Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]2[CH2:9][CH:10]([C:11]([O:13]CC)=[O:12])[CH:5]([N:6]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:4]=1)[CH3:2].C(O)(=O)C.[BrH:34]>>[BrH:34].[C:24]1([CH2:23][N:6]2[CH:7]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:8]3[C:3](=[CH:1][CH3:2])[CH2:4][CH:5]2[CH:10]([C:11]([OH:13])=[O:12])[CH2:9]3)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)C1CC2C(CC)=CC1N(Cc1ccccc1)C2Cc1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: CC=C1CC2C(C(=O)O)CC1C(Cc1ccccc1)N2Cc1ccccc1

Procedure:
A mixture of ethyl 8-ethyl-2,3-di(phenylmethyl)-2-azabicyclo[2.2.2]oct-7-ene-6-carboxylate (132 g, 0.31 mol) in 48% HBr (1300 mL) was refluxed for 30 minutes, then acetic acid (650 mL) was added and the mixture was refluxed for an additional 24 hours. A precipitate formed which was collected by filtration and washed with acetic acid/ether to afford 20.8 g of 2.3-di(phenylmethyl)-8-ethylidene-2-azabicyclo[2.2.2]octane-6-carboxylic acid hydrobromide, m.p. 251°-253° C. (dec.). Additional crops of the product were obtained by cooling the filtrate in an ice-bath and collecting the crystals that formed by filtration. A total of 69.8 g (50%) of the product was obtained in this manner.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[CH2:49]([N:52]([CH2:67][CH2:68][CH3:69])[C:53]1[CH:58]=[CH:57][C:56]([NH:59]C(OC(C)(C)C)=O)=[CH:55][CH:54]=1)[CH2:50][CH3:51]>CN(C=O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:59][C:56]2[CH:55]=[CH:54][C:53]([N:52]([CH2:67][CH2:68][CH3:69])[CH2:49][CH2:50][CH3:51])=[CH:58][CH:57]=2)=[O:21])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCCN(CCC)c1ccc(NC(=O)OC(C)(C)C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCN(CCC)c1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (300 mg) obtained in Example 2-2 was dissolved in DMF (10 ml) and added with DCC (298 mg), HOBt (195 mg), and the compound (185 mg) obtained in Example 15-1, followed by stirring overnight at room temperature. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform, followed by separating the solution into layers by the addition of 1 mol/l hydrochloric acid. The aqueous layer was made basic by the addition of a 1 mol/l sodium hydroxide aqueous solution. Then, the solution was subjected to extraction with chloroform. The extract was washed with saturated saline solution and the organic layer was then dried with anhydrous sodium sulfate. The solvent was distilled off. Subsequently, the residue was treated with hydrochloric acid and then purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (96.4 mg) of the subject compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([NH:26][CH2:27][CH2:28][NH:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][C:34]([S:40]([NH:43][C:44]6[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([C:51]([O:53]C)=[O:52])[CH:45]=6)(=[O:42])=[O:41])=[CH:35][CH:36]=5)[CH:31]=4)=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].C(=O)([O-])[O-].[Na+].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CN(C=O)C>[C:4]([C:3]1[CH:8]=[C:9]([NH:12][S:13]([C:16]2[CH:17]=[C:18]3[C:23]([CH:22]=[CH:21][C:20]([NH:26][CH2:27][CH2:28][NH:29][C:30]4[CH:31]=[C:32]5[C:37]([CH:36]=[CH:35][C:34]([S:40]([NH:43][C:44]6[CH:49]=[CH:48][C:47]([OH:50])=[C:46]([CH:45]=6)[C:51]([OH:53])=[O:52])(=[O:42])=[O:41])=[CH:33]5)=[CH:38][CH:39]=4)=[CH:19]3)=[CH:24][CH:25]=2)(=[O:14])=[O:15])[CH:10]=[CH:11][C:2]=1[OH:1])([OH:6])=[O:5]
Reactant: COC(=O)c1cc(NS(=O)(=O)c2ccc3ccc(NCCNc4ccc5ccc(S(=O)(=O)Nc6ccc(O)c(C(=O)OC)c6)cc5c4)cc3c2)ccc1O
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)c1cc(NS(=O)(=O)c2ccc3ccc(NCCNc4ccc5ccc(S(=O)(=O)Nc6ccc(O)c(C(=O)O)c6)cc5c4)cc3c2)ccc1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 40.4 %

