Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:27]=[CH:26][CH:25]=[CH:24][C:5]=1[C:6]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH2:13][CH2:12]1)=[O:7])([O-])=O>[Pd].CO>[C:6]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[CH2:13][CH2:12]1)(=[O:7])[C:5]1[C:4](=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH2:1]
Reactant: O=C(OCCN1CCN(c2cccc(Cl)c2)CC1)c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: Nc1ccccc1C(=O)OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 74.1 %

Procedure:
5.75 G. (0.015 mol) of 2-(4-m-chlorophenyl-piperazino)-ethyl 2-nitrobenzoate in 100 ml. of methanol is hydrogenated at ambient temperature and at atmospheric pressure, in the presence of 1 g. of 10% palladium on charcoal. The theoretical amount of hydrogen (1 1.) is absorbed in 40 minutes. The catalyst is filtered off, the methanol is evaporated from the filtrate, and the residue is recrystallised from isopropyl alcohol to give 4 g. (yield = 74.1%) of 2-(4-m-chlorophenylpiperazino)-ethyl anthranilate, which melts at 77° and which was shown to be identical, using a mixed melting point, to the product of Examples 14 and 16.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2([C:15]3[C:24]4[C:19](=[CH:20][C:21]([OH:25])=[CH:22][CH:23]=4)[CH2:18][CH2:17][N:16]=3)[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1>>[Cl:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2([C:15]3[C:24]4[C:19](=[CH:20][C:21]([O:25][CH2:2][CH2:1][NH2:3])=[CH:22][CH:23]=4)[CH2:18][CH2:17][N:16]=3)[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: CCN
Reactant: Oc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1
Product: NCCOc1ccc2c(c1)CCN=C2C1(c2ccc(Cl)cc2)CCC1

Procedure:
2-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-yl}oxy)ethanamine was prepared analogously to 2-{1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine using 1-[1-(4-chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-6-ol in place of 1-[1-(4-fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-ol (cf. example 65).
Reaction SMILES: [CH3:1][O:2][C:3]1([C:23](=[O:30])[NH:24][C:25]2([CH3:29])[CH2:28][CH2:27][CH2:26]2)[CH2:8][CH2:7][N:6]([CH:9]2[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[OH:37][C:31]([C:33]([F:36])([F:35])[F:34])=[O:32].[NH:12]1[CH2:13][CH2:14][CH2:15][CH:9]([N:6]2[CH2:7][CH2:8][C:3]([O:2][CH3:1])([C:23]([NH:24][C:25]3([CH3:29])[CH2:26][CH2:27][CH2:28]3)=[O:30])[CH2:4][CH2:5]2)[CH2:10][CH2:11]1
Reactant: COC1(C(=O)NC2(C)CCC2)CCN(C2CCCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC1(C(=O)NC2(C)CCC2)CCN(C2CCCNCC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-butyl 4-{4-methoxy-4-[(1-methylcyclobutyl)carbamoyl]piperidin-1-yl}azepane-1-carboxylate (0.25 g, 0.06 mmol) was dissolved in DCM (4 mL) and TFA (1 mL) was added. The reaction mixture was stirred at rt overnight under nitrogen, then the solvents were removed in vacuo, to give 1-(azepan-4-yl)-4-methoxy-N-(1-methylcyclobutyl)piperidine-4-carboxamide TFA salt (0.26 g), Intermediate 7, as a dark yellow oil which was used directly without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([O:14]CC)=[O:13])=[CH:9][C:8]=2[CH:17]=1)#[N:2].[OH-].[K+]>>[C:1]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8]=2[CH:17]=1)#[N:2]
Reactant: CCOC(=O)c1cc2cc(CC#N)ccc2o1
Agent: [K+]
Agent: [OH-]
Product: N#CCc1ccc2oc(C(=O)O)cc2c1

Procedure:
Ethyl 5-cyanomethylbenzofuran-2-carboxylate was hydrolysed by refluxing with ethanolic potassium hydroxide to give 5-cyanomethylbenzofuran-2-carboxylic acid.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.Br[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C.COCCOC.O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])=[C:21]([N+:32]([O-:34])=[O:33])[CH:20]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1[N+](=O)[O-]
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccccc1-c1ccc(C(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 100.9 %

