Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH3:20][C:21]1([CH3:35])[C:26](=[O:27])[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:22]1>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:27])[CH2:25][CH2:24][N:23]([C:28]([O:30][C:31]([CH3:33])([CH3:32])[CH3:34])=[O:29])[CH2:22][C:21]2([CH3:35])[CH3:20])=[CH:3][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C)(C)C1
Reactant: Fc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)cc2)C(C)(C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A solution of 1-Bromo-4-fluorobenzene (5.32 mL, 48.4 mmol) in THF (100 mL) was cooled to −78° C., and treated with the dropwise addition of 1.6 M BuLi in hexane (30.2 mL, 48.4 mmol), at a rate which did not allow the temperature of the reaction to exceed −60° C. The mixture was stirred at −78° C. for 30 minutes, then treated with the dropwise addition of a solution of tert-butyl 3,3-dimethyl-4-oxopiperidine-1-carboxylate (5 g, 22.00 mmol) in THF (50 mL) at a rate which did not allow the temperature to exceed −60° C. The mixture was stirred at −78° C. for 1.5H, then allowed to warm to 10° C. and quenched with saturated NH4Cl (50 mL). The layers were separated, and the organic phase was concentrated in-vacuo. The aqueous was extracted with ethyl acetate (100 mL), and the organic phase was combined with the residue from the original organic phase. This solution was washed 3× with water, 1× with brine, dried over sodium sulfate, and concentrated in-vacuo. The residue was digested with hexanes (70 mL), and the resulting white powder was collected by filtration, rinsed with hot hexanes, and dried under vacuum to yield the title compound (3.3 g, 10.20 mmol, 46.4% yield). MS (ESI+)=324.4, (M+H)+, 250.3, (M-tBuOH)+.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([Cl:21])[CH:15]=2)[CH2:12][N:11]([C:22]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]([C:32]3([CH3:35])[CH2:34][CH2:33]3)=[O:31])[CH2:26][CH2:25]2)=[O:23])[CH2:10]1)C)(C)(C)C.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:21][C:16]1[CH:15]=[C:14]([CH:13]2[CH:9]([NH:7][CH3:6])[CH2:10][N:11]([C:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([C:32]4([CH3:35])[CH2:33][CH2:34]4)=[O:31])[CH2:26][CH2:25]3)=[O:23])[CH2:12]2)[CH:19]=[CH:18][C:17]=1[Cl:20]
Reactant: CN(C(=O)OC(C)(C)C)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.8 %

Procedure:
To a stirred solution of {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-carbamic acid tert-butyl ester (3.02 g, 5.61 mmol) in CH2Cl2 (30 ml) was added TFA (4.3 ml). The reaction mixture was stirred at RT for 20 hours, aqueous NaHCO3 was added until pH=8 and the product was extracted with CH2Cl2. The combined organic phase were dried over Na2SO4. The product was purified by column chromatography (SiO2, H/EtOAc/MeOH, 50:50:0 to 0:90:10) to afford 1.79 g (73%) of the title product as a light brown oil. ES-MS m/e: 338.3 (M+H+).
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:32]/[C:33](/[C:37]#[C:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[CH:34]/[CH2:35][OH:36].[CH2:45]([O:47][C@@H:48]([CH2:54][C:55]1[CH:60]=[CH:59][C:58](O)=[CH:57][CH:56]=1)[C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH3:46]>C1C=CC=CC=1>[CH2:52]([O:51][C:49](=[O:50])[C@@H:48]([O:47][CH2:45][CH3:46])[CH2:54][C:55]1[CH:60]=[CH:59][C:58]([O:36][CH2:35]/[CH:34]=[C:33](/[CH3:32])\[C:37]#[C:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:57][CH:56]=1)[CH3:53]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: C/C(C#Cc1ccccc1)=C/CO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(/C)C#Cc2ccccc2)cc1)OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1,1′-(azodicarbonyl) dipiperidine (0.504 g, 2.0 mmol) was added at 0° C. to a stirred solution of tributylphosphine (0.493 mL, 2.0 mmol), (Z)-3-methyl-5-phenyl-pent-2-en-4-yn-1-ol (0.172 g, 1.0 mmol) (J. Org. Chem. 1999, 64 (21), 7687–7692), and (S)-ethyl 2-ethoxy-3-(4-hydroxy-phenyl)-propionate (0.262 g, 1.1 mmol) in dry benzene (20 mL), the mixture allowed to warm to room temperature, and stirring continued for 24 h. The resulting mixture was evaporated in vacuo, and the residue purified by flash column chromatography on silica gel (20% ethyl acetate in n-heptane eluent) to give (Z)-(S)-2-ethoxy-3-[4-(3-methyl-5-phenyl-pent-2-en-4-ynyloxy)-phenyl]-propionic acid ethyl ester as an oil; 0.267 g (68%).
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[NH:12][C:13](=[S:15])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl[CH2:22][CH2:23][OH:24]>C(O)C>[CH2:1]([C:8]1[CH:17]=[CH:16][C:11]2[N:12]=[C:13]([S:15][CH2:22][CH2:23][OH:24])[NH:14][C:10]=2[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S=c1[nH]c2ccc(Cc3ccccc3)cc2[nH]1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCSc1nc2ccc(Cc3ccccc3)cc2[nH]1

