Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17]O)=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:30])CC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][F:30])=[C:10]([C:19]([F:22])([F:21])[F:20])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1ccc(CCCCO)c(C(F)(F)F)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccc(CCCCF)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 50.2 %

Procedure:
[4-(4-Hydroxybutyl)-3-trifluoromethylphenyl]carbamic acid tert-butyl ester (190 mg, 0.57 mmol) was dissolved in DCM (2 mL), and DAST (153 mg, 0.95 mmol) was added thereto. The resulting mixture was stirred at room temperature for 2 hours. The reaction solution was quenched with a saturated sodium bicarbonate solution. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (n-hexane:ethyl acetate=5:1) to give [4-(4-fluorobutyl)-3-trifluoromethylphenyl]carbamic acid tert-butyl ester (96 mg, 50%) as a light-yellow oil.
Reaction SMILES: [Mg].[CH2:2](Br)[C:3]#[CH:4].[CH3:6][Si:7]([C:10]#[C:11][C:12]([CH2:14][CH2:15][CH2:16][CH3:17])=[O:13])([CH3:9])[CH3:8]>CCOCC>[CH3:9][Si:7]([C:10]#[C:11][C:12]([OH:13])([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4][C:3]#[CH:2])([CH3:8])[CH3:6]
Reactant: C#CCBr
Reactant: CCCCC(=O)C#C[Si](C)(C)C
Agent: [Mg]
Solvent: CCOCC
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a stirred suspension of 1.29 g. of magnesium and 10 mg. of mercuric chloride in 12 ml. of ether is added 0.4 ml. of propargyl bromide. The reaction is initiated after stirring at room temperature for a few minutes. The stirred mixture is cooled in an ice-water bath and a solution of 9.64 g. of n-butyl trimethylsilylethynyl ketone and 3.51 ml. of propargyl bromide in 13 ml. of ether is added, dropwise so that the mixture is very gently boiling during 40 minutes. After addition, the cooling bath is removed and the mixture is stirred at room temperature for 1.5 hours. The mixture is recooled in an ice-bath and 10 ml. of saturated ammonium chloride solution is added. The resulting white mixture is filtered through diatomaceous earth. The clear mother liquor is washed with saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is evaporated to dryness giving 10.5 g. of a red liquid. This liquid is Kugelrohr-distilled at 60° C./0.25-0.3 mm. The pale yellow liquid distillage which is the desired product weighs 8.5 g.
Reaction SMILES: [C:1]([O:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[C:16]1([C:22]([O:24]O)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.ClCCl.C(OCC)C>[C:1]([O:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=1[C:9]([O:11][O:24][C:22](=[O:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:10])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1ccccc1
Reactant: CC(=O)OCOc1ccccc1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)OCOc1ccccc1C(=O)OOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
5 g (24 mmol) of 2-acetoxymethoxy-benzoic acid (prepared as described in example 1-2) and 3.3 g (24 mmol) of benzenecarboperoxoic acid are dissolved in 150 mL of diethyl ether/dichloromethane mixture, 6/4. The solution is cooled to 0° C., then 4.9 g (24 mmol) of N,N′-dicyclohexylcarbodiimide dissolved in 85 ml of diethyl ether is added dropwise. After stirring for 3 hours at 0° C., the reaction mixture is filtered and then concentrated. The residue is precipitated in diethyl ether and the filtrate is concentrated under reduced pressure. 5 g of (2-acetoxymethoxy-benzoyl)benzoyl peroxide is obtained in the form of white solid at a yield of 63%.
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=2[NH:19][C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=2[F:27])[CH2:4][O:3]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[OH:6][CH:5]([CH2:4][OH:3])[CH2:7][O:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[C:12]=1[NH:19][C:20]1[CH:25]=[CH:24][C:23]([I:26])=[CH:22][C:21]=1[F:27]
Reactant: CC1(C)OCC(CONC(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(NOCC(O)CO)c1ccc(F)c(F)c1Nc1ccc(I)cc1F

