Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[H-].[Na+].Cl[C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=1>CN(C=O)C>[NH2:7][CH2:8][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([O:16][C:21]2[CH:29]=[CH:28][C:24]([C:25]([NH2:27])=[O:26])=[CH:23][N:22]=2)=[CH:14][CH:15]=1
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)NCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NCCc1ccc(Oc2ccc(C(N)=O)cn2)cc1

Procedure:
Treat [2-(4-hydroxyphenyl)ethyl]carbamic acid tert-butyl ester (534.3 mg, 2.2 mmol) with NaH (80% in mineral oil, 78.0 mg (2.6 mmol) in anhydrous DMF (10 mL) at room temperature for 30 minutes. Add 6-chloronicotinamide (343.8 mg, 2.2 mmol) and heat the mixture at 80° C. overnight. Quench the reaction with H2O and concentrate to dryness, using xylenes to remove DMF as an azeotrope. Suspend the residue in MeOH and filter with thorough MeOH and CH2Cl2 rinse. Concentrate the filtrate and purify by flash chromatography, eluting with 75:15:10 EtOAc/CH2Cl2/2.0 M NH3 in MeOH. Deprotect the BOC group with 1:1 TFA/CH2Cl2 (16 mL) at room temperature overnight. Concentrate and purify by an SCX column, washing with MeOH and then eluting with 2.0 M NH3 in MeOH: MS ES+ 297.9 (M+H+K)+, HRMS calcd for C14H16N3O2 258.1243 (M+H)+, found 258.1235 time 0.40 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 5-95% over 19 min], tR=6.93 min. 100% purity.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([C:11]1([C:14]2[CH:49]=[CH:48][CH:47]=[CH:46][C:15]=2[CH2:16][CH2:17][C:18]2[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[C:20]([NH:28][C:29]3[CH:34]=[CH:33][C:32]([CH:35]4[CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]4)=[CH:31][CH:30]=3)[N:19]=2)[CH2:13][CH2:12]1)(=[O:10])[NH2:9]>C(Cl)Cl>[NH:37]1[CH2:38][CH:35]([C:32]2[CH:33]=[CH:34][C:29]([NH:28][C:20]3[N:19]=[C:18]([CH2:17][CH2:16][C:15]4[CH:46]=[CH:47][CH:48]=[CH:49][C:14]=4[C:11]4([C:8]([NH2:9])=[O:10])[CH2:12][CH2:13]4)[C:23]([C:24]([F:26])([F:25])[F:27])=[CH:22][N:21]=3)=[CH:30][CH:31]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)N1CC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4C4(C(N)=O)CC4)n3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)C1(c2ccccc2CCc2nc(Nc3ccc(C4CNC4)cc3)ncc2C(F)(F)F)CC1
Yield: 89.6 %

Procedure:
A solution of TFA (0.916 mL, 12.0 mmol) and tert-butyl 3-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)azetidine-1-carboxylate (A9) (174 mg, 0.299 mmol) in DCM (10 mL) was stirred for 16 hours at room temperature under nitrogen. The volatiles were removed in vacuo and the residue was taken up in MeOH and loaded onto an SCX cartridge (10 g). The column was eluted with 5 column volumes of MeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH to elute the amine product. The ammoniacal filtrate was evaporated under reduced pressure and dried under high vacuum to give the title compound 4 as a yellow solid (129 mg, 90%); 1H NMR (400 MHz, d6-DMSO) δ 10.19 (s, 1H), 8.68 (s, 1H), 7.77-7.67 (m, 2H), 7.38-7.26 (m, 5H), 7.26-7.18 (m, 1H), 6.99 (s, 1H), 6.00 (s, 2H), 3.86 (s, 3H), 3.71 (s, 2H), 3.22-3.13 (m, 2H), 3.13-3.05 (m, 2H), 1.44 (s, 2H), 0.96 (s, 2H). LCMS-A: rt 4.591 min; m/z 482 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14].C(N(CC)CC)C.Cl.[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30].O>C(#N)C>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29]([O:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:14])(=[O:31])=[O:30]
Reactant: COc1cc(I)c2c(c1O)CNC2=O
Reactant: O=S(=O)(Cl)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: COc1cc(I)c2c(c1OS(=O)(=O)c1ccccn1)CNC2=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 69 %

