Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[C:13]([CH3:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH3:19][S:20]([O:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31]OS(C)(=O)=O)=[CH:26][CH:25]=1)(=[O:22])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:31][CH2:30][C:27]2[CH:26]=[CH:25][C:24]([O:23][S:20]([CH3:19])(=[O:21])=[O:22])=[CH:29][CH:28]=2)=[C:13]([CH3:18])[CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(C)c1)OCC
Reactant: CS(=O)(=O)OCCc1ccc(OS(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)c(C)c1)OCC
Yield: 59.2 %

Procedure:
Ethyl 2-ethoxy-3-(4-hydroxy-3-methylphenyl)propanoate (0.27 g, 1.05 mmole) and 4-{2-[(methylsulfonyl)oxy]ethyl}phenyl methanesulfonate (0.62 g, 2.11 mmole) were dissolved in 2-butanone (10 ml). Polyethyleneglycol 400 (0.20 g) and anhydrous potassium carbonate (0.22 g, 1.58 mmole) were added the mixture. After stirring at reflux for 16 hours it was checked with using HPLC whether all the starting material was consumed. The mixture was washed with water dried with magnesium sulfate and evaporated. Purification of the crude product with preparative HPLC (Kromasil C8, 7 μm, 50×250 mm) using actonitrile(60-80%) in ammonium acetate buffer (pH 7) as mobile phase gave 0.28 g (54% yield) of the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=O)=[CH:5][CH:4]=1.[C:13]([CH2:15][C:16]([O:18][CH3:19])=[O:17])#[N:14]>C(O)(=O)C.N1CCCCC1>[C:13](/[C:15](=[CH:11]\[CH2:10][CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)/[C:16]([O:18][CH3:19])=[O:17])#[N:14]
Reactant: COc1ccc(CCC=O)cc1
Reactant: COC(=O)CC#N
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: COC(=O)/C(C#N)=C/CCc1ccc(OC)cc1
Yield: 72.3 %

Procedure:
A solution of 13d (0.616 g, 3.75 mmol) in 0.51 mL glacial acetic acid was treated with NCCH2CO2CH3 (0.338 g, 3.75 mmol, 0.3 mL, 1.0 equiv), then a premixed solution of piperidine (0.0011 g, 0.128 mmol, 13 mL, 3.4 mol %) and 125 mL of acetic acid at room temperature (24 h). The reaction mixture was quenched by the addition of saturated aqueous NaHCO3 (15 mL, pH>7) and extracted with EtOAc (3×15 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo. SGC chromatotron (SiO2, 1 mm, 0-10% EtOAc/hexanes) afforded 15d (0.665 g, 0.920 g theoretical, 72%). For 15d: 1H NMR (CDCl3, 400 MHz) d 7.63 (t, 1H, J=7.5 Hz, CH=C), 7.09 (d, 2H, J=8.5 Hz, Ar C2-H and C6-H), 6.83 (d, 2H, J=8.5 Hz, Ar C3-H and C5-H), 3.83 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 2.70-2.90 (m, 4H, ArCH2CH2); IR (neat) nmax 2955, 1837, 2359, 2341, 1732, 1612, 1513, 1436, 1270, 1248, 1178, 1116, 1061, 1039, 823, 761, 668 cm-1. See FIG. 19c.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1.[C:28](O)(=[O:31])[CH2:29][CH3:30]>>[S:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:28](=[O:31])[CH2:29][CH3:30])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH:6]=[CH:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1
Reactant: CCC(=O)O
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4sccc34)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 4 starting from trans-4-[2-(4-thieno[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate B) (100 mg, 0.22 mmol) and propionic acid (17 mg, 0.23 mmol). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 95:5). White crystals (31 mg, 35%), MS (ISP) m/z=401.3 [(M+H)+].
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[F:12][C:13]([F:24])([F:23])[C:14]1[N:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>C1COCC1>[F:24][C:13]([F:23])([F:12])[C:14]1[CH:15]=[CH:16][C:17]([C:20]2([CH3:8])[CH2:21][O:22]2)=[CH:18][N:19]=1
Reactant: CC(=O)c1ccc(C(F)(F)F)nc1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CC1(c2ccc(C(F)(F)F)nc2)CO1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared by following general procedure 3. DMSO was added to NaH (1 equiv.) and heated to 65° C. for 1 h. THF was added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture was cooled to 0° C. Trimethylsulfonium iodide (1 equiv.) was added and stirred for 10 min. after which the solution of 1-(6-(trifluoromethyl)pyridin-3-yl)ethanone (1 equiv.) in THF was added dropwise. After complete addition, the reaction mixture was stirred at RT for 2 h. The product was detected by LCMS and the reaction mixture was poured into ice water, extracted in diethyl ether (4×50 mL), dried over Na2SO4 and concentrated at 25° C. to obtain the product.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH3:11][N:12]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: Clc1noc2ccccc12
Reactant: CNCCN1CCOCC1
Product: CN(CCN1CCOCC1)c1noc2ccccc12
Temperature: 140 °C
Yield: 23.5 %

