Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:18][C@H:19]1[CH2:23][C:22](=[O:24])[N:21]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C@@H:20]1[CH3:34])(=O)=O>CN(C=O)C.O>[I:1][C:2]1[CH:3]=[N:4][N:5]([CH2:18][CH:19]2[CH:20]([CH3:34])[N:21]([CH2:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)[C:22](=[O:24])[CH2:23]2)[CH:6]=1
Reactant: COc1ccc(CN2C(=O)C[C@H](COS(C)(=O)=O)[C@H]2C)cc1
Reactant: Ic1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC(Cn3cc(I)cn3)C2C)cc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
4-Iodo-1H-pyrazole (0.93 g, 4.77 mmol) and cesium carbonate (2.59 g, 7.95 mmol) were added to a solution of [(2R,3S)-1-(4-methoxybenzyl)-2-methyl-5-oxopyrrolidin-3-yl]methyl rac-methanesulfonate (1.3 g, 3.98 mmol) in DMF (26 mL). The mixture was stirred at 90° C. under a nitrogen atmosphere for 3 hours. After cooling to room temperature, the mixture was diluted with water (50 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (ethyl acetate/petroleum ether) to afford rac-(4R,5R)-4-[(4-iodo-1H-pyrazol-1-yl)methyl]-1-(4-methoxybenzyl)-5-methylpyrrolidin-2-one. MS ESI calc'd. for C17H21IN3O2 [M+H]+ 426. found 426. 1H NMR (400 MHz, CDCl3): δ 7.47 (s, 1H), 7.17 (d, J=8.5 Hz, 2H), 6.95 (s, 1H), 6.90 (d, J=8.5 Hz, 2H), 4.99-4.94 (m, 1H), 4.02-3.99 (m, 1H), 3.90-3.85 (m, 1H), 3.85 (s, 3H), 3.82-3.79 (m, 1H), 3.15-3.06 (m, 1H), 2.69-2.63 (m, 1H), 2.58-2.48 (m, 1H), 2.18-2.09 (m, 1H), 1.06 (d, J=6.5 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[CH:12]=[CH:13][C:14]1[CH:19]=[C:18]([O:20]C)[C:17]([CH:22]([CH3:24])[CH3:23])=[C:16]([O:25]C)[CH:15]=1.Cl.N1C=CC=CC=1>>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[CH:12]=[CH:13][C:14]1[CH:15]=[C:16]([OH:25])[C:17]([CH:22]([CH3:23])[CH3:24])=[C:18]([OH:20])[CH:19]=1
Reactant: COc1cc(C=Cc2c(F)c(F)c(F)c(F)c2F)cc(OC)c1C(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)c1c(O)cc(C=Cc2c(F)c(F)c(F)c(F)c2F)cc1O
Yield: 21 %

Procedure:
This material was prepared from 1-(2,3,4,5,6-pentafluorophenyl)-2-(3,5-dimethoxy-4-i-propylphenyl)ethene and pyridine hydrochloride in 21% yield in the same way as described in example 34. 1HNMR (CDCl3, ppm): δ 1.40 (d, J=7.2 Hz, 6H), 3.53 (d, J=7.2 Hz, 6H), 4.91 (s, 2H), 6.55 (s, 2H), 6.86 (d, J=17 Hz, 1H), 7.28 (d, J=17 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[C:5]2[CH3:13].[CH3:14][NH:15][CH3:16]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:15]([CH3:16])[CH3:14])[CH:6]=[C:5]2[CH3:13]
Reactant: Cc1cc(Cl)nc2ccc(Br)cc12
Reactant: CNC
Solvent: CCO
Product: Cc1cc(N(C)C)nc2ccc(Br)cc12
Temperature: -78 °C
Yield: 134.4 %