Procedure:
4-Hydroxy-5-methoxy-7-iodoisoindolinone (0.465 g, 1.52 mmol) was dissolved in acetonitrile (10.0 mL), and the solution was added with triethylamine (0.850 mL, 6.09 mmol) and 2-pyridinesulfonyl chloride hydrochloride (0.488 g, 2.28 mmol), followed by stirring at room temperature for 5 hours. The reaction mixture was added with water (8.0 mL) and stirred at room temperature for 30 minutes. The precipitated crystal was collected by filtration to obtain 4-(2-pyridinesulfonyloxy)-5-methoxy-7-iodoisoindolinone (0.468 g, yield 69%).
Reaction SMILES: Br[C:2](Br)=[CH:3][CH2:4][CH2:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[Li]CCCC.[CH2:16]=[O:17].[NH4+].[Cl-]>C1COCC1>[CH3:7][Si:6]([CH3:9])([CH3:8])[CH2:5][CH2:4][C:3]#[C:2][CH2:16][OH:17]
Reactant: C=O
Reactant: C[Si](C)(C)CCC=C(Br)Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCC#CCO
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
To a flame dried flask was added (4,4-dibromo-but-3-enyl)trimethylsilane (3.43 g, 12 mmol). Dry THF (150 mL) was added and the mixture was cooled to −78° C. BuLi 1.6N in hexanes (24 mmol, 15 mL) was added and the mixture was stirred 1 h at −78° C., warmed to 22° C., and stirred for an additional 1 h. Finally, paraformaldehyde (1.4 g) was added and the mixture was refluxed. After 3.5 h the reaction was cooled to 22° C. and sat. NH4Cl (50 mL) was added. The contents of the flask were transferred to a separatory funnel and extracted with ether (3×200 mL). The organic layer was dried (Na2SO4), filtered and evaporated to give a crude yellow oil. Flash chromatography on silica gel (pentane/ether 5:1) afforded 1.57 g (84%) of 5-trimethylsilanylpent-2-yn-1-ol: IR (neat, cm−1) 3350, 2953, 2219, 1436, 1412, 1318, 1249, 1178, 1124, 1015, 905, 853; 1H NMR (300 MHz, CDCl3) δ−0.003 (s, 9 H), 0.76 (t, J=8 Hz 2 H), 1.75 (s, 1 H), 2.20-2.24 (m, 2 H), 4.21 (br s, 2 H); 13C NMR (75 MHz, CDCl3) δ−1.3, 13.8, 16.4, 51.7, 78.2, 88.9; HRMS (EI) ml/z calcd for C7H13OSi (M-CH3) 141.0736, found 141.0733 LRMS (EI) m/z 141 (M-CH3), 123, 113, 103, 97, 91, 85, 75, 66, 59.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:12]=[C:11]([CH2:13]O)[CH:10]=[CH:9][C:8]=2[C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=2[F:25])=[CH:5][CH2:4][CH2:3]1.S(Cl)([Cl:29])=O>C(Cl)Cl.CN(C=O)C>[Cl:29][CH2:13][C:11]1[CH:10]=[CH:9][C:8]([C:15]2[CH:20]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:18]=[CH:17][C:16]=2[F:25])=[C:7]([C:6]2[C:2]([CH3:26])([CH3:1])[CH2:3][CH2:4][CH:5]=2)[CH:12]=1
Reactant: CC1(C)CCC=C1c1cc(CO)ccc1-c1cc(C(F)(F)F)ccc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)CCC=C1c1cc(CCl)ccc1-c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.8 %