Procedure:
5.75 g (24 mmoles) of 5-benzyl-benzimidazoline-2-thione, a solution of 1 g of sodium hydroxide and 8 ml of water, 2 ml (30 mmoles) of 2-chloroethanol and 30 ml of ethanol are refluxed for an hour. The reaction mixture is evaporated and extracted with water and dichloromethane, then the aqueous phase is extracted with dichloromethane. The residue of the combined organic phases is solidified under ether. After filtration and crystallization from ethyl acetate 4.63 g (68.1%) of title product are obtained. M.p.: 108°-109° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH:6]=1>[Pd].CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][CH:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)Cc1coc2cc(O)ccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)CC1COc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (6-hydroxy-benzofuran-3-yl)-acetic acid methyl ester (5.00 g), 10% palladium on carbon (0.50 g), and methanol (50 mL) is shaken under hydrogen atmosphere (3 bar) at room temperature for 3 h. The catalyst is separated by filtration and the filtrate is concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 4:1→1:1) to give the racemic title compound. Mass spectrum (ESI+): m/z=209 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8].CO.[OH-].[Na+].Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([O:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cc(OC2CCOCC2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1c(OC2CCOCC2)cc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.5 %

Procedure:
Methyl 5-chloro-2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzoate (from the previous step) was dissolved in MeOH (5.04 mL, 125 mmol) and treated with 8M NaOH (1.869 mL, 14.95 mmol). The reaction was stirred at room temperature for 16 h, at which time the solvent was removed in vacuo and the remaining residue diluted with water (6 mL). The mixture was acidified by drop-wise addition of 6 M HCl (2.91 mL, 17.45 mmol) and the resulting suspension was stirred at room temperature for 30 min. The solids were filtered, washed with water (2 mL), and dried under vacuum to give 5-chloro -2-methyl-3-((tetrahydro-2H-pyran-4-yl)oxy)benzoic acid (422 mg, 1.557 mmol, 62.5% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.23 (br. s., 1H), 7.33 (d, J=2.02 Hz, 1H), 7.29 (d, J=2.02 Hz, 1H), 4.70 (tt, J=3.85, 8.02 Hz, 1H), 3.76-3.88 (m, 2H), 3.51 (ddd, J=3.03, 8.59, 11.62 Hz, 2H), 2.31 (s, 3H), 1.90-2.03 (m, 2H), 1.53-1.67 (m, 2H). MS(ES) [M+H]+ 271.0.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[NH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23]>CCO>[C:22]([NH:21][CH2:20][CH2:19][NH:18][C:8]1[CH:9]=[CH:10][C:5]([C:4]([N:3]([CH2:16][CH3:17])[CH2:1][CH3:2])=[O:15])=[CH:6][C:7]=1[N+:12]([O-:14])=[O:13])(=[O:24])[CH3:23]
Reactant: CC(=O)NCCN
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCNC(C)=O)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 62.3 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (0.200 g, 0.833 mmol), N-(2-aminoethyl)acetamide (0.077 g, 0.757 mmol) in 80% aq. EtOH (5 mL) was heated at 90° C. overnight. After work-up, the crude product was purified by silica gel column chromatography (100% EtOAc to 5% MeOH/EtOAc) to provide the title compound (0.152 g, 63%) as a bright yellow solid. 1H-NMR (CDCl3): δ 8.27 (d overlapping with br s, J=2.0 Hz, 2H), 7.55 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.99 (d, J=9.2 Hz, 1H), 6.06 (br s, 1H), 3.58–3.50 (m, 4H), 3.44 (br s, 4H), 2.02 (s, 3H), 1.22 (t, J=7.2 Hz, 6H). MS (ESI) (M+H)+=323.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].N1C=CN=C1.[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>CN(C=O)C>[Si:18]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Yield: 78.8 %