Procedure:
A solution of 0.26 g (0.00101 mole) of 6-bromo-2-chloro-4-methylquinoline in 50 ml absolute ethanol was placed in a glass bomb liner, cooled to -78° C., and 7.19 g (0.159 mole) of dimethylamine bubbled into the cold ethanolic solution. The mixture was heated to 112° in a sealed autoclave for 3 hours. The solvent and excess dimethylamine were then removed under vacuum, to leave 0.36 g of residue, which was washed with 40 ml H2O to remove the (CH3)2NH.HCl. The product was then taken up in 40 ml absolute ethanol, treated with Norite A alkaline decolourising carbon and filtered through Celite followed by concentration and addition of 7 ml H2O to induce crystallisation after chilling, the product collected was a light yellow crystalline solid, 0.20 g (74.3%), m.p. 81.9°-84.1° C., and Rf 0.11 on silica with 1:1 CH2Cl2 :hexane.
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][C:12]=2[CH3:13])=[N:5][S:4][N:3]=1.[Br:14]N1C(=O)CCC1=O.O.C([O-])([O-])=O.[K+].[K+]>ClC(Cl)(Cl)Cl>[Br:14][CH2:13][C:12]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[C:6]1[C:2]([Cl:1])=[N:3][S:4][N:5]=1
Reactant: Cc1ccncc1-c1nsnc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1nsnc1-c1cnccc1CBr
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(3-chloro-1,2,5-thiadiazol-4-yl)-4-methylpyridine (0.63 g, 3 mmol) in tetrachloromethane (50 ml) was added under nitrogen, N-bromosuccinimide (0.80 g, 4.5 mmol) and α,α-azoisobutyronitril (80 mg, 0.5 mmol). The reaction mixture was stirred at 75° C. overnight. Water (50 ml) was added and after basifying with K2CO3 the reaction mixture was extracted with methylene chloride (3×100 ml). The organic phases were dried (MgSO4) and evaporated. The residue contained a mixture of starting material, the monobromo and the dibromo product. Separation by column chromatography, eluent: ethyl acetate/methylene chloride: 1/10, gave the title compound in 180 mg (20%) yield.
Reaction SMILES: CSC.B.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:13]=[C:12]([CH2:14][C:15]#[N:16])[C:11]=2[CH:17]=1.Cl.[OH-].[Na+]>O1CCCC1>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:13]=[C:12]([CH2:14][CH2:15][NH2:16])[C:11]=2[CH:17]=1
Reactant: COc1ccc2c(c1)C(CC#N)=C2
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(CCN)=C2

Procedure:
4.3 ml (43 mmol) of borane dimethyl sulphide (10M in tetrahydrofuran) are slowly added dropwise, at room temperature, to 5 g (29 mmol) of 2-(5-methoxybenzocyclobuten-1-yl)acetonitrile in 50 ml of tetrahydrofuran. The mixture is then heated under reflux for 30 minutes. Subsequently, while cooling well, 30 ml of 6N hydrochloric acid are added and the mixture is then heated under reflux for a further 30 minutes. The reaction mixture is cooled, adjusted to pH 10 with 4N sodium hydroxide solution and extracted with dichloromethane. The organic phases are combined, dried over sodium sulphate and concentrated under reduced pressure. 2-(5-methoxybenzocyclobuten-1-yl)ethylamine is obtained in the form of a viscous oil; Rf=0.1, toluene/ethanol/conc. aqueous ammonia (90:20:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][C:21]([C:30]3[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=3)([CH2:26][N+:27]([O-])=O)[C:22]([F:25])([F:24])[F:23])=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Ni]>[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH2:20][C:21]([C:30]4[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[CH:31]=4)([C:22]([F:25])([F:24])[F:23])[CH2:26][N:27]=3)=[CH:15][CH:14]=2)([F:12])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C(=O)CC(C[N+](=O)[O-])(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2)C1
Agent: [Ni]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC(F)(c2ccc(C3=NCC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 27 %