Procedure:
To a solution of 66.53B (0.2574 g, 0.706 mmol) in dry DCM (10 mL) and dry DMF (0.07 mL) was added thionyl chloride (0.11 mL, 1.51 mmol)at 0° C. The resulting solution was warmed to room temperature and monitored with TLC and LCMS. After 45 minutes, the reaction was concentrated and then purified by silica gel flash chromatography (0-5% EtOAc/hexane) to afford 66.53C (242.8 mg, 90% yield). 1H NMR (400 MHz, CDCl3) 6 ppm 7.60 (2H, m), 7.40 (1H, m), 7.35 (2H, m), 7.21 (1H, m), 5.52 (1H, td, J=2.4, 0.9 Hz), 4.66 (2H, m), 2.24 (2H, td, J=7.0, 2.3 Hz), 1.68 (2H, m), 0.84 (6H, s).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].C([O-])(=O)C.[Pb+4:17].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](B(O)O)[CH:26]=2)=[CH:21][CH:20]=1>>[C:1]([O-:4])(=[O:3])[CH3:2].[C:5]([O-:8])(=[O:7])[CH3:6].[C:9]([O-:12])(=[O:11])[CH3:10].[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH3:31])=[C:27]([Pb+3:17])[CH:26]=2)=[CH:21][CH:20]=1
Reactant: Cc1ccc(-c2ccc(Cl)cc2)cc1B(O)O
Reactant: [Pb+4]
Agent: CC(=O)[O-]
Product: Cc1ccc(-c2ccc(Cl)cc2)cc1[Pb+3]
Temperature: 40 °C
Yield: 100 %

Procedure:
To a mixture of lead tetraacetate (2.44 g, 5.50 mmol) and mercuric diacetate (0.16 g, 0.50 mmol), thoroughly flushed with nitrogen, is added anhydrous chloroform (6 ml). This mixture is warmed to 40° C., and 4′-chloro-4-methylbiphenyl-3-ylboronic acid (1.23 g, 5.00 mmol) is added in one portion, and the suspension is heated at this temperature for 5 hours. After cooling to room temperature the mixture is concentrated to a small volume, then triturated with hexanes and filtered to yield crude 4′-chloro-4-methylbiphenyl-3-yllead triacetate (2.93 g).
Reaction SMILES: [CH3:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[C:25]1[C:30]([C:31]2[N:36]=[CH:35][N:34]=[C:33]([NH:37][CH3:38])[CH:32]=2)=[CH:29][CH:28]=[CH:27][N:26]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1>O.C(OCC)(=O)C.O1CCOCC1>[CH3:1][C:2]1[C:11]([NH:12][C:25]2[C:30]([C:31]3[CH:32]=[C:33]([NH:37][CH3:38])[N:34]=[CH:35][N:36]=3)=[CH:29][CH:28]=[CH:27][N:26]=2)=[C:10]2[C:5]([C:6]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=3)=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1N
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(Nc4cccc(C(F)(F)F)c4)ncnc23)ncn1
Temperature: 150 °C

Procedure:
A mixture of 7-methyl-N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine (0.083 g, 0.26 mmol) and 6-(2-chloropyridin-3-yl)-N-methylpyrimidin-4-amine (0.058 g, 0.26 mmol) were placed in a clear microwave vial along with 3 ml of dioxane. While stirring, lithium bis(trimethylsilyl)amide in THF (1.6 ml, 1.6 mmol) was added dropwise with a syringe to the reaction. The vial was capped and heated in a Personal Chemistry Smith Synthesizer to 150° C. for 12 minutes. The reaction was diluted with water and ethyl acetate. The organic portion was washed (2×) with an aqueous saturated solution of sodium bicarbonate, then with water and then brine. The residue was purified by HPLC using a gradient of 5% ACN 0.1% TFA to 95% ACN 0.1% TFA in water 0.1% TFA. The pure fractions were neutralized with ammonium hydroxide and the volatiles were removed under reduced pressure. The solid that crashed out of the aqueous layer was filtered off, washed with with water and dried in a vacuum oven at 45 degrees to give 7-methyl-N8-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)-N4-(3-(trifluoromethyl)phenyl)quinazoline-4,8-diamine as a light yellow solid. MS (M+H)+ 474.
Reaction SMILES: I[CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32].[CH3:33][NH2:34].C(OCC)(=O)C>CS(C)=O>[CH3:33][NH:34][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[C:12]3[N:13]=[C:14]([S:27][CH2:28][CH2:29][CH3:30])[N:15]=[C:16]([NH:17][CH:18]4[CH2:20][CH:19]4[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:11]=3[N:10]=[N:9]2)[CH:5]([OH:31])[CH:4]1[OH:32]
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CI)C(O)C3O)c2n1
Reactant: CN
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CNC)C(O)C3O)c2n1
Reaction time: 18 h