Procedure:
To a mixture of 2-methoxy-5-nitrophenol (1.53 g, 9.0 mmol) and imidazole (1.08 g, 15.9 mmol) in anhydrous DMF (40 mL) was added, with stirring, tert-butyldimethylsilyl chloride (2.05 g, 13.6 mmol) and the mixture was allowed to stir at room temperature for 16 h. The solvent was removed in vacuo and the residue was dissolved in 40 mL of 50% ethyl acetate in hexanes and filtered through 10 g of silica gel. The silica gel was washed with an additional 200 mL of 50% ethyl acetate in hexanes and the filtrates were combined and concentrated in vacuo to give 2.01 g of product as a tan crystalline solid. 1H NMR (CDCl3) δ 7.89 (dd, 1H, J=9.0 Hz, 2.8 Hz), 7.69 (d, 1H, J=2.8 Hz), 6.88 (d, 1H, J=9.0), 3.90 (s, 3H), 1.00 (s, 9H), 0.18 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:29])[C@@H:4]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1.O.[OH-].[Li+].Cl>CO.O>[C:25]([O:24][C:22]([NH:21][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[C:8]([P:13]([O:18][CH2:19][CH3:20])([O:15][CH2:16][CH3:17])=[O:14])[CH:7]=1)[C:3]([OH:2])=[O:29])=[O:23])([CH3:26])([CH3:27])[CH3:28]
Reactant: CCOP(=O)(OCC)c1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)ccc1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOP(=O)(OCC)c1cc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 152.4 %

Procedure:
To a cooled (0° C.) solution (S)-2-tert-butoxycarbonylamino-3-[3-(diethoxy-phosphoryl)-4-hydroxy-phenyl]-propionic acid methyl ester (423 mg, 0.98 mmol) in MeOH (4 mL) was added lithium hydroxide monohydrate (84 mg, 2.0 mmol) in H2O (4 mL). After 1 h, the reaction was allowed to warm to rt. After 2.5 h, the solution was carefully acidified to pH 2 using 0.5 N HCl and extracted twice with EtOAc. The organic extracts were pooled, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 379 mg (91%) of a yellow foam. The crude material was carried on without further purification. Electrospray Mass Spectrum (50/50 acetonitrile/water) m/z 416 (M−H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2C(=O)C3=CC=CC=C3C2=O)=[CH:8][C:7]=1[N+:23]([O-:25])=[O:24])[CH3:2].O.NN>COCCOC>[CH2:1]([O:3][C:4](=[O:26])[NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[N+:23]([O-:25])=[O:24])[CH3:2]
Reactant: CCOC(=O)Nc1ccc(N2C(=O)c3ccccc3C2=O)cc1[N+](=O)[O-]
Agent: NN
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)Nc1ccc(N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
1,2-Dimethoxyethane (1.0 L) is added to (2-nitro4-phtalimido-phenyl)-carbamic acid ethyl ester (101 g, 0.28 mol) and the mixture is heated under reflux. Hydrazine monohydrate (19.6 g, 0.39 mol) is added dropwise over 10 minutes and the mixture is stirred at reflux for 1.5 hours. Upon cooling to ambient temperature the mixture is filtered and the solids are washed with dimethoxyethane (250 mL) on the filter. The filtrate is concentrated by means of evaporation and the red crystalline product is recrystallized from toluene (350 mL), precipitated product is filtered off and dried in vacuo. The mother liquor is concentrated to half the original volume and left standing for 16 hours. Precipitated material is filtered off and recrystallized as before. The recrystallized solids are combined to furnish a total of 57.6 g (90%) dark red title compound. LC/MS (m/z) 225.1 (MH+); tR=2.08 min. 1H NMR (CDCl3): 1.33 (t, 3H); 3.77 (s, 2H, NH2); 4.23 (q, 2H); 6.98 (dd, 1H); 7.45 (d, 1H); 8.28 (d, 1H); 9.39 (s, 1H, NH).
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][N:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1.[Cl:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([N:44]=[C:45]=[S:46])=[O:43])=[CH:40][CH:41]=1.[Cl:34][CH2:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]([NH:44][C:45]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][N:18]=3)=[CH:28][CH:29]=2)=[S:46])=[O:43])=[CH:40][CH:41]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (77 mg, yield 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[C:4]([Cl:25])[N:3]=1.[O:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1>>[Cl:25][C:4]1[CH:5]=[C:6]([C:8]2[N:12]3[CH:13]=[C:14]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH2:19]4)[CH:15]=[CH:16][C:11]3=[N:10][CH:9]=2)[CH:7]=[C:2]([C:28]2[CH:29]=[CH:30][O:26][CH:27]=2)[N:3]=1
Reactant: OB(O)c1ccoc1
Reactant: OC1CCCC(Nc2ccc3ncc(-c4cc(Cl)nc(Cl)c4)n3c2)C1
Product: OC1CCCC(Nc2ccc3ncc(-c4cc(Cl)nc(-c5ccoc5)c4)n3c2)C1

