Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1.C(N(C(C)C)CC)(C)C.[O:28]1[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH:12]3[CH2:17][CH2:16][N:15]([CH:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)[CH2:14][CH2:13]3)[C:6]=2[CH:5]=[C:4]([CH3:18])[CH:3]=1
Reactant: O=C1CCOCC1
Reactant: Cc1cc(F)c2[nH]c(=O)n(C3CCNCC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(F)c2[nH]c(=O)n(C3CCN(C4CCOCC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
4-Fluoro-6-methyl-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one (12.5 mmol, 3.6 g) (D5a) was dissolved in dichloromethane (50 ml), diisopropylethylamine (3 eq., 37.6 mmol, ˜6.4 ml), and tetrahydro-4H-pyran-4-one (4 eq., 50 mmol, ˜5 g) were added in that order at room temperature; sodium triacetoxyborohydride (3 eq., 37.6 mmol, ˜8 g) was added at room temperature and the mixture was stirred at room temperature for one overnight. The reaction mixture was diluted with dichloromethane (100 ml) and quenched with NaHCO3 (saturated aqueous solution); methanol was added to dissolve the solid which developed in the organic layer; the two phases were separated and the aqueous phase was extracted with dichloromethane (2×); the combined organics were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated to afford 3.8 g, 92%. The material was triturated with diethyl ether and filtered to afford 3.6 g title compound. This was dissolved in MeOH/DCM and 2 eq of HCl (1M in Et2O) were added. The mixture was stirred at room temperature for 10 minutes, solvent was evaporated and the solid was triturated with Et2O to afford another batch, 3.8 g, pale grey solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[Li]CCCC.CCCCCC.[F:34][C:35]1([F:46])[C:39]([F:40])=[C:38](F)[C:37]([F:43])([F:42])[C:36]1([F:45])[F:44]>C1COCC1>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[S:5][C:4]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)=[CH:3][C:2]=2[C:38]2[C:37]([F:43])([F:42])[C:36]([F:44])([F:45])[C:35]([F:34])([F:46])[C:39]=2[F:40])=[CH:8][CH:9]=1
Reactant: FC1=C(F)C(F)(F)C(F)(F)C1(F)F
Reactant: COc1ccc(-c2sc(-c3ccc(C#N)cc3)cc2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-c2sc(-c3ccc(C#N)cc3)cc2C2=C(F)C(F)(F)C(F)(F)C2(F)F)cc1
Temperature: -50 °C
Reaction time: 0.25 h
Yield: 61.3 %

Procedure:
To a solution of (57) (5.0 g, 13.50 mmol) in dry THF (300 mL) was slowly added n-BuLi hexane solution (2.0 M, 7.43 mL, 14.85 mmol) at −50° C. under an argon atmosphere. The solution was stirred for 15 minutes at −50° C. After the addition of octafluorocyclopentene (5.44 mL, 40.5 mmol), the reaction mixture was stirred for 2 h. The reaction was quenched by the addition of methanol and warmed to RT. The solvents were removed by rotary evaporation and flash chromatography (10% EtOAc in hexanes) afforded a dark yellow oil (4.0 g, 61.3%).