Procedure:
A solution of the product from step (c) (0.25 g) in dimethylsulphoxide (3mil) was treated with a 40% solution of aqueous methylamine (1 ml). The reaction mixture was allowed to stand for 18 hours at room temperature then poured into ethyl acetate (200 ml), washed with a saturated solution of aqueous brine (3×100 ml), dried and concentrated. Purification (SiO2, methanol:chloroform 1:4 as eluant) afforded the subtitle compound (0.27 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([OH:33])=O)=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[NH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)[OH:43])=[C:38]([O:50][CH2:51][C:52]([F:55])([F:54])[F:53])[CH:37]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O.CN(C)C1C=CN=CC=1.O.C(N(CC)CC)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:29])[F:28])[CH2:23][CH2:22][C:21]([C:31]([NH:35][C:36]4[CH:41]=[CH:40][C:39]([CH:42]([OH:43])[C:44]5[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=5)=[C:38]([O:50][CH2:51][C:52]([F:55])([F:53])[F:54])[CH:37]=4)=[O:33])=[CH:20][C:19]=3[CH:34]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3C(=O)C(F)(F)F)cc1
Reactant: Nc1ccc(C(O)c2ccccn2)c(OCC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(OCC(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (1.5 g), [4-amino-2-(2,2,2-trifluoroethoxy)phenyl] (pyridin-2-yl)methanol (0.94 g) and 1-hydroxybenzotriazole (0.72 g) were dissolved in N,N-dimethylformamide (25 ml), and to the solution were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.8 g), triethylamine (2.2 ml) and 4-dimethylaminopyridine (catalytic amount) at room temperature under ice-cooling, and the mixture was stirred overnight. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(pyridin-2-yl)methyl]-3-(2,2,2-trifluoroethoxy)phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (1.5 g) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=2[NH:12][C:13](=[O:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[N:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@H:25]([NH2:29])[CH2:24]1.C(N(CC)CC)C>C(#N)C>[NH2:29][C@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[C:7]([Cl:22])[C:8]=3[NH:12][C:13](=[O:21])[CH2:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[N:3]=2)[CH2:24]1
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Reactant: N[C@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@H]1CCCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 120 °C
Yield: 23.1 %

Procedure:
N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (Example 1(a)) (0.2 g), (3S)-3-piperidinamine (0.089 g) and triethylamine (0.25 mL) were placed into a 10 mL microwave vial followed by the addition of acetonitrile (5 mL). The vial was sealed and heated at 120° C. in a single mode microwave for 30 minutes, and a further 60 minutes at 150° C. The product crystallised from the reaction on cooling and was subsequently filtered and washed with acetonitrile (10 mL). Purification (SiO2, 7M ammonia in methanol:methanol:dichloromethane 1:4:95) gave the title compound (0.055 g).
Reaction SMILES: [C:1]12([CH2:12][C:11](=[O:13])[O:10][C:8](=[O:9])[CH2:7]1)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2.[NH2:14][OH:15].Cl.NO.C(=O)([O-])[O-].[Na+].[Na+]>>[OH:15][N:14]=[C:8]([OH:9])[CH2:7][C:1]1([CH2:12][C:11]([OH:10])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC2(CCCCC2)CC(=O)O1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CC1(CC(O)=NO)CCCCC1
Temperature: 70 °C

