Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([S:14][CH3:15])[C:11]2[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=2)[N:5]=1)([OH:3])=O.[CH2:17]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]([CH:30]([NH2:40])[CH2:31][CH2:32][C:33]([O:35]C(C)(C)C)=[O:34])=[O:29])[CH2:24][CH2:23]1)=[O:21])[CH3:18].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.CN(C=O)C.C(OCC)(=O)C>[CH2:17]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]([CH:30]([NH:40][C:1]([C:4]2[CH:13]=[C:12]([S:14][CH3:15])[C:11]3[C:6](=[CH:7][C:8]([Cl:16])=[CH:9][CH:10]=3)[N:5]=2)=[O:3])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])[CH2:26][CH2:27]1)=[O:21])[CH3:18]
Reactant: CCOC(=O)N1CCN(C(=O)C(N)CCC(=O)OC(C)(C)C)CC1
Reactant: CSc1cc(C(=O)O)nc2cc(Cl)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)N1CCN(C(=O)C(CCC(=O)O)NC(=O)c2cc(SC)c3ccc(Cl)cc3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-carboxy-7-chloro-4-mercaptoquinoline HCl salt (75 mg, 0.31 mmol) in DMF (3 mL) was added Mel (0.0425 mL, 2.5 eq.) and cesium carbonate (340 mg, 3.5 eq.). The resulting reaction mixture was stirred at 70° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with water, brine, and dried over sodium sulfate. The solvent was evaporated. Flash column chromatograpgy with 1%–2% MeOH in methylene chloride afforded 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg). To 2-(methoxycarbonyl)-7-chloro-4-methylthioquinoline (40 mg) was added THF:H2O (2:1, 2 mL) and LiOH (10 mg, 1.5 eq.). The reaction mixture was stirred for 2 hours. The pH was adjusted to pH 4.5 with 1N HCl. Extraction with ethyl acetate, washing with brine, drying over sodium sulfate and evaporation gave 2-carboxy-7-chloro-4-methylthioquinoline (29 mg). To a solution of 2-carboxy-7-chloro-4-methylthioquinoline (29 mg) in THF (6 mL) and DMF (1 mL) was added 4-ethoxycarbonyl-1-(1-amino-3-(1,1-dimethylethoxycarbonyl)propyl)carbonylpiperazine (46 mg, 1.1 eq.), EDCl (28 mg, 1.2 eq.), and HOBt (18 mg, 1.1 eq.). The resulting reaction mixture was stirred at ambient temperature overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 1%–3% MeOH in CH2Cl2afforded the product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-(1,1-dimethylethoxycarbonyl)propyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline (36 mg). The product (32 mg) was treated with TFA:CH2Cl2 (1:1, 1 mL) at ambient temperature for 2 hours. The solvents were then evaporated to afford the desired product, 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-3-carboxypropyl]aminocarbonyl-7-chloro-4-(methylthio)quinoline; NMR (CDCl3) 1.35 (t, 3), 2.10 (m, 1), 2.25 (m, 1), 2.55 (m, 2), 2.7 (s, 3), 3.4–3.9 (m, 8), 4.2 (q, 2), 5.3 (m, 1), 7.55 (d, 1), 7.9 (s, 1), 8.02 (d, 1), 8.15 (s, 1) ppm;
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:30])[N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:32]([Mg]Cl)([CH3:35])([CH3:34])[CH3:33].[Cl-].[NH4+]>C1COCC1>[CH3:33][C:32]([CH3:35])([CH3:34])[C:3](=[O:2])[C:4]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:30]
Reactant: CC(C)(C)[Mg]Cl
Reactant: COC(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a solution of 0.16 g (0.38 mmol) of 5 in anhydrous THF (2 mL) was added dropwise at −78° C. a 2.0M solution of 0.21 mL (0.42 mmol) of tert-butyl magnesium chloride in THF, and the mixture was stirred for 3 hours at −78° C. The solution was poured over saturated ammonium chloride (50 mL) and extracted with EtOAc (3×100 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:4) to yield 0.13 g (76.5%) of 6 as a clear oil. TLC Rf=0.62 (EtOAc/Hexanes, 1:4) 1H NMR (CDCl3, 300 MHz): δ 1.40 (s, 9H); 1.36–2.29 (m, 9H); 2.62–2.82 (m, 4H); 3.39–3.52 (m, 2H); 5.18 (m, 1H); 5.31 (d, 1H, J=6.2); 5.42 (d, 1H, J=5.2); 7.42–7.26 (m, 10H); Anal. (C29H37NO3) C, H, N.