Procedure:
The solution of 3-{4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-phenyl}-3-fluoro-azetidine-1-carboxylic acid tert-butyl ester (1.09 g, 1.881 mmol, 1 eq.) in ethanol (12 mL) was purged with nitrogen gas for 30 minutes. To this reaction mixture was added Raney-Nickel (50% suspension in water, 0.24 g). Resulting reaction mixture was stirred under hydrogen balloon atmosphere for 16 hours at room temperature. After complete consumption of starting material, the reaction mixture was filtered through celite bed and washed with 10% MeOH in DCM (30 mL). Filtrate was concentrated to get off white solid (1.06 g, crude). Crude compound was purified by column chromatography on silica gel using 230-400 mesh. Desired compound was eluted in 7.5% ethyl acetate in n-hexane to give product as off white solid (0.27 g, 27%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 3.45 (d, J=17.4 Hz, 1H), 3.79 (d, J=18.84 Hz, 1H), 4.20-4.27 (m, 2H), 4.38-4.46 (m, 3H), 4.89 (d, J=17.08 Hz, 1H), 7.25-7.27 (m, 2H), 7.36-7.37 (m, 1H), 7.54 (d, J=8.28 Hz, 2H), 7.89 (d, J=8.16 Hz, 2H). LC-MS (m/z): 531.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][C:13]([N:15]([CH3:17])[CH3:16])=O)[C:5]=2[C:4](=O)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].O>O1CCCC1>[CH3:1][C:2]1([CH3:19])[CH2:10][C:9]2[NH:8][CH:7]=[C:6]([CH2:11][CH2:12][CH2:13][N:15]([CH3:17])[CH3:16])[C:5]=2[CH2:4][CH2:3]1
Reactant: CN(C)C(=O)CCc1c[nH]c2c1C(=O)CC(C)(C)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCc1c[nH]c2c1CCC(C)(C)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 3-(6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indol-3-yl)-N,N-dimethyl-propionamide (1.2 g, 4.68 mmol) in tetrahydrofuran (30 mL) was added dropwise a solution of lithium aluminum hydride (0.69 g, 18.3 mmol) in tetrahydrofuran. The mixture was refluxed overnight. Ice was added to the cooled reaction until no more gas was generated followed by 15% sodium hydroxide and water. The reaction was stirred at room temperature for 30 minutes and the insolubles removed by vacuum filtration. The filtrate was concentrated to give [3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-propyl]-dimethyl-amine as an oil. 1H-NMR (360 MHz, dimethylsulfoxide-d6) δ 9.75 (br s, 1H, NH), 6.24 (s, 1H), 3.36 (m, 2H, CH2), 2.07–2.3 (m, 14H, 7×CH2), 1.53 (m, 2H, CH2), 1.40 (m, 2H, CH2), 0.92 (s, 6H, 2×CH3). MS m/z 234 [M+].
Reaction SMILES: C([Li])CCC.[F:6][C:7]1([F:16])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8]1.C[O:18][B:19](OC)[O:20]C.Cl.[Cl-].[Na+]>O1CCCC1.O>[F:16][C:7]1([F:6])[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[C:12]([B:19]([OH:20])[OH:18])[C:10]=2[O:11]1
Reactant: FC1(F)Oc2ccccc2O1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: OB(O)c1cccc2c1OC(F)(F)O2
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A solution of n-butyllithium (5.57 mL of a 2.5M solution in hexanes, 13.9 mmol) was added to dry tetrahydrofuran (75 mL) at room temperature under a nitrogen atmosphere. The resulting solution was cooled to -15° C. and N,N,N',N'-tetramethylenediamine (2.10 mL, 13.9 mmol) was added dropwise. The reaction was stirred at -15° C. for 0.5 h and then 2,2-difluoro-1,3-benzodioxole was added dropwise while maintaining the reaction temperature below -10° C. After the addition was complete, the reaction was stirred at -15° C. for 1 h before a solution of trimethylborate (1.58 mL, 13.9 mmol) in dry tetrahydrofuran (5 mL) was added dropwise while maintaining the reaction temperature below -10° C. The reaction mixture was stirred at -10° C. for 1 h and then allowed to come to room temperature while stirring overnight. To the