Procedure:
50 g. 1,1-Cyclohexane-diacetic anhydride was introduced portionwise, while stirring, into an aqueous solution of hydroxylamine, prepared from 23.4 g. hydroxylamine hydrochloride and 21.12 g. sodium carbonate. After completion of the addition, the reaction mixture as heated for 2 hours at 70° C.; an oil separated out. After cooling, the pH was adjusted to 2 with 2N hydrochloric acid and the crystalline precipitate was filtered off with suction. The precipitate was washed with water, taken up in methanol, any undissolved material was removed and, after the addition of water, it was evaporated in a vacuum. There was obtained 45.5 g of 1,1-cyclohexane-diacetic acid N-hydroxyimide; m.p. 104° C.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([C:16]1([CH2:22][OH:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:12][CH2:13][CH2:14][CH3:15]>C(Cl)Cl>[CH2:11]([C:16]1([CH:22]=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1)[CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC1(CO)CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCCCCC1(C=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
DMSO (930 L) was added to a −78° C. solution of oxalyl chloride (3.2 mL, 2 M/toluene) in CH2Cl2 (44 mL). After 15 min., a solution of alcohol 2-3 (968 mg, 5.3 mmol) in 14 mL CH2Cl2 was added by cannula, rinsing with 2 mL CH2Cl2. The reaction was stirred for 15 min. and Et3N (5.9 mL) was added. The reaction was allowed to warm to 0° C. and after 2 h, 100 mL saturated NaHCO3 solution was added. The resulting mixture was extracted with CH2Cl2 (3×) and the combined CH2Cl2 solution was washed with H2O and brine and then was dried (Na2SO4), filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=O)[C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2.[OH-].[K+]>O.NN>[CH3:1][C:2]1([CH3:19])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]([OH:17])=[O:16])[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)C(=O)O)ccc21
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(CC(=O)O)ccc21

Procedure:
4.68 g (18 mmol) of 5,6,7,8-tetrahydro-5,5,8,8,tetramethyl-2-naphthylglyoxylic acid and 50 ml of hydrazine hydrate are introduced into a round-bottomed flask and the mixture is heated to reflux until dissolution has taken place. At 100° C., 8 g of potassium hydroxide are added in small portions and the mixture is heated to reflux for four hours. The reaction medium is evaporated to dryness, the residue is taken up with water, the mixture is acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl ether, and the organic phase is separated after settling has taken place, then dried over magnesiumsulphate and evaporated. The residue obtained is purified by chromatography on a silica column and eluted with a mixture of dichloromethane and ethyl ether (95:5). After evaporation of the solvents, 3.8 g (86%) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid, melting point 149°-150° C., are collected.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH:11]2[CH2:16][CH2:15][CH2:14][N:13](C(=O)C(F)(F)F)[CH2:12]2)[NH:4][CH:3]=1.Cl.[OH-].[Na+].C(=O)([O-])[O-:27].[K+].[K+]>>[NH:13]1[CH2:14][CH2:15][CH2:16][CH:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[CH2:2][C:3](=[O:27])[NH:4]3)[CH2:12]1
Reactant: O=C([O-])[O-]
Reactant: O=C(N1CCCC(c2cccc3[nH]cc(Cl)c23)C1)C(F)(F)F
Agent: Cl
Agent: [K+]
Agent: [Na+]
Product: O=C1Cc2c(cccc2C2CCCNC2)N1

Procedure:
A mixture of 11 g of the product of Step B and 600 ml of N hydrochloric acid was refluxed for 3 hours and was then cooled to 20°-25° C. Concentrated sodium hydroxide was added to the mixture to make it alkaline and the mixture was then saturated with potassium carbonate. The mixture was extracted with ethyl acetate and the organic phase was dried and evaporated to dryness. The 3.65 g of residue were chromatographed over silica gel and eluted with a 7-2-1 chloroform-methanol-triethylamine mixture to obtain 3.6 g of 1,3-dihydro-4-(piperidin-3-yl)-2H-indole-2-one.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH:10]=2)[C:5](=[O:19])[N:4]([CH3:20])[CH:3]=1.[CH2:21]([S:23]([NH:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)(=[O:25])=[O:24])[CH3:22].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[CH3:20][N:4]1[CH:3]=[C:2]([C:31]2[CH:32]=[C:27]([NH:26][S:23]([CH2:21][CH3:22])(=[O:24])=[O:25])[CH:28]=[CH:29][CH:30]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[CH:10]=2)[C:5]1=[O:19]
Reactant: Cc1ccc(-c2ccc3c(=O)n(C)cc(Br)c3c2)cn1
Reactant: CCS(=O)(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCS(=O)(=O)Nc1cccc(-c2cn(C)c(=O)c3ccc(-c4ccc(C)nc4)cc23)c1
Yield: 14.1 %

