Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OO.[C:3]([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([OH:20])[C:14]([CH3:22])([CH3:21])[CH2:13]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.S([O-])([O-])=O.[Na+].[Na+].[C:29]([OH:33])([CH3:32])([CH3:31])[CH3:30]>>[C:3]([O:11][CH:12]1[CH2:13][C:14]([CH3:22])([CH3:21])[N:15]([O:20][CH2:30][C:29]([OH:33])([CH3:32])[CH3:31])[C:16]([CH3:18])([CH3:19])[CH2:17]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Reactant: CC(C)(C)O
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Product: CC(C)(O)CON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C

Procedure:
A solution of 50% aqueous hydrogen peroxide is added slowly to a mixture of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and ferrous chloride tetrahydrate in tert-butyl alcohol at 30-60° C. Excess peroxide is decomposed by aqueous sodium sulfite solution. The organic layer is concentrated and the residue is purified by flash chromatography to afford the title compound.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:18]([CH3:31])[C:19]([C:21]1[CH:30]=[CH:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=1)=O>O1CCCC1>[C:3]1([C:2]2[NH:9][C:18]([CH3:31])=[C:19]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(N)c1ccccc1
Reactant: CC(Br)C(=O)c1ccc2ccccc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1[nH]c(-c2ccccc2)nc1-c1ccc2ccccc2c1
Reaction time: 2 h

Procedure:
A suspension consisting of 45.1 g (0.288 mol) of benzamidine hydrochloride, 119.4 g (0.864 mol) of potassium carbonate, and 240 mL of tetrahydrofuran was heated under reflux for one hour, and the foregoing toluene solution of 2-bromo-2′-propionaphthone was added dropwise over 40 minutes. After completion of addition, heating under reflux was continued for 2 hours. Next, the reaction mixture was concentrated in vacuo, the resulting concentrate was diluted with 200 mL of toluene, and the solution was poured into 600 mL of water. The mixture was stirred to precipitate a solid. This solid was collected by filtration, successively washed with toluene and water, and then dried to obtain a crude crystal as a desired material. This crude crystal was recrystallized from acetonitrile to obtain 55.0 g (yield: 67.2%) of a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:11])[CH:3]=1.C(=O)([O-])O.[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Cc1cc(O)ccc1C(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(O)ccc1C(=O)OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of 4-hydroxy-2-methylbenzoic acid (300 mg) in dimethylformamide (3 ml) was added with potassium hydrogencarbonate (236.9 mg), the mixture was stirred for 10 minutes, and then added with benzyl bromide (0.35 ml), and the mixture was stirred at 40° C. for 2 hours. The mixture was added with distilled water, the mixture was extracted with ethyl acetate, and the organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane to hexane ethyl acetate=50:1 to 20:1 to 2:1) to obtain the title compound (351.8 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].CC1C=C([OH:18])C=C(C)C=1>>[CH3:1][C:2]1[CH:7]=[C:6]([OH:18])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: Cc1cc(C)cc(O)c1
Reactant: Cc1cccc(C)c1O
Product: Cc1cc(O)cc(C)c1O

Procedure:
By following in the same manner as in Example 53, except that 100 g. (819 m. moles) of 2,6-dimethylphenol were used instead of 3,5-dimethylphenol, 1.04 g. (7.5 m. moles) of 2,6-dimethylhydroquinone were obtained. The yield of dihydric alkylphenol was 14.7 percent.
Reaction SMILES: [CH3:1][Li].[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)([OH:6])=O.O>CCOCC>[ClH:3].[C:4]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:16]=1[CH2:15][CH:14]([N:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[CH2:13][CH2:12]2)(=[O:6])[CH3:1]
Reactant: CCCN(CCC)C1CCc2cccc(C(=O)O)c2C1
Reactant: [Li]C
Agent: Cl
Solvent: CCOCC
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(C(C)=O)c2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 56 %

