Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].[H-].[Na+].[CH3:22][CH:23]1OS(=O)(=O)[N:26]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:25][CH2:24]1>CN(C=O)C>[C:34]([O:33][C:31]([NH:26][CH2:25][CH2:24][CH:23]([N:1]1[C:5]2=[N:6][C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:22])=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC1CCN(C(=O)OC(C)(C)C)S(=O)(=O)O1
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(C(C)CCNC(=O)OC(C)(C)C)c2n1
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution of diethyl 1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (Intermediate D, 1.00 g, 3.81 mmol) in DMF (15 mL) cooled to 0° C. is added 60% sodium hydride in mineral oil (168 mg, 4.19 mmol). The mixture is stirred at 0° C. for 20 min after which a solution of tert-butyl 6-methyl-1,2,3-oxathiazinane-3-carboxylate 2,2-dioxide (1.05 g, 4.19 mmol) in DMF (2 mL) is added. After being stirred overnight, the mixture is concentrated under reduced pressure and the residue is partitioned between ethyl acetate and saturated NaHCO3 solution. The layers are separated and the aqueous layer is further extracted with ethyl acetate. The combined organic phases are washed with brine, and are dried (Na2SO4). The solvent is removed in vacuo and the crude material is purified via flash column chromatography using a gradient elution of 0-30% ethyl acetate/heptanes to afford the title compound as a yellow oil (1.20 g, 73%). LCMS: 434.89 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25](I)[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[CH:29]([C:31]1[O:32][C:33](B(O)O)=[CH:34][CH:35]=1)=[O:30].COCCOC.CO>[Pd].C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[NH:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:33]3[O:32][C:31]([CH:29]=[O:30])=[CH:35][CH:34]=3)[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: Fc1cccc(COc2ccc(Nc3ncnc4ccc(I)cc34)cc2Cl)c1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: COCCOC
Solvent: CO
Product: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5cccc(F)c5)c(Cl)c4)c3c2)o1
Temperature: 50 °C

Procedure:
To a reaction vessel was added N-{3-chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-iodo-4-quinazolinamine (100 mg; 0.198 mmol), 2-formylfuran-5-boronic acid (Frontier Scientific, 42 mg; 0.297 mmol), 10% palladium on activated carbon (5 mg; 0.05 wt), DME (2.0 mL), MeOH (1.0 mL) and triethylamine (83 μL). After heating at 50° C. for 14 h, a HPLC indicated 98.5% clean conversion. 1H NMR (d6-DMSO) δ: 11.44 (s, 1H), 9.38 (s, 2H), 9.11 (s, 1H), 8.90 (s, 1H), 8.39 (dd, 1H, J=8 and 4 Hz), 7.89 (d, 1H, J=12 Hz), 7.84 (d, 1H, J=4 Hz), 7.60 (dd, 1H, J=8 and 4 Hz), 7.47–7.42 (m, 2H), 7.44 (AA′BB′, 2H, JAB=8 Hz), 7.35–7.25 (m, 3H), 7.24 (d, 1H, J=4 Hz), 7.16 (dt, 1H, J=8 and 4 Hz), 7.06 (AA′BB′, 2H, JAB=8 Hz, 6.84 (d, 1H, J=4 Hz), 5.27 (s, 2H), 4.43 (s, 2H), 3.61–3.50 (m, 2H), 3.47–3.36 (m, 2H), 3.09 (s, 3H), 2.23 (s, 6H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].Br[C:34]1[S:35][C:36]([CH:39]=[O:40])=[CH:37][N:38]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:34]4[S:35][C:36]([CH:39]=[O:40])=[CH:37][N:38]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
Reactant: O=Cc1cnc(Br)s1
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ncc(C=O)s4)cc23)CC1
Reaction time: 0.33 h

