Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(CC)C.[CH:6]1([C:9]([N:11]2[CH2:17][CH2:16][CH:15]3[CH2:18][N:19](C(OC(C)(C)C)=O)[CH2:20][CH2:21][N:14]3[C:13]3[N:29]=[CH:30][CH:31]=[CH:32][C:12]2=3)=O)[CH2:8][CH2:7]1.[OH-].[Na+].FC(F)(F)C(O)=O>O1CCCC1.CO>[CH:6]1([CH2:9][N:11]2[CH2:17][CH2:16][CH:15]3[CH2:18][NH:19][CH2:20][CH2:21][N:14]3[C:13]3[N:29]=[CH:30][CH:31]=[CH:32][C:12]2=3)[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCN2c3ncccc3N(C(=O)C3CC3)CCC2C1
Agent: CCN(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: C1CCOC1
Product: c1cnc2c(c1)N(CC1CC1)CCC1CNCCN21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution alane-N,N-dimethylethylamine (0.5 M in toluene, 2.84 mL, 1.42 mmol) was added under nitrogen to an ice-cooled solution of the product of Example 72B (176 mg, 0.473 mmol) in tetrahydrofuran (8 mL). The reaction was stirred with ice cooling for 15 minutes and then warmed to room temperature and stirred for 30 minutes. Methanol (1 mL) was added followed after 5 minutes by addition of 25% NaOH (1 mL). The mixture was stirred for 10 minutes and then concentrated under vacuum. The residue was taken up with brine (10 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic phases were dried (Na2SO4) and concentrated under vacuum. The residue was dissolved in CH2Cl2 (5 mL) and stirred with ice cooling under nitrogen for 10 minutes. Trifluoroacetic acid (1.0 mL, 13 mmol) was added gradually over 0.5 minute, and the reaction was stirred with ice cooling for 1 hour and then warmed to room temperature for 1 hour. The solution was concentrated under vacuum, and the residue was purified by HPLC (30×100 mm, C18, Waters XBridge™ column eluted with 0.1 M aqueous (NH4)2CO3-methanol, 80:20-0:100 over 15 minutes) to provide the title compound: 1H NMR (300 MHz, CD3OD) δ ppm 0.18-0.27 (m, 2H), 0.51-0.60 (m, 2H), 0.93-1.09 (m, 1H), 1.67-1.80 (m, 1H), 1.80-1.94 (m, 1H), 2.73-2.86 (m, 2H), 2.87-3.04 (m, 4H), 3.11-3.28 (m, 3H), 3.41-3.51 (m, 2H), 6.84 (dd, J=7.8, 5.1 Hz, 1H), 7.12 (dd, J=8.0, 1.5 Hz, 1H), 7.70 (dd, J=5.1, 1.7 Hz, 1H); MS (DCI) m/z 259 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.N1C=CC=CC=1>O1CCOCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:5]2[C:6]([CH3:8])=[CH:7][C:2]([CH3:1])=[C:3]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]2=[O:9])=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1c(C)cc(C)[nH]c1=O
Reactant: OB(O)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CCOC(=O)c1c(C)cc(C)n(-c2ccc(F)cc2)c1=O
Temperature: 80 °C
Yield: 16.6 %