Procedure:
To 64 mg (0.08 mmol) of compound 120 was added 20 mL of saturated sodium carbonate, 76 mg of sodium hydrosulfite (Na2S2O4), and 2 mL of DMF. The reaction was allowed to stir at ambient temperature for 22 hours. Then, the reaction was extracted with ethyl acetate and 1 N HCl. The organic layer was dried (MgSO4), filtered, and the volatiles removed by rotary evaporation. The product was purified by reverse-phase HPLC (C18, 250×20 mm column) using trifluoroacetic acid (TFA) buffer system (Buffer A: 5% acetonitrile, 95% water, 0.05% TFA; Buffer B: 95% acetonitrile, 5% water, 0.05% TFA; 17 mL/min; 0–50% B in 10 min., 50% B for 17 min., 50–100% B in 20 min). Fractions containing the product were combined and lyophilized to provide 24 mg of compound 121.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][C:12]([CH3:28])=[C:13]([CH:15]([C:17]2[C:18]([Cl:27])=[N:19][CH:20]=[CH:21][C:22]=2[C:23]([F:26])([F:25])[F:24])[OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[N+]1([O-])CCOCC1>C(Cl)Cl.C(#N)C.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH2:1]([O:8][C:9]1[C:10]([O:29][CH3:30])=[CH:11][C:12]([CH3:28])=[C:13]([CH:14]=1)[C:15]([C:17]1[C:18]([Cl:27])=[N:19][CH:20]=[CH:21][C:22]=1[C:23]([F:26])([F:24])[F:25])=[O:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C)c(C(O)c2c(C(F)(F)F)ccnc2Cl)cc1OCc1ccccc1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: ClCCl
Product: COc1cc(C)c(C(=O)c2c(C(F)(F)F)ccnc2Cl)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 83.9 %

Procedure:
(5-benzyloxy-4-methoxy-2-methylphenyl)(2-chloro-4-trifluoromethyl-3-pyridyl)methanol (5.9 g) was dissolved in a mixed solvent of anhydrous methylene chloride (50 ml) and acetonitrile (5 ml), and tetrapropylammonium perruthenate (95 ml), N-methylmorpholine-N-oxide (2.38 g) and molecular sieve 4A (6.8 g) were sequentially added thereto, followed by stirring in a stream of argon at room temperature for three nights. The reaction mixture was distilled off under reduced pressure, the residue thus obtained was suspended in methylene chloride and subjected to filtration by celite, and the residue was adequately washed with methylene chloride (200 ml). The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain 4.93 g (yield 84%) of 3-(5-benzyloxy-4-methoxy-2-methylbenzoyl)-2-chloro-4-trifluoromethylpyridine (compound No. 27; m.p. 116-117° C.), and its structure was confirmed by nuclear magnetic resonance spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[N:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47](O)=[O:48])=[CH:42][CH:41]=1>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([N:16]3[CH2:17][CH2:18][N:19]([C:47](=[O:48])[CH2:46][C:43]4[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=4)[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2N1CCNCC1
Reactant: O=C(O)Cc1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cc1ccncc1)N1CCN(C2c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
To a mixture of 8.5 g (27.2 m mole) of 8-chloro-11-(1-piperazinyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine (Preparative Example 7) in 256 mL of anhydrous DMF at room temperature and under an argon atmosphere was added 2.98 g (27.2 m mole of 4-methylmorpholine, 7.81 g (27.2 m mole) of DEC, 3.68 g (27.2 m mole) of HOBT, and 3.72 g (27.2 m mole) of 4-pyridylacetic acid. The mixture was stirred at room temperature for 22 hours. The mixture was poured into 3300 mL of CH2Cl2 and washed with 500 mL of water. The aqueous layer was extracted with 500 mL of CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography using a solution of 1.5% (10% NH4OH in MeOH) in CH2Cl2. The product was obtained as a white amorphous solid, M.S. (Mass Spec) M+=433.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[S:5][C:6]=1[CH2:7]O.S(Cl)([Cl:21])=O.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[Cl:21][CH2:7][C:6]1[S:5][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[N:3][C:2]=1[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)sc1CCl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
To a solution of [4-methyl-2-(3-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol (1.2 g, 4.4 mmol) in chloroform (7 ml) was added thionyl chloride (0.64 ml, 8.8 mmol) at −10° C. under an argon atmosphere. The reaction mixture was stirred for 30 min, saturated aqueous sodium bicarbonate solution/ice water 1/1 was added and the layers were separated. The aqueous layer was extracted two times with dichloromethane. The combined organic layers were washed with ice water/brine 1/1 and dried over sodium sulfate. The solvent was evaporated in vacuo to give the title compound (1.2 g, 4.1 mmol, 94%) as yellow oil which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+].[F-].[K+]>CN(C=O)C.[Cu]>[N:10]1([C:2]2[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][CH:9]=2)[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: c1c[nH]cn1
Reactant: OCc1cccc(I)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [F-]
Solvent: CN(C)C=O
Product: OCc1cccc(-n2ccnc2)c1
Yield: 86.7 %