Reaction SMILES: Cl.[CH:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:24][NH:23][CH2:22]4)[CH:20]=3)[N:13]3[CH:28]=[CH:29][N:30]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3].C(#N)C.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:46][C:47]([F:50])([F:49])[F:48])(=O)=O>C(Cl)Cl>[CH:2]([N:5]1[CH:9]=[C:8]([C:10]2[N:15]=[C:14]([C:16]3[CH:17]=[N:18][N:19]([C:21]4([CH2:25][C:26]#[N:27])[CH2:22][N:23]([CH2:46][C:47]([F:50])([F:49])[F:48])[CH2:24]4)[CH:20]=3)[N:13]3[CH:28]=[CH:29][N:30]=[C:12]3[CH:11]=2)[CH:7]=[N:6]1)([CH3:4])[CH3:3]
Reactant: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CNC4)c3)n2)cn1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)n1cc(-c2cc3nccn3c(-c3cnn(C4(CC#N)CN(CC(F)(F)F)C4)c3)n2)cn1
Yield: 47 %

Procedure:
To a flask charged with 2-(3-(4-(7-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile hydrochloride (0.050 g, 0.10 mmol) was added 1 mL of acetonitrile, potassium carbonate (0.10 g, 0.75 mmol), and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.040 g, 0.17 mmol) at ambient temperature with stirring. The reaction flask was then sealed and allowed to proceed at ambient temperature over the weekend. The reaction was diluted with DCM and the suspension was loaded directly onto a silica gel column pre-wetted and eluted with 75% ethyl acetate in Hexanes with 1% ammonium hydroxide to afford the title compound (0.022 g, 0.047 mmol, 47% yield). MS (apci) m/z=470.2 (M+H).
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH:3]([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:1][CH:2]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(C)N
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)C(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1,2-dimethylpropylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 mL) was slowly added a solution of 1,3-propane sultone (13.7 g, 110 mmol) in THF (20 mL). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with THF (50 mL) and EtOH (50 mL). The resulting solid was dried in vacuo, to afford compound DQ (17.5 g, 76%). 1H NMR (D2O, 500 MHz) δ ppm 3.07 (m, 3H), 2.88 (t, 2H, J=7.3 Hz), 1.97 (m, 3H) 1.10 (d, 3H, J=6.8 Hz), 0.85 (d, 3H, J=6.8 Hz), 0.81 (d, 3H, J=6.8 Hz). 13C NMR (D2O, 125 MHz) δ ppm 59.79, 48.19, 44.18, 29.72, 21.51, 18.44, 15.02, 10.71. ES-MS 232 (M+Na).
