Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](=[S:7])[NH:5][NH2:6].[N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)=[N+:14]=[N-:15]>CCO.ClCCl.C(O)(=O)C>[N:13]([CH2:16][CH2:17][CH2:18][C:19]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][N:5]=[C:4]([C:3]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:2]=2[F:1])[S:7]1)=[N+:14]=[N-:15]
Reactant: [N-]=[N+]=NCCCC(=O)c1ccccc1
Reactant: NNC(=S)c1cc(F)ccc1F
Solvent: CCO
Solvent: CC(=O)O
Solvent: ClCCl
Product: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a solution of 2,5-difluorobenzothiohydrazide (Example 1, Steps A and B; 1.5 g, 7.97 mmol) in EtOH/dichloromethane (3:1, 16 mL) was added 4-azido-1-phenylbutan-1-one (1.36 g, 7.17 mmol). After stirring at room temperature for 16 hours, acetic acid (2 drops) was added, and the mixture was stirred for another 16 hours. The reaction mixture was then concentrated under reduced pressure and chromatographed (9:1 hexanes/ethyl acetate) to provide the product (1.41 g, 41%) as a bright yellow syrup.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][NH2:24])=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:13][C:14]([F:25])([F:26])[C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:12])=[CH:19][CH:20]=1
Reactant: NCCCc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 20.1 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (1.13 g, 4.9 mmol), 3-(4-trifluoromethyl-phenyl)-propylamine (1 g, 4.9 mmol), and K2CO3 (1.13 g, 8.17 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-[3-(4-trifluoromethyl-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.314 g, 20%). 1H NMR (300 MHz, CDCl3): δ (ppm) 2.02 (m, 2H), 2.76 (t, 2H), 3.69 (t, 2H), 4.36 (s, 2H), 7.29-7.56 (m, 7H), 7.83 (d, 1H). GC-MS: m/z 319 (M)+.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])[S:8]1(=[O:25])=[O:24].[CH:26]1([NH2:30])[CH2:29][CH2:28][CH2:27]1>CO>[F:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([F:22])[C:16]=1[N:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:30][CH:26]2[CH2:29][CH2:28][CH2:27]2)[S:8]1(=[O:25])=[O:24]
Reactant: NC1CCC1
Reactant: O=S1(=O)N(CCOCCBr)c2ccccc2N1c1c(F)cccc1F
Solvent: CO
Product: O=S1(=O)N(CCOCCNC2CCC2)c2ccccc2N1c1c(F)cccc1F

Procedure:
In an analogous manner to general procedure V, 1-[2-(2-bromoethoxy)ethyl]-3-(2,6-difluorophenyl)-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (0.1 g, 0.23 mmol) was treated with cyclobutylamine (0.8 mL, 9.2 mmol) in methanol to give N-(2-{2-[3-(2,6-difluorophenyl)-2,2-dioxido-2,1,3-benzothiadiazol-1(3H)-yl]ethoxy}ethyl)cyclobutanamine which was treated with 1N hydrochloric acid in ether to give its hydrochloride salt as a white solid (0.59 g, 56%). HRMS: calcd for C20H23F2N3O3S+H+, 424.15009; found (ESI, [M+H]+Obs'd), 424.1497.
Reaction SMILES: C[O:2][C:3]([C:5]1[NH:6][CH:7]=[N:8][CH:9]=1)=[O:4].C(N(CC)CC)C.Cl[C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[Li+].Cl>C(Cl)Cl.O>[C:18]([N:8]1[CH:9]=[C:5]([C:3]([OH:2])=[O:4])[N:6]=[CH:7]1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COC(=O)c1cnc[nH]1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
3H-Imidazole-4-carboxylic acid methyl ester (9.86 g, 78.2 mmol) is taken up in 150 mL DCM, triethylamine (11.9 mL, 86.0 mmol) is added and the reaction mixture is stirred for 5 min at RT. Chlorotriphenylmethane (24.0 g, 86.0 mmol) is added and the reaction mixture is stirred overnight at RT. The reaction mixture is extracted with an aqueous 5% NaHCO3 solution, the organic phase is dried over MgSO4 and concentrated under reduced pressure. The residue (20.7 g) is taken up in 100 mL MeOH, a solution of lithium hydroxide (4.80 g, 24.0 mmol) in 20 mL water is added drop wise and the reaction mixture is stirred over weekend at RT. The reaction mixture is acidified to pH 4 with 6N hydrochloric acid, 200 mL DCM is added and the two phase mixture is stirred vigorously. The phases are separated and the organic phase is dried over MgSO4 and concentrated under reduced pressure. Yield: 19.2 g. HPLC-MS: double peak tR=2.55/2.67 min, (M−H)−=353.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].C(O)C>[Fe].O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([OH:13])[CH3:12])=[CH:8][CH:9]=1
Reactant: CC(O)Cc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(O)Cc1ccc(N)cc1
Yield: 78 %