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]1[NH:17][C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:35]I>CN(C)C=O>[CH2:1]([O:8][C:9]([CH2:11][NH:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH3:35])[C:19]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:18]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: O=C(CNCCCc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(CCCNCC(=O)OCc2ccccc2)nc(-c2ccccc2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
A solution of 6.4 g (0.015 mol) of 2-[3-(N-benzyloxycarbonylmethylamino)propyl]-4,5-diphenylimidazole in 120 ml of dimethylformamide is treated at 15°-20° under argon with 0.018 mol of sodium hydride (0.8 g of a 55% dispersion in mineral oil) and thereupon stirred at room temperature for a further 30 minutes. A solution of 1.85 ml (0.03 mol) of methyl iodide in 10 ml of dimethylformamide is added thereto at 15°-20° within 15 minutes and the mixture is stirred at room temperature for a further 3 hours. After concentration under reduced pressure the residue is partitioned between ice-water and ethyl acetate. The organic phase, dried over sodium sulphate, is evaporated and the residual oil is chromatographed on 100 g of silica gel with ethyl acetate as the elution agent. The 2-[3-(N-benzyloxycarbonylmethylamino)propyl]-1-methyl-4,5-diphenylimidazole (6.4 g of oil) obtained is dissolved in 300 ml of methanol and hydrogenated at room temperature and normal pressure in the presence of 1 g of 5% palladium-on-active charcoal. The product, isolated in the usual manner, is chromatographed on 70 g of silica gel with methanol/concentrated ammonium hydroxide (100:1) as the elution agent. There are obtained 2.95 g (64%) of 1-methyl-2-[3-(methylamino)propyl]-4.5-diphenylimidazole as a thick oil.
Reaction SMILES: [OH:1][CH:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8].[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(OCC)C>[C:29]([O:1][CH:2]([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[S:7]([CH3:10])(=[O:9])=[O:8])(=[O:31])[CH3:30]
Reactant: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC(O)COc1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CC(=O)OC(CCCN(CCCCCCC(=O)O)S(C)(=O)=O)COc1ccc(F)cc1
Reaction time: 18 h

Procedure:
A mixture of 7-{N-[4-hydroxy-5-(4-fluorophenoxy)-pentyl]methanesulfonamido}heptanoic acid (12.3 g., 0.03 mole) (Example 1, Step E) and acetic anhydride (6.1 g., 0.06 mole) is kept at room temperature for 18 hours. This mixture is taken up in 80 ml. of ethyl ether. The solution is extracted with an ice-cold solution of 8 g. of sodium hydroxide in 150 ml. of water. The basic solution is separated and acidified with concentrated hydrochloric acid. The crude product that separates is extracted into ether, washed with water and dried over sodium sulfate. The ether is evaporated and the residual oil is purified by chromatography on silica gel using 2% methanol in chloroform as the eluting solvent. There is obtained 7-{N-[4-acetoxy-5-(4-fluorophenoxy)pentyl]methanesulfonamido}-heptanoic acid as a viscous oil.
Reaction SMILES: C(O[C:4](=S)[S:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Br:16])[CH:7]=1)C.[OH-].[K+].[CH2:20](Br)C.C([O-])([O-])=O.[K+].[K+]>O.CCO>[Br:16][C:8]1[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=[C:6]([S:5][CH2:4][CH3:20])[CH:7]=1
Reactant: CCOC(=S)Sc1cc(Br)cc(C(F)(F)F)c1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCSc1cc(Br)cc(C(F)(F)F)c1
Yield: 45.3 %

Procedure:
Dithiocarbonic acid S-(3-bromo-5-trifluoromethyl-phenyl) ester O-ethyl ester (3.3 g, 10.3 mmoles) was dissolved into 30 mL of EtOH, 10 mL of H2O, and was sealed under nitrogen. To this stirring mixture was added KOH (2.8 g, 50 mmoles) and this mix was stirred at reflux (under nitrogen) for 12 hours. After this period the reaction mixture was evaporated in vacuo and combined with 50 mL of water. The pH was adjusted to <2 using 6N HCl and the resulting mixture was extracted with diethyl ether (3×50 mL). The combined ethereal layer was washed with brine and dried over anhydrous MgSO4. Following evaporation in vacuo the crude thiol was dissolved into 50 mL of acetone. Ethyl bromide (1.5 mL, 20.1 mmoles) and K2CO3 (5 g, 36.2 mmoles) were added, and the mixture was stirring at ambient temperature (under nitrogen) for 6 hours. After this period the mixture was gravity filtered, and evaporated in vacuo to yield crude product. The crude product was purified using flash silica chromatography (0-1% EtOAc/Hexane) to yield 1-bromo-3-ethylsulfanyl-5-trifluoromethyl-benzene (1.33 g, 45% yield) as a yellowish liquid. 1H-NMR (CDCl3): δ 7.56 (s, 1H), 7.52 (s, 1H), 7.43 (s, 1H), 3.0 (q, J=7.3 Hz, 2H), 1.36 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:35][C:36]1[C:41]([O:42][CH3:43])=[CH:40][C:39]([O:44][CH3:45])=[CH:38][C:37]=1[O:46][CH3:47])[C:10](=[O:34])[CH2:11][CH2:12][C:13]1([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]C)=[O:31])=[CH:26][CH:25]=2)[C:18](=[O:19])[O:17]C(C)(C)[O:15][C:14]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCOCC1.[OH-].[Na+]>O>[CH2:1]([O:8][N:9]([CH2:35][C:36]1[C:37]([O:46][CH3:47])=[CH:38][C:39]([O:44][CH3:45])=[CH:40][C:41]=1[O:42][CH3:43])[C:10](=[O:34])[CH2:11][CH2:12][C:13]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=1)([C:14]([OH:22])=[O:15])[C:18]([OH:19])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(CC2(CCC(=O)N(Cc3c(OC)cc(OC)cc3OC)OCc3ccccc3)C(=O)OC(C)(C)OC2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CCC(Cc2ccc(C(=O)O)cc2)(C(=O)O)C(=O)O)c(OC)c1
Temperature: 100 °C
Yield: 91 %

Procedure:
To 5-{3-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropyl}-2,2-dimethyl-5-[4-(methoxycarbonyl)phenyl]methyl-[1,3]dioxane-4,6-dione (5.38 g, 8.3 mmol) were added 50 mL of water, then 40 mL of 1,4-dioxane and finally a solution of NaOH (1.65 g, 41.4 mmol) in 20 mL of water. This mixture was heated at 100° C. for 2 h. The solution was then allowed to cool to rt. The solvent was removed under reduced pressure and the residue was partitioned between 100 mL of 10% KHSO4 and 100 mL of EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated to give 4.5 g of 2-{3-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropyl}-2-(4-carboxyphenyl)methyl-malonic acid as an off white powder (95% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1.C([Li])CCC.[CH:20]([O:23][C:24]1[C:25](=O)[C:26](=[O:32])[C:27]=1[O:28]C(C)C)([CH3:22])[CH3:21]>O1CCCC1>[CH:20]([O:23][C:24]1[C:27](=[O:28])[C:26](=[O:32])[C:25]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)([CH3:22])[CH3:21]
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Reactant: Cc1ccc(-c2ccccc2Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(-c2ccccc2-c2c(OC(C)C)c(=O)c2=O)cc1
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
To a solution of 2-bromo-4'-methylbiphenyl (9.0 g; obtainable as described in Example 3 (a) and in Gomberg and Pernert, J. Am. Chem. Soc. (1926) Vol 48 p 1373) in tetrahydrofuran (60 ml) was added butyllithium (2.5M in hexanes, 15.3 ml) dropwise at -70° C. under a nitrogen atmosphere over a period of 3 minutes. The mixture was stirred for 10 minutes at -70° C. then added to a solution of 3,4-diisopropoxycyclobut-3-ene-1,2-dione (7.6 g) in tetrahydrofuran (100 ml) at -70° C. under nitrogen over a period of 1 minute. The solution obtained was stirred for an additional 30 minutes