Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2=[C:7]3[C:15](=[CH:16][CH:17]=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[NH:8]3.[Al+3].[Cl-].[Cl-].[Cl-].[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:17]([CH:5]([CH2:4][CH2:3][CH2:2][CH3:1])[CH2:6][N:8]1[C:7]2[C:15](=[CH:16][C:17]([C:27]([C:26]3[CH:30]=[CH:31][C:23]([F:22])=[CH:24][CH:25]=3)=[O:28])=[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:6]3=2)[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH3:16]
Reactant: c1ccc2c(c1)ccc1c3ccccc3[nH]c21
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC(CC)Cn1c2ccccc2c2cc(C(=O)c3ccc(F)cc3)c3ccccc3c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.9 %

Procedure:
To 11H-benzo[a]carbazole (8.24 g, 25.0 mmol) in CH2Cl2 (80 ml) are added AlCl3 (3.33 g, 25.0 mmol) and 4-fluorobenzoyl chloride (4.04 g, 25.5 mmol) at 0° C. After stirring at room temperature for 4 hours, the reaction mixture is poured into ice-water. The crude product is extracted with CH2Cl2, and washed with water and brine. After drying over MgSO4 and concentration, the crude product is purified by column chromatography on silica gel eluting with a mixed solvent of CH2Cl2 and n-hexane (1:9) to obtain a yellow solid (4.96 g, 44%). The structure is confirmed by 1H-NMR spectrum (CDCl3). δ [ppm]: 0.82-0.91 (m), 1.18-1.47 (m), 2.21-2.30 (m), 4.67-4.78 (m), 7.16 (t), 7.30 (t), 7.50 (t), 7.55-7.59 (m), 7.63-7.67 (m), 7.96-8.00 (m), 8.05 (d), 8.31 (s), 8.51 (d), 8.63 (d); 19F-NMR spectrum (CDCl3). δ [ppm] −105.89.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].C(N(CC)C(C)C)(C)C.[Cl-].[Mg+2].[Cl-].[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30]C(Cl)=O)=[CH:26][CH:25]=1>C(#N)C>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:3](=[O:5])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:26][CH:25]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 38.8 %

Procedure:
To a suspension of potassium ethyl malonate (17.12 g, 100.6 mmol) in acetonitrile (150 mL) were added N,N-diisopropylethylamine (28 mL, 160 mmol) and magnesium chloride (12.11 g, 127.2 mmol). The resulting mixture was stirred for 1 hour. A solution of 4-chlorophenylacetyl chloride (10.12 g, 53.53 mmol) in acetonitrile (100 mL) was then added and the mixture was heated to 60° C. and stirred for 20 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was suspended in 1N aqueous HCl (250 mL) and was extracted with EtOAc (100 mL×2). The combined organic phases were dried Over anhydrous MgSO4 and insoluble materials were removed by filtration. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography on silica, elution with a 0%-80% mixture of EtOAc in hexane (linear gradient, 45 min) to obtain ethyl 4-(4-chlorophenyl)-3-oxobutanoate (5.0 g, 39%) as a yellow oil. LC/MS (FA) ES− 239. 1H NMR (d6-DMSO, 400 MHz): δ: 7.37 (2H, d, J=13.8 Hz), 7.20 (2H, d, J=13.8 Hz), 4.07 (2H, q, J=7.2 Hz), 3.89 (2H, s), 3.66 (2H, s), 1.17 (3H, t, J=7.2 Hz).
Reaction SMILES: [N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH2:22][CH2:21][CH2:20]NC3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C1(C(Cl)=[O:27])CC1>C(Cl)Cl>[N:1]1([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]3[CH:21]([CH:20]=[O:27])[CH2:22]3)[N:11]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc2c(c1)nnn2-c1ccnc(NC2CCCNC2)n1
Solvent: ClCCl
Product: O=CC1CC1Nc1nccc(-n2nnc3ccccc32)n1
Temperature: 25 °C