Procedure:
A mixture of 1-(4-nitrophenyl)-2-propanol (Schadt, F. L.; et al. J. Am. Chem. Soc., 1978, 100, 228., 2.2 g, 12.3 mmol), iron powder (3.3 g, 59.1 mmol), ammonium chloride (370 mg, 6.9 mmol), ethanol (48 mL) and water (24 mL) was heated at reflux temperature for 2 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with ethyl acetate (200 mL) and washed with water (2×100 mL). The organic layer was dried (MgSO4), and concentrated. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (1:1) to afford 1.45 g (78%) of the title compound as a yellow oil: 1H-NMR (CDCl3) δ 7.00 (2H, d, J=8.6 Hz), 6.64 (2H, d, J=8.8 Hz), 3.99-3.89 (1H, m), 3.60 (2H, br s), 2.72-2.52 (2H, m), 1.22 (3H, d, J=6.2 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[CH3:15][C:16]([CH3:21])([CH3:20])[C:17](Cl)=[O:18]>C(Cl)Cl>[Br:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17](=[O:18])[C:16]([CH3:21])([CH3:20])[CH3:15])=[N:3][CH:4]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cnc(Br)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1cnc(Br)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.2 %

Procedure:
A solution of 2-amino-5-bromopyrazine (10.00 g, 57.47 mmol) and pyridine (5.6 mL, 68.96 mmol) in methylene chloride (144 mL) was cooled to 0° C. and then was treated slowly with trimethylacetyl chloride (8.6 mL, 68.96 mmol). The resulting reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred for 18 h. At this time, the reaction mixture still contained the starting material 2-amino-5-bromopyrazine. The reaction mixture was treated with an additional amount of trimethylacetyl chloride (4.3 mL, 34.48 mmol) and then stirred at 25° C. for 4 h. The reaction mixture was then concentrated in vacuo to remove methylene chloride. The resulting residue was diluted with ethyl acetate (700 mL). The organic layer was washed with a 1N aqueous hydrochloric acid solution (2×200 mL) and a saturated aqueous sodium chloride solution (1×200 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 65M, Silica, 1/9 ethyl acetate/hexanes) afforded N-(5-bromo-pyrazin-2-yl)-2,2-dimethyl-propionamide (12.19 g, 82%) as a white solid: mp 122–124° C.; (ES)+-HRMS m/e calcd for C9H12BrN3O (M+H)+ 258.0237, found 258.0240.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH:7]([CH3:21])[CH:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH3:9].C(N(CC)CC)C>CCOCC>[CH3:9][CH:8]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20])[CH:7]([O:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH3:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C(C)N1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C(C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Methanesulfonyl chloride (9.7 mL, 56 mmol) was added to a solution of 10.5 g (48 mmol) of 2-(2-hydroxy-1-methylpropyl)-1H-isoindole-1,3(2H)-dione (JP 01242569 A2) and 8.1 mL (58 mmol) of triethylamine and the mixture was stirred at room temperature overnight. The mixture was diluted with ether and washed with water and brine. Drying (MgSO4) and removal of solvent gave an oil which slowly solidified. Trituration with hexanes gave 11.8 g of 2-[1-methyl-2-[(methylsulfonyl)oxy]propyl]-1H-isoindole-1,3(2H)-dione as a white solid, mp 67–73° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([Cl:15])=[O:14])[CH2:12][CH2:11][CH2:10]1.[N:16]12[CH2:23][CH2:22][CH:19]([CH2:20][CH2:21]1)[CH:18]([OH:24])[CH2:17]2>>[ClH:15].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([O:24][CH:18]2[CH:19]3[CH2:22][CH2:23][N:16]([CH2:21][CH2:20]3)[CH2:17]2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: COc1ccccc1C1(C(=O)Cl)CCC1
Reactant: OC1CN2CCC1CC2
Product: COc1ccccc1C1(C(=O)OC2CN3CCC2CC3)CCC1
Product: Cl