Procedure:
The title compound is prepared from (1SR,3RS)-3-[3-(2,6-dichloro-pyridin-4-yl)-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol (Intermediate S) and 3-furyl boronic acid using a procedure analogous to that described in Example 2.3.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:5]=2[CH2:4][CH2:3][NH:2]1)=[CH:12][CH:11]=[CH:10][CH:9]=3.CC1C=CC(S(O[CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([CH3:39])[CH:34]=3)[CH2:28][CH2:27]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:39][C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[C:32]([N:29]1[CH2:28][CH2:27][CH:26]([CH2:25][N:2]2[CH2:3][CH2:4][C:5]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[CH2:1]2)[CH2:31][CH2:30]1)=[O:40]
Reactant: Cc1ccc(S(=O)(=O)OCC2CCN(C(=O)c3cccc(C)c3)CC2)cc1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C(=O)N2CCC(CN3CCc4c([nH]c5ccccc45)C3)CC2)c1
Temperature: 100 °C
Reaction time: 5 h
Yield: 31 %

Procedure:
1.7 g (10 mmol) of 1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, 3,9 g (10 mmol) of [1-(3-methylbenzoyl)-4-piperidyl]methyl 4-methylbenzenesulphonate, 2.9 g (20 mmol) of potassium carbonate and 25 ml of dimethylformamide are introduced under an argon atmosphere into a 100-ml round-bottomed flask. The mixture is stirred at 100° C. for 5 h and hydrolysed, and the aqueous phase extracted with ethyl acetate. The organic phase is washed with water and then with saturated aqueous sodium chloride solution and dried over sodium sulphate, and the solvents are evaporated off under reduced pressure. The residue is purified by chromatography on a silica column, eluting with a 9:1 dichloromethane/methanol mixture, and, after recrystallization in ethyl acetate, 1.2 g of pure base are obtained.
Reaction SMILES: C(OC1C=C(F)C=C2C=1C(CC(N1CC3C(=CC=CC=3)C1)=O)=[CH:12][N:13]2CC)C1C=CC=CC=1.[CH2:33]([O:40][C:41]1[C:49]([F:50])=[CH:48][C:47]([Br:51])=[C:46]2[C:42]=1[C:43]([CH2:53][C:54]([OH:56])=O)=[CH:44][N:45]2[CH3:52])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([O:40][C:41]1[C:49]([F:50])=[CH:48][C:47]([Br:51])=[C:46]2[C:42]=1[C:43]([CH2:53][C:54]([NH:13][CH3:12])=[O:56])=[CH:44][N:45]2[CH3:52])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cn1cc(CC(=O)O)c2c(OCc3ccccc3)c(F)cc(Br)c21
Reactant: CCn1cc(CC(=O)N2Cc3ccccc3C2)c2c(OCc3ccccc3)cc(F)cc21
Product: CNC(=O)Cc1cn(C)c2c(Br)cc(F)c(OCc3ccccc3)c12
Yield: 96 %

