Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22](O)=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][S:40]([N:43]1[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)(=[O:42])=[O:41].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([N:46]3[CH2:47][CH2:48][N:43]([S:40]([CH3:39])(=[O:42])=[O:41])[CH2:44][CH2:45]3)=[O:23])=[C:15]2[CH2:14]1)=[O:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CCN(S(C)(=O)=O)CC3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 106.3 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.15 g, 0.27 mmol), 1-methanesulfonyl-piperazine (0.109 g, 0.55 mmol) and triethylamine (0.38 mL, 2.7 mmol) were dissolved in 10 mL of dichloromethane under stirring, and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.139 g, 0.55 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-methanesulfonyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 22a (0.2 g) as a white solid.
Reaction SMILES: [CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]=[O:22])[CH2:5][CH2:4][CH:3]=[CH:2]1.C1(C2C=C3C(C(=O)CC(C)(C)O3)=C(OC)C=2C=O)CC=CC1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([C:6]2[CH:15]=[C:14]3[C:9]([C:10](=[O:18])[CH2:11][C:12]([CH3:17])([CH3:16])[O:13]3)=[C:8]([O:19][CH3:20])[C:7]=2[CH:21]=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: [H][H]
Reactant: COc1c(C=O)c(C2C=CCC2)cc2c1C(=O)CC(C)(C)O2
Agent: [Pd]
Agent: COc1c(C=O)c(C2CC=CC2)cc2c1C(=O)CC(C)(C)O2
Solvent: CCOC(C)=O
Product: COc1c(C=O)c(C2CCCC2)cc2c1C(=O)CC(C)(C)O2
Reaction time: 1 h

Procedure:
Under argon, 3.3 g (11 mmol) of the mixture of 7-cyclopent-2-en-1-yl-5-methoxy-2,2-dimethyl-4-oxochroman-6-carbaldehyde and 7-cyclopent-3-en-1-yl-5-methoxy-2,2-dimethyl-4-oxochroman-6-carbaldehyde (Example 4A/5A) are dissolved in 200 ml of ethyl acetate, 500 mg of palladium-on-carbon (10%) are added and hydrogen gas is charged at room temperature under atmospheric pressure. After one hour, the mixture is filtered through a layer of silica gel, the filter cake is washed thoroughly with ethyl acetate and the filtrate is concentrated. This gives 3.3 g (99% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[O:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(O)CCC>[Br:1][C:2]1[N:7]2[C:8]([CH3:11])=[CH:9][N:10]=[C:6]2[C:5]([NH:23][C:22]2[CH:21]=[CH:20][C:19]([N:16]3[CH2:17][CH2:18][O:13][CH2:14][CH2:15]3)=[CH:25][CH:24]=2)=[N:4][CH:3]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: Cc1cnc2c(Br)ncc(Br)n12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cnc2c(Nc3ccc(N4CCOCC4)cc3)ncc(Br)n12
Yield: 52.6 %