Procedure:
The title compound was prepared in an analogous manner to that in Example 36. 1-(2-Methoxyphenyl)cyclobutanecarbonyl chloride, prepared from the compound prepared in Example 17, was reacted with 3-quinuclidinol at 80° C. for 25 h. A crude product was obtained which was rechromatographed on a reverse-phase PEP RPC HR 30/26 column using a gradient of 25-50% CH3CN with 0.1% TFA. The yield was 0.2 g (6%); mp 121-123° C.; 1H NMR (D2C) δ 1.70-1.85 (m, 2H), 1.93-2.03 (m, 2H), 2.10 (m, 1H), 2.19 (m, 1H), 2.39 (m, 1H), 2.54 (m, 2H), 2.77 (m, 2H), 3.01 (q, 1H), 3.18 (d, 1H), 3.28-3.37 (m, 3H), 3.75 (m, 1H), 3.85 (s, 3H), 5.24 (m, 1H), 7.13 (d, 1H), 7.17 (t, 1H), 7.45 (t, 1H), 7.53 (d, 1H). Anal. (C19H25NO2.HCl.H2O) C, H, N.
Reaction SMILES: [CH:1]([C:3]1[C:16]([OH:17])=[CH:15][C:14]([OH:18])=[C:13]2[C:4]=1[N:5]=[C:6]1[C:11](=[N:12]2)[C:10]([C:19]([OH:21])=O)=[CH:9][CH:8]=[C:7]1[OH:22])=O.[C:23]([N:30]1[CH:34]=[CH:33][N:32]=[CH:31]1)(N1C=CN=C1)=O.[CH3:35][N:36]([CH3:40])[CH2:37][CH2:38][NH2:39]>CN(C)C=O>[CH3:31][N:30]([CH3:23])[CH2:34][CH2:33][NH:32][C:19]([C:10]1[C:11]2[C:6](=[N:5][C:4]3[C:13]([N:12]=2)=[C:14]([OH:18])[CH:15]=[C:16]([OH:17])[C:3]=3[CH:1]=[N:39][CH2:38][CH2:37][N:36]([CH3:40])[CH3:35])[C:7]([OH:22])=[CH:8][CH:9]=1)=[O:21]
Reactant: O=Cc1c(O)cc(O)c2nc3c(C(=O)O)ccc(O)c3nc12
Reactant: CN(C)CCN
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(C)CCN=Cc1c(O)cc(O)c2nc3c(C(=O)NCCN(C)C)ccc(O)c3nc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
6-Formyl-4,7,9-trihydroxy-1-phenazinecarboxylic acid (520 mg, 1.73 mmoles) was suspended in 15 ml of dry dimethylformamide (DMF) and 1,1'-carbonyldiimidazole (700 mg, 4.32 mmoles) dissolved in 4 ml of DMF was added. The reaction mixture was stirred for 20 minutes at 25° C. until a clear solution had formed. The solution was then cooled in an ice bath and N,N-dimethylethylenediamine (0.6 ml) added. After stirring for 15 minutes at 25° C. the excess reagents were removed under vacuum to yield N-[2-(dimethylamino)ethyl]-6-[[[2-(dimethylamino)ethyl]imino]methyl]-4, 7,9-trihydroxy-1-phenazinecarboxamide. The retention time for this product in the HPLC system described above in Example 3 is 5.0 minutes.
Reaction SMILES: B.C1COCC1.[CH3:7][NH:8][C:9]([C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1)=O>CO>[CH3:7][NH:8][CH2:9][C:11]1[O:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[CH:15]=1
Reactant: CNC(=O)c1cc2ccccc2o1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2o1
Temperature: 25 °C
Yield: 12.4 %

Procedure:
To a solution of 1.0 M BH3/THF (30 mL, 30 mmole) at 0° C. was added N-methylbenzofuran-2-carboxamide (1.75 g, 10 mmole). The reaction mixture was allowed to warm to RT, then was heated at reflux overnight. The reaction was cooled to 0° C. and excess methanol was added. The resulting solution was concentrated in vacuo and the residue was purified by flash chromatography on silica gel (3% MeOH/CH2Cl2). The tile compound (0.2 g, 12%) was obtained as a white solid: MS (ES) m/e 162 (M+H)+.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10](Cl)=[O:11].[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)CCCCC(=O)Cl
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In a 2-liter three-necked flask equipped with a stirring device, a thermometer and a nitrogen substituting device, 700 milliliters of benzene was introduced and 177.0 g of aluminum chloride was added with ice cooling. Then, a solution of 101.6 g of adipoyl chloride in 300 milliliters of benzene was added dropwise for 35 minutes. After stirring for one day and one night with warming back to the room temperature, the solution was poured in 3 liters of ice water containing dilute hydrochloric acid, and extracted with 2.5 liters of toluene. Thereafter, the solution was washed with a 0.5N aqueous solution of sodium hydroxide and water, and then dried with anhydrous magnesium sulfate. After removing off the solvent by a rotary evaporator, 128.4 g of 1,6-diphenylhexane-1,6-dione was obtained as crystals by recrystallizing the obtained crystals from ethyl acetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][CH:21]=1)[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]1[C:16]([OH:18])=[O:17])#[N:2].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P([N:44]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C>>[C:16]([OH:18])(=[O:17])[CH3:8].[CH2:22]([NH:29][C:16]([C:8]1[N:7]([CH2:6][C:5]2[CH:19]=[CH:20][CH:21]=[C:3]([C:1](=[NH:44])[NH2:2])[CH:4]=2)[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:18])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: N#Cc1cccc(Cn2c(C(=O)O)cc3ccccc32)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: NCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)O
Product: N=C(N)c1cccc(Cn2c(C(=O)NCc3ccccc3)cc3ccccc32)c1
Yield: 97 %