Procedure:
To a sealed tube was added 3-chloro-1,2-benzisoxazole (3.0 g) and N-methyl-N-[2-(4-morpholinyl)ethyl]-amine (12.7 g). The reaction was heated to 140° C. over 72 hours and then cooled to room temperature. The residue was partitioned between EtOAc and water, extracted again with EtOAc, and the organic phase was dried over MgSO4 and concentrated in vacuo. Hash column chromatography (silica gel) eluting with 1-3% MeOH/DCM provided the product (1.2 g), as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:15])=[C:5]([CH2:12][C:13]#[N:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=O>C(O)C.[Pd]>[NH2:9][C:8]1[CH:7]=[CH:6][C:5]([CH2:12][C:13]#[N:14])=[C:4]([CH3:15])[C:3]=1[O:2][CH3:1]
Reactant: COc1c([N+](=O)[O-])ccc(CC#N)c1C
Agent: [Pd]
Solvent: CCO
Product: COc1c(N)ccc(CC#N)c1C
Reaction time: 3.5 h
Yield: 103.5 %

Procedure:
To a solution of (3-methoxy-2-methyl-4-nitro-phenyl)-acetonitrile (1.03 g, 5.0 mmole) in ethanol (100 mL) was added a small amount of 10% palladium on charcoal catalyst and the mixture hydrogenated on the Parr hydrogenator at 45 psi for 3.5 hours. The reaction mixture was filtered through celite and evaporated under reduced pressure to give the (4-amino-3-methoxy-2-methyl-phenyl)acetonitrile as a solid (0.912 g, 100%). 1H NMR (CDCl3) δ: 2.25 (s, 3H), 3.56 (s, 2H), 3.72 (s, 3H), 3.85 (br, 2H), 6.60 (d, 1H, J=8.1 Hz), 6.90 (d, 1H, J=8.1 Hz).
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[NH2:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[NH2:20])[C:15]#[N:16]>C(O)(=O)C>[C:15]([C:14]1[CH:13]=[C:12]2[C:19](=[CH:18][CH:17]=1)[NH:20][C:1](=[O:8])[C:2](=[O:4])[NH:11]2)#[N:16]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: N#Cc1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C

Procedure:
The title compound was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (3.90 g, 27.6 mmol) and 3,4-diaminobenzonitrile (275 mg, 2.06 mmol) was heated to reflux under N2 for 2 h. The reaction was allowed to cool to room temperature and the solid collected by vacuum filtration and rinsed with EtOH. The yellow brown solid was air dried to yield 156.6 mg (40.8%) which was >98% pure by 1H NMR. An analytically pure sample was prepared by recrystallization of 100 mg in 10 mL glacial acetic acid to give 21.2 mg of fine white crystals. 1H NMR (d6 -DMSO) δ7.20 (d, J=8.1, 1H, ArH), 7.39 (d, J=1.2, 1H, ArH), 7.50 (dd, J=1.2, J=8.4, 1H, ArH), 12.09 (s, 1H, NH), 12.22 (s, 1H, NH). EIMS m/z 187(87, M+), 159 (100, bp), 131(83), 104 (77), 77 (65), 53 (43), 28 (30). EIHRMS calc. for C9H5N3O2 187.0381, found 187.0377.
Reaction SMILES: C([Li])(C)(C)C.I[C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1.[CH2:13]([N:20]1[CH:25]2[CH2:26][CH2:27][CH:21]1[CH2:22][C:23](=[O:28])[CH2:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(OCC)C.C(OCC)(=O)C>[CH2:13]([N:20]1[CH:21]2[CH2:27][CH2:26][CH:25]1[CH2:24][C:23]([C:7]1[CH:12]=[N:11][CH:10]=[CH:9][N:8]=1)([OH:28])[CH2:22]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C1CC2CCC(C1)N2Cc1ccccc1
Reactant: Ic1cnccn1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: OC1(c2cnccn2)CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.1 %