Procedure:
A suspension of ethyl 4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carboxylate (5.0 g, 0.025 mol), 4-fluorophenylboronic acid (10.7 g, 0.077 mol), cupric acetate (1.33 g, 0.007 mol), pyridine (6.86 mL), and 4 A molecular sieves (5.0 g) in 1,4-dioxane (80 mL) is heated at 80° C. for 68 hours. The solids are filtered off and the filtrate is concentrated. The residue is partitioned with EtOAc (50 mL) and 2N HCl (70 mL). The precipitated solid is collected by filtration and washed with EtOAc to give the title product (1.2 g). The EtOAc filtrate is separated, dried and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc:MeOH (40:20:1) to give another portion of product (0.12 g), (1.32 g total, 17.8% yield). MS (m/z): 290.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=2)[C:10]2[CH:15]=[CH:14][C:13]([N:16]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[C:17]3[CH:27]=[CH:26][C:20]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH3:51][S:52](Cl)(=[O:54])=[O:53]>CN(C)C1C=CN=CC=1>[CH3:51][S:52]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:20]1[CH:26]=[CH:27][C:17]([N:16]([C:13]2[CH:12]=[CH:11][C:10]([N:9]([C:36]3[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=3)[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[CH:15][CH:14]=2)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:18][CH:19]=1)(=[O:54])=[O:53]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCO)cc3)cc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: COc1ccc(N(c2ccc(OC)cc2)c2ccc(N(c3ccc(OC)cc3)c3ccc(OCCCOS(C)(=O)=O)cc3)cc2)cc1
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
To a dry schlenk flask was added 3-(4-((4-(bis(4-methoxyphenyl)amino)phenyl)(4-methoxyphenyl)amino)phenoxy)propan-1-ol (1.16 g, 2.01 mmol) and 4-dimethylaminopyridine (0.012 g, 0.100 mmol. The flask was evacuated under vacuum and filled with nitrogen before addition of anhydrous tetrahydrofuran (2.0 mL). The mixture was placed in an ice bath and allowed to stir for 10 minutes. Triethylamine (0.712 g, 7.04 mmol) was added and the reaction was allowed to stir for 10 minutes. Added methanesulfonyl chloride (0.691 g, 6.03 mmol) and allowed mixture to stir for 5 minutes. The ice bath was removed and the mixture was stirred at room temperature while being monitored by thin layer chromatography (1:2 hexanes:ethyl acetate). Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 100 mL of cold water. The product was extracted using 3×50 mL ether. The organic layers were combined and washed with 3×50 mL of water, sodium bicarbonate solution, and sodium chloride solution. The resulting ether layers were dried over MgSO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure. The residual solvent was removed in vacuo. The material was purified by flash chromatography (silica gel, 4:2 toluene:ethyl acetate) to yield an off-white solid (0.967 g, 73.3%). 1H NMR (400 MHz, C3D6O) δ 6.96 (m, 8H), 6.85 (m, 8H), 6.80 (s, 4H), 4.43 (t, J=6.3 Hz, 2H), 4.09 (t, J=6.0 Hz, 2H), 3.74 (s, 9H), 3.09 (s, 3H), 2.19 (q, J=6.2 Hz, 2H). 13C{1H} NMR (400 MHz, C3D6O) δ 156.42, 156.39, 155.30, 143.73, 143.49, 142.62, 142.26, 142.22, 126.33, 126.28, 126.00, 123.91, 123.69, 116.14, 115.41, 67.94, 64.61, 55.63, 36.97, 29.87. HRMS-EI (m/z): [M]− calcd for C37H38N2O7S, 654.24. found, 654.1). Anal. Calcd for C37H38N2O7S: C, 67.87; H, 5.85; N, 4.28. Found: C, 67.61; H, 5.77; N, 4.26.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:12][CH:13]2[CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15][N:14]2C(OC(C)(C)C)=O)=[N:4][NH:3]1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[NH:14]1[CH2:15][CH2:16][NH:17][CH2:18][CH:13]1[CH2:12][C:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:2](=[O:1])[NH:3][N:4]=1.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)CC1Cc1n[nH]c(=O)c2c1CCCC2
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]nc(CC2CNCCN2)c2c1CCCC2

Procedure:
A solution of EXAMPLE 258 (35 mg, 0.1 mmol) in trifluoroacetic acid (5 ml) was stirred at room temperature for 1 hour, and was concentrated. The residue was purified by HPLC (Zorbax® C-18 ODS packing material [Agilent Technologies, Santa Clara, Calif.], 0.1% trifluoroacetic acid/CH3CN/H2O) to provide the title compound as a trifluoroacetic acid salt. MS (DCI/NH3) m/z 249 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH:18]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19]2)[CH2:13][CH2:12]1.C([O-])(=O)C([O-])=O>>[CH2:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH:18]1[CH2:17][N:14]1[CH2:13][CH2:12][CH:11]([C:7]2[C:6]3[C:10](=[CH:2][CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH2:16][CH2:15]1
Reactant: Clc1cccc2c(C3CCN(CC4Cc5ccccc5C4)CC3)c[nH]c12
Agent: O=C([O-])C(=O)[O-]
Product: c1ccc2c(c1)CC(CN1CCC(c3c[nH]c4ccccc34)CC1)C2