Procedure:
A 5% solution of methyl lithium in ether (0.6 ml, 0.96 mmol) was added to a chilled slurry of (±)-8-Carboxy-2-(dipropylamino)tetralin hydrochloride (100 mg, 0, 32 mmol) in ether. The mixture was stirred at room temperature and under nitrogen for three days. Water was added carefully and the mixture was extracted with ether. The organic layer was dried (potassium carbonate) and concentrated. The residue was purified by chromatography on an alumina column eluted with ether/light petroleum 1:4. The pure fractions were pooled, concentrated and converted into the hydrochloride. Recrystallization from acetonitrile/ether gave 55 mg (56%) of pure 8-acetyl-2-(dipropylamino)tetralin hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:28]#[N:29])([CH3:27])[CH3:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:31]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:28]([C:25]([C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[N:3]=3)[CH:6]=2)[CH:12]=1)=[O:30])([CH3:27])[CH3:26])#[N:29]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)c1
Reactant: O=C(Cl)C1CC1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.486 mmol) in N,N-dimethylacetamide (2.0 mL) was added cyclopropanecarbonyl chloride (46 μL, 0.510 mmol), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was diluted with ethyl acetate (100 mL), washed with 5% aqueous sodium hydrogen carbonate solution (50 mL) and saturated brine (50 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (NH silica gel, hexane/ethyl acetate=50/50→0/100), and fractions containing the desired product were concentrated under reduced pressure. The residue was triturated with ethyl acetate and diisopropyl ether to give the title compound (100 mg, 43%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][CH:3]=1.[Cl:16]N1C(=O)CCC1=O.CN(C)C=O>O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]([CH3:15])[NH:10][C:11](=[O:14])[NH:12][N:13]=2)=[CH:6][C:7]=1[Cl:16]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(N)c(Cl)c1
Yield: 8.6 %

Procedure:
A mixture of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.2 g), N-chlorosuccinimide (0.135 g) and dimethylformamide (3 ml) was stirred with ice-cooling for an hour. The reaction mixture was poured into water and extracted with chloroform. The extract was concentrated to dryness under reduced pressure and the residue was crystallized from chloroform to give 6-(4-amino-3-chlorophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (0.02 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:28])[N:13]([C:16]4[C:21]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:19]=[CH:18][C:17]=4[CH:25]([CH3:27])[CH3:26])[C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2.[Cu][C:30]#[N:31].O>CN1CCCC1=O>[C:30]([C:2]1[C:11]2[C:6]3=[C:7]([C:12](=[O:28])[N:13]([C:16]4[C:17]([CH:25]([CH3:27])[CH3:26])=[CH:18][CH:19]=[CH:20][C:21]=4[CH:22]([CH3:24])[CH3:23])[C:14](=[O:15])[C:5]3=[CH:4][CH:3]=1)[CH:8]=[CH:9][CH:10]=2)#[N:31]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(Br)ccc(c23)C1=O
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cccc3c(C#N)ccc(c23)C1=O
Yield: 71.8 %