Procedure:
5,8-Dibromo-3-methylimidazo[1,2-a]pyrazine (270 mg, 0.93 mmol) and 4-morpholinoaniline (200 mg, 1.1 mmol) are combined in nBuOH (10 mL) and DIPEA (240 μL, 1.4 mmol) is added. The mixture is heated at reflux for 10 h, cooled and the solvent removed under reduced pressure. The residue is purified by silica chromatography, eluting with 12% -100% EtOAc in cyclohexane, to afford the title compound as a red-brown solid (190 mg).
Reaction SMILES: C(=O)(O)[O-].[Na+].[CH2:6]([O:13][C:14]([NH:16][CH:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][CH:23]=1)[C:18]([OH:20])=O)=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:29][CH2:30][CH:31]([OH:38])[CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][CH3:35].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[Br:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH:17]([NH:16][C:14](=[O:15])[O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:18]([NH:29][CH2:30][CH:31]([OH:38])[CH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][CH3:35])=[O:20])=[CH:23][CH:24]=1
Reactant: CCC(C)(C)CC(O)CN
Reactant: O=C(NC(Cc1ccc(Br)cc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClCCl
Product: CCC(C)(C)CC(O)CNC(=O)C(Cc1ccc(Br)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium bicarbonate (17.36 g, 207 mmol) was added to an ambient temperature solution of 2-{[(benzyloxy)carbonyl]amino}-3-(4-bromophenyl)propanoic acid (7.79 g, 20.7 mmol), 1-amino-4,4-dimethylhexan-2-ol (3 g, 20.7 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (7.92 g, 41.4 mmol) and 1-hydroxybenzotriazole (5.58 g, 41.4 mmol) in methylene chloride (150 mL). After stirring at ambient temperature overnight, the reaction mixture was quenched with water and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded benzyl {1-(4-bromobenzyl)-2-[(2-hydroxy-4,4-dimethylhexyl)amino]-2-oxoethyl}carbamate.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([O:19]C)[C:16]([O:21]C)=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:23]#[N:24].Cl.N1C=CC=CC=1.[OH-].[NH4+]>>[Cl:1][C:2]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]3[CH:18]=[C:17]([OH:19])[C:16]([OH:21])=[CH:15][C:12]=3[CH:13]=2)[N:8]=[CH:7][C:6]=1[C:23]#[N:24]
Reactant: COc1cc2cc3ncc(C#N)c(Nc4ccc(Cl)cc4Cl)c3cc2cc1OC
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: c1ccncc1
Product: N#Cc1cnc2cc3cc(O)c(O)cc3cc2c1Nc1ccc(Cl)cc1Cl
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A mixture of 252.6 mg (0.6 mmol) of 4-(2,4-dichloroanilino)-7,8-dimethoxybenzo[g]quinoline-3-carbonitrile and 5.0 g of pyridine hydrochloride is heated at 215–220° C. for 40 minutes under nitrogen. After cooling, the mixture is neutralized with 3% ammonium hydroxide aqueous solution and stirred for 30 minutes. The precipitate is collected, washed with water and dried in vacuo. The crude product is passed through a short column of silica gel, eluting with a gradient of methylene chloride/methanol 90:10 to 50:50, to provide 122.8 mg (51.7%) of the product as a brown solid, mp>260° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[OH-].[K+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[CH2:12]([O:1][C:2]1[C:3]([CH2:8][OH:9])=[N:4][CH:5]=[CH:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ncccc1O
Reactant: BrCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: OCc1ncccc1OCc1ccccc1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a solution of 3-hydroxy-2-(hydroxymethyl)pyridine (10.00 g) and KOH (7.00 g) in anhydrous EtOH was added benzyl bromide (7.30 mL) at room temperature under stirring. The reaction mixture was heated to reflux for 24 h, then cooled to rt and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) DCM/MeOH) to give the title compound as a pale yellow solid (7.50 g, 65.00%), HPLC: 95.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 216.4 (M+1); 1H NMR (400 MHz, CDCl3) δ: 4.39 (br s, 1H), 4.82 (s, 2H), 5.11 (s, 2H), 7.16-7.17 (m, 2H), 7.34-7.40 (m, 5H), 8.15-8.17 (m, 1H) ppm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)[CH:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[F:16][C:17]([F:24])([F:23])[C:18](OCC)=[O:19].C[O-].[Na+]>C(OC)(C)(C)C>[F:16][C:17]([F:24])([F:23])[C:18](=[O:19])[CH2:14][C:13]([C:3]1[CH:4]=[CH:5][C:6]([C:8]2[N:9]=[CH:10][S:11][CH:12]=2)=[CH:7][C:2]=1[F:1])=[O:15]
Reactant: CC(=O)c1ccc(-c2cscn2)cc1F
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cscn2)cc1F
Reaction time: 3 h
Yield: 100.3 %

Procedure:
To a stirred solution of 1-[2-fluoro-4-(1,3-thiazol-4-yl)phenyl]-1-ethanone (2.03 g, 9.18 mmol) in t-butylmethylether (60 ml) was added ethyl trifluoroacetate (1.56 g, 11.01 mmol), sodium methoxide (28 wt. % solution in methanol; 2.49 ml, 11.01 mmol) at 0° C., and the mixture was stirred for 3 hours. The mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo to give title compound (2.92 g, 99% yield). The compound was used for next reaction without purification.
Reaction SMILES: C([O:3][C:4](=[O:27])[CH:5]([CH2:12][C:13]1[CH:14]=[N:15][C:16]([NH:19]C(OC(C)(C)C)=O)=[CH:17][CH:18]=1)[CH:6]([S:8]C(=O)C)[CH3:7])C>Cl>[NH2:19][C:16]1[N:15]=[CH:14][C:13]([CH2:12][CH:5]([CH:6]([SH:8])[CH3:7])[C:4]([OH:27])=[O:3])=[CH:18][CH:17]=1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(C)SC(C)=O
Agent: Cl
Product: CC(S)C(Cc1ccc(N)nc1)C(=O)O
Temperature: 25 °C