reaction mixture was added a 1N solution of hydrochloric acid and then concentrated hydrochloric acid until the solution was strongly acidic. The acidic solution was poured into water. The resulting mixture was saturated with sodium chloride and extracted with diethyl ether three times. The combined organic extracts were dried (MgSO4), filtered, and concentrated under reduced pressure to give a dark-brown oil. The oil was suspended in boiling petroleum ether and the hot solution filtered to remove a small amount of brown solid. The filtrate was then cooled and filtered to obtain a light-gray solid. The filtrate was concentrated under reduced pressure to give a light-brown solid which was combined with the gray solid obtained from recrystallization to afford the title compound of Step F (1.28 g, 50%). 1H NMR (CDCl3): δ4.92 (s,2H), 7.15 (m,2H), 7.5 (d, 1H). 19F NMR (CDCl3): δ-50.33 (s,2F).
Reaction SMILES: N#N.[NH:3]1[C:11]2[C:6](=[CH:7][C:8](/[C:12](/[C:24]3[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]/[C:32]([O:34]CC)=[O:33])=[CH:26][CH:25]=3)=[C:13](/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22]C)\[CH2:14][CH3:15])=[CH:9][CH:10]=2)[CH:5]=[N:4]1.B(Br)(Br)Br.[Li+].[OH-].Cl>C(Cl)Cl.C1COCC1.CCO.O>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1/[C:13](/[CH2:14][CH3:15])=[C:12](\[C:24]1[CH:25]=[CH:26][C:27](/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33])=[CH:28][CH:29]=1)/[C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[NH:3][N:4]=[CH:5]2
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccccc2OC)c2ccc3[nH]ncc3c2)cc1
Agent: BrB(Br)Br
Agent: Cl
Agent: N#N
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1ccccc1O
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A 10-mL recovery flask equipped with a magnetic stir bar, a rubber septum and N2 inlet was charged with (E)-ethyl 3-(4-((E)-1-(1H-indazol-5-yl)-2-(2-methoxyphenyl)but-1-en-1-yl)phenyl)acrylate (145 mg, 0.32 mmol, an intermediate in the synthesis of Compound 12) in DCM (6 mL). This solution was cooled down to −78° C. in an IPA/dry ice-bath. Then, BBr3 (241 mg, 0.96 mmol) was added dropwise via a syringe. The reaction mixture was gradually warmed to 0° C. for 1 h. Upon completion, the reaction was quenched with methanol (5 mL) at 0° C. The resulting mixture was concentrated under reduced pressure to give the crude product. Then, this crude product was dissolved in THF-EtOH (1:1, 6 mL), and aqueous LiOH (0.15 g, 6.4 mmol) was added at room temperature. The resulting mixture was stirred at this temperature overnight. Reaction was monitored by LCMS. Upon completion, 1N aqueous HCl was added until pH was 3. Then, the mixture was diluted with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (100 mL), washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated to give the crude product. This crude material was purified on a reversed phase C-18 column eluted with 40-100% acetonitrile in water in the presence of 0.1% TFA affording the title compound. 1H NMR (300 MHz, DMSO-d6): δ 13.07 (s, 1H), 12.34 (br, 1H), 9.33 (br, 1H), 8.08 (d, 1H), 7.65 (s, 1H), 7.53 (d, 1H), 7.40 (d, 1H), 7.32 (d, 2H), 7.15 (dd, 1H), 7.00-6.94 (m, 3H), 6.81-6.76 (m, 2H), 6.57 (dt, 1H), 6.34 (d, 1H), 2.43-2.30 (m, 2H), 0.88 (t, 3H); LCMS: 411 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:25][NH2:26])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([NH:26][CH2:25][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[CH:14][CH:15]=2)[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[O:6]
Reactant: Cc1ccc(Cl)c(C(=O)O)c1
Reactant: Cc1ccc(C2(CN)CCOCC2)cn1
Product: Cc1ccc(Cl)c(C(=O)NCC2(c3ccc(C)nc3)CCOCC2)c1