Procedure:
To a stirring solution of N-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide (3.03 g, 5.81 mmol) in methanol (30 mL) and water (3 mL) at ambient temperature was added p-toluene sulfonic acid (0.11 g, 0.581 mmol). After 18 hours another 0.11 g of added p-toluene sulfonic acid and 2 mL of water was added. After an additional 24 hours the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water. The organic layer was washed twice with saturated NaHCO3 solution and twice with saturated brine solution. The organic layers were collected, dried over Na2SO4, filtered and concentrated in vacuo affording a light brown solid, which was crystallized from ethyl acetate/hexanes to afford N-(2,3-dihydroxy-propoxy)-3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-benzamide as a white solid. m.p.=135.5-137.3° C.; 1NMR (400 MHz, DMSO-d6) δ 11.87 (s, 1H), 8.69 (s, 1H), 7.54 (dd, 1H, J=10.9, 1.5), 7.32-7.38 (m, 2H), 7.17 (dd, 1H, J=16.8, 9.0), 6.61-6.66 (cm, 1H), 4.82 (bs, 1H), 4.58 (bs, 1H), 3.84-3.85 (m, 1H), 3.71-3.64 (cm, 2H), 3.33 (2H, partially hidden by HDO); MS(APCI+)=483.0; Anal.calcd/found for C16H14F3IN2O4: C, 39.85/40.12; H, 2.93/2.84; N, 5.81/5.65; F, 11.82/11.47.
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[CH3:16][C:17]([CH3:19])=O>>[C:4]([C:3]1[CH2:16][CH2:17][CH2:19][O:7][C:2]=1[CH3:1])(=[O:6])[CH3:5]
Reactant: CC(C)=O
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Product: CC(=O)C1=C(C)OCCC1

Procedure:
A mixture of 130.4 g. (1.3 moles) of 2,4-pentanedione, 251.9 g. (1.6 moles) of 1,3-bromochloropropane, 168 g. (1.2 moles) of anhydrous potassium carbonate, 1 g. of anhydrous sodium iodide and 250 ml. of dry acetone is refluxed for 20 hours, under exclusion of humidity, with stirring. After cooling the mixture is filtered, washed with four 150-ml. portions of dry acetone, the combined acetone extract is evaporated, and the residue is subjected to fractionated distillation in vacuum, on a Vigreux column.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:41])([CH3:40])[C:14]([N:16]([C:18]2[C:19]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH3:39])=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][OH:31])[CH2:26][CH2:25]3)=[N:22][CH:23]=2)[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:44][S:45](Cl)(=[O:47])=[O:46].C(N(CC)CC)C>ClCCl.O>[F:43][C:2]([F:1])([F:42])[C:3]1[CH:4]=[C:5]([C:13]([CH3:40])([CH3:41])[C:14]([N:16]([CH3:17])[C:18]2[C:19]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][C:33]=3[CH3:39])=[CH:20][C:21]([N:24]3[CH2:25][CH2:26][CH:27]([CH2:30][O:31][S:45]([CH3:44])(=[O:47])=[O:46])[CH2:28][CH2:29]3)=[N:22][CH:23]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(CO)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1cc(N2CCC(COS(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 60.9 %

Procedure:
To a solution of 0.42 g (0.69 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4′-(4-fluoro-2-methyl-phenyl)-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-yl]-N-methyl-isobutyramide in 7 ml dichloromethane were added 83 mg (0.72 mmol) methanesulfonyl chloride and 73 mg (0.72 mmol) triethylamine at 0° C. After 30 min the reaction mixture was diluted with water and extracted with three portions of dichloromethane. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.29 g (63%) of the title compound as a white solid.
Reaction SMILES: C([Mg]Cl)(C)C.[Cl:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][C:13](I)=[CH:12]2.[Cu]C#N.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26]>O1CCCC1>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([C:13]2[CH:14]=[N:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:6])=[O:26])[CH:28]=[CH:29][CH:30]=1
Reactant: Clc1cccc2cc(I)cnc12
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: N#C[Cu]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: O=C(c1cccc(Cl)c1)c1cnc2c(Cl)cccc2c1
Temperature: -40 °C
Reaction time: 0.3 h
Yield: 59.6 %