Procedure:
3-Iodobenzylalcohol (5.17 g, 21.0 mmol), imidazole (1.73 g, 25.2 mmol), potassium carbonate (3.78 g, 27.3 mmol), copper (0) powder (275 mg, 4.33 mmol) and potassium fluoride (260 mg, 4.44 mmol) in DMF (30 ml) were refluxed at 175° C. for 6 h. The reaction was filtered, the solid washed with DCM and washing and filtrate concentrated. Purification by silica chromatography using DCM followed by DCM:MeOH (15:1 then 10:1) yielded (3-imidazol-1-yl-phenyl)-methanol as an orange oil (3.17 g, 72%).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].Cl[C:19]1[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=1[C:21]#[N:22].O>CS(C)=O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:19]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][C:20]=2[C:21]#[N:22])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: 60 °C
Yield: 94.1 %

Procedure:
To a solution of 11.4 g (0.0575 moles) of 4-hydroxybenzophenone dissolved in 150 ml of DMSO was added 2.3 g (0.0575 moles) of NaOH. The mixture was heated to 60° C. and 10.0 g (0.0548 moles) of 2-chloro-5-nitrobenzonitrile was added and the mixture heated at 75° C. for 3 hrs. The reaction mixture was cooled and poured into a solution of 100 ml of 2 N aqueous NaOH and 700 ml of water. The product was collected by filtration, washed well with water and dried to obtain 17.75 g of product (89.6% yield). Recrystallization from a mixture of ethanol and dimethylformamide and a second recrystallization from chloroform afforded purified 2-(4-benzoylphenoxy)-5-nitrobenzonitrile, mp 179.5°-180.5° C.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH:51]([CH3:53])[CH3:52])[N:43]=1>C(Cl)(Cl)Cl>[Cl:20][C:14]1[C:15]([F:19])=[C:16]([F:18])[CH:17]=[C:12]2[C:13]=1[N:41]([C:42]1[C:47]([F:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][CH:51]([CH3:53])[CH3:52])[N:43]=1)[CH:4]=[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:11]2=[O:22]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)Nc1nc(N)c(F)cc1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(-c2nc(NC(C)C)c(F)cc2F)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.33 h

Procedure:
To 2.5 ml of chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.70 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 600 mg of 2-amino-3,5-difluoro-6-isopropylaminopyridine. The solution was concentrated under reduced pressure. To the residue were added 600 mg of anhydrous potassium carbonate and 2 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 20 minutes and allowed to cool. The solution was separated by adding 30 ml of chloroform and 400 ml of distilled water, and the chloroform layer was washed twice with 400 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 620 mg of the title compound as a pale yellow powder.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:13][N:12]=3)[CH:9]=2)[N:4]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([CH3:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH:3]=1.[CH:34]([NH:37][C:38]1[CH:43]=[N:42][CH:41]=[C:40]([Sn](CCCC)(CCCC)CCCC)[N:39]=1)([CH3:36])[CH3:35].N#N>CN(C=O)C.[Cu]I.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>[CH:34]([NH:37][C:38]1[N:39]=[C:40]([C:2]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:11]4[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[S:13][N:12]=4)[CH:9]=3)[N:4]([S:24]([C:27]3[CH:28]=[CH:29][C:30]([CH3:31])=[CH:32][CH:33]=3)(=[O:26])=[O:25])[CH:3]=2)[CH:41]=[N:42][CH:43]=1)([CH3:36])[CH3:35]
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cncc(NC(C)C)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cncc(NC(C)C)n3)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Temperature: 90 °C
Yield: 80.9 %