Procedure:
t-Butyl lithium (1.7 M, 1.18 mL, 2.00 mmol) was added dropwise to a solution of 2-iodopyrazine (0.1 mL, 1.0 mmol) in diethyl ether (10 mL) at −78° C. under nitrogen and stirred for 30 minutes. A solution of 8-benzyl-8-aza-bicyclo[3.2.1]octan-3-one (0.19 g, 0.88 mmol) in diethyl ether (5 mL) was added dropwise and stirred at −78° C. for 1 hour. It was warmed to room temperature, water and ethyl acetate were added, the organics separated, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 1:1 ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.06 g). LCMS m/z 296.3 [M+H]+. R.T.=1.97 min (Analytical Method 3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:17])=[C:11]([CH2:13][C:14]([OH:16])=O)[N:12]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[Cl:50][C:51]1[CH:52]=[C:53]([CH:64]=[CH:65][C:66]=1[Cl:67])[C:54]([N:56]1[CH2:61][CH2:60][O:59][C@@H:58]([CH2:62][NH2:63])[CH2:57]1)=[O:55]>CN(C)C=O>[Cl:50][C:51]1[CH:52]=[C:53]([CH:64]=[CH:65][C:66]=1[Cl:67])[C:54]([N:56]1[CH2:61][CH2:60][O:59][C@@H:58]([CH2:62][NH:63][C:14](=[O:16])[CH2:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[O:9][C:10]=2[CH3:17])[CH2:57]1)=[O:55]
Reactant: NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Reactant: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1oc(-c2ccc(F)cc2)nc1CC(=O)NC[C@H]1CN(C(=O)c2ccc(Cl)c(Cl)c2)CCO1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 99.1 %

Procedure:
A mixture of Intermediate 12 (0.015 g), 1-hydroxybenzotriazole (0.0097 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.012 g) and N,N-diisopropylethylamine (0.027 ml) in N,N-dimethylformamide (2 ml) was stirred at 20° C. for 10 min. The mixture was treated with Intermediate 31 (0.023 g) and stirred at 20° C. for 96 h. The mixture was applied sequentially to a sulphonic acid ion exchange cartridge (1 g SCX, prewashed with methanol) and IsoluteR aminopropyl solid phase extraction cartridge (1 g), eluting both cartridges with methanol (5 ml). The solvent was removed in vacuo to give the title compound as a yellow gum (0.032 g).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:13]2[CH3:18])C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:13]2[CH3:18]
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2n1C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2c(O)cccc2n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.8 %

Procedure:
To a solution (200 ml) of ethyl 4-benzyloxy-1-methylindole-2-carboxylate (13.0 g) in ethanol was added 10% palladium-carbon (1.3 g), and the mixture was stirred at room temperature for 8 hr under a hydrogen atmosphere. The palladium-carbon was filtered off with celite and the reaction mixture was concentrated under reduced pressure to give the title compound (8.0 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6](O)=[O:7].CCN(CC)CC.ClC(OCC)=O.[BH4-].[Na+].OS([O-])(=O)=O.[Na+]>C1COCC1.CO>[CH3:1][O:2][C:3](=[O:17])[CH2:4][CH:5]([NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])[CH2:6][OH:7]
Reactant: COC(=O)CC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CCOC(=O)Cl
Agent: O=S(=O)([O-])O
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(CO)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 34.9 %