Procedure:
A mixture of 4-bromo-2-methyl-6-(6-methylpyridin-3-yl)isoquinolin-1-one (135 mg, 0.41 mmol), [3-(ethylsulfonylamino)phenyl]boronic acid (141 mg, 0.62 mmol), Pd(dppf)Cl2 (35 mg, 0.05 mmol) and aqueous 1M K3PO4 (1.03 mL) in dioxane (6 mL) was microwaved at 100° C. for 1 h. Purification by silica gel chromatography (PE:EA=3:1 to 1:2) followed by preparative HPLC gave the title compound (25 mg, 14.1%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.74 (d, J=2.0 Hz, 1H), 8.41 (d, J=8.4 Hz, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.75 (s, 1H), 7.58 (s, 1H), 7.47 (t, J=8.0 Hz, 1H), 7.39 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 3.59 (s, 3H), 3.59 (s, 3H), 3.15 (q, J=7.2 Hz, 2H), 1.19 (t, J=7.2 Hz, 3H). LCMS: 434.1 (M+H)+.
Reaction SMILES: BrC1C=CC(C=O)=CC=1.C(C1C=CC=CN=1)(=O)C.[I-].BrC1N=C(C(=O)C[N+]2C=CC=CC=2)C=CC=1.Br[C:37]1[N:42]=[C:41]([C:43]2[CH:48]=[C:47]([C:49]3[CH:54]=[CH:53][C:52]([Br:55])=[CH:51][CH:50]=3)[CH:46]=[C:45]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[N:44]=2)[CH:40]=[CH:39][CH:38]=1.[CH:62]1[C:74]2[C:73]3[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=3[NH:67][C:66]=2[CH:65]=[CH:64][N:63]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].C1(C)C=CC=CC=1.C(Cl)(Cl)Cl.ClC1C=CC=CC=1Cl.CS(C)=O>[Br:55][C:52]1[CH:53]=[CH:54][C:49]([C:47]2[CH:46]=[C:45]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=3)[N:44]=[C:43]([C:41]3[CH:40]=[CH:39][CH:38]=[C:37]([N:67]4[C:68]5[CH:69]=[CH:70][CH:71]=[CH:72][C:73]=5[C:74]5[CH:62]=[N:63][CH:64]=[CH:65][C:66]4=5)[N:42]=3)[CH:48]=2)=[CH:50][CH:51]=1
Reactant: Brc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(Br)n3)c2)cc1
Reactant: c1ccc2c(c1)[nH]c1ccncc12
Agent: [Cu]
Agent: CC(=O)c1ccccn1
Agent: O=C(C[n+]1ccccc1)c1cccc(Br)n1
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Solvent: Clc1ccccc1Cl
Product: Brc1ccc(-c2cc(-c3ccccn3)nc(-c3cccc(-n4c5ccccc5c5cnccc54)n3)c2)cc1
Temperature: 120 °C
Reaction time: 7 h
Yield: 62 %

Procedure:
As in Example 1,3-(4-bromophenyl)-1-(pyridin-2-yl)propenone was synthesized from 4-bromobenzaldehyde and 2-acetylpyridine, and further subjected to a reaction with [2-(6-bromopyridin-2-yl)oxoethyl]pyridinium iodide to synthesize 6-bromo-4′-(4-bromophenyl)-[2,2′;6′,2″]terpyridine. To 15.3 g of the resulting 6-bromo-4′-(4-bromophenyl)-[2,2′;6′,2″]terpyridine were added 5.6 g of 5H-pyrido[4,3-b]indole, 1.0 g of a copper powder, 6.8 g of potassium carbonate, 1.0 mL of dimethyl sulfoxide, and 80 mL of o-dichlorobenzene, followed by heating and stirring at 120° C. for 7 hours. After cooling to room temperature, 200 mL of chloroform was added thereto to remove an insoluble matter by filtration, and the filtrate was concentrated under a reduced pressure to obtain a concentrate. To the concentrate, 2 L of toluene was added and insoluble matter was removed by filtration. NH silica gel was added to the filtrate to perform adsorptive purification. Thereafter, the filtrate was concentrated under a reduced pressure to obtain a crude product. The crude product obtained was washed with methanol to obtain 11.3 g (yield, 62%) of 4′-(4-bromophenyl)-6-(5H-pyrido[4,3-b]indol-5-yl)-[2,2′;6′,2″]terpyridine as a brown powder.