Procedure:
To DCM (8 mL) was added (4-benzotriazol-1-yl-pyrimidin-2-yl)-piperidin-3-ylamine (0.15 g), cyclopropylformyl chloride (40.5 μL) and TEA (0.285 mL), and the mixture stirred at RT. The product was purified by column chromatography on silica, using 100% DCM to 10% MeOH/DCM, then recrystallized from EtOAc to provide [3-(4-benzotriazol-1-yl-pyrimidin-2-ylamino)]-cyclopropylmethanone. Mp=99.0-100.0° C., 1H nmr (300 MHz, DMSO-d6): δ ppm 0.54-0.82 (m, 4H), 1.40-1.77 (m, 2H), 1.78-1.93 (m, 2H), 2.01-2.19 (m, 2H), 3.13 (t, J=11.11 Hz, 2H), 3.84-4.10 (m, 2H), 4.32 (d, J=11.68 Hz, 1H), 7.37 (d, J=5.27 Hz, 1H), 7.48-7.61 (m, 1H), 7.62-7.74 (m, 1H), 8.08-8.23 (d, 1H), 8.51 (d, J=5.27 Hz, 1H), 8.67 (d, J=8.29 Hz, 1H).
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=[O:5])[CH2:3][CH2:2]1.[Br:7][CH2:8][C:9](Br)=[O:10]>O1CCOCC1>[Br:7][CH2:8][C:9]([NH:6][C:4]([CH:1]1[CH2:3][CH2:2]1)=[O:5])=[O:10]
Reactant: NC(=O)C1CC1
Reactant: O=C(Br)CBr
Solvent: C1COCCO1
Product: O=C(CBr)NC(=O)C1CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 97.1 %

Procedure:
Cyclopropanecarboxamide (58.7 g, 690 mmol) in 1,4-Dioxane (1600 ml) was added 2-bromoacetyl bromide (59.9 ml, 690 mmol) at room temperature and stirred for 4 h at 60° C. The reaction mixture was concentrated to dryness. The residue was dissolved in EtOAc and carefully washed with satd. NaHCO3, water then with brine solution, dried over Na2SO4 and concentrated to get N-(2-bromoacetyl)cyclopropanecarboxamide (138 g, 670 mmol, 97% yield) as an off white solid. This material was used without purification. ESI-MS:m/z 208.0 (M+2H)+.
Reaction SMILES: C([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5]1=[O:29])C=C.C[N+]1([O-])CC[O:35]CC1.[CH3:39][C:40]([CH3:42])=[O:41]>O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:6]([CH:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[C:5](=[O:29])[C@:4]([CH2:39][CH:40]([OH:41])[CH2:42][OH:35])([CH3:30])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N(C(CC)CC)C1=O
Reactant: CC(C)=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Solvent: O
Product: CCC(CC)N1C(=O)[C@@](C)(CC(O)CO)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.07 h

Procedure:
To a solution of 298 mg (0.67 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-(pentan-3-yl)piperidin-2-one (Example 71, Step E) in a mixture of acetone (11.5 mL) and water (4 mL) added a catalytic amount of osmium tetroxide. After 4 min, 275 mg (2.35 mmol) of N-methylmorpholine-N-oxide was added. The resulting brown solution was stirred at room temperature for 3.5 h, and then was partitioned between water and DCM (3×). The combined organic layers were dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by flash chromatography on silica gel (1 to 20% MeOH/DCM, gradient elution) provided the title compound (mixture of alcohol epimers) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:18])=[C:4]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6].[CH:19]([O-])([O-])[O:20][CH2:21][CH3:22].C(OC(=O)C)(=O)C>>[Br:1][C:2]1[C:3]([F:18])=[C:4]([CH:13]=[C:14]([F:17])[C:15]=1[F:16])[C:5]([C:7](=[CH:19][O:20][CH2:21][CH3:22])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:6]
Reactant: CCOC([O-])[O-]
Reactant: CCOC(=O)CC(=O)c1cc(F)c(F)c(Br)c1F
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Br)c1F
Temperature: 130 °C
Reaction time: 4.5 h
Yield: 99.5 %

