Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)=[CH:9][CH:8]=1.C([O-])(=O)C([O-])=O.CN(C)CCN(C)C.[Cl:33][C:34]1[CH:48]=[CH:47][C:37]([C:38]([C:40]2[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][CH:41]=2)=[O:39])=[CH:36][CH:35]=1>CCCCCC.O1CCCC1>[Cl:6][C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH:16]=[CH:15][N:14]=[C:13]2[C:38]([C:37]2[CH:47]=[CH:48][C:34]([Cl:33])=[CH:35][CH:36]=2)([C:40]2[CH:41]=[CH:42][C:43]([Cl:46])=[CH:44][CH:45]=2)[OH:39])=[CH:9][CH:8]=1
Reactant: Clc1ccc(Cn2ccnc2)cc1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: CN(C)CCN(C)C
Agent: O=C([O-])C(=O)[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)(c1ccc(Cl)cc1)c1nccn1Cc1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
In the course of one hour, 64 ml. (0.105 mol) of 15% butyl lithium in n-hexane were added dropwise at -65° to -70° C. and under a nitrogen atmosphere, to a solution of 19.3 g (0.1 mol) of 1-(p-chlorobenzyl)imidazole (prepared from the oxalate described under (A) and 12.2 g (0.105 mol) of N,N,N',N'-tetramethylethylenediamine in 150 ml. of anhydrous tetrahydrofuran. The reaction mixture was stirred for one hour and then a suspension of 25.1 g (0.1 mol) of 4,4'-dichlorobenzophenone in 150 ml. of anhydrous tetrahydrofuran was added quickly under the same reaction conditions. Stirring was continued for one hour and then the cooling means was removed and the reaction mixture was kept standing overnight at room temperature. 20 ml. of water were added and the organic phase was separated off and concentrated. The residue was suspended in a mixture of water and diethyl ether. The solid matter formed was filtered off and the ethereal layer was separated off, dried over sodium sulphate and concentrated. The residue was twice crystallised from methanol. 1-(p-Chlorobenzyl)-α,α-bis-(p-chlorophenyl)imidazole-2-methanol was obtained. Melting point 171°-173° C.
Reaction SMILES: N#N.[Cl:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][NH:11][C:12](=O)[C:6]=2[CH:5]=1.O=P(Cl)(Cl)[Cl:20]>C1(C)C=CC=CC=1>[Cl:20][C:12]1[C:6]2[CH:5]=[C:4]([Cl:3])[CH:17]=[CH:16][C:7]=2[N:8]([CH3:15])[C:9](=[O:14])[CH2:10][N:11]=1
Reactant: CN1C(=O)CNC(=O)c2cc(Cl)ccc21
Reactant: O=P(Cl)(Cl)Cl
Agent: N#N
Solvent: Cc1ccccc1
Product: CN1C(=O)CN=C(Cl)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 87.1 %

Procedure:
In a 1 L 2-neck RBF equipped with mechanical stir, condenser and N2 inlet, C1 (42.5 g, 0.189 mol) was suspended into 400 mL of toluene. To this was added N,N-dimethylanaline (45.5 g. 0.375 mol) followed by the addition of POCl3 (29 g, 0.189 mol) and the reaction mixture stirred for 3 minutes at room temperature (RT). Reaction flask was placed in a 90° C. oil bath and the reaction mixture stirred/heated for 7 h and then at RT for 9 h. The reaction was quenched by adding 500 mL of ice water and stirred for 15 min. Organic layer was separated and quickly washed with cold 0.5 M HCl (300 mL), cold water (300 mL), and then cold saturated NaHCO3 (300 mL). Organic layer was dried (MgSO4), filtered and concentrated on a rotary evaporator to give 40 g of yellow solid. Yield 87.5%. 1H NMR (300 MHz, DMSO-d6) δ 3.25 (s, 3H), 3.8-3.9 (s, 1H, br), 4.3-4.4 (s, 1H, br), 7.4 (d, 1H), 7.7-7.8 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[N:8]1([C:13]([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1>O1CCOCC1>[O:5]=[C:4]([N:19]1[CH2:18][CH2:17][N:16]([CH2:15][C:13](=[O:14])[N:8]2[CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:21][CH2:20]1)[CH2:3][CH2:2][C:1]([OH:6])=[O:7]
Reactant: O=C1CCC(=O)O1
Reactant: O=C(CN1CCNCC1)N1CCCC1
Solvent: C1COCCO1
Product: O=C(O)CCC(=O)N1CCN(CC(=O)N2CCCC2)CC1
Temperature: 25 °C
Reaction time: 4.75 h