Procedure:
A mixture of tert-butyl (3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.6 g, 1.0 mmol) and N-isopropyl-6-(tributylstannyl)pyrazin-2-amine (0.429 g, 1.0 mmol) in DMF (10 mL) was bubbled N2 gas for 15 min. To the mixture was added CuI (95 mg, 0.5 mmol.) and Pd(PPh3)4 (12 mg, 0.1 mmol) and N2 gas was bubbled for another 15 min. The reaction was heated at 90° C. for 1 h. The mixture was quenched with H2O (10 mL) and extracted with CHCl3 (2×25 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by neutral alumina column chromatography (eluent: 20% EtOAc in petroleum ether) to give tert-butyl (3-(3-(6-(isopropylamino)pyrazin-2-yl)-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (0.49 g, 81%). MS (ESI, pos. ion) m/z: 606.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](=[O:24])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1.[CH3:29][Mg]Br>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])([CH3:29])[CH3:23])=[C:18]([CH3:25])[CH:17]=2)=[C:12]([CH:26]([CH3:28])[CH3:27])[N:11]=[N:10]1
Reactant: C[Mg]Br
Reactant: CC(=O)c1ccc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)cc1C
Solvent: C1CCOC1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1C(C)(C)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 80.1 %

Procedure:
To a −78° C. solution of 1-{4-[3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenyl}-ethanone (500 mg, 1.19 mmol) in THF (12 mL) is added methylmagnesium bromide (2.0 mL, 5.98 mmol, 3.0 M in THF) dropwise. The reaction mixture is warmed to room temperature. After 4 h, the reaction is cooled to 0° C., quenched with NH4Cl and warmed to room temperature. The reaction mixture is concentrated and the residue is partitioned between Et2O and 1N HCl. The aqueous layer is extracted with Et2O and the combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed eluting with 0% to 30% EtOAC/Hexane to yield the title compound (414 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 7.49-7.46 (m, 2H), 7.43-7.38 (m, 1H), 7.23-7.19 (m, 2H), 6.70 (d, 1H, J=8.8 Hz), 4.89 (s, 2H), 3.20 (sept, 1H, J=6.6 Hz), 2.04 (s, 3H), 1.53 (s, 6H), 1.45 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[CH:5][C:6](=[O:9])[C:7]=1[CH3:8].C(O[C:17]([CH3:26])([CH:23]([CH3:25])[CH3:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20])(C(O)=O)=O>>[CH3:1][C:2]1[C:3](=[O:10])[CH:4]=[C:5]([C:17]([CH3:26])([CH:23]([CH3:25])[CH3:24])[CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: COC(=O)CC(C)(OC(=O)C(=O)O)C(C)C
Reactant: CC1=C(C)C(=O)C=CC1=O
Product: COC(=O)CC(C)(C1=CC(=O)C(C)=C(C)C1=O)C(C)C
Yield: 36 %

Procedure:
Using an analogous procedure to that described in the first paragraph of the portion of Example 21 which is concerned with the preparation of starting materials, 2,3-dimethyl-1,4-benzoquinone was reacted with methyl 3-oxalooxy-3,4-dimethylpentanoate to give methyl 3-(2,3-dimethyl-1,4-benzoquinonyl)-3,4-dimethylpentanoate in 36% yield; NMR Spectrum: (CDCl3) 0.6 (d, 3H), 0.86 (d, 3H), 1.02 (s, 3H), 1.93 (s, 3H), 1.94 (s, 3H), 2.32 (, 1H), 2.45 (d, 1H), 3.31 (d, 1H), 3.45 (s, 3H), 6.38 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[O:7])=[C:4]([OH:21])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl>CC(C)=O.C(OCC)(=O)C>[CH2:33]([O:32][C:30](=[O:31])[CH2:29][O:21][C:4]1[CH:3]=[C:2]([F:1])[CH:20]=[CH:19][C:5]=1[C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH3:34]
Reactant: O=C(NCc1cccc([N+](=O)[O-])c1)c1ccc(F)cc1O
Reactant: CCOC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)ccc1C(=O)NCc1cccc([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 165 %