Procedure:
A solution of 3-acetylsulfanyl-2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-butyric acid ethyl ester/A (45 mg; 0.11 mmol) in concentrated HCl (2 mL) was refluxed under argon for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to afford 28.4 mg of the title compound as the hydrochloride salt.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]2[C:20]3[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=3[O:18][N:17]=2)[CH2:9]1.[OH:30][C:31]1([C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[OH:30][C:31]1([C:38]2[CH:39]=[N:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=2)[CH2:32][CH2:33][CH:34]([N:8]2[CH2:11][CH:10]([NH:12][C:13](=[O:29])[CH2:14][NH:15][C:16]3[C:20]4[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=4[O:18][N:17]=3)[CH2:9]2)[CH2:35][CH2:36]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: O=C(CNc1noc2ccc(C(F)(F)F)cc12)NC1CNC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4noc5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of (N-Azetidin-3-yl-2-(5-trifluoromethyl-benzo[d]isoxazol-3-ylamino)-acetamide TFA salt (as prepared in Example 1, Step D) and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone, using the procedure described in Step E of Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH:13][CH2:14][CH2:15][NH2:16])[S:11][CH:12]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:25](Cl)([O:27]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([N:13]3[CH2:14][CH2:15][NH:16][C:25]3=[O:27])[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: NCCNc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NCCN1c1nc(-c2ccc(Br)cc2)cs1
Temperature: 0 °C
Reaction time: 3 h
Yield: 20.8 %

Procedure:
N-[4-(4-bromophenyl)-1,3-thiazol-2-yl]ethane-1,2-diamine (1.1 g, 3.7 mmol), prepared in the previous step, was dissolved in 30 mL methylene chloride and triethylamine (5.1 mL, 36.9 mmol) was added. The mixture was cooled to 0° C., triphosgene (2.7 g, 9.2 mmol) was added, and the mixture was stirred for 3 h. The mixture was diluted with ethyl acetate, washed with NaHCO3, water, brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Flash chromatography (2% methanol/methylene chloride) afforded the title compound (250 mg, 21%) as a white solid; mp 230-233° C. HRMS: calcd for C12H10BrN3OS+H+, 323.98007; found (ESI, [M+H]+), 323.9808. Analytical HPLC: retention time 9.7 min, 210-370 nm the Xterra® RP18 column, 3.5%, 150×4.6 mm 40° C. 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min, 1.2 mL/min 5 μL injection.
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10]OC(=O)C1C=CC=CC=1.[SH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[CH2:10][S:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Cn1c([N+](=O)[O-])cnc1COC(=O)c1ccccc1
Reactant: Sc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c([N+](=O)[O-])cnc1CSc1ccccn1
Temperature: 80 °C

Procedure:
26.1 Grams (0.1 mol) of 1-methyl-2-benzoyloxymethyl-5-nitro-imidazole were dissolved while stirring in 150 ml of dimethylformamide; then 11.1 g (0.1 mol) of 2-mercaptopyridine and 13.8 g of potash (free from water and powdered) were added. A very faintly exothermic reaction was perceptible only. The reaction mixture was heated to 80°C for 1 hour, whereupon the color of the mixture changed from yellow toward light brown and a white precipitate formed. The mixture was then cooled to room temperature and the end product was precipitated by stirring it into about 500 ml of ice water. The product was suction-filtered, thoroughly washed with water and recrystallized from about 3000 ml of isopropanol. 18.0 Grams (72 % of the theoretical yield) of 1-methyl-2-(2-pyridylthiomethyl)-5-nitro-imidazole were obtained as a faintly yellow crystallized powder, m.p. 146°-147°C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH:9]=[CH:8]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:25])C=1>C(Cl)Cl>[CH2:1]([CH:3]([CH2:13][CH2:14][CH2:15][CH3:16])[CH2:4][O:5][CH2:6][CH:7]1[CH2:12][CH2:11][CH:10]2[CH:9]([O:25]2)[CH2:8]1)[CH3:2]
Reactant: CCCCC(CC)COCC1C=CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCCCC(CC)COCC1CCC2OC2C1