at -70° C. then quenched with trifluoroacetic anhydride (6.4 ml), followed by saturated aqueous ammonium chloride (40 ml). The resulting mixture was allowed to warm to ambient temperature, then partitioned between diethyl ether (300 ml) and aqueous sodium bicarbonate (5%, 300 ml). The aqueous layer was re-extracted with diethyl ether (200 ml) and the combined organic layers were washed with brine, dried over magnesium sulphate, and evaporated to give a yellow oily solid which was purified by flash chromatography on silica gel (eluting with 10% rising to 20% ethyl acetate in petroleum ether (b.p. 60°-80° C.)) to give the intermediate compound 3-isopropoxy-4-(4'-methylbiphenyl-2-yl)cyclobut-3-ene-1,2-dione as a yellow solid (6.7 g), substantially identical to the product of Example 1(b). The above method is described in Reed et al, Journal of Organic Chemistry (1988) Vol.53, p 2477.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH3:9].[Cl:10]N1C(=O)CCC1=O.O.[OH-].[NH4+]>CS(O)(=O)=O>[NH2:1][C:2]1[C:7]([Cl:10])=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1c(N)cccc1O
Agent: CS(=O)(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Cc1c(O)ccc(Cl)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
To a stirred solution of 3-amino-o-cresol (60 g) in anhydrous methanesulfonic acid (300 ml) was added N-chlorosuccinimide (68.3 g in five equal portions) over 2h and 10 min, keeping the reaction temperature between 10 and 12° C. by use of a cooling bath. The dark mixture was allowed to stir overnight and warm to room temperature. It was then added to 1000 ml water with stirring (final temperature approx. 51 ° C.). Concentrated ammonium hydroxide (370 ml) was added with stirring, keeping the temperature between 50 and 60° C. by use of a cooling bath. The product crystallized out near the end of the addition at 50-53° C. The product slurry was cooled to ice bath temperature and held for 1 h. The product, isolated in 70.5% yield by filtration, washing with ice water, and drying in vacuo at 50° C., was 98.44% pure by area-normalized HPLC with correction for relative response factors. It contained only 0.8% of the 6-chloro isomer and 0.68% of the 4,6-dichloro impurity. Recrystallization from isopropanol-water with charcoal treatment gave, in 94% recovery, purified product that was 99.67% pure by HPLC (mp 143-144° C.).
Reaction SMILES: C([Mg]Cl)(C)C.CON(C)[C:9](=[O:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH3:11].[O:22]1[CH2:27][CH2:26][O:25][C:24]2[CH:28]=[C:29]([Mg]Br)[CH:30]=[CH:31][C:23]1=2.Cl>C1COCC1.O>[O:22]1[C:23]2[CH:31]=[CH:30][C:29]([C@@H:9]([OH:20])[C@@H:10]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:16])([CH3:17])[CH3:18])[CH3:11])=[CH:28][C:24]=2[O:25][CH2:26][CH2:27]1
Reactant: Br[Mg]c1ccc2c(c1)OCCO2
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)[C@H](O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Isopropylmagnesium chloride, 2M in THF (6.5 mL, 13.00 mmol) was added to a suspension of (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (3 g, 12.92 mmol) in THF (30 mL) keeping the temperature below −10° C. (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)magnesium bromide, 0.7M in THF (20 mL, 14.00 mmol) was added. The reaction mixture was stirred at room temperature for 17 hours. 1N HCl (300 mL) was cooled on ice bath to +10° C., the reaction mixture was poured into the acidic water solution and extracted with TBME=tert-butyl methyl ether. The ether phases were washed with water, brine and dried (Na2SO4). Filtration and evaporation of solvents afforded a crude product as a slightly yellow oil that was purified by flash chromatography using TBME:Heptane=1:2 as eluent.