Procedure:
From 2-chloro-5-methylbenzoic acid and C-[4-(6-methylpyridin-3-yl)-tetrahydropyran-4-yl]methylamine. LCMS (MH+): m/z=359.0, tR (minutes, Method B)=0.74
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:4][CH:3]=1.[NH2:25][C@H:26]([CH2:28][OH:29])[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][O:14][C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:25][C@@H:26]([CH3:27])[CH2:28][OH:29])=[O:21])=[CH:17][N:16]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H](N)CO
Reactant: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccc(Cl)cc2)c1COc1ccc(C(=O)N[C@@H](C)CO)cn1
Yield: 94 %

Procedure:
As described for example 254, 6-[3-(4-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid (100 mg, 0.29 mmol) was converted, using L-alaninol instead of 2-amino-2-methyl-1-propanol, to the title compound (110 mg, 94%) which was obtained as a white solid. MS: m/e=402.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([N+:18]([O-])=O)[CH:11]=2)=[CH:4][CH:3]=1.[Sn](Cl)Cl>C(O)C>[NH2:18][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[NH:16][CH3:17])[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)=[O:21]
Reactant: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CNc1ccc(C(=O)Nc2ccc(Br)cc2)cc1N

Procedure:
Prepared analogously to example 303b from N-(4-bromo-phenyl)-4-methylamino-3-nitro-benzamide and tin(II)chloride in ethanol.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CSC.[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][Br:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1OCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CSC
Product: BrCc1ccccc1OCc1ccccc1
Reaction time: 0.17 h

Procedure:
A solution of N-Bromosuccinimide (1.84 g, 10.36 mmol) in 50 mL of CH2Cl2 was cooled in a wet ice/acetone bath. Dimethyl sulfide (0.91 mL, 12.44 mmol) was added and the reaction stirred for 10 minutes. The product from Step L (1.48 g, 6.91 mmol) in 25 mL of CH2Cl2 was added and the reaction was stirred at 0° C. for 4.5 hours. The reaction was poured into water/ice and separated layers. The organic portion was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the benzyl bromide.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[CH3:33])=[C:23]([O:34][CH3:35])[CH:22]=3)=[O:20])[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[C:38]1([CH:44]([NH2:46])[CH3:45])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[CH3:35][O:34][C:23]1[CH:22]=[C:21]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:46][CH:44]([C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH3:45])=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:20])[CH:26]=[CH:25][C:24]=1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH3:33]
Reactant: CC(N)c1ccccc1
Reactant: COc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1-c1ccccc1C
Product: COc1cc(C(=O)N2Cc3ccc(C(=O)NC(C)c4ccccc4)n3Cc3ccccc32)ccc1-c1ccccc1C

Procedure:
The title compound was prepared in the manner of Example 36 from 2,2,2-trichloro-1-{10-[(2-methoxy-2′-methyl-1,1′-biphenyl-4-yl)carbonyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 35 and (±)-1-phenylethylamine. Purification was performed using HPLC with a normal phase column by eluting with a two phase solvent system (A=hexane, B=dichloromethane/methanol, 4:1) that gave the title compound in 63% yield, m.p. 211° C. MS [(+)ESI, m/z]: 554 [M+H]+ Anal. Calcd for C36H33N3O3: C, 77.81; H, 5.99; N, 7.56. Found: C, 77.65; H, 6.01; N, 7.45.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1.O>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[C:1]([NH:10][C:11]1[CH:16]=[C:15]([CH2:17][C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])[CH:14]=[CH:13][N:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cc2ccnc(N)c2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1ccc(C(=O)Cc2ccnc(NC(=O)c3ccccc3)c2)cc1
Temperature: 70 °C
Reaction time: 12 h
Yield: 55.6 %