Procedure:
Water (9.0 mL), sodium carbonate (2.6 g), 2-methoxyphenylboronic acid (1.8 g), and bis(triphenylphosphine)palladium(II) dichloride (0.14 g) were added to an ethylene glycol dimethyl ether (30 mL) solution of tert-butyl 4-bromo-2-nitrobenzoate (3.0 g), followed by heating to reflux under a nitrogen atmosphere for 2 hours and 30 minutes. The reaction mixture was cooled to room temperature, and then a 10% aqueous solution of citric acid and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 99-91% hexane/ethyl acetate] to obtain 3.3 g of tert-butyl 4-(2-methoxyphenyl)-2-nitrobenzoate as a light yellow oily substance.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:15][C:16]1[CH:34]=[CH:33][C:19]([CH2:20][C:21]2[O:25][N:24]=[C:23]([C:26]3[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=3)[N:22]=2)=[CH:18][CH:17]=1)C1C=CC=CC=1.C1(SC)C=CC=CC=1.C(=O)([O-])O.[Na+]>O>[NH2:32][C:27]1[C:26]([C:23]2[N:22]=[C:21]([CH2:20][C:19]3[CH:18]=[CH:17][C:16]([OH:15])=[CH:34][CH:33]=3)[O:25][N:24]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Nc1ncccc1-c1noc(Cc2ccc(OCc3ccccc3)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Solvent: O
Product: Nc1ncccc1-c1noc(Cc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 102.8 %

Procedure:
To a solution of TFA (2 mL) of 3-(5-(4-benzyloxy-benzyl)-[1,2,4]-oxadiazol-3-yl)-pyridin-2-ylamine (52 mg) described in Example 13 was added thioanisole (68 μL) at 0° C., which was stirred for 2 hours and 40 minutes at room temperature. Sodium hydrogencarbonate and water were added at 0° C. to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate, and filtered, after which the solvent was evaporated from the filtrate under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=20:1) to obtain the titled compound (40 mg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[OH:27][CH2:26][CH2:25][CH2:24][NH:23][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:22])[C:9]([N:19]([CH3:21])[CH3:20])([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: CCC(Cc1ccccc1)(C(=O)c1ccc(F)cc1)N(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCC(Cc1ccccc1)(C(=O)c1ccc(NCCCO)cc1)N(C)C
Reaction time: 12 h

Procedure:
15.0 g (0.050 mol) of 1-(4-fluorophenyl)-2-dimethylamino-2-benzyl-butan-1-one and 26.3 g (0.35 mol) of 3-amino-1-propanol are dissolved in 30 ml of dry dimethylacetamide, and the solution is heated up to 150° C. together with 13.8 g (0.1 mol) of potassium carbonate, and stirred overnight (about 12 h). After the solution is cooled down, it is poured into 300 ml of water and extracted with ethyl acetate. The organic phase is washed with water and saturated sodium chloride solution, and dried over MgSO4. After distilling off the ethyl acetate, the residue is purified by means of column chromatography on silica gel with ethyl acetate-hexane (1:1) as an eluent, and an oily product is obtained. The structure is confirmed by the 1H-NMR spectrum (CDCl3): δ [ppm]: 0.68 (t, 3H), 1.52 (br, 1H), 1.82-1.94 (m, 3H), 2.00-2.07 (m, 1H), 2.35 (s, 6H), 3.17 (d, 1H), 3.20 (d, 1H), 3.32-3.37 (m, 2H), 3.81-3.85 (m, 2H), 4.42 (br, 1H), 6.52 (d, 2H), 7.14-7.28 (m, 5H), 8.32 (d, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]([CH3:20])[CH3:19])[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[N+:29]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[CH:18]([N:13]1[C:12]([C:35]2[CH:36]=[CH:37][C:32]([N+:29]([O-:31])=[O:30])=[CH:33][CH:34]=2)=[C:11]2[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]2)=[N:14]1)([CH3:19])[CH3:20]
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)n1nc2c(c1OS(=O)(=O)C(F)(F)F)CCN(C(=O)OC(C)(C)C)CC2
Product: CC(C)n1nc2c(c1-c1ccc([N+](=O)[O-])cc1)CCNCC2
Yield: 17.7 %