Reaction SMILES: [CH3:1][Si:2]1([CH3:12])[O:7][Si:6]([CH3:9])([CH3:8])[O:5][Si:4]([CH3:11])([CH3:10])[O:3]1.[C:13]([O:18][Si:19](C)([CH3:21])[CH3:20])(=[O:17])[C:14]([CH3:16])=[CH2:15].F[C:24](F)(F)S(O)(=O)=O>C(N(CC)CC)C>[CH3:24][Si:2]([CH3:12])([CH3:1])[O:3][Si:4]([CH3:11])([CH3:10])[O:5][Si:6]([CH3:9])([CH3:8])[O:7][Si:19]([CH3:21])([CH3:20])[O:18][C:13](=[O:17])[C:14]([CH3:16])=[CH2:15]
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O1
Reactant: C=C(C)C(=O)O[Si](C)(C)C
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C

Procedure:
5 g of hexamethylcyclotrisiloxane, 3.5 g of trimethylsilyl methacrylate, 0.016 g of trifluoromethane sulfonic acid were stirred for 24 h at room temperature. 0.5 ml of triethylamine was then added, and the salts were filtered to furnish nonamethyl-1-methacryloyloxy-tetrasiloxane.
Reaction SMILES: [C:1]([OH:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[OH-].[CH2:16]([N+:20]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>CO>[C:1]([O-:14])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11].[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32].[CH2:29]([N+:20]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:30][CH2:31][CH3:32]
Reactant: O=C(O)CCCCCCCCC(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: O=C([O-])CCCCCCCCC(=O)[O-]

Procedure:
The procedure used was the same as described above by titration of sebacic acid (0.814 g, 4.02×10-3 mol) with 1 M tetrabutylammonium hydroxide solution in methanol. After removal of solvent, a quantitative yield (2.75 g) of salt was obtained. FIG. 45 shows a 1H NMR spectrum and FIG. 46 shows a 13C NMR spectrum of the salt in CDCl3.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:3]=1[C:4]([NH:6][C:7]1[C:8]([C:12]2[NH:16][C:15]3[CH:17]=[CH:18][C:19]([C:21]([N:33]4[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]4)=[O:23])=[CH:20][C:14]=3[N:13]=2)=[N:9][NH:10][CH:11]=1)=[O:5]
Reactant: CN1CCNCC1
Reactant: O=C(O)c1ccc2[nH]c(-c3n[nH]cc3NC(=O)c3c(F)cccc3F)nc2c1
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CN1CCN(C(=O)c2ccc3[nH]c(-c4n[nH]cc4NC(=O)c4c(F)cccc4F)nc3c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 26.5 %

Procedure:
A mixture of 2-[4-(2,6-difluoro-benzoylamino)-1H-pyrazol-3-yl]-1H-benzimidazole-5-carboxylic acid (115 mg, 0.30 mmol), 1-methyl-piperazine (50.0 μL, 0.45 mmol), EDC (104 mg, 0.54 mmol) and HOBt (73.0 mg, 0.54 mmol) in DMF (5 ml) was stirred at ambient temperature for 14 h. The residue was reduced in vacuo, taken up in EtOAc and washed with water and brine, dried (MgSO4) and reduced in vacuo to give 2,6-difluoro-N-{3-[5-(4-methyl-piperazine-1-carbonyl)-1H-benzimidazol-2-yl]-1H-pyrazol-4-yl}-benzamide (37 mg, 26%) as a pale yellow solid. (LC/MS: Rt 1.78, [M+H]+ 466.09).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[I:28]N1C(=O)CCC1=O.ClC(Cl)C(O)=O>ClC(Cl)C>[Br:1][C:2]1[C:3](=[O:27])[N:4]([C:19]2[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=2[F:26])[C:5]([CH3:18])=[C:6]([I:28])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Reactant: O=C1CCC(=O)N1I
Agent: O=C(O)C(Cl)Cl
Solvent: CC(Cl)Cl
Product: Cc1c(I)c(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1c(F)cccc1F
Yield: 32.4 %

Procedure:
A solution of 3-Bromo-4-[(2,4-difluorobenzyl)oxy]-1-(2,6-difluorophenyl)-6-methylpyridin-2(1H)-one (0.3 g, 0.00068 mol) and N-iodosuccinimide (0.22 g, 0.00098 mol) in dichloroethane, containing dichloroacetic acid (0.1 mL) was heated to reflux for 6 h under argon atmosphere. After the removal of the solvents under reduced pressure, the residue was partitioned between, dichloromethane (20 mL) and 5% sod. sulphite (10 mL). The organic phase was washed with water, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (25% EtOAc in hexane) to afford the title compound (0.125 g, 32%) as a pale yellow powder: 1H NMR (CDCl3/400 MHz) δ 7.68 (m, 1H), 7.46 (m, 1H), 7.11 (m, 2H), 6.95 (m, 1H), 6.85 (m, 1H), 5.23 (s, 2H), and 2.38 (s, 3H); 19F NMR (CDCl3) δ−109.15 (m), −112.95 (m), −118.50 (m); ES-HRMS m/z 567.9014 (M+H C19H12NO2F4BrI requires 567.9027).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:8][NH:7][CH2:6][C@H:5]2[C:9]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=3[O:11][CH2:12][C@H:4]12.[Br:19]Br>C(O)(=O)C>[Br:19][C:13]1[C:10]2[O:11][CH2:12][C@@H:4]3[C@@H:3]([CH2:2][OH:1])[CH2:8][NH:7][CH2:6][C@H:5]3[C:9]=2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=1
Reactant: BrBr
Reactant: COc1ccc2c(c1)[C@@H]1CNC[C@H](CO)[C@H]1CO2
Solvent: CC(=O)O
Product: COc1cc(Br)c2c(c1)[C@@H]1CNC[C@H](CO)[C@H]1CO2
Reaction time: 1.5 h

Procedure:
To a stirred solution of 8.66 g (±)-[4R*,4aS*,10bR*]-4-(hydroxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2H-[1]benzopyrano[4,3-c]pyridine in 90 ml acetic acid is added dropwise 1.96 ml bromine at 25°. After stirring 1.5 h, the solution is concentrated under reduced pressure and treated with 100 ml 2N NaOH. The aqueous phase is extracted with three 100 ml portions of CH2Cl2. The organic extracts are dried over Na2SO4, filtered, concentrated and flash chromatographed with CH2Cl2 /ammonia saturated methanol (90:10) to give the title compound as the major product; m.p. 281°-285° dec (HCl salt).
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Na+].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:26])([CH3:25])[CH:23]=O)=[CH:18][CH:17]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCOCC>[CH3:25][C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)=[CH:17][CH:18]=1)([CH3:26])[CH:23]=[CH2:1]
Reactant: CC(C)(C=O)c1ccc(-c2ccco2)cc1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC(C)(C)c1ccc(-c2ccco2)cc1
Reaction time: 0.5 h
Yield: 111 %

Procedure:
To a cooled slurry (0° C.) of methyltriphenylphosphonium bromide (18.8 g, 52.6 mmol) in THF (60 mL) is added dropwise (1M)sodium bis(trimethylsilyl)amide (52.6 mL, 52.6 mmol) and the resulting mixture stirred for 30 min. To the mixture is added a solution of 2-(4-furan-2-yl-phenyl)-2-methyl-propionaldehyde (5.64 g, 26.3 mmol) (reference example 52) in THF (25 mL) and the resulting mixture stirred for 45 min. The mixture is diluted with ether, washed with water and brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (eluting with 10% ethyl acetate in hexanes) to give 6.2 g of title compound as a yellow oil. 1H NMR (CDCl3) δ 1.41 (s, 6H), 5.03 (s, 1H), 5.08 (d, J=7 Hz, 1H), 6.03 (m, 1H), 6.45 (m, 1H), 6.60 (d, J=3 Hz, 1H), 7.36 (d, 8 Hz, 2H), 7.44 (s, 1H), 7.60 (d, J=8 Hz, 2H). MS (EI) m/z 212 (M+).
