Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:9]([C:10]([O:12]C)=[O:11])[C:8]=1[C:17]([O:19]C)=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5].[OH-].[Na+].Cl>CO>[CH2:1]([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[C:17]([OH:19])=[O:18])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCOc1cccc(C(=O)OC)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCCOc1cccc(C(=O)O)c1C(=O)O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
3-Hydroxyphthalic anhydride (1.0 g, 6.6 mmol) was dissolved in methanol (20 ml), and a catalytic amount of p-toluene sulfonic acid was added to this solution. The mixture was stirred with refluxing under heating for 5 hours, and concentrated under reduced pressure to give a crude product of dimethyl 3-hydroxyphthalate. The crude product of dimethyl 3-hydroxyphthalate was dissolved in DMF (20 ml), and potassium carbonate (6 g, 43 mmol) and n-amyl bromide (3 ml, 24 mmol) were added to this solution. The mixture was stirred at 90° C. for 1.5 hours, and solids were removed by filtration through Celite. The filtrate was concentrated under reduced pressure to give a crude product of dimethyl 3-pentyloxyphthalate. The crude product of dimethyl 3-pentyloxyphthalate was dissolved in methanol (10 ml), and a 1N aqueous sodium hydroxide solution (20 ml) was added to this solution. The mixture was stirred at 90° C. for 2 hours, and a 3N aqueous hydrochloric acid solution (15 ml) was added to the reaction nixture. The mixture was extracted with ethyl acetate (30 ml×3), and washed with saturated brine (20 ml). The organic layer was dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of 3-pentyloxyphthalic acid. The crude product of 3-pentyloxyphthalic acid was dissolved in acetic acid (20 ml), and a mine hydrochloride (1.0 g, 7.3 mmol) was added. The mixture was stirred at 90° C. for 2 hours and concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give N-2-(4-hydroxyphenyl)ethyl-3-pentyloxyphthalimide (0.8 g, 2.3 mmol, 35%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH:11]1([CH2:14]Br)[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:11]1([CH2:14][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[OH:1])[CH2:13][CH2:12]1
Reactant: BrCC1CC1
Reactant: O=Cc1ccc(O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCC2CC2)c(O)c1
Yield: 7.3 %

Procedure:
A mixture of 3,4-dihydroxybenzaldehyde (4.14 g, 30 mmol), cyclopropylmethyl bromide (3.06 mL, 31.5 mmol), potassium carbonate (8.29 g, 60 mmol) in acetone (90 mL) is heated at 50 C overnight. After filtration, the solution is dried to a gum, which is dissolved in ethyl acetate, and washed with water. It is dried to an oil and then chromatographed to yield 0.42 g (7%) of the title compound as a white powder. MS (ESI) m/z 191.2 (M−H)−1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:17]C)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8].B(Br)(Br)Br>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:17])=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:8]
Reactant: COc1ccc(Br)cc1C(=O)c1ccc(C)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1ccc(C(=O)c2cc(Br)ccc2O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 190 mg (0.6 mmol) of 5-bromo-2-methoxy-4′-methylbenzophenone (Compound H) in 15 mL of dichloromethane was added 0.9 mL (0.9 mmol) of boron tribromide (1M in dichloromethane) at ambient temperature. The orange solution was stirred at ambient temperature for 3 hours under a blanket of argon. The reaction mixture was cooled to −78° C., quenched with methanol and then extracted between ethyl acetate and sat. NaHCO3 (aq.) solution. The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a pale yellow solid. Purification by flash chromatography (silica, 5% ethyl acetate in hexane) gave the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5](O)=[O:6].C(Cl)(=O)C([Cl:18])=O>C(OCC)C.CN(C)C=O>[F:1][C:2]1[C:3]2[O:14][CH2:13][O:12][C:9]([C:10]=1[F:11])=[CH:8][C:4]=2[C:5]([Cl:18])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cc2c(F)c(F)c1OCO2
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(Cl)c1cc2c(F)c(F)c1OCO2
Temperature: 0 °C
Reaction time: 60 h
Yield: 101.4 %