Procedure:
A mixture of ethyl 3-bromo-2,4,5-trifluorobenzoylacetate (1.5 g), ethyl orthoformate (1.0 g) and acetic anhydride (1.2 g) was stirred at 130° C. for 4.5 hours and then concentrated to give the title compound (1.75 g) as yellow oil.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([N:13]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH:37]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:38]([O:40][CH3:41])=[O:39].O>CN(C=O)C.C(Cl)Cl>[CH3:41][O:40][C:38](=[O:39])[CH:37]([N:27]1[CH2:28][CH2:29][CH:24]([N:13]([C:10]2[CH:11]=[C:12]3[C:7]([CH2:6][CH2:5][N:4]3[C:1](=[O:3])[CH3:2])=[CH:8][CH:9]=2)[C:14](=[O:23])/[CH:15]=[CH:16]/[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:25][CH2:26]1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCNCC3)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(c1ccccc1)N1CCC(N(C(=O)/C=C/c2ccccc2)c2ccc3c(c2)N(C(C)=O)CC3)CC1
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To a solution of trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-phenyl-N-piperidin-4-yl-acrylamide (Example 41, Step C; 49 mg, 0.13 mmol) in DMF (0.5 mL) and DCM (2 mL) was added Na2CO3 (41 mg, 0.39 mmol) followed by methyl α-bromophenylacetate (26 μL, 0.16 mmol). After stirring overnight, the reaction mixture was poured into H2O and DCM was added. The organic fraction was washed with brine (3×), dried (Na2SO4), and concentrated. Purification by silica gel chromatography (2% methanol (2 M NH3) in DCM) afforded 59 mg (84%) of the title compound. 1H NMR (400 MHz, CDCl3): 8.04 (br d, J=12.4 Hz, 1H), 7.62 (d, J=15.4 Hz, 1H), 7.38-7.22 (m, 10H), 7.18 (dd, J=8.8, 8.0 Hz, 1H), 6.73 (dd, J=17.2, 7.8 Hz, 1H), 6.15 (d, J=15.6 Hz, 1H), 4.74 (br dd, J=12.4, 12.1 Hz, 1H), 4.17 (dd, J=8.8, 8.3 Hz, 2H), 3.94 (d, J=3.8 Hz, 1H), 3.65 (s, 3H), 3.31-3.24 (m, 2H), 3.01-2.94 (m, 1H), 2.76-2.69 (m, 1H), 2.34-2.22 (m, 1H), 2.24 (d, J=5.3 Hz, 3H), 2.02-1.76 (m, 2H), 1.76-1.63 (m, 1H), 1.61 (s, 3H), 1.58-1.40 (m, 1H). MS: exact mass calculated for C33H35N3O4, 537.3; m/z found, 538.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([F:32])=[CH:4][N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1B(O)O)#[N:34].C(=O)([O-])[O-:45].[K+].[K+].O1CCOCC1>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>[CH3:31][O:30][C:23]1[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:22]=1[CH2:21][N:15]([C:16]1[S:17][CH:18]=[CH:19][N:20]=1)[S:12]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]([NH2:34])=[O:45])=[N:3][CH:4]=[C:5]2[F:32])(=[O:13])=[O:14]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccccc1B(O)O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)ncc(F)c3c2)c(OC)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccccc4C(N)=O)ncc(F)c3c2)c(OC)c1