Procedure:
iso-Propyl magnesium chloride (2M solution in tetrahydrofuran) (2.85 ml, 5.7 mmol) was added dropwise over 5 mins to a stirred solution of 8-chloro-3-iodoquinoline (D1)(1.5 g, 5.2 mmol) in tetrahydrofuran (15 ml) at −40° C. under argon. After stirring the solution at this temperature for 0.3 h, copper (I) cyanide (0.47 g, 5.2 mmol) was added in portions over 5 mins. The whole mixture was left to stir at −40° C. for a further 10 mins and then 3-chlorobenzoyl chloride (1.0 g, 5.7 mmol) was added dropwise over 10 mins. The temperature was maintained at −40° C. for 0.5 h and then the reaction was warmed to 0° C. at which temperature it was quenched by the addition of a saturated solution of sodium chloride (100 ml). The mixture was extracted with ethyl acetate (2×50 ml). The combined extracts were dried (MgSO4) and concentrated in vacuo to a solid. The solid was purified by chromatography over silica gel eluting with a gradient of acetone/toluene to give the title compound (D5) as a white solid (0.95 g, 3.1 mmol, 60%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14](O)=[O:15])[C:9]2=[O:17])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1.CN1CCOCC1>ClCCl.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH2:12][CH2:11][N:10]([CH2:13][C:14]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([C:32]([F:31])([F:40])[F:41])=[CH:34][CH:35]=3)=[O:15])[C:9]2=[O:17])=[CH:6][CH:7]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.200 g, 0.604 mmol; Example 58D) in dichloromethane (2 mL) was added a catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane) (0.453 mL, 0.905 mmol). After stirring for 30 minutes, the reaction was concentrated. The residue was dissolved in dichloromethane (2 mL) and 4-(trifluoromethyl)aniline (0.056 mL, 0.453 mmol) followed by 4-methylmorpholine (0.100 mL, 0.905 mmol) were added. After stirring for 1 hour, the reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 65% ethyl acetate/hexanes (Flow=30 mL/minute) over 30 minutes to give the title compound. 1H NMR (300 MHz, CDCl3) δ 8.37 (s, 1H), 7.51 (d, J=8.6, 2H), 7.40 (d, J=8.5, 2H), 7.34-7.27 (m, 4H), 7.06-6.96 (m, 4H), 4.16 (s, 2H), 3.60 (t, J=6.5, 2H), 2.82 (t, J=6.5, 2H); MS (ESI+) m/z 474.8 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][S:12]([C:15]2[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=2)[C:18]([O:20]CC[Si](C)(C)C)=[O:19])(=[O:14])=[O:13])[CH2:7][CH2:6]1)=[O:4].[CH2:30](I)[CH3:31].C(=O)([O-])[O-].[K+].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1.O.CN(C=O)C>[CH2:30]([N:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6][CH2:7]1)[S:12]([C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[C:18]([OH:20])=[O:19])(=[O:13])=[O:14])[CH3:31]
Reactant: CCI
Reactant: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)c2cccc(C(=O)OCC[Si](C)(C)C)c2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CCN([C@H]1CC[C@H](C(=O)OC)CC1)S(=O)(=O)c1cccc(C(=O)O)c1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A mixture of 450 mg of 2-(trimethylsilyl)ethyl 3-{[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoate, 0.15 mL of ethyl iodide, 422 mg of potassium carbonate, and 4.5 mL of DMF was stirred at 65° C. overnight. To the reaction mixture was added water, followed by extraction with ethyl acetate. Then, the organic layer was washed with water and saturated brine in this order, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain a colorless oily substance. To the obtained oily substance were added a solution of tetrabutyl ammonium fluoride (TBAF) in THF (1.0 M, 2.0 mL) and 4.5 mL of THF, followed by stirring at room temperature for 2 hours. To the reaction mixture was added 0.2 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with 0.2 M hydrochloric acid, water, and saturated brine in this order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 355 mg of 3-{ethyl[trans-4-(methoxycarbonyl)cyclohexyl]sulfamoyl}benzoic acid as a colorless solid.
Reaction SMILES: [CH:1]([S:4]([C:7](=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)SC)[C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2].[NH2:22][CH:23]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH3:24]>>[CH:1]([S:4]([C:7](=[C:10]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1)[NH:22][CH:23]([CH3:24])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:8]#[N:9])(=[O:6])=[O:5])([CH3:3])[CH3:2]
Reactant: COc1cccc(NC(SC)=C(C#N)S(=O)(=O)C(C)C)c1
Reactant: CC(N)C(C)(C)C
Product: COc1cccc(NC(NC(C)C(C)(C)C)=C(C#N)S(=O)(=O)C(C)C)c1
Yield: 80 %