Procedure:
0.72 g of succinic anhydride and then 1.5 cm3 of 95% 1-(pyrrolidinocarbonylmethyl)-piperazine are added to 20 cm3 of dioxane in a round-bottomed flask kept under a nitrogen atmosphere. After stirring for 4.75 hours at room temperature, the solvent is evaporated under reduced pressure (2.7 kPa) at 20° C., to give 2.4 g of 4-oxo-4-[4-(2-oxo-2-pyrrolidin-1-ylethyl)piperazin-1-yl]butyric acid in the form of a pale yellow paste which is used as it is.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH:18]1[C:19]2[N:6]([CH2:5][CH2:4][OH:3])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CN1c2ccccc2Oc2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCN1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of ethyl-2-(10H-phenoxazin-10-yl)acetate (5.5 g, 20.44 mmol) in dry tetrahydrofuran (20 ml) was added dropwise to a suspension of lithium aluminum hydride (1.16 g, 30.52 mmol) in dry tetrahydrofurane (20 ml) at 0° C. The reaction mixture was warmed to room temperature and stirred for additional 1 h. The excess lithium aluminum hydride was quenched with a solution of saturated sodium sulfate at 0° C. The reaction mixture was filtered and the residue was washed with hot ethyl acetate (2×75 ml). The combined organic layers were dried (Na2SO4), filtered and the solvent was evaporated under reduced pressure to afford the title compound (4.6 g, 99%) as a colourless solid. The compound is used in the next step without further purification. mp: 113-115° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:19][C:20]1[CH:27]=[C:25]([I:26])[C:24]([O:28][C:29]2[CH:36]=[C:34]([I:35])[C:33]([OH:37])=[C:31]([I:32])[CH:30]=2)=[C:22]([I:23])[CH:21]=1)[NH:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[O:11].[C:39]1(=[O:46])[O:45][C:43](=[O:44])[CH2:42][O:41][CH2:40]1.O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:38])[C@H:4]([CH2:19][C:20]1[CH:21]=[C:22]([I:23])[C:24]([O:28][C:29]2[CH:30]=[C:31]([I:32])[C:33]([OH:37])=[C:34]([I:35])[CH:36]=2)=[C:25]([I:26])[CH:27]=1)[NH:5][C:6](=[O:18])[CH2:7][O:8][CH2:9][C:10]([N:12]1[CH2:13][CH2:14][N:15]([C:43](=[O:44])[CH2:42][O:41][CH2:40][C:39]([OH:46])=[O:45])[CH2:16][CH2:17]1)=[O:11]
Reactant: O=C1COCC(=O)O1
Reactant: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCNCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1cc(I)c(Oc2cc(I)c(O)c(I)c2)c(I)c1)NC(=O)COCC(=O)N1CCN(C(=O)COCC(=O)O)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-(Piperazinocarbonylmethoxyacetyl)thyroxine methyl ester from step 1 (3.1 g, 0.0034 mole) and diglycolic anhydride (0.6 g, 0.0046 mole) in chloroform (200 mL) were heated to 50°-60° C. (hot water) and allowed to stir at ambient temperature for 16 hours. Chloroform (200 mL) was added. The mixture was washed with 5% HCl solution (2×100 mL), water (100 mL), saturated NaCl solution (100 mL), dried over anhydrous magnesium sulfate, filtered, and the solvent removed on a rotary evaporator in vacuo. This material was used directly in the next step.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([NH:5][CH2:6][C:7]#[C:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=2)[N:11]([CH:21]2[CH2:25][CH:24]([OH:26])[CH:23]([CH2:27][OH:28])[O:22]2)[CH:10]=1)=[O:4].[H][H].C1(C)C=CC=CC=1.C(OC(=O)C)C.CO>[Pd].C(O)C>[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:21]1[CH2:25][CH:24]([OH:26])[CH:23]([CH2:27][OH:28])[O:22]1)[CH:10]=[C:9]2[CH2:8][CH2:7][CH2:6][NH:5][C:3](=[O:4])[C:2]([F:30])([F:29])[F:1]
Reactant: [H][H]
Reactant: O=C(NCC#Cc1cn(C2CC(O)C(CO)O2)c2ccc([N+](=O)[O-])cc12)C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Nc1ccc2c(c1)c(CCCNC(=O)C(F)(F)F)cn2C1CC(O)C(CO)O1