Procedure:
7-Chloro-3-[1-(indan-2-ylmethyl)piperidin-4-yl]-1H-indole, oxalate 21c. Prepared from 11c.
Reaction SMILES: CCOCC.[N:6]([O-])=O.[Na+].[NH:10]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]=[CH:14][C:13]=1[C:25]#[N:26])[NH2:11].Cl>O>[N:10]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[Cl:24])[N:15]=[CH:14][C:13]=1[C:25]#[N:26])=[N+:11]=[N-:6]
Reactant: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1NN
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: N#Cc1cnn(-c2ccc(Cl)cc2Cl)c1N=[N+]=[N-]
Yield: 43 %

Procedure:
10 ml of ether and then 0.85 g (0.012 mol) of sodium nitrite in 10 ml of water are added to 2.7 g (0.01 mol) of 5-hydrazino-4-cyano-1-(2,4-dichlorophenyl)-pyrazole in a solution of 1.9 ml of concentrated hydrochloric acid in 10 ml of water at 0° C. When the addition has ended, a further 20 ml of water and 30 ml of ether are added, the mixture is filtered, the ether phase is separated off, dried over calcium chloride and concentrated in vacuo and the oil thus obtainable is purified by chromatography (silica gel; mobile phase: methylene chloride/acetone 9:1). 1.2 g (43% of theory) of 5-azido-4-cyano-1-(2,4-dichlorophenyl)-pyrazole are obtained as an oil.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH3:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]Br)=[CH:11][CH:10]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH3:13])=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: Cc1ccc(CBr)cc1
Reactant: OCCNCCO
Product: Cc1ccc(CN(CCO)CCO)cc1

Procedure:
2-[(2-Hydroxy-ethyl)-(4-methyl-benzyl)-amino]-ethanol was prepared according to the general method as outlined in Example 1 (Step 4). Starting from diethanolamine (4.84 g, 46 mmol) and 4-methylbenzyl bromide (8.5 g, 46 mmol), 8.2 g of the product was isolated. Yield, (85%); white solid; MS: 210.1 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[CH3:6][C:7]1[CH:8]=[C:9]([CH:11]=[C:12]([CH3:21])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:16])=[O:15])[NH2:10].[F:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1.O>O1CCCC1>[CH3:21][C:12]1[CH:11]=[C:9]([NH:10][S:29]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)(=[O:31])=[O:30])[CH:8]=[C:7]([CH3:6])[C:13]=1[S:14]([CH2:17][N+:18]([O-:20])=[O:19])(=[O:15])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(NS(=O)(=O)c2ccc(F)cc2)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Yield: 36.4 %