Procedure:
Benzoyl chloride (4.4 g, 31 mmol) and 4-dimethylaminopyridine (0.57 g, 4.7 mmol) were added to a solution of 2-(2-amino-4-pyridyl)-1-(4-methoxyphenyl)ethanone (3.8 g, 16 mmol) in N,N-dimethylacetamide (80 mL) and the mixture was stirred at 70° C. for 12 hours. After the reaction mixture was cooled to room temperature, water (50 mL) was added. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in tetrahydrofuran (80 mL) and methanol (20 mL) and 1N-aqueous solution of sodium hydroxide (50 mL) was added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated and water (100 mL) was added. The mixture was extracted with ethyl acetate and the organic layer was washed with a saturated aqueous solution of sodium chloride. The layer was dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized from ethyl acetate-hexane to obtain 3.1 g of the title compound (8.9 mmol, yield 57%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1.C(O)C>CS(C)=O>[CH3:15][C:16]1[CH:24]=[C:23]2[C:19]([C:20]([CH:25]3[CH2:30][CH2:29][N:28]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:27][CH2:26]3)=[CH:21][NH:22]2)=[CH:18][CH:17]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc2c(C3CCNCC3)c[nH]c2c1
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1ccc2c(C3CCN(C[C@H](O)COc4cccc5[nH]ccc45)CC3)c[nH]c2c1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.145 g, 0.767 mmol) and 6-methyl-3-(piperidin-4-yl)-1H-indole (0.150 g, 0.697 mmol) using ethanol as reaction solvent. Yield 0.140 g (49%) as a tan foam. FDMS m/e=403 (M+ of free base). α[D]589 =+3.8 (c=0.98, dimethylsulfoxide).
Reaction SMILES: C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[F:23][C:24]([F:46])([F:45])[C:25]1[CH:26]=[C:27]2[C:31](=[C:32]([CH:34]([OH:36])[CH3:35])[CH:33]=1)[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:44])([CH3:43])[CH3:42])[CH:29]=[CH:28]2.[Cl:47][C:48]([Cl:52])([Cl:51])[C:49]#[N:50]>C(OCC)C>[Cl:47][C:48]([Cl:52])([Cl:51])[C:49](=[NH:50])[O:36][CH:34]([C:32]1[CH:33]=[C:25]([C:24]([F:23])([F:45])[F:46])[CH:26]=[C:27]2[C:31]=1[N:30]([CH2:37][O:38][CH2:39][CH2:40][Si:41]([CH3:42])([CH3:44])[CH3:43])[CH:29]=[CH:28]2)[CH3:35]
Reactant: CC(O)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Reactant: N#CC(Cl)(Cl)Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CCOCC
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2ccn(COCC[Si](C)(C)C)c12
Reaction time: 0.17 h

Procedure:
Diazabicycloundecene (33.0 mg, 0.217 mmol) was added to a solution of (±)-1-(5-(trifluoromethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-7-yl)ethanol (390 mg, 1.09 mmol) in diethyl ether (10 ml) and stirred for 10 min. Trichloroacetonitrile (235 mg, 1.627 mmol) was then added and the reaction stirred 16 h at ambient temperature. The solvent was evaporated and the residue purified by chromatography on silica gel with a gradient of ethyl acetate/hexanes from 5% to 40% to give 290 mg (53%) as a brown oil. 1H-NMR (CDCl3, 400 MHz) δ 8.23 (s, 1H), 7.82 (s, 1H), 7.69 (s, 1H), 7.17 (d, J=33 Hz, 1H), 6.76 (q, J=6.5 Hz, 1H), 6.57 (d, J=3.2 Hz, 1H), 6.19 (d, J=11.5 Hz, 1H), 5.30 (d, J=11.5 Hz, 1H), 3.48 (dd, J=9.0, 8.0 Hz, 2H), 1.75 (d, J=6.4 Hz, 3H), 0.92 (m, 2H), −0.07 (s, 9H); LC/MS (HPLC method 4): tR=4.31 min, 342.16(M-OC2NHCl3)+.