Procedure:
4.0 g (9.3 mmol) 2,2,2-Trifluoro-N-{3-[1-(4-hydroxy-5-hydroxymethyl-tetrahydro-furan-2-yl)-5-nitro-1H-indol-3-yl]-prop-2-ynyl}-acetamide and 650 mg 5% (w/w) palladium on charcoal (Fluka No: 75992) were suspended in 100 ml anhydrous ethanol and placed under argon atmosphere in a flask. The argon was substituted by hydrogen (Whatman hydrogen generator). The hydrogenation was monitored by TLC (Silica Gel Merck F60, developing solvent: toluene/acetic acid ethyl ester/methanol 4:1:1 (v/v/v)) and stopped when the starting material was no longer detectable. The catalyst was removed by filtration and the solvent evaporated to dryness in a vacuum on a rotary evaporator. The product was used without further purification (yield: 3.7 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH:17]=1)[C:12]([OH:14])=O.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:47][NH:48][CH:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:49]1([N:48]([CH3:47])[C:12](=[O:14])[C:11]2[CH:15]=[C:16]([O:18][CH2:19][CH2:20][NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[CH:17]=[C:9]([CH3:8])[CH:10]=2)[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: CNC1CCCCC1
Reactant: Cc1cc(OCCNc2ccncc2)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(OCCNc2ccncc2)cc(C(=O)N(C)C2CCCCC2)c1
Reaction time: 64 h

Procedure:
A stirred solution of 3-methyl-5-[2-(pyridin-4-ylamino)-ethoxy]-benzoic acid trifluoroacetate salt (0.031 g) in DMF (1 ml) was treated with HOBt (0.011 g), DIPEA (0.028 ml), N-methylcyclohexylamine (0.010 ml), and TBTU (0.026 g). The resulting solution was retained in a sealed flask for 64 h. The reaction mixture was concentrated under reduced pressure and the resulting gum subjected to preparative hplc. The required fraction was concentrated and then dried by addition of methanol and concentration under reduced pressure, addition of toluene and again concentration under reduced pressure giving the title compound as a colourless gum (0.034 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.CC1(C)C(C)(C)OB([C:17]2[CH:26]=[CH:25][C:24]3[C:23]([CH3:28])([CH3:27])[CH2:22][CH2:21][C:20]([CH3:30])([CH3:29])[C:19]=3[CH:18]=2)O1>C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.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>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:26]2[CH:17]=[CH:18][C:19]3[C:20]([CH3:30])([CH3:29])[CH2:21][CH2:22][C:23]([CH3:28])([CH3:27])[C:24]=3[CH:25]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: CC1(C)CCC(C)(C)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
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: [Na+]
Solvent: COCCOC
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(Br)n3)ccc21
Temperature: 80 °C
Reaction time: 16 h