Procedure:
A solution of 4-fluoro-2-hydroxy-N-(3-nitro-benzyl)-benzamide (5.00 g, 17.2 mmol) in acetone (86.0 mL) was treated with aq 2 N K2CO3 (13.0 mL, 25.8 mmol) and ethyl bromoacetate (1.50 mL, 9.66 mmol) and heated to 50° C. for 2 h. The solution was cooled to 0° C. and acidified to pH of 1 with 2 N HCl. The solution was diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over MgSO4, filtered and concentrated. Purification by MPLC(10-100% ethyl acetate in heptane, 23 mL/min, 75 min) to give [5-fluoro-2-(3-nitro-benzylcarbamoyl)-phenoxy]-acetic acid ethyl ester as a pale yellow solid (6 g, 93%): mp 78-80° C.; Rf 0.26 (40% ethyl acetate in heptane); 1H NMR (DMSO-d6 300 MHz) δ 9.01 (t, J=6 Hz, 1H), 8.19 (t, J=1.8 Hz, 1H), 8.10 (dd, J1=8.1 Hz, J2=1.5 Hz, 1H), 7.89 (dd, J1=8.7 Hz, J2=6.9 Hz, 1H),7.79 (d, J=7.5 Hz, 1H), 7.61 (t, J=8.1 Hz, 1H), 7.11 (dd, J1=11.1 Hz, J2=2.4 Hz, 1H), 6.92 (dt, J1=8.4 Hz, J2=2.4 Hz, 1H), 5.0 (s, 2H), 4.63 (d, J=6.3 Hz, 2H), 4.15 (q, J=7.2 Hz, 2H) 1.17 (t, J=6.5 Hz, 3H). ESI-LC/MS m/z calcd for C18H17FN2O6: 376.4. Found 377.0 (M+1)+. Anal. calcd for C18H17FN2O6: C, 57.45; H, 4.55; N, 7.44. Found : C, 57.47; H, 4.64; N, 7.28.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[C:9]#[N:10].C(N(CC)CC)C.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[O:5][CH2:4][CH2:3][NH:2][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([NH2:21])=[CH:23][CH:24]=1)#[N:10]
Reactant: N#Cc1cccc(OCCN)c1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCCNC(=O)c2ccc(N)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.00 g (20.4 mmol) of 3-(2-aminoethoxy)benzonitrile hydrochloride was dissolved in 50 ml of dimethylformamide. 6.2 ml (43.8 mmol) of triethylamine, 2.00 g (14.6 mmol) of p-aminobenzoic acid, 1.98 g (14.6 mmol) of 1-hydroxybenzotriazole and 2.80 g (14.6 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added to the solution at 0° C., and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extractant in an ordinary manner, the product was purified by the silica gel chromatography to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]3[CH2:18][N:19]([CH3:22])[CH2:20][CH2:21][C:9]2=3)[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]1[C:32]2[C:27](=[CH:28][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:30][CH:31]=2)[CH:26]=[CH:25]1.C([O-])([O-])=O.[K+].[K+].O>COCCOC.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>[CH3:22][N:19]1[CH2:20][CH2:21][C:9]2[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:29]4[CH:28]=[C:27]5[C:32](=[CH:31][CH:30]=4)[N:24]([CH3:23])[CH:25]=[CH:26]5)[CH:3]=3)[C:16]3[CH:15]=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=3[C:10]=2[CH2:18]1
Reactant: Cn1ccc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: Cc1ccc2c(c1)c1c(n2-c2cccc(Br)c2)CCN(C)C1
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: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2-c2cccc(-c3ccc4c(ccn4C)c3)c2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a de-aerated solution of 5-(3-bromophenyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.281 mmol), 1-methylindole-5-boronic acid pinacol ester (144 mg, 0.560 mmol) and K2CO3 (116 mg, 0.845 mmol) in DME (4 mL)-water (2 mL) was added Pd(PPh3)4 (16 mg, 0.013 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL) and washed with water (20 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude, which was purified by reverse phase HPLC to yield 2,8-dimethyl-5-(3-(1-methyl-1H-indol-5-yl)phenyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (TFA salt, CD3OD) δ (ppm): 7.82 (s, 1H), 7.8 (d, 1H), 7.62 (dd, 2H), 7.46 (dd, 2H), 7.35 (m, 2H), 7.2 (m, 2H), 7.04 (d, 1H), 6.5 (d, 1H), 4.6 (m, 2H), 3.8 (s, 3H), 3.7 (m, 2H), 3.11 (m, 5H), 2.41 (s, 3H).