Procedure:
24.8 g of 4-bromo-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide and 7.5 g of copper(I) cyanide in 150 ml of N-methylpyrrolidone were heated at 210° C. for 4 hours. After cooling, water was added to the reaction mixture, producing a precipitate. The precipitate was filtered off, washed and dried. Column chromatography of the precipitate on silica gel (eluent: dichloromethane) gave 15.6 g of 4-cyano-N-(2,6-diisopropylphenyl)naphthalene-1,8-dicarboximide having a melting point of 291° C.
Reaction SMILES: [CH2:1]([O:7][C:8](=[O:21])[C:9]([CH2:11][C:12]([O:14]CCCCCC)=O)=[CH2:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:22]([CH:24]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:25][NH2:26])[CH3:23]>>[CH2:1]([O:7][C:8]([CH:9]1[CH2:11][C:12](=[O:14])[N:26]([CH2:25][CH:24]([CH2:22][CH3:23])[CH2:27][CH2:28][CH2:29][CH3:30])[CH2:10]1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C=C(CC(=O)OCCCCCC)C(=O)OCCCCCC
Reactant: CCCCC(CC)CN
Product: CCCCCCOC(=O)C1CC(=O)N(CC(CC)CCCC)C1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
Bis(hexyl)itaconate (400 g; 1.34 Mol) was charged to a 1 L reaction vessel and the material stirred mechanically under nitrogen while heating to 45° C. 2-Ethylhexylamine (1.05 equiv.; 1.41 Mol; 182 g) was charged to a pressure-equalizing addition funnel and the amine added dropwise to the stirred diester over the course of one hour. During the addition, a moderate exotherm was observed. When the addition was complete, the mixture was heated to 75° C. and held for one hour before cooling to room temperature overnight. The following day, the vessel was equipped with a distillation sidearm/condenser and heated to 90° C. under reduced pressure (−25″ Hg) (−635 mm) in order to remove hexanol and excess amine. When stripping was complete, H-NMR analysis of the product was consistent with the expected lactam structure. 136.6 g was recovered of yellow moderately viscous liquid. Sample materials were collected from this preparation and designated 1-(2-ethylhexyl)-5-oxo-3-pyrrolidinecarboxylic acid hexyl ester for comparison testing described in the Examples below.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CI.[CH2:37]([OH:39])[CH3:38]>>[O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:20]=[CH:21][C:22]([NH:23][C:37](=[O:39])[CH3:38])=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reactant: CCO
Solvent: CI
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Reaction time: 20 h

Procedure:
4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (600 mg, 0.00168 mol), (prepared according to a method analogous to that described in Example 28) is suspended in ethanol (30 ml) at 0° C. Triethylamine (0.235 ml, 0.00168 mol) and methyl iodide (0.136 ml, 0.0022 mol) are added. The mixture is stirred for 20 hours then evaporated to dryness. The residue obtained is adsorbed on silica then purified by chromatography on a Biotage-type silica column (eluent: ethyl acetate-heptane: 4-6 to 5-5). After washing with diethyl ether and isopentane, a beige-coloured powder is obtained.
Reaction SMILES: [N+]([C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])([O-])=O.C(=O)([O-])[O-].[K+].[K+].[CH3:22][CH:23]([SH:26])[CH2:24][CH3:25].O>C(#N)C>[CH3:22][CH:23]([S:26][C:4]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH2:24][CH3:25]
Reactant: N#Cc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCC(C)S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCC(C)Sc1cc(C(F)(F)F)ccc1C#N
Yield: 74.9 %

Procedure:
2-Nitro-4-trifluoromethylbenzonitrile (10.8 g) and potassium carbonate (8.3 g) were heated to reflux in acetonitrile. A solution of 1-methylpropanethiol (5 g) in acetonitrile was added. The resultant suspension was heated at reflux for 4.5 hours. After cooling water was added and the mixture extracted with ethyl acetate. The organic extracts were washed with water. The organic extracts were washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness and the residue purified by column chromatography eluting with ethyl acetate in cyclohexane to give 2-(1-methylpropylsulphenyl)-4-trifluoromethylbenzonitrile (9.7 g) as a yellow oil, NMR (CDCl3) 1.0(t,3H), 1.2(d,3H), 1.5(m,2H), 3.4(m,1H), 7.3(m,1H), 7.6(m,2H).
Reaction SMILES: [CH:1]1([CH:7]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:26])=[CH:21][CH:20]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]([N:27]([CH3:35])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:26])=[CH:23][CH:24]=2)[C:8]2[S:16][C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[C:9]=2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3ncccc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)sc2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.6 %