Procedure:
200 mg (0.84 mmol) of 2,6-dibromopyridine and 265 mg (0.84 mmol) of 4,4,5,5-tetramethyl-2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3,2-dioxaborolane are dissolved in 6 ml of 2M sodium carbonate solution and in 2.5 ml of dimethoxyethane. The reaction mixture is degassed a number of times, and 49 mg (0.04 mmol) of tetrakis(triphenylphosphine)palladium are added under nitrogen atmosphere, the mixture is stirred at 80° C. for 16 h and subsequently irradiated in the microwave for 30 min. The reaction mixture is evaporated, and saturated sodium hydrogencarbonate solution is added. This mixture is extracted three times with ethyl acetate and three times with dichloromethane, the combined organic phases are dried over Na2SO4 and evaporated. The crude product is reacted further without further purification.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=2)[C:3]=1[CH3:21].C(O)C.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[C:4]([C:11]3[CH:16]=[CH:15][C:14]([S:17](=[O:20])(=[O:19])[NH2:18])=[CH:13][CH:12]=3)[C:3]=2[CH3:21])=[CH:29][CH:28]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(OC)cc2)c(C)c1-c1ccc(S(N)(=O)=O)cc1
Temperature: 97.5 °C
Yield: 83.8 %

Procedure:
To the solution of methyl 5-bromo-4-methyl-3-(4-sulfamoylphenyl)thiophene-2-carboxylate (compound 7c, 3.0 g, 7.69 mmol) in a mixture of toluene:ethanol (25:75 ml) was added (4-methoxyphenyl)boronic acid (1.28 g, 8.46 mmol) and potassium carbonate (3.18 g, 23.07 mmol) at 25° C. Nitrogen gas was bubbled through reaction mixture for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.487 g, 0.422 mmol) under nitrogen and reaction mixture was heated at 95-100° C. for 1 hr under stirring. The progress of reaction was monitored by TLC. The reaction mixture was cooled to 25° C. and filtered through celite, and then washed with ethyl acetate (50 ml). The filtrate was concentrated under reduced pressure to obtain a crude product, that was then purified by column chromatography over silica gel (100-200 mesh) using 50% ethyl acetate in hexanes as an eluent to obtain the title compound (20% ethyl ester as trans esterified product was observed) (2.69 g, 84%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]([CH3:29])[CH3:28])[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH:15]=[CH:14]4)[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:27]([CH3:29])[CH3:28])[N:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)n1nc(-c2ccc3c(ccn3C(=O)OC(C)(C)C)c2)c2c(N)ncnc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1nc(-c2ccc3[nH]ccc3c2)c2c(N)ncnc21
Yield: 74.6 %

Procedure:
Tert-butyl 5-(4-amino-1-isopropyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-1-carboxylate (BA86, 9 mg, 0.022 mmol) was dissolved in 50:50 CH2Cl2:TFA and stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA89 (4.8 mg, 75% yield). ESI-MS (M+H)+ m/z calcd 293.1, found 293.0.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[C:9]([O:21][CH3:22])[CH:8]=1)=[O:5].[NH2:33]C1C=C(OC2C=CC=CC=2)C=CC=1C(NC1C=CC(OCCN2CCCC2)=C(OC)C=1)=O>>[CH3:22][O:21][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[CH:23]=[CH:24][C:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:26][C:2]=3[N:1]=[N:33]2)[CH:12]=[CH:11][C:10]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: COc1cc(NC(=O)c2ccc(Oc3ccccc3)cc2N)ccc1OCCN1CCCC1
Reactant: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2N)ccc1OCCN1CCCC1
Product: COc1cc(-n2nnc3cc(-c4ccccc4)ccc3c2=O)ccc1OCCN1CCCC1

Procedure:
This amine was treated in the manner of 2-amino-N-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-4-phenoxy-benzamide in Example C1 to give the title compound;
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([O:21][C:22]4[CH:27]=[CH:26][C:25]([N+:28]([O-])=O)=[CH:24][C:23]=4[N+:31]([O-])=O)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[H][H]>C(O)C.[C].[Pd]>[NH2:31][C:23]1[CH:24]=[C:25]([NH2:28])[CH:26]=[CH:27][C:22]=1[O:21][C:16]1[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]2[O:12][C:11]([CH3:35])([CH3:36])[CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]=1[CH3:34]
Reactant: Cc1c(C)c2c(c(C)c1Oc1ccc([N+](=O)[O-])cc1[N+](=O)[O-])C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1Oc1ccc(N)cc1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Yield: 101.2 %