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH2:18][C:19]1([CH3:24])[O:23][CH2:22][CH2:21][O:20]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:17].C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[CH3:1][C:2]([CH3:25])([CH2:18][C:19]1([CH3:24])[O:23][CH2:22][CH2:21][O:20]1)[CH2:3][N:4]1[C:16]2[C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:9]([O-:34])=[CH:8][C:7]=2[N:6]=[C:5]1[CH3:17]
Reactant: Cc1nc2cnc3ccccc3c2n1CC(C)(C)CC1(C)OCCO1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: Cc1nc2c[n+]([O-])c3ccccc3c2n1CC(C)(C)CC1(C)OCCO1

Procedure:
The general method described in Steps 9 and 10 of Example 1 was used to aminate 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinoline (5.80 g, 17.1 mmol) by reaction with m-CPBA (7.5 g) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-5-oxido-1H-imidazo[4,5-c]quinoline followed by reaction with p-toluenesulfonyl chloride (5.7 g, 30 mmol) and ammonium hydroxide solution (150 mL) to provide 1-[2,2-dimethyl-3-(2-methyl-[1,3]dioxolan-2-yl)propyl]-2-methyl-1H-imidazo[4,5-c]quinolin-4-amine as a light brown solid after recrystallization from a mixture of acetonitrile, methanol, and water, mp 209-211° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH3:12][O:13][C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)=[O:15]>N1C=CC=CC=1>[CH3:12][O:13][C:14]([C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[CH2:5]3)=[O:21])=[CH:18][CH:17]=1)=[O:15]
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C(=O)Nc2ccc3c(c2)CC(=O)N3)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.4 %

Procedure:
A mixture of 82.0 mg 5-amino-2-oxindole and 131.0 mg 4-methoxycarbonylbenzoyl chloride in pyridine was stirred at room temperature for 3 hr and poured into ice water. The precipitate was filtered, washed with water and dried in a vacuum oven to give 138.0 mg of 5-(4-methoxycarbonylbenzamido)-2-oxindole (81% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[C:13]4[CH:25]=[CH:24][CH:23]=[N:22][C:14]=4[NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:11]3=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:5]=[CH:4][C:3]=1[C:33]1([NH:37]C(=O)OC(C)(C)C)[CH2:36][CH2:35][CH2:34]1.[ClH:45]>ClCCl.O1CCOCC1>[ClH:45].[F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[C:13]4[CH:25]=[CH:24][CH:23]=[N:22][C:14]=4[NH:15][C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[C:11]3=[N:10][C:9]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:5]=[CH:4][C:3]=1[C:33]1([NH2:37])[CH2:36][CH2:35][CH2:34]1
Reactant: Cc1ccccc1-c1nc2n(c1-c1ccc(C3(NC(=O)OC(C)(C)C)CCC3)c(F)c1)-c1cccnc1Nc1ccccc1-2
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccccc1-c1nc2n(c1-c1ccc(C3(N)CCC3)c(F)c1)-c1cccnc1Nc1ccccc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate (0.035 g) in dichloromethane (0.5 mL) was added 4.0 M HCl in dioxane (0.05 mL). The reaction was stirred at room temperature for 3 hours. The product was removed by filtration under reduced pressure and dried to give 1-(2-fluoro-4-(2-(o-tolyl)-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutanamine hydrochloride as a yellow solid (0.025 g, 74% based on tris HCl salt). 1H NMR (DMSO-d6) 400 MHz δ 8.77 (br. s, 1 H), 8.73 (br. s, 3H), 8.19 (d, J=4.4 Hz, 1H), 7.91 (dd, JA=7.6 Hz, JB=1.2 Hz, 1H), (7.41 (t, J=6.8 Hz, 1H), 7.36-7.31 (m, 3H), 7.30-7.25 (m, 2H), 7.24-7.18 (m, 1H), 7.12 (t, J=7.6 Hz, 1H), 6.99 (d, J=7.2 Hz, 1H), 6.89-6.84 (m, 3H), 2.68-2.57 (m, 2H), 2.54-2.44 (m, 2H), 2.36-2.25 (m, 1H), 2.17 (s, 3H), 1.88-1.74 (m, 1H); LCMS: 488 [M+H]; Calc. for C31H26N5F.2.59HCl.1.05 dioxane: C, 62.68; H, 5.53; N, 10.38. Found C, 62.69; H, 5.67; N, 10.39.