Procedure:
To a mixture of ethyl 3-{[(4-{[cyclohexyl(3-methylthieno[2,3-b]pyridin-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (333 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (275 mg, 88%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][C@@H:19]([CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][C@@H:19]([CH2:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: COC(=O)[C@@H](N)CCc1ccccc1
Product: COC(=O)[C@H](CCc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl (S)-2-amino-4-phenylbutanoate (prepared from (+)-α-amino-4-phenylbutyric acid (Bachem) using General Procedure AG), the title compound was prepared as a solid (mp=147-149.5° C). The reaction was monitored by tlc (Rf=0.32 in 50% EtOAc/hexanes) and the product was purified by flash chromotography using EtOAc/hexanes as the eluent.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][CH2:10][C:11]([CH:14]1[CH2:16][CH2:15]1)([OH:13])[CH3:12])=[O:8].[Cl:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[C:31]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:25])([F:26])[F:27])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][CH2:10][C:11]([CH:14]2[CH2:16][CH2:15]2)([OH:13])[CH3:12])=[O:8])[CH:32]=[CH:33][CH:34]=1
Reactant: CC(O)(CNC(=O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1
Reactant: OB(O)c1cccc(Cl)c1
Product: CC(O)(CNC(=O)c1cc(-c2cccc(Cl)c2)c(OCC(F)(F)F)nc1C(F)(F)F)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-(2-cyclopropyl-2-hydroxy-propyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 3-chlorophenylboronic acid as starting materials, MS (ISP) 531.0, 497.1 (M)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[NH:7][C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]2[N:7]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:6]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3c(F)cc(Cl)cc3c2C1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)cc(F)c3n2CCc2ccc(C(F)(F)F)nc2)C1
Reaction time: 0.17 h
Yield: 2.9 %

Procedure:
To a solution of 8-chloro-6-fluoro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (300 mg, 1.26 mmol) in NMP (3.0 ml), powdered KOH (705 mg, 12.57 mmol) was added and stirred for 10 min at 25 deg C. After which 2-(trifluoromethyl)-5-vinylpyridine (435 mg, 2.5 mmol) was added slowly to the above solution and stirred for 24 h at 25 deg C. After completion of the reaction (monitored by LCMS), DM water was added to the crude and extracted with the ethylacetate. The organic layer was separated, dried and concentrated. The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 15 mg of 8-chloro-6-fluoro-5-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole as TFA salt.
Reaction SMILES: BrCCCOC1C=CC2SC=[N:11]C=2C=1.[Na+].[I-].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:46]=[C:45]3[C:40]([CH2:41]CC(=O)[NH:44]3)=[CH:39][CH:38]=2)[CH2:27][CH2:26]1.CCN(C(C)C)C(C)C>CC#N>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]1[CH2:31][CH2:30][CH2:29][N:28]([CH2:32][CH2:33][CH2:34][CH2:35][O:36][C:37]2[CH:46]=[C:45]3[C:40]([CH:41]=[N:11][NH:44]3)=[CH:39][CH:38]=2)[CH2:27][CH2:26]1
Reactant: BrCCCOc1ccc2scnc2c1
Reactant: O=C1CCc2ccc(OCCCCN3CCCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cccc(N2CCCN(CCCCOc3ccc4cn[nH]c4c3)CC2)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 58.6 %

Procedure:
A mixture of intermediate 51 (54.2 mg, 0.20 mmol) and NaI (60.3 mg, 0.40 mmol) in CH3CN (3 mL) was heated to reflux for 30 min and then cooled to rt. To this mixture was added intermediate 2 (62.4 mg, 0.22 mmol), followed then by DIEA (0.077 mL, 0.44 mmol). The resulting mixture was heated to reflux and stirred for 4 h. Precipitated crystals were filtered off and the filtrate was evaporated under reduced pressure. The residue was extracted with EtOAc. The combined EtOAc layers were washed with brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by ISCO to give 6-(4-(4-(2,3-dichlorophenyl)-1,4-diazepan-1-yl)butoxy)-1H-indazole (compound 47) (50.8 mg, 59%). HPLC: 99%, RT 4.526 min. MS (ESI) m/z 433.20 [M+H]+.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)[C:10]1=[O:27])=O)(C)(C)C.[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:36]2)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:38]=[C:37]2[C:32]([CH:33]=[CH:34][C:35]([S:39]([NH:8][C@H:9]3[CH2:13][CH2:12][N:11]([NH:14][CH:15]4[CH2:16][CH2:17][N:18]([C:21]5[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=5)[CH2:19][CH2:20]4)[C:10]3=[O:27])(=[O:41])=[O:40])=[CH:36]2)=[CH:31][CH:30]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(NC2CCN(c3ccncc3)CC2)C1=O
Reactant: O=S(=O)(Cl)c1ccc2ccc(Cl)cc2c1
Product: O=C1[C@@H](NS(=O)(=O)c2ccc3ccc(Cl)cc3c2)CCN1NC1CCN(c2ccncc2)CC1
Yield: 30 %