Procedure:
3-(4-Isopropylphenyl)-5-(2,4-dinitrophenyloxy)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (800 mg, 1.63 mmol) and 10% palladium-carbon (hydrate) (80 mg) were dispersed in ethanol (40 mL), and the mixture was stirred in a hydrogen atmosphere at 60° C. for 4 hours. The reaction mixture, from which was removed the catalyst through filtration, was concentrated under reduced pressure to obtain 5-(2,4-diaminophenoxy)-3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (710 mg). Acetyl chloride (0.26 mL, 3.63 mmol) was added to a solution of the thus-obtained compound (710 mg, 1.65 mmol) and triethylamine (290 mg, 1.70 mmol) in chloroform (30 mL) at 0° C., and the mixture was stirred for 1 hour at the same temperature. The reaction mixture was poured into water (30 mL), and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=1/5) to obtain the title compound (640 mg, yield 76%). This was amorphous.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[NH:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:16][C:6]1[C:7]2[NH:11][C:10]([C:12]([F:15])([F:13])[F:14])=[N:9][C:8]=2[C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2[nH]c(C(F)(F)F)nc12
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c2[nH]c(C(F)(F)F)nc12
Reaction time: 2 h
Yield: 13.4 %

Procedure:
A solution of 7-methoxy-2-trifluoromethylbenzimidazole (50 g) in chloroform (100 ml) was cooled to 0° C., and N-bromosuccinimide (4.5 g) added. The mixture was stirred for 2 h. It was then washed with 5% aqueous sodium metabisulphite (50 ml), dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 25% ethyl acetate in hexane to yield the title compound as a white solid (1.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:18][CH2:17]3)=[CH:12][N:11]=[C:10]([C:19]([OH:21])=O)[N:9]=2)=[CH:4][CH:3]=1.Cl.[F:23][C:24]([F:33])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH2:31])[O:27][N:26]=1>>[F:33][C:24]([F:23])([F:32])[C:25]1[N:29]=[C:28]([CH2:30][NH:31][C:19]([C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[CH:12][N:11]=2)=[O:21])[O:27][N:26]=1
Reactant: NCc1nc(C(F)(F)F)no1
Reactant: O=C(O)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1
Agent: Cl
Product: O=C(NCc1nc(C(F)(F)F)no1)c1ncc(OCC2CC2)c(-c2ccc(Cl)cc2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 4-(4-chloro-phenyl)-5-cyclopropylmethoxy-pyrimidine-2-carboxylic acid (example T) and C-(3-trifluoromethyl-[1,2,4]oxadiazol-5-yl)-methylamine hydrochloride (CAS registry No. 944905-93-5; example AK) as starting materials; LC-MS (UV peak area/ESI) 100%, 454.0901 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].[CH:10](Cl)(Cl)Cl.[Cl-].C[N+](C(=O)CCCCCCC)(C(=O)CCCCCCC)C(=O)CCCCCCC.[OH-].[Na+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[N+:4]#[C-:10]
Reactant: ClC(Cl)Cl
Reactant: Cc1cccc(C)c1N
Agent: CCCCCCCC(=O)[N+](C)(C(=O)CCCCCCC)C(=O)CCCCCCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: ClCCl
Product: [C-]#[N+]c1c(C)cccc1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A reaction flask was charged with 48.4 g (0.4 mole) of 2,6-dimethylaniline, 50 ml of chloroform, 50 ml of methylene chloride, and 1.0 g of methyl tricaprylylammonium chloride (designated by the trade name "Aliquat 336®" and obtained from General Mills Co., Chemical Division, Kankakee, Ill.). The flask was placed in a water bath at room temperature. As the flask contents were vigorously stirred, 150 ml of 50% aqueous sodium hydroxide was added. Stirring was continued overnight. The reaction mixture was then poured into 400 ml of ice water and extracted with 200 ml of diethyl ether. The ether phase was separated and washed with water, dried, and stripped. The residue was then extracted with 200 ml of hot hexane which was subsequently stirred with 20 g of Florisil® silica absorbent material and filtered. The filtrate was chilled in a dry ice/acetone bath and filtered to yield 35.2 g of a tan-colored solid. The structure indicated by the above title was confirmed by infrared spectra, nuclear magnetic resonance, and mass spectroscopy.
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:16][CH2:15][C@@H:14]([CH3:17])[CH2:13][C:5]21[CH:7]([C:8]([O:10]CC)=[O:9])[CH2:6]2)([CH3:3])[CH3:2].C1(C(OCC)=O)C2(CCCCC2)C1>>[CH:1]([C@@H:4]1[CH2:16][CH2:15][C@@H:14]([CH3:17])[CH2:13][C:5]21[CH:7]([C:8]([OH:10])=[O:9])[CH2:6]2)([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1CC12C[C@H](C)CC[C@H]2C(C)C
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC(C)[C@@H]1CC[C@@H](C)CC12CC2C(=O)O