Procedure:
The title compound (34 mg) was prepared according to Example 189 using 274 mg of 2-isopropyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 189, Step A) and 321 mg of 4-nitrophenylboronic acid. MS (ESI): exact mass calculated for C16H20N4O2, 300.16; found, m/z 301.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 8.42-8.40 (m, 2H), 7.62-7.60 (m, 2H), 4.37 (m, 1H), 3.43-3.41 (m, 2H), 3.21-3.18 (m, 2H), 2.82-2.79 (m, 2H), 1.41 (d, J=8.2 Hz, 6H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][NH:8][C:7]=2[C:6](=[O:12])[N:5]([CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:4]1=[O:25])[CH3:2].Br[CH2:27][CH2:28][CH3:29]>>[CH2:1]([N:3]1[C:11]2[N:10]=[CH:9][N:8]([CH2:27][CH2:28][CH3:29])[C:7]=2[C:6](=[O:12])[N:5]([CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:18][CH2:19][CH3:20])[O:21][CH2:22][CH3:23])[C:4]1=[O:25])[CH3:2]
Reactant: CCOP(=O)(CCCCn1c(=O)c2[nH]cnc2n(CC)c1=O)OCC
Reactant: CCCBr
Product: CCCn1cnc2c1c(=O)n(CCCCP(=O)(OCC)OCC)c(=O)n2CC

Procedure:
The title substance was prepared from 8.2 mmol of diethyl [4-(3-ethyl-xanthin-1-yl)butyl]phosphonate and 9.8 mmol of bromopropane analogously to Example 30 and chromatographed on silica gel (eluent: dichloromethane/methanol 20:1).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5].S(Cl)([Cl:18])(=O)=O>C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[Cl:18][CH:3]([C:2](=[O:1])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Agent: CCCCCCCC(=O)CC(=O)OC
Solvent: Cc1ccccc1
Product: CCCCCCCC(=O)C(Cl)C(=O)OC
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
In 500 ml of toluene was dissolved 160 g (0.8 mol) of the resulting methyl 3-oxodecanoate, the solution was cooled to 0 to 5° C., and 108 g (0.8 mol) of sulfuryl chloride was added thereto dropwise, followed by stirring at room temperature overnight. Toluene was removed by evaporation to give 187.8 g (0.8 mol; yield: 100% from methyl 3-oxodecanoate) of the title compound.
Reaction SMILES: O1CCCC1.C(N(CC)CC)C.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].[CH3:19][C:20]1[CH:26]=[C:25](I)[C:24]([CH3:28])=[CH:23][C:21]=1[NH2:22]>[Cu](I)I.C(OCC)(=O)C.O>[CH3:19][C:20]1[CH:26]=[C:25]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:24]([CH3:28])=[CH:23][C:21]=1[NH2:22]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(I)c(C)cc1N
Agent: I[Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(C#C[Si](C)(C)C)c(C)cc1N
Temperature: 50 °C
Reaction time: 15 h
Yield: 75.8 %

Procedure:
Tetrahydrofuran (100 ml), 100 ml of triethylamine, 7.6 g of trimethylsilyl acetylene, 1.25 g of palladium chloride-ditriphenylphosphine complex, and 0.34 g of copper iodide were added to 14.7 g of 2,5-dimethyl-4-iodoaniline, and the mixture was stirred at 50° C. for 15 hours. After completion of the reaction, water was added to the reaction solution, and extraction was performed 3 times with ethyl acetate. The organic layer was collected, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=5:1), thereby obtaining 9.8 g of 2,5-dimethyl-4-(2-trimethylsilyl-1-ethynyl)aniline (Compound 4-27).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Br:15])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:15][C:4]1[S:3][C:2]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)=[N:6][C:5]=1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: OB(O)c1ccncc1
Reactant: Clc1ccc(Cc2nc(Br)sc2Br)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: Clc1ccc(Cc2nc(-c3ccncc3)sc2Br)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a solution of 2,5-dibromo-4-(4-chlorobenzyl)thiazole (12.9 grams, 35.1 mmol) in DME (365 mL) was added pyridine-4-boronic acid (5.61 g, 45.6 mmol), 1M sodium carbonate (70.2 mL, 70.2 mmol), and PdCl2(dppf) (2.89 g, 3.51 mmol). The reaction was degassed with argon and stirred at 85° C. overnight. The reaction was cooled and taken up in ethyl acetate (400 mL) and saturated sodium bicarbonate (200 mL). The insolubles were filtered through celite and the bed was washed with ethyl acetate (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/DCM=0/100→70/30) followed by another silica gel chromatography (ethyl acetate/hexanes=0/100→100/0) to give 3.3 grams of the title compound as a brown solid (26% yield). LC/MS (FA) ES+ 365, 367. 1H NMR (300 MHz, CDCl3) δ: 8.70-8.67 (m, 2H), 7.70-7.67 (m, 2H), 7.28-7.26 (m, 4H), 4.13 (s, 2H).
Reaction SMILES: [N:1]1[C:6]2[NH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[NH:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:32])[CH:24]=1.O>CN(C)C=O>[Br:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([C:15]2[C:8]3[NH:7][C:6]4[N:1]=[CH:2][CH:3]=[CH:4][C:5]=4[CH2:11][NH:10][C:9]=3[CH:12]=[CH:13][CH:14]=2)=[O:28])=[C:25]([Cl:32])[CH:24]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: c1cnc2c(c1)CNc1ccccc1N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Br)cc1Cl)c1cccc2c1Nc1ncccc1CN2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 53.9 %