Procedure:
A solution of 15.0 grams (0.0742 mole) of 3,4-difluoromethylenedioxybenzoic acid in 200 mL of diethyl ether was stirred and cooled to 0° C. To this was added one drop of dimethylformamide followed by the dropwise addition of 11.3 grams (0.0890 mole) of oxalyl chloride. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature where it stirred for 60 hours. After this time the reaction mixture was concentrated under reduced pressure to yield 16.6 grams of 3,4-difluoromethylenedioxybenzoyl chloride.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[N:17]=[CH:16][N:15]=[C:14](Cl)[C:13]=3[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[N:26]1([C@H:32]2[CH2:37][CH2:36][C@H:35]([OH:38])[CH2:34][CH2:33]2)[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C@H:11]1[CH2:22][CH2:21][C:20]2[S:19][C:18]3[C:13](=[C:14]([O:38][CH:35]4[CH2:34][CH2:33][CH:32]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)[CH2:37][CH2:36]4)[N:15]=[CH:16][N:17]=3)[C:12]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(Cl)c3c21
Reactant: O[C@H]1CC[C@H](N2CCOCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
For the preparation of the starting material compound 25.1, see Example 25. Sodium hydride (60% dispersion in mineral oil, 130 mg, 3.25 mmol, 4.00 equiv) was treated with trans-4-(morpholin-4-yl)cyclohexan-1-ol (192 mg, 1.04 mmol, 1.27 equiv) in freshly distilled THF (15 mL) at 0° C. under nitrogen. After stirring for 30 min at room temperature, then (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (300 mg, 0.81 mmol, 1.00 equiv) was added and the resulting solution was allowed to react, with stirring, for an additional 2 hr at room temperature. The reaction was then quenched with saturated aqueous NH4Cl, extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8) to provide (3R)-3-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (378 mg, 90%) as a yellow oil. MS (ES): m/z 518 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:16]=[CH:15][C:14]3[N:13]([CH3:17])[C:12](=[O:18])[C@@H:11]([CH2:19][CH3:20])[N:10]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[C:9]=3[N:8]=2)[CH:6]=1.C([Sn](CCCC)(CCCC)[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)CCC>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:21]1([N:10]2[C:9]3[N:8]=[C:7]([N:5]4[CH:6]=[C:2]([C:31]5[N:32]=[CH:33][S:34][CH:35]=5)[N:3]=[CH:4]4)[N:16]=[CH:15][C:14]=3[N:13]([CH3:17])[C:12](=[O:18])[C@H:11]2[CH2:19][CH3:20])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(Br)c3)nc2N1C1CCCC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC[C@@H]1C(=O)N(C)c2cnc(-n3cnc(-c4cscn4)c3)nc2N1C1CCCC1
Temperature: 100 °C
Reaction time: 19 h
Yield: 18.7 %

Procedure:
(R)-2-(4-bromo-1H-imidazol-1-yl)-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one (Example 43, 0.11 g, 0.271 mmol), 4-(tributylstannyl)thiazole (0.10 g, 0.271 mmol, see Example 355) and Pd(PPh3)4 (31 mg, 0.0271) were dissolved in DMF in a screw cap vial and a stream of nitrogen was bubbled through the mixture for 2 minutes. The vial was sealed and the resulting solution was stirred at 100° C. for 19 h. The reaction mixture was diluted with brine, extracted with EtOAc, dried with Na2SO4 then purified by flash chromatography with a silica gel column by eluting with a mixture of Hexane:EtOAc and then further purified by preparative HPLC to give the title compound (20.7 mg). LCMS: 410.1 m/z (M+H)+; ret. Time: 3.94 (Analytical Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[OH:12]O>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[CH3:9])[CH:5]=[CH:4][N+:3]=1[O-:12]
Reactant: OO
Reactant: CC(F)(F)c1ccnc(Cl)c1
Solvent: O=C(O)C(F)(F)F
Product: CC(F)(F)c1cc[n+]([O-])c(Cl)c1

Procedure:
To a solution of 2-chloro-4-(1,1-difluoro)ethylpyridine (1.27 g, 7 mmol) in trifluoroacetic acid was added 30% hydrogen peroxide (6 mL) and the solution was heated at reflux 2.5 h. The reaction was concentrated in vacuo and the residue poured into ice-cold water. The mixture was neutralized with Na2CO3 and then extracted with EtOAc and CH2Cl2. The pooled organic layers were filtered and concentrated in vacuo to give 2-chloro-4-(1,1-difluoroethyl)-pyridine 1-oxide (1.00 g) as a brown oil. 1H NMR (CDCl3): δ 8.39 (d, J=6.6 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.33 (dd, J=6.6, 2.4 Hz, 1H), 1.94 (t, J=18 Hz, 3H). GC/MS: m/z 193 [M+].
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:18]2[NH:19][C:20]([C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:21][N:22]=2)[C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:28]N1C(=O)CCC1=O.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCCl>[Cl:28][C:21]1[N:22]=[C:18]([CH:7]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[NH:19][C:20]=1[C:23]([CH:25]1[CH2:27][CH2:26]1)=[O:24]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2ncc(C(=O)C3CC3)[nH]2)cc1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCCl
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)c2nc(Cl)c(C(=O)C3CC3)[nH]2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 9 %