Procedure:
This compound was prepared from 1-(3-cyano-benzyl)-1H-indole-2-carboxylic acid (example 1/2) and benzylamine by using diphenylphosphoryl azide and diisopropylethylamine as described in example 3/1. The crude material was purified by flash chromatography on silica gel with toluene/ethanol 19:0.5 to give the desired product in 97% yield. M.p. 129-131° C. MS: 366.2 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH2:11]O)=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:11][CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:2]([F:14])([F:13])[F:1])=[CH:4][CH:5]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCc1ccc(C(F)(F)F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: FC(F)(F)c1ccc(CCCBr)cc1
Reaction time: 3 h
Yield: 81 %

Procedure:
Compound 11-1 (9.53 g) was dissolved in methylene chloride (100 ml), triphenylphosphine (13.3 g) and N-bromosuccinimide (8.97 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 1 hr, and further at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (200 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (10.1 g) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12].C(OC)(OC)OC.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:10]([N:13]([CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]
Reactant: CCCNCCC
Reactant: O=Cc1ccc(O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: CCCN(CCC)Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In methanol, 4-hydroxybenzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (1.00 g) was dissolved. Then, the solution was added with dipropylamine (1.24 ml), trimethyl orthoformate (1.0 ml), and acetic acid (500 μl) and stirred at room temperature for 15 minutes. The solution was cooled to 0° C. and added with sodium cyanoborohydride (773 mg), followed by stirring for 6 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was then dissolved in chloroform, followed by the addition of water. The solution was adjusted to about pH 7 with a 1 mol/l sodium hydroxide aqueous solution and then subjected to extraction with chloroform. The resulting organic layer was washed with saturated saline solution and then dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off under reduced pressure and the residue was then purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (76.8 mg) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.CC([O-])(C)C.[K+].[SiH:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[CH2:20][CH3:21]>O1CCCC1>[CH2:20]([Si:19]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:12]1[C:3]([O:2][CH3:1])=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=1)[CH3:21]
Reactant: COc1ccc2ccccc2c1
Reactant: CC[SiH](CC)CC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc2ccccc2cc1OC
Yield: 58 %

Procedure:
The reaction was conducted according to the General Procedure by heating 2-methoxynaphthalene (79 mg, 0.5 mmol, 1 equiv.), KOt-Bu (19.6 mg, 0.18 mmol, 0.35 equiv.) and Et3SiH (319 microliters, 2.0 mmol, 4 equiv.) in 1 mL of tetrahydrofuran for 48 hours at 65° C. After aqueous work up, the crude reaction mixture was purified by chromatography on silica eluting with hexanes (isochratic) to obtain 79 mg (58%) of the title compound as colourless oil. 1H NMR (500 MHz, THF-d8) δ 7.84 (s, 1H), 7.78-7.73 (d, 1H), 7.73-7.68 (d, 1H), 7.38 (ddd, J=8.2, 6.8, 1.3 Hz, 1H), 7.27 (ddd, J=8.1, 6.8, 1.2 Hz, 1H), 7.15 (s, 1H), 3.90 (s, 3H), 1.01-0.90 (m, 9H), 0.68-0.53 (m, 6H). 13C NMR (126 MHz, THF-d8) δ 163.03, 137.88, 136.83, 130.10, 128.58, 128.09, 127.29, 127.21, 124.03, 104.57, 55.25, 8.02, 7.48.
Reaction SMILES: [C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=2[CH:18]=1)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].C=O.Cl.[CH3:24]NC.Cl>CN(C)C=O.C(O)(=O)C>[CH2:24]=[C:2]([CH:3]([CH3:5])[CH3:4])[C:1]([C:7]1[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]2[O:14][CH:13]([C:15]([OH:17])=[O:16])[CH2:12][C:11]=2[CH:18]=1)=[O:6]
Reactant: CNC
Reactant: Cc1c(C(=O)CC(C)C)cc2c(c1C)OC(C(=O)O)C2
Agent: C=O
Agent: Cl
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: C=C(C(=O)c1cc2c(c(C)c1C)OC(C(=O)O)C2)C(C)C
Temperature: 0 °C