Procedure:
To a solution of 6,11-dihydro-5H-pyrido[2,3-b][1,5] benzodiazepine (3 g, 15.2 mmol) in N,N-dimethylformamide under nitrogen were added solid potassium carbonate (6.3 g, 45.6 mmol). The mixture was treated dropwise with a solution of the crude 4-bromo-2-chlorobenzoyl chloride (22.9 mmol) in N,N-dimethylformamide. After stirring at room temperature for 15 minutes, water was added under stirring. The resulting solid was collected, dissolved in chloroform, and the solution washed with 1N NaOH and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to dryness. The residue (purple foam) was dissolved in dichloromethane and absorbed onto a silica Merck-60 flash column. Elution with 20% ethyl acetate in hexane provided 3.4 g of the title compound as a foam which crystallized as a white solid by trituration from ethanol-ether, m.p. 165-168° C.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[CH:11]=[CH:10][NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[H-].[Na+].[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35](Cl)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]>C1COCC1>[CH3:18][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:26][CH2:27][O:28][CH2:29][CH2:30]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:9]3[CH:10]=[CH:11][C:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])=[CH:8]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:14])[CH2:16][CH3:17]
Reactant: CC(C)NC(=O)c1cc[nH]c1
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)Cl)ccc2n1CC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(C)(C)c1nc2cc(S(=O)(=O)n3ccc(C(=O)NC(C)C)c3)ccc2n1CC1CCOCC1
Yield: 63.1 %

Procedure:
Following the same procedure in Example 29, using N-isopropyl-1H-pyrrole-3-carboxamide (76 mg, 0.50 mmol) (see following step B for preparation), sodium hydride (159 mg, 60%, 3.97 mmol) and 2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazole-5-sulfonyl chloride (535 mg, 1.39 mmol) in THF (15 mL). The crude product was purified by MPLC using Hex/EtOAc (3:7) on silica gel to give 158 mg (64%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.77 (t, J=7.42 Hz, 3 H), 1.15 (d, J=6.64 Hz, 6 H), 1.39-1.56 (m, 4 H), 1.59 (s, 6 H), 1.94 (q, J=7.42 Hz, 2 H), 2.19-2.38 (m, 1 H), 3.23-3.35 (m, 2 H), 3.83-3.96 (m, 2 H), 4.01-4.15 (m, 1 H), 4.41 (d, J=7.62 Hz, 2 H), 6.67 (dd, J=3.32, 1.56 Hz, 1 H), 7.28 (dd, J=3.12, 2.34 Hz, 1 H), 7.79-7.86 (m, 1 H), 7.88-7.99 (m, 2 H) 8.26 (d, J=1.17 Hz, 1 H); MS (ESI) (M+H)+=501.3; Anal. Calcd for C26H36N4O4S+1.2 TFA+0.1H2O (615.50): C, 55.33; H, 6.11; N, 9.09. Found: C, 55.38; H, 6.16; N, 9.04.
Reaction SMILES: [CH2:1]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:29][C:30](OC(C)=O)=[O:31].CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>>[C:30]([N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[C:7]1[C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([O:25][CH2:26][C:27]#[N:28])[CH:19]=[CH:18]2)(=[O:31])[CH3:29]
Reactant: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)[nH]c2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCCCCc1c(-c2ccc3cc(OCC#N)ccc3c2)n(C(C)=O)c2ccccc12
Temperature: 70 °C
Reaction time: 24 h
Yield: 49.1 %

