mL) was cooled to −10° C. before adding a 2.5 M solution of n-butyllithium (380 μL, 0.94 mmol). The stirred mixture was warmed to 0° C. for 10 min before cooling to −78° C. A solution of Compound 1 (102 mg, 0.188 mmol) in anhydrous dimethylformamide (1.5 mL) and anhydrous tetrahydrofuran (1.5 mL) was added dropwise over 2 min followed by the addition of 2,2,2-trifluoroethyl trifluoromethanesulfonate (135 μL, 0.94 mmol). The reaction mixture was stirred at −78° C. under a nitrogen atmosphere then allowed to gradually warm to RT. The reaction mixture was quenched with the addition of a saturated aqueous solution of ammonium chloride (15 mL). The mixture was extracted with ethyl acetate (2×15 mL). The extract was dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography using 1:9 acetone/ethyl acetate to give a colorless gum (65 mg). The gum was further purified by reverse phase chromatography, using a 10 g C18 cartridge eluted with 2:3 acetonitrile/water. The partially evaporated fractions were extracted with ethyl acetate (2×15 mL). The extract was dried over sodium sulfate, filtered and evaporated to yield the title product (17 mg, 30%) as a white solid. 1H NMR (300 MHz, CDCl3) 0.92 (d, J=6.7 Hz, 3H), 0.96 (d, J=6.9 Hz, 3H), 1.32 (d, J=7.1 Hz, 3H), 1.39 (d, J=7.1 Hz, 3H), 1.50 (d, J=6.7 Hz, 3H), 1.74-1.85 (m, 1H), 1.86-2.08 (m, 3H), 2.10-2.40 (m, 3H), 2.57-2.78 (m, 2H), 3.19-3.31 (m, 1H), 3.49 (app t, J=6.7 Hz, 1H), 3.58-3.79 (m, 4H), 3.81-4.18 (m, 2H), 4.49 (br d, J=12.3 Hz, 1H), 5.03-5.17 (m, 1H), 5.32-5.47 (m, 1H), 6.14-6.30 (m, 1H), 6.37-6.72 (m, 4H), 7.06-7.30 (m, 4H). LCMS (m/z) 624.3 [M+H], Tr=2.57 min.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([C:35](=[O:37])[CH3:36])=[CH:31][C:30]=1[O:38][CH3:39].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][CH2:27][O:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]([OH:37])[CH3:36])=[CH:31][C:30]=3[O:38][CH3:39])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)O)ccc1OCCCCN1CCC(c2noc3ccccc23)CC1
Temperature: 75 °C
Yield: 94.2 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.3 g, 0.018 mol), K2CO3 (5.5 g, 0.04 mol), and 1-[4-(4-bromobutoxy)-3-methoxyphenyl]ethanone (5.5 g, 0.018 mol), and dimethylformamide (60 ml) was stirred and heated at 75° C. for 16 hours. The reaction was poured into water and was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and the solvent concentrated to afford 7.2 g of a beige solid. Recrystallization (twice) from ethyl alcohol yielded 3.3 g (43%) of 1-[4-[4-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]butoxy]-3-methoxyphenyl]ethanone, m.p.=99°-101° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C@H:13]([OH:15])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22]>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][CH2:22][CH:21]=[CH2:20])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCO[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
To a stirred solution of (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanol (5.00 g) in tetrahydrofuran (20 ml) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 1.16 g). After 30 minutes, allyl bromide (3.35 ml) was added and the mixture refluxed for 16 hours. The reaction was quenched by careful addition of saturated NH4Cl solution at 0° C. and diluted with diethyl ether. The organics were dried (brine, MgSO4) and concentrated under reduced pressure to afford the title compound as a crude oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH2:1][NH:2][CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[N:31]=4)=[CH:26][CH:25]=3)=[O:37])[CH:18]=2)[NH:13][CH:12]=1)#[N:10]
Reactant: CNCCCC(=O)O
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(CNCCCC(=O)O)n4)cc3)cc12

Procedure:
Using 4-(methylamino)-butyric acid and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates. MS (ion spray) m/z 483 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>O>[C:14]([O:13][C:11]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[N:3]=2)[CH2:20][CH2:19]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1cc(Cl)c(Cl)nc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(Cl)c(Cl)cc2Cl)CC1
Yield: 100.6 %

Procedure:
To a mixture of 2,3,5,6-tetrachloropyridine (10 g), 1-Boc-piperazine (8.6 g) and potassium carbonate (13 g) was added 2-butanone (140 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g). To a mixture of 4-(3,5,6-trichloropyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (17 g), palladium (II) acetate (516 mg), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.9 g), potassium fluoride (24 g) and methylboronic acid (12 g) was added tetrahydrofuran (140 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g). 4-(3,5,6-Trimethylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (14 g) was dissolved in chloroform (28 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (100 mL) was added, and the mixture was filtered to give the title compound (11 g).