Reaction SMILES: [NH2:1][C:2]([CH3:8])([CH3:7])[C:3]([O:5][CH3:6])=[O:4].CN1CCOCC1.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1)=[O:18]>C(Cl)Cl>[CH3:7][C:2]([NH:1][C:17]([O:19][C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=1)=[O:18])([CH3:8])[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)C(C)(C)NC(=O)Oc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of Methyl 2-amino-2-methylpropanoate (5 g, 32 mmol) and N-Methyl morpholine (11 mL, 98 mmol) in DCM (30 mL) was added in one portion 4-nitrophenyl chloroformate (9.8 g, 49 mmol). Diluted reaction with DCM (50 mL) washed with 1N HCl (2×20 mL) and sat. NaHCO3 (2×20 mL), dried organic fraction over magnesium sulfate, filtered and evaporated volatiles in vacuo.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Br:9]Br>C(O)(=O)C>[Br:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C(O)c1ccsc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(O)c1csc(Br)c1
Reaction time: 0.25 h
Yield: 50 %

Procedure:
To a stirred solution of 3-thiophenecarboxylic acid (1.00 g, 7.80 mmol) in glacial acetic acid (9 mL) at ambient temperature under nitrogen atmosphere was slowly added bromine (0.39 mL, 7.53 mmol) in glacial acetic acid (6 mL). The reaction mixture was stirred for 15 minutes, then quenched with cold water (50 mL). The precipitate was filtered, washed with water and dried in vacuum oven at 50° C. to afford 5-bromo-3-thiophenecarboxylic acid as a colorless solid (0.78 g, 50%): mp 133-135° C.; 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J=1.5 Hz, 1H), 7.51 (d, J=1.5 Hz, 1H).
Reaction SMILES: CC1(C)C2C=C(C#C[C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)C=CC=2C(=O)CC1.[C:27]([C:29]1[CH:38]=[C:37]2[C:32]([C:33]([CH3:45])([CH3:44])[CH2:34][CH2:35][C:36]2=[C:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[CH:31][CH:30]=1)#[CH:28]>>[CH3:45][C:33]1([CH3:44])[C:32]2[CH:31]=[CH:30][C:29]([C:27]#[C:28][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)=[CH:38][C:37]=2[C:36](=[C:39]([CH2:42][CH3:43])[CH2:40][CH3:41])[CH2:35][CH2:34]1
Reactant: C#Cc1ccc2c(c1)C(=C(CC)CC)CCC2(C)C
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(=C(CC)CC)CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1), 235 mg (0.94 mmol) of 7-ethynyl-3,4-dihydro-1(2H)-(3-pentylidene)-4,4-dimethylnaphthalene (Compound X) was converted into the title compound using 236 mg (0.85 mmol) of ethyl 4-iodobenzoate, 57 mg (0.3 mmol) of cuprous iodide and 220 mg (0.31 mmol) of bis(triphenylphosphine)palladium(II) chloride.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[CH:28]=1>>[Cl:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Clc1cccc(OCCCBr)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cccc(Cl)c3)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.832 g of 1-(3-bromopropoxy)-3-chlorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.55.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>C(OCC)C.[Cu]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(Br)cc1
Reactant: Oc1ccc(Cl)cc1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 100 °C

Procedure:
A mixture of 67 g (0.520 mol) of p-chlorophenol and 29.5 g (0.520 mol) of KOH pellets is heated to 100° C. for 2 hours under a pressure of about 5 mm Hg. Thereafter 117 g (0.625 mol) of p-bromoanisole and 1 g of copper powder are added and the mixture is then heated to about 220°-230° C. for 5 hours. The cooled reaction mixture is taken up in diethyl ether and after removing the inorganic salts by filtration the filtrate is washed with 2 N sodium hydroxide solution and with water. The solvent is driven off under reduced pressure, drying is carried out with sodium sulphate and 133 g of an orange-coloured oil are obtained. Purification of this oil by distillation under reduced pressure given 70 g of a white crystalline mass which is insoluble in water.