Procedure:
1.65 g (16.5 mmol) of calcium carbonate are added to a solution of 2.0 g (8.19 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 40 ml of anhydrous tetrahydrofuran, followed by portionwise addition of 2.4 g (12.3 mmol) of 4-fluorobenzenesulphonyl chloride. The reaction medium is refluxed for 50 hours. After cooling, it is poured into 200 ml of water and extracted with 3 times 100 ml of methylene chloride. The combined organic extracts are washed with 100 ml of water, dried over sodium sulphate and concentrated to dryness under reduced pressure. The oily residue obtained is purified by chromatography on a column of silica (eluent: methylene chloride) and recrystallization from a mixture of hexane and ethyl acetate, to give 1.2 g (36%) of N-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-4-fluorobenzenesulphonamide.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Br:13][C:14]1[C:15]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[N:16][C:17]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23][CH:22]=2)=[N:18][CH:19]=1.[NH2:38][CH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][CH2:44][C:43]1=[O:47].ON1C2C=CC=CC=2N=N1.[Cl-].[Na+]>CN(C=O)C.O>[Br:13][C:14]1[C:15]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[N:16][C:17]([NH:20][C:21]2[CH:22]=[CH:23][C:24]([C:27](=[O:28])[NH:38][CH2:39][CH2:40][CH2:41][N:42]3[CH2:46][CH2:45][CH2:44][C:43]3=[O:47])=[CH:25][CH:26]=2)=[N:18][CH:19]=1
Reactant: NCCCN1CCCC1=O
Reactant: O=C(O)c1ccc(Nc2ncc(Br)c(Nc3ccc(F)cc3)n2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCCCN1CCCC1=O)c1ccc(Nc2ncc(Br)c(Nc3ccc(F)cc3)n2)cc1
Reaction time: 16 h
Yield: 74.3 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (52 mg, 0.27 mmol) was added to a mixture of 5-bromo-2-(4-carboxyanilino)-4-(4-fluoroanilino)pyrimidine (Method 7; 100 mg, 0.25 mmol), N-(3-aminopropyl)-2-pyrrolidinone (38 mg, 0.27 mmol) and 1-hydroxybenzotriazole (44 mg, 0.32 mmol) in DMF (0.5 ml). The mixture was stirred for 16 hours and then a 1:1 mixture of saturated sodium chloride solution and water (10 ml) was added. The precipitated solid was collected by filtration and dried to a constant weight in a vacuum oven at 40° C. to give the product as an off-white solid (98 mg, 75%). MS (MH+): 528; HPLC (RT): 4.01.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:10][C@H:11]1[CH2:16][NH:15][CH2:14][CH2:13][NH:12]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>CC(N(C)C)=O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][C@H:11]1[NH:12][CH2:13][CH2:14][N:15]([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[C:4]#[N:5])[CH2:16]1
Reactant: N#Cc1ccccc1Br
Reactant: C[C@H]1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(c2ccccc2C#N)CCN1
Yield: 48.8 %

Procedure:
A mixture 2-bromobenzonitrile (1.0 g, 5.494 mmol), (S)-(+)-2-methylpiperazine (0.60 g, 5.99 mmol), Pd2(dba)3 (0.503 g, 0.549 mmol), rac-BINAP (1.026 g, 1.648 mmol) and NaOtBu (2.11 g, 21.976 mmol) in DMA (27 mL) was heated at 80° C. for 2.5 h. The mixture was allowed to cool, diluted with EtOAc and washed with water. The organic layer was washed with sat.aq. NaHCO3, brine and dried (Na2SO4). Chromatography (EtOAc/MeOH) afforded 2-((R)-3-methyl-piperazin-1-yl)-benzonitrile (540 mg) as a white solid. 1H (400 MHz, d6-DMSO) δ: ppm; m/z (M+1) 202.21.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][CH2:31][C:32]([O:34]C)=[O:33])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:13][CH:12]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:5]1[O:9][C:8]([NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]45[O:29][C:26]([CH2:30][CH2:31][C:32]([OH:34])=[O:33])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[CH:19][CH:18]=3)=[CH:15][CH:16]=2)=[N:7][N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCC12CCC(c3ccc(-c4ccc(Nc5nnc(C(C)(C)C)o5)cc4)cc3)(CC1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1nnc(Nc2ccc(-c3ccc(C45CCC(CCC(=O)O)(CC4)O5)cc3)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
To a solution of methyl 3-(4-(4′-((5-(tert-butyl)-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-7-oxabicyclo[2.2.1]heptan-1-yl)propanoate (100 mg, 0.21 mmol) in THF (3.4 mL) and methanol (0.85 mL) was added 1N NaOH solution (0.63 mL, 0.63 mmol) and the reaction was let stir at rt for 2 h. The resulting yellow reaction mixture was partially concentrated by rotary revaporation (rt water bath) to remove THF. The resulting yellow mixture was diluted with methanol, filtered and purified on preparative HPLC (10-50% acetonitrile:5 mM NH4OH) and lyophilized to afford 83 mg (86%) of the title compound as a white solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 1.56-1.82 (m, 6H), 2.01-2.10 (m, 2H), 2.10-2.19 (m, 2H), 2.30-2.39 (m, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.62-7.67 (m, 4H) 10.51 (br. s., 1H). 13C NMR (100 MHz, DMSO-d6): δ ppm 174.5, 165.9, 159.5, 141.7, 138.3, 138.2, 133.1, 127.1, 125.8, 125.4, 117.1, 86.1, 85.5, 37.9, 34.9, 31.7, 30.2, 30.1, 27.8. ESI-MS m/z: 462.1 [M+H]+, retention time 1.13 min (condition E). HR/MS [M+H]+: found 462.2371. calc. 462.2393. RT: 1.96 (Condition L).
Reaction SMILES: C([O-])(=O)C.[K+].[NH2:6][C:7]1[C:12]2[N:13]=[C:14]([CH2:26][CH2:27][CH3:28])[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:11]=2[CH:10]=[CH:9][N:8]=1.[Br:29]Br>C(O)(=O)C>[NH2:6][C:7]1[C:12]2[N:13]=[C:14]([CH2:26][CH2:27][CH3:28])[N:15]([CH2:16][CH2:17][O:18][CH2:19][CH2:20][NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:11]=2[C:10]([Br:29])=[CH:9][N:8]=1
Reactant: CCCc1nc2c(N)nccc2n1CCOCCNS(C)(=O)=O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CCCc1nc2c(N)ncc(Br)c2n1CCOCCNS(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 76.7 %