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10]Br.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][NH2:23].C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][CH2:21][CH2:22][N:23]1[CH2:10][C:5]2[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:3]1=[O:12]
Reactant: NCCCc1ccccc1Cl
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccccc1Cl
Temperature: 100 °C
Reaction time: 2 h
Yield: 53.2 %

Procedure:
A mixture of 2-bromomethyl-benzoic acid methyl ester (0.115 g, 0.5 mmol), 3-(2-chloro-phenyl)-propylamine (0.102 g, 0.6 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (3 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-(2-chloro-phenyl)-propyl]-2,3-dihydro-isoindol-1-one (0.076 g, 51%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.99 (m, 2H), 2.79 (t, 2H), 3.69 (t, 2H), 4.41 (s, 2H), 7.14-7.58 (m, 7H), 7.88 (d, 1H). GC-MS: m/z 285 (M)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]1(=O)[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>C(O)(=O)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]2[C:14](=[O:15])[C:13]3[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11]2=[O:16])=[CH:5][CH:4]=1
Reactant: NNc1ccc(Br)cc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)N1Nc1ccc(Br)cc1
Temperature: 130 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
To a stirred solution of (4-bromophenyl)hydrazine hydrochloride (0.5 g, 2.2 mmol) in glacial acetic acid (8 mL) was added phthalic anhydride (0.398 g, 2.690 mmol), and the reaction mixture was stirred at 130° C. for 1 h under a nitrogen atmosphere. The reaction mixture was quenched with satd aq. NaHCO3 solution and filtered to give a solid. Purification by column chromatography (SiO2, 0-10% EtOAc in petroleum ether) afforded the title compound as a solid (60 mg, 84%): mp 205-206° C.; 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.99 (m, 4H), 7.32 (d, J=8.8 Hz, 2H), 6.79 (d, J=8.8 Hz, 2H); ESIMS m/z 314.95 ([M−H]−).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=4)=[N:14][NH:13][C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32](I)[CH3:33].O>CN(C)C=O>[CH3:1][O:2][C:3]1[C:4]([O:24][CH3:25])=[CH:5][C:6]2[C:7]3[C:15]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)=[N:14][N:13]([CH2:32][CH3:33])[C:8]=3[CH:9]=[N:10][C:11]=2[CH:12]=1
Reactant: CCI
Reactant: COc1cc2ncc3[nH]nc(-c4ccc(C#N)cc4)c3c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(-c2ccc(C#N)cc2)c2c3cc(OC)c(OC)cc3ncc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 34000 %

Procedure:
4-(7,8-Dimethoxy-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (132 mg, 400 μmol) is dissolved in N,N-dimethylformamide (5 ml). Potassium carbonate (111 mg, 800 μmol) and ethyl iodide (37 μl, 440 μmol) is subsequently added. The reaction mixture is stirred at room temperature for 3 h. The mixture is subsequently poured into water (100 ml) and extracted twice with ethyl acetate (100 ml each time). The combined organic phases are washed once with water (50 ml), dried over Na2SO4, filtered with suction, and the filtrate obtained is evaporated to dryness in vacuo. The residue is chromatographed over flash silica gel (solvent gradient n-heptane/0-100% by vol. of ethyl acetate/ethanol 0-30% by vol.). After evaporation of the product fractions, the residue is dissolved in a little tetrahydrofuran, and 2-propanol (5 ml) is added, and the mixture is evaporated. The precipitate obtained is filtered off with suction and dried in a high vacuum, giving the title compound 4-(7,8-dimethoxy-3-ethyl-3H-pyrazolo[3,4-c]quinolin-1-yl)benzonitrile (49 mg, 136 mmol) as a solid having a melting point of 227.4° C. MS: 359.0 (M+H+), TLC (HPTLC): Rf=0.51 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [O:1]1[C@@H:7]2[C@@H:2]1[C:3]([CH3:18])([CH3:17])[O:4][C:5]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([O:15][CH3:16])=[CH:8][C:6]=12.Cl([O-])(=O)(=O)=O.[Li+].[Cl-].[NH4+:26]>O1CCOCC1>[CH3:16][O:15][C:9]1[C:10]([N+:12]([O-:14])=[O:13])=[CH:11][C:5]2[O:4][C:3]([CH3:18])([CH3:17])[C@H:2]([OH:1])[C@@H:7]([NH:26][CH2:2][CH2:7][C:6]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:5]=3)[C:6]=2[CH:8]=1