Procedure:
2-Isopropylsulfonyl-3-(3-methoxyphenylamino)-3-methylsulfanyl-2-propenenitrile(0.500 g, 1.53 mmol) was stirred in 2-amino-3,3-dimethylbutane (2 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane,washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and evaporated to afford 450 mg (80%) of the title compound as white crystals. Mp 59-62 ° C.1H NMR (200 MHz, CDCl3): δ=0.84 (s, 9H), 0.96 (d, 3H), 1.40 (d, 6H), 3.00-3.33 (m, 2H), 3.82 (s, 3H), 6.70 (dd, 1H), 6.81 (dd, 1H), 7.31 (dd, 1H), 7.73-7.94 (m, 1H) 8.95 (br s, 1H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:71]1[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]1>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32]([N:71]5[CH2:76][CH2:75][NH:74][CH2:73][CH2:72]5)=[O:33])=[CH:30][CH:29]=4)=[O:37])=[CH:23][CH:24]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: C1CNCCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: O=C(Nc1ccc(C(=O)N2CCNCC2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 30.3 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with piperazine (34 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (17.2 mg, 30% yield); MS (ESI) m/z=573.6
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Cl[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C([O-])([O-])=O.[K+].[K+].O>CN1C(=O)CCC1>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCCCCCCl
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=Cc1ccc(OCCCCCCO)cc1
Reaction time: 24 h
Yield: 51.6 %

Procedure:
4-Hydroxybenzaldehyde (15 g, 122 mmol) was dissolved in 150 ml of NMP. 6-Chlorohexanol (20.16 g 146 mmol), anhydrous K2CO3 (20.36 g, 146 mmol) and a catalytic amount of KI were added. The batch was stirred at 90 C for 24 hours. Water was added to the cooled solution, which was subsequently extracted with EtOAc (3×100 mL). The combined extracts were washed with 5% KOH (2×100 mL), brine solution and then dried over MgSO4. The concentrated product was then recrystallized from a 1:1 mixture of EtOAc/hexane to give 14 g of an off-white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([NH:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[CH3:37].P(Cl)(Cl)Cl>ClC(Cl)C>[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([N:45]([CH:46]([CH3:47])[CH3:48])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:41][CH:40]=1)[CH3:37]
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Reactant: CCOc1ccc(NC(C)C)cn1
Solvent: CC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CCOc1ccc(N(C(=O)CN2C(=O)C(Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 20.9 %

Procedure:
Following the procedure described for Example 2(A), [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (300 mg, 0.65 mmol) was reacted with (6-ethoxy-pyridin-3-yl)-isopropyl-amine (Preparation 2(B)) (117 mg, 0.65 mmol) and PCl3 in dichloroethane at 100° C. Purification by medium pressure chromatography eluting with a solvent gradient (5% of 0.5% NH4OH/MeOH in CH2Cl2 to 10% of 0.5% NH4OH/MeOH in CH2Cl2) provided 85.1 mg of N-(6-ethoxy-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CD3OD) δ 8.05 (d, 1H), 7.62 (m, 3H), 7.38-7.52 (m, 6H), 7.24 (d, 1H), 7.11 (m, 2H), 6.99 (t, 1H), 6.89 (m, 3H), 4.78 (m, 1H), 4.53 (m, 1H), 4.35 (q, 2H), 4.12 (m, 1H), 3.88 (t, 1H), 3.78 (dd, 1H), 3.69 (dd, 1H), 1.38 (t, 3H), 0.99 (m, 6H); MS 626.7 (M+1), 624.6 (M−1).
Reaction SMILES: O[C:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:2]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[C:8]([N:13]2[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]2)=[CH:7][C:6]=1[OH:19])([CH3:4])[CH3:3]
Reactant: COc1cc(C(C)(C)O)c(O)cc1N1CCNCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(C)C)c(O)cc1N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.8 %