Procedure:
Similarly to Example 86 and using (3S)-3-(tert-butoxycarbonylamino)-1-[1-(4-pyridyl)-4-piperidinylamino]-2-pyrrolidone (220 mg) and 7-chlornaphthalene-2-sulfonyl chloride (170 mg), the title compound (88 mg) was obtained as colorless crystals.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[O:11]1[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]1.[Cl:19][CH2:20][CH2:21][CH2:22]I>C1COCC1.CCOCC>[Cl:19][CH2:20][CH2:21][CH2:22][C:14]1([C:17]#[N:18])[CH2:15][CH2:16][O:11][CH2:12][CH2:13]1
Reactant: ClCCCI
Reactant: N#CC1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: N#CC1(CCCCl)CCOCC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99.6 %

Procedure:
To a stirred solution of 1 M LiHMDS (25 mL, 25 mmol) in THF (10 mL) at −78° C. was added dropwise a solution of tetrahydro-2H-pyran-4-carbonitrile (2.23 g, 20 mmol) in THF (15 mL) over 10 minutes. After 40 min, 1-chloro-3-iodopropane (2.7 mL, 25 mmol) was added at once, stirred at −78° C. for 1 h and 4 h room temperature. Then the reaction mixture was diluted with ether (100 mL), washed with water (20 mL) and brine (20 mL), dried (Na2SO4), filtered and concentrated to give yellow oil which was purified by flash column chromatography using 10-30% EtOAc/Hexanes to afford the title compound as a colorless liquid (3.74 g, 99%). 1H NMR (500 MHz, CDCl3) δ: 3.97 (2H, dd, J=11.3, 3.7 Hz), 3.71 (2H, td, J=12.2, 1.8 Hz), 3.61 (2H, t, J=6.3 Hz), 2.05-1.98 (2H, m), 1.88 (2H, dd, J=13.4, 1.8 Hz), 1.77-1.74 (2H, m), 1.65-1.59 (2H, m).
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2].Br[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.[Mg].S(=O)(=O)(O)O>O1CCCC1.[Cu]Cl.C1(C)C=CC=CC=1>[C:1]([P:5]([C:6]([CH3:9])([CH3:8])[CH3:7])[C:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Brc1cccc2ccccc12
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)P(c1cccc2ccccc12)C(C)(C)C
Reaction time: 3 h
Yield: 86.6 %

Procedure:
In a 500 ml four-necked flask thoroughly purged with nitrogen, 18.1 g (0.1 mol) of di-tert-butylphosphinous chloride, 0.20 g (0.002 mol (corresponding to 2% by mol)) of copper(I) chloride, 20 ml of tetrahydrofuran and 20 ml of toluene were placed. To the contents of the flask, a Grignard reagent solution previously prepared from 24.8 g (0.12 mol) of 1-bromonaphthalene and 3.5 g (0.14 mol) of metallic magnesium in 180 ml of tetrahydrofuran was dropwise added over a period of 1 hour with maintaining the temperature at 25° C. to 30° C. After the dropwise addition was completed, stirring was conducted at 65° C. for 3 hours. After the temperature of the reaction solution was returned to room temperature, disappearance of di-tert-butylphosphinous chloride was confirmed by gas chromatography. Thereafter, 30 ml of toluene and 30 ml of a 5% sulfuric acid aqueous solution were added to the reaction solution to perform liquid separation. Then, the organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily substance. The oily substance was recrystallized from 150 ml of methanol to obtain 23.6 g (purity: 98.5%) of the aimed di-tert-butyl(1-naphthyl)phosphine as white crystals. The yield was 85.4%. Melting point: 95-97° C.