Procedure:
A microwave vial was charged with 1-chloro-N-(2,4-dimethoxybenzyl)-4-fluoro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate PPP; 0.060 g, 0.121 mmol), (2-cyanophenyl)boronic acid (0.027 g, 0.182 mmol), tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol), and potassium carbonate (0.084 g, 0.607 mmol). Dioxane (0.607 mL) and Water (0.202 mL) were added, the vial was flushed with argon and sealed, and microwaved at 100° C. for 30 minutes. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 12 g, gradient elution 0-100% EtOAc:Heptane) to afford 2-(6-(N-(2,4-dimethoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-4-fluoroisoquinolin-1-yl)benzamide. (ESI) 579.2 (M+H)+.
Reaction SMILES: [CH:1]([Si:4]([CH:13]([CH3:15])[CH3:14])([CH:10]([CH3:12])[CH3:11])[N:5]1[CH:9]=[CH:8][CH:7]=[CH:6]1)([CH3:3])[CH3:2].[Br:16][C:17]1[CH:18]=[C:19]([C:23]#[CH:24])[CH:20]=[CH:21][CH:22]=1>CC#N.C(N(CC)CC)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.[Cu]I>[Br:16][C:17]1[CH:18]=[C:19]([C:23]#[C:24][C:7]2[CH:8]=[CH:9][N:5]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:10]([CH3:12])[CH3:11])[CH:13]([CH3:15])[CH3:14])[CH:6]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: C#Cc1cccc(Br)c1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C#Cc2cccc(Br)c2)c1
Temperature: 25 °C
Yield: 670.9 %

Procedure:
A solution of N-triisopropylsilylpyrrole (3.49 g, 1 mmol), 3-bromo-1-ethynylbenzene (1.81 g, 1 mmol), Pd(PPh3)4 (800 mg) and CuI (185 mg) in CH3CN (15 ml) and triethylamine (35 ml) is refluxed for 5 h. The reaction mixture is cooled to room temperature and the solvent is evaporated on a rotary evaporator. The crude material is purified by flash chromatographied (silica gel, 100% hexane) to afford 3-[(3-bromophenyl)ethynyl]-1-(triisopropylsilyl)-1H-pyrrole (2.7 g, 85%) as a clear oil.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH:45]1[CH2:50][CH2:49][CH:48]([N:51]2[CH2:57][CH2:56][C:55]3[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=3[NH:53][C:52]2=[O:62])[CH2:47][CH2:46]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:45]2[CH2:46][CH2:47][CH:48]([N:51]3[CH2:57][CH2:56][C:55]4[CH:58]=[CH:59][CH:60]=[CH:61][C:54]=4[NH:53][C:52]3=[O:62])[CH2:49][CH2:50]2)=[O:34])[CH2:18][CH2:17]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.4 %

Procedure:
Triethylamine (7.0 μL, 0.05 mmol) was added to a solution of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (17 mg, 0.05 mmol) and 4-nitrophenyl chloroformate (10.0 mg, 0.05 mmol) in tetrahydrofuran (3 mL) at 0° C. After 20 min, the hydrochloride salt of 3-piperidin-4-yl-1,3,4,5-tetrahydro-2H-1,3-benzodiazepin-2-one (14 mg, 0.05 mmol) and triethylamine (21 μL, 0.15 mmol) were added and the mixture allowed to warm to ambient temperature. After 1 h, saturated aqueous sodium carbonate was added and the mixture was extracted with dichloromethane (3×). The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→93% dichloromethane/methanol) gave the title compound (22 mg). MS 617.2609 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][CH2:29][CH2:30][O:31][Si](C(C)(C)C)(C)C)[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1.C(Cl)Cl.CCOCC>[ClH:20].[Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28][CH2:29][CH2:30][OH:31])[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(N3CCC[C@@H](NCCO)C3)c12)c1ccc(F)c(Cl)c1
Reaction time: 0.17 h
Yield: 114.2 %