Reactant: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@@H]1O[C@@H]21
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Li+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc2c(cc1[N+](=O)[O-])OC(C)(C)[C@H](O)[C@H]2NCCc1ccccc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of (3R*,4S*)-3,4-epoxy-6-methoxy-2,2-dimethyl-7-nitro-3, 4-dihydro-2H-1-benzopyran (2.50 g, 9.95 mmol) in 1,4-dioxane (5.0 mL), lithium perchlorate (1.06 g, 9.95 mmol) and 4-(phenylethyl)amine (1.50 mL, 11.9 mmol) were added at room temperature and the mixture was stirred at 80° C. for 1 hour. Upon the completion of the reaction, an aqueous solution of saturated ammonium chloride was added to the reaction solution, and the resulting solution was extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by column chromatography (hexane/ethyl acetate=6/4) and the aimed product was obtained as orange amorphous substance (quantitative yield).
Reaction SMILES: [CH2:1]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:9][CH2:10][CH2:11][C:12]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)OCC[O:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O.C(OCC)(=O)C>[CH2:1]([N:8]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[NH:9][CH2:10][CH2:11][C:12](=[O:13])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)NCCC1(c2ccccc2)OCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)NCCC(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 65C (3.86 g) in acetone (5 mL) and water (5 mL) was added pyridinium p-toluenesulfonate (120 mg). The mixture was stirred at 100° C. in a Biotage Initiator microwave reactor for 10 minutes. The mixture was diluted with ethyl acetate (200 mL) and washed with water and brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the crude product which was used without further purification in the next reaction.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]2[CH:13]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:14][C:15]([C:24]([O:26][CH3:27])=[O:25])=[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:11]23[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].C(OCC)C>C1COCC1.O>[CH2:1]([N:8]1[CH:12]2[CH:13]([CH2:28][C:29]([CH3:40])([CH3:39])[CH2:30][OH:31])[CH2:14][C:15]([C:24]([O:26][CH3:27])=[O:25])=[C:16]3[NH:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=4[C:11]23[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C2Nc3ccccc3C23CCN(Cc2ccccc2)C3C(CC(C)(C)CO[Si](C)(C)C(C)(C)C)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C1=C2Nc3ccccc3C23CCN(Cc2ccccc2)C3C(CC(C)(C)CO)C1
Temperature: 20 °C
Reaction time: 1.5 h
Yield: 97.3 %

Procedure:
To a solution of 873 mg (1.56 mmol) of methyl 3-benzyl-1,2,3,3a,4,5-hexahydro-4-[2,2-dimethyl-3-(t-butyldimethylsilyloxy)propyl]-7H-pyrrolo(2,3-d)carbazole-6-carboxylate in 30.5 mL of THF and 15 mL of water was added 5.24 g (20 eq) of p-toluenesulfonic acid. The reaction mixture was stirred for 90 min. at 20° C. and saturated aqueous K2CO3 solution was added until a pH=9-10 was obtained. Ethyl ether (100 mL) was added and the two layers were separated. The aqueous layer was extracted once with 100 mL of ethyl ether and twice with 100 mL of CH2Cl2. The combined organic layers were dried over MgSO4 and the solvents evaporated in vacuo (aspirator). The crude product was purified by column chromatography on silica gel (40 g). Elution with CH2Cl2 followed by ethyl ether gave 0.678 g (97.5%) of the title compound as a white foam. TLC: (Silica) Rf 0.50 (ethyl ether), detection with CAS (blue with developing yellow center), UV (long and short wave length).