Procedure:
To a solution (12 mL) of (2-{2-cyclopentyl-1-[4-(methylsulfonyl)phenyl]ethyl}-1H-imidazol-5-yl)(cyclopropyl)methanone in 1,2-dichloroethane was added N-chlorosuccinimide (0.091 g) and the mixture was stirred at 100° C. for 6 hr. To the reaction mixture were successively added saturated aqueous sodium hydrogen carbonate solution and 1 mol/L aqueous sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was successively purified by silica gel column chromatography (ethyl acetate:hexane=10:90-50:50, volume ratio) and thin layer chromatography (ethyl acetate:hexane=50:50), and recrystallized from diisopropyl ether-hexane to give the title compound (0.016 g, yield 9%) as colorless crystals. melting point 95-97° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.C(OCC)(=O)C>[CH2:10]([NH:17][C:7](=[O:9])[C@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[NH:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: O=C1CC[C@H](C(=O)O)N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C1CC[C@H](C(=O)NCc2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5-Oxo-D-proline (5.0 g), benzylamine (4.65 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.5 g) and 1-hydroxybenzotriazole (6.3 g) were mixed in acetonitrile (100 mL) under ice-cooling, and the mixture was allowed to warm to room temperature and stirred for 3 hr. The mixture was diluted with ethyl acetate (200 mL), and washed successively with 1M hydrochloric acid (50 mL), saturated aqueous sodium hydrogen carbonate solution (50 mL) and brine (50 mL). The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The precipitated solid was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (4.02 g) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28]Cl)[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1.[CH3:31][NH:32][CH3:33]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:30])[C:10]2[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([O:17][CH3:18])[C:11]=2[NH:19][C:20]([C:22]2[S:23][CH:24]=[C:25]([CH2:28][N:32]([CH3:33])[CH3:31])[C:26]=2[Cl:27])=[O:21])=[N:6][CH:7]=1
Reactant: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CCl)c1Cl
Reactant: CNC
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(C(=O)Nc2ccc(Cl)cn2)c1NC(=O)c1scc(CN(C)C)c1Cl

Procedure:
In a manner similar to Paragraph E above, N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide(1.0 g, 2.0 mmol) in DMF (5 mL) was reacted with dimethylamine (1.33 M in tetrahydrofuran, 7.5 mL, 10 mmol) to give N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; which was purified by lyophilization from aqueous HCl to afford N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; hydrochloric acid salt, as a white solid; NMR (DMSO-d6/TFA) 10.9 (s, 1), 10.1 (br s, 1), 9.5 (s, 1), 8.3 (d, 1), 8.2 (s, 1), 8.1 (d, 1), 7.8 (dd, 1), 7.3 (dd, 2), 4.3 (br s, 2), 3.9 (s, 3), 2.8 (br s, 6) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:16]=1)[C:7]([NH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[O:8].[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:33][CH2:34][CH3:35])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:23]=O)[CH3:18]>>[CH2:34]([O:33][C:26]1[CH:25]=[C:22]([CH:21]=[C:20]([O:19][CH2:17][CH3:18])[C:27]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:23][N:13]1[CH2:12][CH2:11][CH:10]([NH:9][C:7](=[O:8])[C:6]2[CH:16]=[C:2]([CH3:1])[CH:3]=[N:4][CH:5]=2)[CH2:15][CH2:14]1)[CH3:35]
Reactant: Cc1cncc(C(=O)NC2CCNCC2)c1
Reactant: CCOC(=O)c1c(OCC)cc(C=O)cc1OCC
Product: CCOC(=O)c1c(OCC)cc(CN2CCC(NC(=O)c3cncc(C)c3)CC2)cc1OCC
Yield: 32 %

Procedure:
The title (15 mg, 32%) compound was prepared analogously to example 30 from 5-methyl-N-(piperidin-4-yl)-nicotinamide and 3,5-diethoxy-4-ethoxycarbonyl-benzaldehyde. MS: 470.5 (MH+)
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8](=[O:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1.[Si]([C:26]([F:29])([F:28])[F:27])(C)(C)C.[F-].[Cs+]>COCCOC.CCCC[N+](CCCC)(CCCC)CCCC.[F-].O>[Br:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][CH2:7][C:8]([C:26]([F:29])([F:28])[F:27])([OH:19])[CH2:9][N:10]3[C:18]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH:12]=[C:11]3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C1COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: OC1(C(F)(F)F)COc2ccc(Br)cc2-c2cc3ccccc3n2C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.9 %