Procedure:
A solution of (R)—N-(5-bromo-4-(3-(2-(tert-butyldimethylsilyloxy)ethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide (30 mg, 0.048 mmol) in THF (2 mL) at room temperature was treated with TBAF (0.048 mL, 0.048 mmol) and stirred for 10 minutes. The mixture was then concentrated in vacuo and purified by reverse phases HPLC (Gilson). The residue obtained was dissolved in a minimal amount of DCM and added to a stirring solution of 1M HCl in ether. The solid formed was filtered, washed with ether and dried to give (R)—N-(5-bromo-4-(3-(2-hydroxyethylamino)piperidin-1-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide hydrochloride (0.015 g, 54% yield). 1H NMR (400 MHz, D2O) δ 8.19 (s, 1H), 7.98-7.94 (m, 1H), 7.82-7.76 (m, 1H), 7.38 (s, 1H), 7.34-7.29 (m, 1H), 3.64-3.61 (m, 2H), 3.42-2.94 (m, 7H), 1.90-1.82 (m, 1H), 1.70-1.62 (m, 1H), 1.44-1.36 (m, 2H); LCMS (APCI+) m/z 510, 512 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:36][C@H:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([NH:43][C:44]([C:46]3[N:47]=[CH:48][N:49]([CH3:51])[CH:50]=3)=[O:45])[CH2:38]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)=[N:6][CH:7]=1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=O>ClCCl>[F:1][C:2]1[C:3]([NH:36][C@H:37]2[CH2:42][CH2:41][CH2:40][C@@H:39]([NH:43][C:44]([C:46]3[N:47]=[CH:48][N:49]([CH3:51])[CH:50]=3)=[O:45])[CH2:38]2)=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)=[N:6][CH:7]=1
Reactant: Cn1cnc(C(=O)N[C@@H]2CCC[C@H](Nc3nc(-c4nn(C(c5ccccc5)(c5ccccc5)c5ccccc5)c5ncccc45)ncc3F)C2)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1cnc(C(=O)N[C@@H]2CCC[C@H](Nc3nc(-c4n[nH]c5ncccc45)ncc3F)C2)c1
Reaction time: 1 h

Procedure:
To a solution of N-[(1R,3S)-3-[[5-fluoro-2-(1-tritylpyrazolo[3,4-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-1-methyl-imidazole-4-carboxamide, 25, (0.235 g, 0.347 mmol) in dichloromethane (6.90 mL) at room temperature was added Et3SiH (1.661 mL, 10.40 mmol) followed by TFA (0.401 mL, 5.200 mmol). The reaction mixture was stirred for 1 hour. The mixture was diluted with dichloromethane and quenched with aqueous saturated Na2CO3 solution. The organic phase was extracted with ethyl acetate, washed with brine (10 mL), dried over sodium sulfate and concentrated in vacuo. The crude residue was purified by silica chromatography (0-7% MeOH [2N NH3] in ethyl acetate) to give the desired product: LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, RT=1.46 min (M+H)=436.62.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[Na+].C1(O)CCCCC1>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:12][CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: Cc1ccc(Cl)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: OC1CCCCC1
Product: CCOC(=O)N1CCC(Nc2ccc(C)cc2[N+](=O)[O-])CC1
Temperature: 150 °C
Yield: 43.1 %

Procedure:
A mixture of 69 g of 4-chloro-3-nitro-toluene, 50 g of ethyl 4-amino-1-piperidinecarboxylate, 24 g of sodium carbonate, 0.1 g of sodium iodide and 120 ml of cyclohexanol was heated to 150° C. for 72 h. After cooling the cyclohexanol was distilled off under reduced pressure and the residue partitioned between 1 L of ethyl acetate and 1 L of water. The organic extract was dried over MgSO4 and concentrated under reduced pressure. Chromatography over silica gel, eluting with 20% ethyl acetate in cyclohexane gave 38.5 g (42.3%) of ethyl 4-(4-methyl-2-nitroanilino)-1-piperidinecarboxylate as an orange crystalline solid. 1H NMR (400 MHz, CDCl3) 8.0 (s, 1H), 7.27 (t, J=9 Hz, 1H), 6.8 (d, J=9 Hz, 1H), 4.15 (q, J=7 Hz, 2H), 4.05 (br m, 2H), 3.67 (br m, 1H), 3.10 (br t, J=11 Hz, 2H), 2.27 (s, 3H), 2.06 (br d, J=11 Hz, 2H), 1.6 (m, 2H), 1.27 (t, J=7 Hz, 4H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11]2)=[CH:2]1.Cl.[Cl:17]CCC[N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.Cl.CN(C)[CH2:30][CH2:31][CH2:32]Cl>>[ClH:17].[NH:21]1[CH2:22][CH2:23][CH2:24][CH:25]([CH2:30][CH2:31][CH2:32][N:12]2[CH2:13][CH2:14][CH2:15][CH:10]([C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[CH2:11]2)[CH2:26]1
Reactant: CN(C)CCCCl
Reactant: ClCCCN1CCCCC1
Reactant: c1ccc2c(C3CCCNC3)c[nH]c2c1
Agent: Cl
Product: c1ccc2c(C3CCCN(CCCC4CCCNC4)C3)c[nH]c2c1