Procedure:
To a solution of DL-2-tert-butoxycarbonylamino-succinic acid 4-methyl ester (5 g, 0.02 mol) in dry THF (100 mL) at −10° C. Et3N (3.1 mL, 0.022 mol) was added, followed by ethyl chloroformate (2.1 mL, 0.022 mol). After 10 min, NaBH4 (2.27 g, 0.06 mol) was added and then MeOH was dropped into the mixture over a period of 20 min at 0° C. The reaction mixture was stirred for 1 hour at 0° C. and for 2 hours at room temperature then neutralized with sat. aq. NaHSO4. The organic solvent was removed and the product was extracted with AcOEt three times. The combined organic phases were washed consecutively with sat. aq. NaHSO4, water, sat. aq. NaHCO3, water and dried over anh. Na2SO4. The solvent was evaporated and the residue was purified by flash chromatography (n-hexane/AcOEt 5:1), affording the title compound (1.63 g, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:17]#[N:16])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: Fc1cc2cc[nH]c2cc1Br
Solvent: CN(C)C=O
Product: N#Cc1c[nH]c2cc(Br)c(F)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
To 6-bromo-5-fluoro-1H-indole (9.4 g, 43.9 mmol) in DMF (50 mL) at −78° C. was added chlorosulfonyl isocyanate (4.6 mL, 53 mmol). After complete addition the mixture was allowed to warm to room temperature and stir for 2 hrs. The reaction mixture was poured into ice water and stirred for 30 minutes. The precipitate was collected on a filter, washed with ice water and dried in a vacuum oven to give 6-bromo-5-fluoro-1H-indole-3-carbonitrile as a light-beige solid (10.5 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH:12]([CH3:14])[CH3:13])=[C:7]([CH2:15][NH:16]C(OC(C)(C)C)=O)[CH:6]=1.[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28]>C(Cl)Cl>[F:25][C:26]([F:31])([F:30])[C:27]([OH:29])=[O:28].[NH2:16][CH2:15][C:7]1[CH:6]=[C:5]([NH:4][C:3](=[O:24])[O:2][CH3:1])[CH:10]=[CH:9][C:8]=1[O:11][CH:12]([CH3:14])[CH3:13]
Reactant: COC(=O)Nc1ccc(OC(C)C)c(CNC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Nc1ccc(OC(C)C)c(CN)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
8G (17 mg, 0.05 mmol) was dissolved in CH2Cl2 (1 mL) and trifluoroacetic acid (0.2 mL) was added. After stirring at rt for 10 min, the reaction was concentrated to provide 8H (10 mg, 57%). LC-MS: 239.21 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3([CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[NH:35][C:34]4=[O:42])[CH2:26][CH2:25]3)[N:21]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:20]2)=[CH:14][CH:13]=1)([CH3:10])[C:3]([O:5]C(C)(C)C)=[O:4].Cl>O1CCOCC1>[CH3:10][C:2]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[C:23](=[O:24])[C:22]3([CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][N:33]4[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=5[NH:35][C:34]4=[O:42])[CH2:26][CH2:25]3)[N:21]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:20]2)=[CH:14][CH:13]=1)([CH3:1])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(Oc1ccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccccc54)CC3)C2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To tert-butyl 2-methyl-2-(4-((4-oxo-8-(3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)phenoxy)propanoate (0.2 g, 0.3 mmol) was added 4M solution of HCl in dioxane (3 mL). After stirring at room temperature for 4 hours, the reaction mixture was concentrated in vacuo and lyophilized in acetonitrile/water (1:1) to obtain the title compound as a hydrochloride salt (0.19 g, 99%); 1H NMR (DMSO-d6): δ 1.49 (s, 6H), 1.90 (d, 2H, J=14.4 Hz), 2.12-2.15 (m, 2H), 2.87-2.93 (m, 2H), 3.19-3.22 (m, 2H), 3.44-3.72 (m, 4H), 3.90 (t, 2H, J=6.4 Hz), 4.48 (s, 2H), 4.60 (s, 2H), 6.77-6.81 (m, 3H), 6.97-7.05 (m, 5H), 7.19-7.23 (m, 5H), 10.39 (br, 1H), 10.90 (s, 1H), 13.01 (br, 1H); MS for C34H39N5O5 m/z 598.21 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][CH:14]([OH:16])[CH3:15])[C:5]2=[CH:4][CH:3]=1.[CH3:31]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(OCC)C>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]=[C:9]([CH2:17][N:18]3[C:22]4[CH:23]=[N:24][CH:25]=[CH:26][C:21]=4[N:20]([CH:27]4[CH2:29][CH2:28]4)[C:19]3=[O:30])[N:10]([CH2:11][CH2:12][CH2:13][C:14]([OH:16])([CH3:31])[CH3:15])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Reactant: CC(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(O)CCCn1c(Cn2c(=O)n(C3CC3)c3ccncc32)nc2nc(Cl)ccc21