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 42B for the product from Example 1A. MS m/z 210 (M)+.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35](Cl)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1>C1(C)C=CC=CC=1>[Cl:20][C:21]1[C:22]([O:28][C:29]2[CH:40]=[CH:39][C:32]([O:33][CH:34]([CH3:38])[C:35]([O:12][CH:10]([CH3:11])[CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:36])=[CH:31][CH:30]=2)=[N:23][CH:24]=[C:25]([Cl:27])[CH:26]=1
Reactant: CC(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)Cl
Reactant: CC(O)COCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(COCc1ccccc1)OC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Temperature: 0 °C

Procedure:
16.6 g of 1-benzyloxy-2-propanol and 10.6 g of triethylamine were dissolved in 200 ml of toluene, then cooled to 0° C. To this solution was dropwise added a solution of 34.7 g of 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]-propionyl chloride in 80 ml of toluene at 0° to 5° C. with stirring. After the dropwise addition, the mixture was gradually heated and, at 40° to 50° C., it was stirred for one hour to complete the reaction. After cooling to room temperature, it was washed successively with 1% strength by weight sodium hydroxide aqueous solution and water, followed by drying. Upon distilling off toluene under reduced pressure, there were obtained 43.3 g of pale yellow, viscous, oily 1-methyl-2-benzyloxyethyl 2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionate. nD20 1.5710
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21]([OH:23])=O)=[CH:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)[C:25]([Cl:27])=O.[N+](=C)=[N-].Cl>>[CH2:1]([O:8][C:9]([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][C:21](=[O:23])[CH2:25][Cl:27])=[CH:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: C=[N+]=[N-]
Agent: Cl
Product: O=C(CCl)Cc1cn(C(=O)OCc2ccccc2)c2ccccc12
Yield: 87 %

Procedure:
The procedure described above for the synthesis of 1-chloro-3-[2-(3-methylbenzo[b]thiophen-2-yl)propan-2-one was followed, reacting 1-(benzyloxycarbonyl)indol-3-yl acetic acid (22.49 g, 72.7 mmol) with oxalyl chloride (7.0 mL, 10 g, 80 mmol, then ethereal diazomethane, then dry HCl gas. Flash chromatography over silica gel (15-20% ethyl acetate in hexanes) gave pure product (21.64 g, 87% yield): 1H NMR (400 MHz, CDCl3) δ 3.97 (d, J=1.0 Hz, 2H) 4.15 (s, 2H) 5.45 (s, 2H) 7.27-7.30 (m, 1H) 7.33-7.51 (m, 7H) 7.63 (s, 1H) 8.19 (br. s, 1H); HRMS (ESI+) calcd for C19H17ClNO3 (MH+) 342.0892, found 342.0900.