Procedure:
Using 3-(3-indolyl)piperidine (104 mg, 0.44 mmol) and 1-(3-chloropropyl)piperidine hydrochloride (122 mg, 0.62 mmol) instead of 4-(3-indolyl)piperidine and 3-dimethylaminopropyl chloride hydrochloride respectively, reaction, extraction, and concentration were carried out in the same procedure as Example 4. The resulting crude product was purified by column chromatography on a silica gel (silica gel NH-DM 1020 produced by Fuji Silysia Chemical Ltd., eluent; chloroform) to afford a free form (125 mg) of the title compound as a pale yellow viscous oil. After adding hydrochloric acid/methanol to a solution of the free form in methanol, the mixture was concentrated and was then freeze-dried to afford the title compound (129 mg, yield: 74%) as a white amorphous solid.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](=O)([O-])[O-].[K+].[K+].C[C:15]1[C:25]2[CH:24](Cl)[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH2:21][O:20][C:19]=2[CH:18]=[CH:17][C:16]=1[C:31]([OH:33])=[O:32]>CN(C)C=O.O>[C:1]1([S:7][CH:24]2[C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[CH2:21][O:20][C:19]3[CH:18]=[CH:17][C:16]([C:31]([O:33][CH3:8])=[O:32])=[CH:15][C:25]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)ccc2c1C(Cl)c1ccccc1CO2
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)C(Sc1ccccc1)c1ccccc1CO2
Reaction time: 0.17 h

Procedure:
Add 0.12 ml of benzenethiol to a 70° C. suspension of 0.5 gm of potassium carbonate in 5 ml of dimethylformamide. Stir under a nitrogen atmosphere for 10 minutes. Add 0.27 gm of methyl 6,11-dihydro-11-chlorodibenz[b,e]oxepin-2-carboxylic acid and stir for 15 minutes. Dilute with water and extract with ether. Wash the extract with 5% aqueous potassium hydroxide and with saturated aqueous sodium chloride solution. Dry over anhydrous sodium sulfate and concentrate to dryness to obtain the title product (Yield 0.226 gm).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH3:23])[C:11](=[O:24])[CH2:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O>CN(C=O)C>[C:2]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]([CH3:23])[C:11](=[O:24])[CH2:10][N:9]=2)[CH:3]=1
Reactant: COc1cc2c(cc1OC)N(C)C(=O)CN=C2c1cccc(Br)c1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)N(C)C(=O)CN=C2c1cccc(-c2ccccc2)c1
Temperature: 115 °C
Yield: 12.9 %

Procedure:
Heat at 115° C. for 12 hours under an inert atmosphere a mixture of 100 mg (0.26 mmol) of 5-(3-bromophenyl)-7,8-dimethoxy-1-methyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one IIax, 38 mg (0.31 mmol) of benzene boronic acid, 63 mg (0.30 mmol) of K3PO4, 9 mg (0.020 mmol) of tetrakis(triphenylphosphine)Pd(0) in 1 ml of DMF. Allow to cool to room temperature. Add 80 ml of H2O and extract three times with 50 ml of Et2O. Dry the organic fractions on Na2SO4. Purify by chromatography (AcOEt 1/hexane 1). Recrystallize in EtOH. One obtains 13 mg of the abovenamed powder as colorless crystals. Yield: 13%. M: 127° C. 1H-NMR (CDCl3, 200 MHz): d 3.42 (s, 3H, NCH3), 3.77 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 4.34 (AB system, ?d=1.00, JAB=10.5, 2H, CH2), 6.78 (s, 1H Ar), 6.80 (s, 1H Ar), 7.39–7.90 (m, 9H Ar).