Procedure:
A mixture of 2-bromo-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7(8H)-one (60 mg, 0.18 mmol), TMSCF3 (275 mg, 0.194 mmol) and CsF (3 mg, 0.018 mmol) in DME (1 mL) was stirred at room temperature for 3 hours. The mixture was then diluted with TBAF (5 mL) and stirred for 1 hour at room temperature. The mixture was then diluted with water (25 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using prep-TLC (petroleum ether:EA=3:1) to provide 2-bromo-7-(trifluoromethyl)-7,8-dihydro-6H-benzo[2,3][1,5]oxazocino[5,4-a]indol-7-ol (40 mg, yield: 55.6%). MS (M+H)+: 412/414.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.[CH:15]([Si:18]([CH3:40])([CH3:39])[C:19]1[CH:38]=[CH:37][C:22]([CH2:23][NH:24][CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[CH:21][CH:20]=1)([CH3:17])[CH3:16]>>[CH:15]([Si:18]([CH3:40])([CH3:39])[C:19]1[CH:38]=[CH:37][C:22]([CH2:23][N:24]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:21][CH:20]=1)([CH3:16])[CH3:17]
Reactant: CC(C)[Si](C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Product: CC(C)[Si](C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [4-(isopropyl-dimethyl-silanyl)-benzyl]-[2-(3-trifluoromethyl-phenyl)-ethyl]-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [4-(isopropyl-dimethyl-silanyl)-benzyl]-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine. MS (ISP) 575.3/576.4/577.3 (100/46/40) (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([S:20][C:21]([F:24])([F:23])[F:22])=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:25]Br>C(Cl)(Cl)Cl.BrBr.C(Cl)Cl>[Br:25][C:11]1[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:15])=[O:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[NH:9][C:10]=1[S:20][C:21]([F:24])([F:22])[F:23]
Reactant: BrBr
Reactant: O=S(=O)(c1cc(SC(F)(F)F)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1c(-c2ccc(Cl)cc2)[nH]c(SC(F)(F)F)c1Br)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.9 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]-5-[(trifluoromethyl)thio]pyrrole (0.5 g, 0.00122 mol) in chloroform (10 mL) is cooled with an ice bath, treated with a solution of bromine (0.21 g, 0.00134 mol) in chloroform (5 mL), stirred for two hours, warmed to room temperature, treated with two drops of additional bromine and stirred for one hour. The reaction mixture is diluted with methylene chloride, washed with water, saturated sodium hydrogen carbonate solution, saturated sodium metabisulfite solution and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a syrup. Flash chromatography of the syrup using silica gel and a 1:5 ethyl acetate/hexanes solution gives the title product as a white solid (0.25 g, mp 122°-125° C.) which is identified by 1HNMR and 13CNMR spectral analyses.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].[Cl:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(C(C)C)C(C)C)C>C(O)C>[ClH:31].[ClH:30].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: ClCCN1CCCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CCN1CCCC1)CC2
Temperature: 60 °C

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (180 mg, 0.46 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (95 mg, 0.56 mmol), (i-Pr)2EtN (0.25 mL, 1.4 mmol) were combined in ethanol (2 mL) and heated at 60° C. for 2 h. Purification by preparative HPLC and conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound as a white solid: mp 285-289° C.; 1H NMR (300 MHz, D2O) δ 7.50 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.42-7.31 (m, 6H), 6.96 (dd, J=8.3, 1.6 Hz, 1H), 6.27 (dd, J=7.7, 2.6 Hz, 1H), 6.10 (d, J=2.6 Hz, 1H), 5.90 (s, 2H), 4.59 (br s, 2H), 3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J=5.7 Hz, 2H), 3.18-3.05 (br m, 2H), 2.15-1.90 (m, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B) 98.8% (AUC), tR=11.3 min.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH:7]=[O:8].I[CH2:10][CH3:11].O>C1COCC1>[CH2:10]([N:3]1[C:2]([CH3:1])=[C:6]([CH:7]=[O:8])[N:5]=[CH:4]1)[CH3:11]
Reactant: CCI
Reactant: Cc1nc[nH]c1C=O
Solvent: O
Solvent: C1CCOC1
Product: CCn1cnc(C=O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.6 %

Procedure:
To a solution of 4-methyl-1H-imidazole-5-carbaldehyde (5.0 g, 45.4 mmol) in anhydrous THF (50 mL) was added diaza(1,3)bicyclo[5.4.0]undecane (DBU, 6.8 mL, 45.4 mmol) and iodoethane (3.4 mL, 45.4 mmol). The reaction mixture was stirred at room temperature overnight. Water (50 mL) was added before THF was evaporated. The mixture was extracted with EtOAc (1×50 mL) and 2-butanol (2×50 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-1% MeOH/DCM), affording 1-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (730 mg, 12% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=3[S:11][CH:10]=2)O1.Br[C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:31][C:30]([F:33])([F:32])[C:28]([C:9]1[C:18]2[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:13][C:12]=2[S:11][CH:10]=1)=[CH2:29]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(B3OC(C)(C)C(C)(C)O3)csc2C1
Reactant: C=C(Br)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(c1csc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
A mixture of tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (300 mg), 2-bromo-3,3,3-trifluoropropene (0.2 ml), tetrakis(triphenylphosphine)palladium(0) (25.5 mg), saturated aqueous sodium carbonate solution (7 ml) and dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (140 mg, 50.9%) as an oil.