Procedure:
A 500 mL round bottom flask equipped with a stirrer bar was charged with 22.4g (0.10 mol) 3-(2-ethylhexoxymethyl)cyclohexene, and 50 mL of methylene chloride. m-Chloroperbenzoic acid (28.3 g, 85% in purity; 0.138 mol) in methylene chloride (200 mL) was added dropwise to above mixture over 1 hr in an ice bath. After the above mixture was reacted at room temperature overnight, the reaction mixture was filtered. The solid was washed with hexane (3×30 mL). The precipitate was filtered, 50 mL of hexane was added into filtrate to further precipate m-chlorobenzoic acid. The solid was filtered and washed with hexane (2×20 mL). The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:9]2=[N:10][CH:11]=[C:12]([O:14]C(=O)C3C=CC=CC=3)[CH:13]=[C:8]2[CH:7]=1)=[O:5].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CO>[CH3:1][CH2:2][O:3][C:4]([C:6]1[N:23]([C:24]([O:26][C:27]([CH3:28])([CH3:30])[CH3:29])=[O:25])[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(O)cnc2n1C(=O)OC(C)(C)C
Yield: 100 %

Procedure:
To a solution of 2.20 g (5.36 mmol) 5-benzoyloxy pyrrolo[2,3-b]pyridine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester in 20 mL methanol was added 0.81 g (5.90 mmol) potassium carbonate. After 1 h the reaction was poured into ethyl acetate and extracted with 10% aqueous citric acid solution. The phases were separated and the organic layer was washed with brine, dried over magnesium sulfate and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:1) to give the product as a colourless oil (100%).
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:25]=[CH:24][C:20]([CH:21]2[O:23][CH2:22]2)=[CH:19][CH:18]=1.[H-].[Na+].FC(F)(F)C([O-])=O>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:22][CH:21]([C:20]3[CH:24]=[CH:25][C:17]([CH3:16])=[CH:18][CH:19]=3)[OH:23])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Reactant: Cc1ccc(C2CO2)cc1
Agent: O=C([O-])C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2CC(O)c2ccc(C)cc2)C1
Yield: 17.9 %

Procedure:
Preparation of the title compound was carried out according to General Method 6. 2-Ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (See Example 5) (400 mg, 2.0 mmol), 4-methylstyrene oxide (2.01 g, 15 mmol) and NaH (240 mg, 6 mmol) were heated in DMF (6 mL) at 120° C. for 16 h to obtain 120 mg of racemic-2-(2-ethyl-1,2,3,4-tetrahydropyrido[4,3-b]indol-5-yl)-1-p-tolylethanol as a trifluoroacetate salt after purification by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% 13 to 80% B in 30 min, injection vol. 5 mL).
Reaction SMILES: [F:1][C:2]([F:17])(S(F)(=O)=O)[C:3]([F:12])([F:11])[C:4]([F:10])([F:9])[S:5]([F:8])(=[O:7])=[O:6].C(N(CC)CC)C.C(OCC)(=O)C>C1COCC1>[F:10][C:4]([F:9])([S:5]([F:8])(=[O:6])=[O:7])[C:3]([F:11])([F:12])[CH:2]([F:1])[F:17]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)S(=O)(=O)F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=S(=O)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
12.4 Gram of 4-(2-aminoethyl)phenol and 9.15 g of triethylamine were dissolved in 100 mL of N-methylpyrrolidone, and the solution was cooled to 0° C. in a nitrogen stream. Thereto, 9.45 g of methacryloyl chloride was added dropwise over 0.2 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 4 hours. After adding 500 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated to obtain 12.2 g of N-(4-hydroxyphenethyl)methacrylamide as a brown oil. Thereafter, 7.49 g of the oil and 11.5 g of 1,1,2,2,3,3-hexafluoropropane-1,3-disulfonyl difluoride were dissolved in 100 mL of THF, and the resulting solution was cooled to 0° C. Thereto, 4.43 g of triethylamine was added dropwise over 0.3 hours, and the obtained reaction solution was stirred at 0° C. for 1 hour and further stirred at room temperature for 3 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with an aqueous saturated sodium hydrogencarbonate solution and twice with water and dried over sodium sulfate. The solvent was concentrated, and the brown oil as residue was dissolved in 100 ml of methanol. Thereto, 10 g of sodium hydrogencarbonate as solid was added, and the mixture was stirred at 50° C. for 6 hours. After adding 200 mL of ethyl acetate, the organic layer was washed, in sequence, twice with saturated brine and twice with water and dried over sodium sulfate to obtain 15.7 g of 3-((4-(2-methacrylamido)ethyl)phenoxy)sulfonyl)-1,1,2,2,3,3-hexafluoropropane-1-sulfonylfluoride as a brown oil. Thereafter, 7.29 g of this brown oil was dissolved in 100 mL of methanol, and 4.81 g of triphenylsulfonium bromide was added thereto, followed by stirring at room temperature for 3 hours. After adding 200 mL of chloroform, the organic layer was washed with water, and the solvent was concentrated, as a result, 10.1 g of a brown transparent oily compound was obtained. 1H-NMR (300 MHz, CDCl3) δ 1.91 (s, 3H), 2.87 (t, 2H), 3.50 (quartet, 2H), 5.27 (s, 1H), 5.66 (s, 1H), 6.39 (bs, 1H), 7.14 (d, 2H), 7.23 (d, 2H), 7.67-7.76 (m, 15H), 19F-NMR (300 MHz, CDCl3) δ −107.4 (m, 2F), −114.0 (m, 2F), −118.1 (m, 2F).
Reaction SMILES: [CH2:1](Br)[CH2:2][OH:3].Cl.[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:1][CH2:2][OH:3])[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: OCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCCN1CCN(c2cccc(Cl)c2)CC1
Yield: 78.6 %