Procedure:
Solid potassium acetate (0.62 g, 6.32 mmol) was added to a solution of N-{2-[2-(4-amino-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}methanesulfonamide (1.8 g, 5.27 mmol) in acetic acid (32 mL). After the potassium acetate had dissolved bromine (1.26 g, 7.91 mmol) was added dropwise. The reaction was stirred at ambient temperature for 40 minutes at which time analysis by thin layer chromatography indicated that the reaction was complete. Excess bromine was quenched by the addition of saturated aqueous sodium bisulfite (˜1 mL). The pH of the reaction mixture was adjusted to pH 7 by the addition of saturated aqueous sodium bicarbonate (100 mL) followed by the addition of solid sodium bicarbonate. The reaction mixture was extracted with dichloromethane (2×100 mL). The combined extracts were washed sequentially with water, saturated aqueous sodium bicarbonate (100 mL) and brine (100 mL), dried over sodium sulfate, filtered and then concentrated under reduced pressure to provide a brown gooey solid. This material was purified by chromatography (silica gel eluting with 95:5 dichloromethane:methanol) to provide 1.7 g of N-{2-[2-(4-amino-7-bromo-2-propyl-1H-imidazo[4,5-c]pyridin-1-yl)ethoxy]ethyl}methanesulfonamide as a white waxy solid, mp 129–131° C.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1.[CH3:21][C@H:22]1[CH2:27][NH:26][CH2:25][CH2:24][NH:23]1.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[C:10]2[C:9]([N:26]3[CH2:25][CH2:24][NH:23][C@@H:22]([CH3:21])[CH2:27]3)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:3]=1
Reactant: C[C@H]1CNCCN1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CCN1
Temperature: 80 °C
Yield: 75 %

Procedure:
To a mixture of pyrrolopyrimidine from step B (76 mg, 0.2 mmol) and (S)-2-methylpiperazine (21 mg, 0.2 mmol) in isopropanol (2 ml) was added triethylamine (0.11 ml, 0.8 mmol). The mixture was heated at 80° C. for 5 mins via microwave and concentrated under vacuum to give crude (S)-5-bromo-4-(3-methylpiperazin-1-yl)-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidine (65 mg, 0.15 mmol, 75%) which was used directly for the next step. MS (ES+) [M+H]+=437.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1.[CH:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[CH2:18]>[OH-].[Na+].[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:18][CH2:17][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:16])[CH2:14][CH2:15][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Reactant: C=Cc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CN1CCc2c(n(CCc3ccccn3)c3ccc(Cl)cc23)CC1
Temperature: 80 °C
Yield: 39.2 %