Procedure:
Following the procedure (step 1, scheme 31) used to prepare compound 31-2, compound 33-4 gave compound 33-5 in 96% yield as a yellow solid. LRMS: calc 404.0 and found: 405.0 [M+1].
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:13]=[N:14][C:15]([N:19]([CH3:21])[CH3:20])=[CH:16][C:17]=3[CH3:18])[N:7]([CH2:22][CH2:23][CH2:24][CH2:25]O)[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.O>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[C:17]([CH3:18])=[CH:16][C:15]([N:19]([CH3:21])[CH3:20])=[N:14][CH:13]=4)[CH2:25][CH2:24][CH2:23][CH2:22][N:7]3[C:6]=2[C:5]([CH:27]([CH2:30][CH3:31])[CH2:28][CH3:29])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3cnc(N(C)C)cc3C)n(CCCCO)c12
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: O
Solvent: c1ccncc1
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCCCN3c1cnc(N(C)C)cc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.8 %

Procedure:
To a solution of 4-[4-chloro-2-{[6-(dimethylamino)-4-methylpyridin-3-yl]amino}-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butan-1-ol (Reference Example 40; 100 mg, 0.23 mmol) in pyridine (2.3 mL) was added methanesulfonyl chloride (0.088 mL, 1.13 mmol) dropwise at 0° C. The mixture was warmed to room temperature and stirred for 4 hr. Aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude mesylate was dissolved in N,N-dimethylformamide (4.6 mL) and potassium carbonate (96 mg, 0.69 mmol) was added. The mixture was stirred at 80° C. for 16 hours. Water was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound (44 mg, 0.103 mmol, 45%) as a colorless solid.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[O:48]CC(C)=CC=C)(=[O:41])=[O:40])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.CCO.[Pd]>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)=[C:15]1[CH2:36][CH2:37][NH:38][S:39]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[OH:48])(=[O:40])=[O:41])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=CC=C(C)COc1ccccc1S(=O)(=O)NCCc1c(CCOc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)c3ccccc3O)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Yield: 104.9 %

Procedure:
4-[2-(1-Benzhydryl-5-chloro-2-{2-[2-(2-methyl-penta-2,4-dienyloxy)-benzenesulfonylamino]-ethyl}-1H-indol-3-yl)-ethoxy]-benzoic acid (0.55 g, 0.70 mmole), (Step 1, Example 183) and 10% Pd/C (55 mg) in MeOH (30 ml) and EtOH (20 ml) was hydrogenated. The resulting mixture was filtered through Celite and concentrated. The residue was chromatographed with 35–40% EtOAC/hexane to give the desired product (0.50 g, 95%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[C:10](=[O:22])[C:11]4[CH:12]=[CH:13][C:14]([Br:21])=[CH:15][C:16]=4[C:17](=[O:20])[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:23](=[CH:24][CH:25]=1)[C:7]1=[CH:8][C:9]3[CH:10]([OH:22])[C:11]4[CH:12]=[CH:13][C:14]([Br:21])=[CH:15][C:16]=4[CH:17]([OH:20])[C:18]=3[CH:19]=[C:6]1[C:5]2([CH3:27])[CH3:26]
Reactant: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(=O)c1cc(Br)ccc1C3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC1(C)c2cc(Br)ccc2-c2cc3c(cc21)C(O)c1cc(Br)ccc1C3O
Temperature: 0 °C
Reaction time: 5 h
Yield: 75.2 %

Procedure:
2,9-Dibromo-13,13-dimethyl-6H-indeno[1,2-b]anthracene-6,11(13H)-dione (20 g, 1 eq, 0.041 mol) was placed in a flask, and MeOH (150 ml) was added thereto. Then, sodium borohydride (6.2 g, 4 eq, 0.164 mol) was gradually added at 0° C., the reaction mixture was stirred for five hours, and ice water was gradually added thereto. The reaction solution was extracted with MC and recrystallized from hexane to give 2,9-dibromo-13,13-dimethyl-11,13-dihydro-6H-indeno[1,2-b]anthracene-6,11-diol (15 g, yield=78%).