Procedure:
Ethylene bromohydrin (5.4 g) was added dropwise to a mixture of 1-(3-chlorophenyl)piperazine hydrochloride (5 g), potassium carbonate powder (12 g) and N,N-dimethylformamide (35 ml) with stirring. The mixture was further stirred at room temperature overnight, then diluted with 100 ml of water and extracted with ethyl ether. The ethyl ether layer was washed with saturated aqueous sodium chloride and dried over Na2SO4. The solvent was distilled off and the residue was purified by silica gel chromatography [eluent: ethyl acetate-methanol (4:1)] to give 4.06 g (78.6%) of 4-(3-chlorophenyl)-1-piperazineethanol as an oil.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1.[C:11]1([C:17](Cl)([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:17]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6][CH2:5]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCC1CCC(O)CC1
Solvent: c1ccncc1
Product: OC1CCC(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
4-(2-Hydroxyethyl)cyclohexanol (crude from the previous reaction) (1.88 g, 0.0130 mol) was dissolved in pyridine (20.00 mL) and was cooled at 0° C. To the reaction was added triphenylmethyl chloride (4.0 g, 0.014 mol) and this mixture was stirred at 0° C. for 2 hours and at 25° C. for 16 hours. The reaction was concentrated using a rotary evaporator and the concentrate was extracted with ethyl acetate. The organic extracts were washed with water, and saturated NaCl, then dried (MgSO4) and concentrated in vacuo. The concentrate was chromatographed on silica gel (30% EtOAc/hexanes) to give the trans isomer (1.98 g)
Reaction SMILES: [CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][NH:5][C:6]1[C:14]2[NH:13][C:12]([CH3:15])=[N:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.CI.[C:23](=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>C(#N)C>[CH3:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:16]([CH3:20])[C:3]=1[CH2:4][NH:5][C:6]1[C:14]2[N:13]=[C:12]([CH3:15])[N:11]([CH3:23])[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: Cc1nc2cccc(NCc3c(C)cccc3C)c2[nH]1
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Solvent: CI
Product: Cc1cccc(C)c1CNc1cccc2c1nc(C)n2C
Temperature: 25 °C
Reaction time: 20 h
Yield: 8.6 %

Procedure:
4-(2,6-dimethylbenzylamino)-2-methylbenzimidazole (0.2 g 0.75 mmol) was dissolved in acetonitrile (15 ml). To the solution were added methyl iodide (0.05 ml 0.82 mmol) and potassium carbonate (0.2 g 1.4 mmol) and the reaction mixture was stirred at ambient temperature for 20 h. The solids were removed by filtration and was washed with methylene chloride. Vacuum evaporation of the solvent gave an oily residue which was subjected to flash chromatography on silica gel, methylene chloride: methanol (10:1). Crystallization from acetonitrile gave 0.018 g (9%) of the title compound.