Procedure:
To the alcohol 67 (380 mg, 0.89 mmoles) dissolved in DCM (30 mL) was added dess-martin periodinane (509 mg, 1.35 eq, CAS 87413-09-0). The resulting mixture was stirred at Rt overnight. Diethylether was added (150 mL) and the mixture was stirred for 15 minutes. The mixture was filtrated and the filtrate washed quickly with an aqueous Na2S2O3 solution, dried on Na2SO4, filtrated and evaporated. The resulting solid was purified by flash chromatography (10% MeOH in DCM) and the aldehyde 75 was obtained as a light yellow solid (218 mg, 58% yield). LCMS m/z=425 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[NH:27][CH:26]=[CH:25]2>CN(C=O)C.O>[Br:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[C:28](=[O:32])[N:27]([CH2:8][C:9]([CH3:20])([CH3:19])[CH2:10][O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH:26]=[CH:25]2
Reactant: CC(C)(CBr)CO[Si](C)(C)C(C)(C)C
Reactant: O=c1[nH]ccc2cc(Br)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1ccc2cc(Br)ccc2c1=O
Temperature: 25 °C

Procedure:
Cesium carbonate (53.3 g) and (3-bromo-2,2-dimethylpropoxy)(tert-butyl)dimethylsilane (27.62 g) were added to a solution of 6-bromoisoquinolin-1(2H)-one (Example 26a, 18.33 g) in DMF (125 mL) with stirring at room temperature under nitrogen. The resulting mixture was stirred at 100° C. for 6 h, diluted with water (300 mL), and extracted with diethyl ether (300 mL×3). The combined organic extracts were dried (MgSO4), filtered and evaporated.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([CH:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:3]=1.C(O)C>[Pd].C(N(CC)CC)C>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[CH:3][C:4]=1[CH:13]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)CCCCCC(c1ccccc1)c1cc(Cl)c2ccccc2c1O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CCCCCC(c1ccccc1)c1ccc2ccccc2c1O
Reaction time: 16 h
Yield: 92.6 %

Procedure:
Using ethyl 7-(4-chloro-1-hydroxy-2-naphthyl)-7-phenylheptanoate (4.3 g), 10% palladium-on-carbon (0.4 g), ethanol (90 ml), and triethylamine (10 ml), a catalytic hydrogenation reaction was carried out at 50° C. and atmospheric pressure for 16 hours. The reaction mixture was then filtered and the filtrate was concentrated and applied to a silica gel column (hexane-ethyl acetate) to provide the title compound (3.65 g).
Reaction SMILES: [CH3:1][C:2]1[C:3](OS(C(F)(F)F)(=O)=O)=[C:4]([CH:9]=[C:10]([N+:12]([O-:14])=[O:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1B(O)O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:23]([O:30][C:31]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=1[C:3]1[C:2]([CH3:1])=[CH:11][C:10]([N+:12]([O-:14])=[O:13])=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(C)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)cc1OCc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])cc(C)c1-c1ccc(F)cc1OCc1ccccc1
Yield: 70 %

Procedure:
A mixture of methyl 3-methyl-5-nitro-2-trifluoromethylsulfonyloxybenzoate (Reference Compound No. 1-4-(3), 13.26 g, 38.6 mmol), 2-benzyloxy-4-fluorophenylboronic acid (14.3 g, 58.1 mmol), potassium phosphate (21.3 g, 100 mmol) and tetrakis(triphenylphosphine)palladium(0) (3.23 g, 2.80 mmol) was suspended in anhydrous 1,4-dioxane (200 mL), and then the mixture was refluxed for 3 days. After cooling down, ethyl acetate (500 mL) was added thereto, and then the whole was washed with water (500 mL) and saturated brine (50 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 (10.7 g) as a pale brown solid. (Yield 70%)
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=[C:5]([O:13][CH3:14])[CH:4]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:14][O:13][C:5]1[CH:4]=[C:3]([CH2:2][N:25]2[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:21])[CH2:27][CH2:26]2)[C:11]2[O:10][CH2:9][C:8](=[O:12])[C:7]=2[CH:6]=1
Reactant: COc1cc(CBr)c2c(c1)C(=O)CO2
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)c2c(c1)C(=O)CO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 13.8 %

Procedure:
A solution of 7-(bromomethyl)-5-methoxybenzofuran-3(2H)-one (0.040 g, 0.16 mmol) in methylene chloride (2.0 mL) was added with 1-tert-butoxycarbonylpiperazine (0.032 g, 0.17 mmol), and triethylamine (0.021 g, 0.20 mmol), and the mixture was stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (eluted with chloroform/methanol (95:5)) to obtain tert-butyl 4-[(5-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.008 g, 14%).