Procedure:
To a stirred suspension of 2-(1-Hydroxy-1-methyl-ethyl)-4-methoxy-5-piperazin-1-yl-phenol (0.5 g, 1.9 mmol) in dichloromethane under nitrogen at room temperature was added trifluoroacetic acid (7.2 mL, 93.86 mmol) followed by triethyl silane (3.0 mL, 18.8 mmol). The reaction mixture was stirred for 18 hours at room temperature, and then was evaporated under reduced pressure. The residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The organic layer was separated, washed with water, dried (MgSO4), filtered, and evaporated under reduced pressure to afford 0.47 g (99%) of 2-Isopropyl-4-methoxy-5-piperazin-1-yl-phenol as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[C:17]([F:25])[CH:16]=1.[Cl-].C(C1C=CC=C(CCC)C=1[N+]1C=CN(C2C(CCC)=CC=CC=2CCC)C=1)CC.CCCC[O-].[Na+]>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[C:17]([F:25])[CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Agent: CCCC[O-]
Agent: CCCc1cccc(CCC)c1-n1cc[n+](-c2c(CCC)cccc2CCC)c1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(F)(F)F)c(F)c2)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
Tert-butyl-1-piperazine-carboxylate (740 mg, 3.05 mmol) and 4-bromo-2-fluoro-1-trifluoromethyl-benzene (530 mg. 2.85 mmol) were dissolved in anhydrous toluene (6 mL, degassed). In a separate, septum-equipped vial were placed tri(dibenzylideneacetone)dipalladium (0) (152 mg, 0.17 mmol), 1,3-bis(2,6-di-1-propylphenyl)imidazolium chloride (283 mg, 0.67 mmol) and sodium 1-butoxide (400 mg, 4.2 mmol). This “catalytic” vial was equipped with a magnetic stirbar and flushed with dry nitrogen. The reactant solution was next transferred to the “catalytic” vial and the mixture was stirred at 100° C. for 5 hours. After this period the mixture was combined with 20 mL of hexane/EtOAc (2:1) and was passed through a pad of Celite. The resulting filtrate was concentrated and purified using silica gel chromatography (0-20% EtOAc/Hexane) to yield 853 mg (86%) of 4-(3-Fluoro-4-trifluoromethyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as a yellow residue. 1H NMR (400 MHz, CDCl3) δ 7.44-7.40 (m, 1H), 6.65-6.58 (m, 2H), 3.59-3.56 (m, 4H), 3.27-3.25 (m, 4H), 1.49 (s, 9H).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[N:3]=[C:4]([CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH3:7])[CH3:5].C([N-]C(C)C)(C)C.[Li+].[CH:35](=[O:37])[CH3:36].O.C(Cl)Cl>C1COCC1>[CH3:26][N:2]([CH3:1])[N:3]=[C:4]([CH2:5][CH:35]([OH:37])[CH3:36])[CH:6]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:24])([F:23])[F:25])=[CH:18][CH:17]=2)=[CH:11][CH:10]=1)[CH3:7]
Reactant: CC(=NN(C)C)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(O)CC(=NN(C)C)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 1 h

Procedure:
To a solution of 3-[4-(4-trifluoromethylphenoxy)phenoxy]-2-butanone N,N-dimethylhydrazone (5.4 mmol) in THF (15 ml) under nitrogen is added lithium diisopropylamide (6.6 mmol) in THF (15 ml) at 0° for 4 hours. The resulting solution is cooled to -78°, and to it is added ethanal (6.6 mmol). After 1 hour at -78°, the reaction mixture is allowed to warm to 0° and is poured into water/methylene chloride (3:1). The organic phase is separated (3X), and the combined organic extracts are dried over sodium sulfate and concentrated to give 5-hydroxy-2-[4-(4-trifluoromethylphenoxy)phenoxy]-3-hexanone N,N-dimethylhydrazone (cpd. 25, Table C).