Procedure:
To a stirred solution of {[6-(3-pentyl-1H-indol-2-yl)-2-naphthyl]oxy}acetonitrile (0.300 g, 0.814 mmol) in Ac2O (3 mL, 3.18 mmol) at rt was added a catalytic amount of CSA (0.019 g, 0.0814 mmol). The reaction was heated to 70° C. for 18 h, and by TLC the reaction was about one half complete. Another 19 mg of CSA added and kept at 70° C. for an additional 24 h. After this time, the reaction mixture was quenched with 1 N HCl (˜2 mL). The resulting solution was extracted with EtOAc (100 mL). The organic layer was washed with 1 N HCl (10 mL), sat. aq. NaHCO3 (10 mL), and brine (10 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (10 to 20% EtOAc:petroleum ether gradient) to afford the product (0.164 g, 49%) as a solid; 1H NMR (DMSO-6) δ 0.73 (t, J=7.2 Hz, 3H), 1.03-1.23 (m, 4H), 1.47-1.61 (m, 2H), 1.92 (s, 3H), 3.24-3.42 (m, 2H), 5.34 (s, 2H), 7.27-7.43 (m, 3H), 7.52-7.70 (m, 3H), 7.94-8.08 (m, 3H), 8.33 (d, J=8.8 Hz, 1H); mass spectrum [(+) ESI], m/z 411 (M+H)+, 433 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].OC1C=CC(C(O)=O)=CN=1.[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[Br:1][C:2]1[C:3](=[O:12])[N:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cnc(O)c(Br)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)c(=O)n(-c2ccccc2)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
6 g of methyl 5-bromo-6-hydroxynicotinate synthesized by a known method from 6-hydroxynicotinic acid, and 6.3 g of phenylboronic acid were dissolved in 200 ml of tetrahydrofuran. To the mixture were added 939 mg of copper acetate and 1 ml of pyridine, followed by stirring at room temperature for 3 nights. Aqueous ammonia was added to the reaction solution, and the solution was extracted with chloroform. The organic layer was washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue obtained as a solid was washed with diethyl ether, to give 7.35 g of 3-bromo-5-(methoxycarbonyl)-1-phenyl-1,2-dihydropyridin-2-one as whit crystals. 5 g of the product was dissolved in 100 ml of dimethylformamide, followed by adding 4.6 g of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 7.9 g of cesium carbonate and 375 mg of tetrakistriphenylphosphine palladium, and stirring at 140° C. for 1 hour in nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water, and extracted with ethyl acetate. Then, the extract was successively washed with water and brine, and dried over anhydrous magnesium sulfate. Then, the solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 3.23 g of the title compound.
Reaction SMILES: [C-:1]#[N:2].[K+].C1OCCOCCOCCOCCOCCOC1.Br[CH2:23][CH2:24][CH:25]1[C:34]2[C:29](=[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1.C(P(CCCC)CCCC)CCC>C(#N)C.CCOCC.C(Cl)(Cl)(Cl)Cl>[C:1]([CH2:23][CH2:24][CH:25]1[C:34]2[C:29](=[C:30]([O:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1)#[N:2]
Reactant: COC(=O)COc1cccc2c1CCCC2CCBr
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCP(CCCC)CCCC
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)COc1cccc2c1CCCC2CCC#N
Reaction time: 0.25 h
Yield: 70.5 %

Procedure:
A mixture of potassium cyanide (1.16 g) and 18-Crown-6 (registered trade mark, 236 mg) in acetonitrile (18 ml) was stirred for 15 min under an atmosphere of argon. To the mixture was added a solution of methyl [1-(2-bromoethyl)-1,2,3,4-tetrahydronaphthalen-5-yloxy]acetate (2.92 g) and tributylphosphine (1.99 g) in acetonitrile (10 ml). To the mixture was added dropwise a solution of carbon tetrachloride (0.95 ml) in acetonitrile (10 ml) under cooling with ice. The mixture was stirred overnight at room temperature. The mixture was diluted with ether, and the mixture was washed with 10% aqueous solution of citric acid. To this solution was added carbon tetrachloride (10 ml), and washed with water and a saturated aqueous solution of sodium chloride, successively, dried over anhydrous magnesium sulfate, and evaporated. The residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:9) to give the title compound (1.72 g) having the following physical data.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[C:23]([F:35])=[C:24]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:25](O)=O>>[Cl:21][C:22]1[C:23]([F:35])=[C:24]([C:25]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:28]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(C(F)(F)F)cc(Cl)c1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(C(F)(F)F)cc(Cl)c3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 65 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 3-chloro-2-fluoro-5-(trifluoromethyl)benzoic acid: MS (ESI): m/z 487 (M−1).