Procedure:
The title compound was prepared by following general procedure 4. To a solution of 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (150 mg, 0.6 mmol) in 50% aq. NaOH solution (7 mL), tetra n-butyl ammonium chloride (9 mg, 0.03 mmol) was added followed by 2-vinylpyridine (74 mg, 0.7 mmol) The reaction mixture was heated at 80° C. for 14 h. After completion of reaction, the reaction mixture was diluted with water, extracted with ethyl acetate; the organic layer was dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by reverse phase chromatography to afford 80 mg of 9-chloro-3-methyl-6-(2-(pyridin-2-yl)ethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as the TFA salt.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:17]=1[CH2:18][C:19]1[O:23][N:22]=[C:21]([C:24](O)=[O:25])[N:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:24]([C:21]1[N:20]=[C:19]([CH2:18][C:17]2[CH:27]=[C:28]([F:31])[CH:29]=[CH:30][C:16]=2[F:15])[O:23][N:22]=1)=[O:25]
Reactant: O=C(O)c1noc(Cc2cc(F)ccc2F)n1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2cc(F)ccc2F)n1
Yield: 12.4 %

Procedure:
This compound was prepared following Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g; 0.424 mmol), 5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylic acid (0.102 g; 0.424 mmol), HATU (0.161 g: 0.424 mmol) and N,N-diisopropylethylamine (0.222 mL; 1.27 mmol) in DMF (3 mL). The purification by flash chromatography on silica gel (eluent: 1 to 10% of ethyl acetate in dichloromethane) gave 0.022 g (12%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(2,5-difluorobenzyl)-1,2,4-oxadiazole-3-carboxamide as a solid.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][NH:23][CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8].[C:39]1(B(O)O)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:7]([O:11][CH:12]([C:17]1[C:18]([CH:36]([CH3:38])[CH3:37])=[N:19][C:20]2[C:21]([CH3:35])([CH3:34])[CH2:22][N:23]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:24][C:25]=2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[C:13]([O:15][CH3:16])=[O:14])([CH3:10])([CH3:9])[CH3:8]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CNCC2(C)C
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)C(OC(C)(C)C)c1c(C(C)C)nc2c(c1-c1ccc(F)cc1)CN(c1ccccc1)CC2(C)C
Reaction time: 0.08 h

Procedure:
A mixture of Cu(OAc)2 (8.21 mg, 0.045 mmol) and pyridine (3.66 μl, 0.045 mmol) in CH2Cl2 (0.5 mL) was stirred for 5 min. Added to this were methyl 2-tert-butoxy-2-(4-(4-fluorophenyl)-2-isopropyl-8,8-dimethyl-5,6,7,8-tetrahydro-1,6-naphthyridin-3-yl)acetate (intermediate 5) (10 mg, 0.023 mmol), phenylboronic acid (5.51 mg, 0.045 mmol) and 17 mg molecular sieves. The resulting mixture was stirred at room temperature open to air for 17 h. The mixture was adsorbed directly onto silica gel and purified by flash chromatography (Biotage; 0%-50% EtOAc/hexane). 1H NMR (500 MHz, CDCl3) δ ppm 7.38 (ddd, J=8.4, 5.8, 2.3 Hz, 1H), 7.27-7.16 (m, 5H), 6.87-6.73 (m, 3H), 4.86 (s, 1H), 3.94 (d, J=15.6 Hz, 1H), 3.73 (s, 3H), 3.69 (d, J=15.6 Hz, 1H), 3.55 (dt, J=13.0, 6.4 Hz, 1H), 3.44-3.34 (m, 1H), 3.28 (d, J=12.5Hz, 1H), 1.49 (d, J=3.7 Hz, 6H), 1.33 (d, J=6.1 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H), 1.01 (s, 9H). 19F NMR (500 MHz, CDCl3) δ ppm −113.64. LCMS (M+H) calcd for C32H40FN2O3: 519.30. found: 519.45.