Procedure:
A mixture 2,3-dihydro-5-isovaleryl-6,7-dimethylbenzofuran-2-carboxylic acid (8.5 g.), paraformaldehyde (2.0 g.), dimethylamine hydrochloride (3.3 g.) and acetic acid (1 ml.) is heated at 95° for 2.5 hours, treated with dimethylformamide (75 ml.), heated an additional 3.5 hours then poured into ice water (300 ml.) containing hydrochloric acid (5 ml.). The product is extracted into ether, washed with water, dried over magnesium sulfate and the solvent evaporated at reduced pressure to afford 2,3-dihydro-5-(2-methyleneisovaleryl)-6,7-dimethylbenzofuran-2-carboxylic acid which melts at 97°C. after recrystallization from cyclohexane.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>CN1C(=O)CCC1.C(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20][N:36]4[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]4)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Reactant: CN1CCNCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1CCN(Cc2cc(Nc3ccnc4cc(Cl)ccc34)ccc2N2CCOCC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (compound of step C of example 31) (0.105 g, 0.26 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to 4-methylpiperazine (0.86 mL, 7.75 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (Et2O/MeOH/NH4OH//80/20/1) to yield expected compound as a yellow solid (120 mg, 99% yield). LC-MS: m/z (ESI) 452.2 [M+H]+.
Reaction SMILES: [OH:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2.[H-].[Na+].I[CH2:14][CH3:15]>C1COCC1>[CH2:14]([O:1][C:2]12[CH2:6][C:4]([NH:7][C:8](=[O:10])[CH3:9])([CH2:5]1)[CH2:3]2)[CH3:15]
Reactant: CCI
Reactant: CC(=O)NC12CC(O)(C1)C2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC12CC(NC(C)=O)(C1)C2

Procedure:
To a anhydrous THF (5 mL) solution of N-(3-hydroxybicyclo[1.1.1]pentan-1-yl)acetamide (1) (1 mmol) is added NaH (60% dispersion in mineral oil, 3 mmol) portionwise at 0° C. After addition, the mixture is stirred until the evolution of gas stops. Iodoethane (1 mmol) is then added by syringe slowly. The reaction is monitored by LCMS and TLC. After consumption of starting material, the reaction mixture is quenched by adding water (3 mL) and extracted with ethyl acetate (3×). The organic layers are combined, dried (magnesium sulfate), filtered, and concentrated. The crude residue is subjected to flash chromatography (silica gel, EtOAc/hexanes) to afford N-(3-ethoxybicyclo[1.1.1]pentan-1-yl)acetamide (2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:21])([CH3:20])[CH:10]=[C:9]3[CH3:22])[C:6](=[O:23])[O:5]2.C(=O)([O-])[O-].[K+].[K+].[C:30]([O:33][CH2:34]C)(=O)C.C(OCC)C>CN(C)C=O>[CH3:30][O:33][CH2:34][O:1][C:2]1[CH:3]=[C:4]2[C:17](=[CH:18][CH:19]=1)[C:16]1[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]([CH3:20])([CH3:21])[CH:10]=[C:9]3[CH3:22])[C:6](=[O:23])[O:5]2
Reactant: CC1=CC(C)(C)Nc2ccc3c(c21)c(=O)oc1cc(O)ccc13
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCOc1ccc2c(c1)oc(=O)c1c3c(ccc12)NC(C)(C)C=C3C
Temperature: 50 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 8-hydroxy-2,2,4-trimethyl-1,2-dihydro-6-oxa-1-azachrysen-5-one (Reference Compound No. 1-(4), 1.00 g, 3.25 mmol), chlorodimethylether (420 μL, 5.53 mmol) and potassium carbonate (1.35 g, 9.77 mmol) was suspended in anhydrous N,N-dimethylformamide (15 mL) and the suspension was stirred at 50° C. overnight. After cooling down, ethyl acetate (100 mL) and diethylether (100 mL) were added thereto. The whole was washed with water (150 mL, 100 mL) and saturated brine (100 mL) successively, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (747 mg) as a yellow solid. (Yield 66%)