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (500 mg, 1.1 mmol) in dioxane (12 mL) and H2O (4 mL) was added 2-bromo-1,3-thiazole-5-carbaldehyde (634 mg, 3.3 mmol), potassium carbonate (898 mg, 8.8 mmol) and tetrakis(triphenylphosphine)palladium(0) (210 mg, 0.181 mmol). Reaction was run in the microwave at 150° C. for 20 min. Aqueous work-up performed to give crude product. The reaction was then repeated in the microwave at 150° C. for 30 min to give 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-formyl-1,3-thiazol-2-yl)-1H-indole-7-carboxamide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([CH3:34])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[N:22]([CH3:31])[C:21]=2[CH2:32][OH:33])[CH:15]=[CH:16][C:17]=1[CH3:18].CCN(CC)CC>C(Cl)Cl>[CH3:11][C:12]1[CH:13]=[C:14]([N:19]([CH3:34])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23](=[O:30])[N:22]([CH3:31])[C:21]=2[CH:32]=[O:33])[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccc(N(C)c2c(CO)n(C)c(=O)c3ccccc23)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: Cc1ccc(N(C)c2c(C=O)n(C)c(=O)c3ccccc23)cc1C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of oxalyl chloride (0.015 mL, 0.172 mmol) in DCM (5 mL) at −70° C. was added dropwise DMSO (0.024 mL, 0.344 mmol). After 15 min a solution of 4-[(3,4-dimethylphenyl)(methyl)amino]-3-(hydroxymethyl)-2-methyl-1(2H)-isoquinolinone (25 mg, 0.078 mmol) in DCM (1 mL) was added slowly, and the mixture was kept at −78° C. for 30 min. Then NEt3 (38 uL) was added and the reaction was kept at −78° C. for 1 hour. The mixture was quenched with aq. NaHCO3 and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to give the crude title compound as yellow oil (16.9 mg, 61.4%). 1H NMR (400 MHz, CDCl3) δ ppm 9.97-9.78 (m, 1 H), 8.64-8.46 (m, 1 H), 7.75-7.54 (m, 2 H), 7.51-7.42 (m, 1 H), 7.07-6.92 (m, 1 H), 6.59-6.38 (m, 2 H), 3.87 (s, 3 H), 3.40 (s, 3 H), 2.18 (d, J=6.3 Hz, 6 H); ES-LCMS: 321.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH:31]OS([O-])=O.[K+]>CC(C)=O.O.C(=O)(O)[O-].[Na+]>[C:4]([C:3]1[CH:7]=[CH:8][C:9]([C:11]2[N:16]=[C:15]3[N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N+:27]([O-:31])=[CH:26][CH:25]=[CH:24]5)[N:18]=[N:19][C:14]3=[CH:13][CH:12]=2)=[CH:10][C:2]=1[Cl:1])(=[O:5])[NH2:6]
Reactant: O=S([O-])OO
Reactant: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1Cl
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: NC(=O)c1ccc(-c2ccc3nnn(Cc4ccc5c(ccc[n+]5[O-])c4)c3n2)cc1Cl
Yield: 28.9 %

Procedure:
To a solution of example 108 (0.100 g, 0.241 mmol) in acetone (0.6 ml), oxone (0.74 g, 1.20 mmol) in water (2 ml) was added and heated under reflux for 20 h. The mixture was diluted with aqueous 10% sodium bicarbonate solution and extracted with dichloromethane, the organic layer dried over anhydrous sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound (0.030 g, 29%) as a pale brown solid. M.P.: 182-183° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.71 (d, J=8.8 Hz, 1H), 8.55 (d, J=6.1 Hz, 1H), 8.52 (d, J=9.1 Hz, 1H), 8.29 (s, 1H), 8.23 (m, 2H), 8.12 (s, 1H), 7.95-7.83 (m, 3H), 7.67 (s, 1H), 7.61 (d, J=7.9 Hz, 1H), 7.47 (dd, J=8.4, 6.2 Hz, 1H), 6.24 (s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([C:19]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:20])=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[BH4-].[Na+].CC(C)=O>C(O)C>[CH2:1]([C:3]1[N:13]([CH2:14][C:15]2[CH:28]=[CH:27][C:18]([CH:19]([OH:20])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(=O)c2ccccc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(C)=O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc(C(O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.1 %

Procedure:
Compound 1 (2.27 g, 6.14 mmol) was dissolved in ethanol (50 mL), and sodium borohydride (0.465 g, 12.3 mmol) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was added with acetone and stirred for 30 minutes, then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1), and obtained crystals were triturated with diethyl ether-hexane to obtain Compound 2 (2.10 g, yield 92%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([NH2:26])[C:21]=4[C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[CH2:16][CH2:15]3)[N:11](C)[CH:12]=2)=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].BrC1C(N)=NC=NC=1N1CCC(C2NC=C(C3C=CC=C(C(F)(F)F)C=3)N=2)CC1>>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:21]2[C:22]([NH2:26])=[N:23][CH:24]=[N:25][C:20]=2[N:17]2[CH2:16][CH2:15][CH:14]([C:10]3[NH:11][CH:12]=[C:8]([C:5]4[CH:6]=[CH:7][CH:2]=[C:3]([C:35]([F:38])([F:37])[F:36])[CH:4]=4)[N:9]=3)[CH2:19][CH2:18]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4ccc(F)c(C(F)(F)F)c4)cn3C)CC2)cc1
Agent: Nc1ncnc(N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)c1Br
Product: COc1ccc(-c2c(N)ncnc2N2CCC(c3nc(-c4cccc(C(F)(F)F)c4)c[nH]3)CC2)cc1

Procedure:
The title compound was prepared in an analogous manner as 6-{4-[4-(4-Fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-5-(4-methoxy-phenyl)-pyrimidin-4-ylamine using 5-Bromo-6-{4-[4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidin-4-ylamine instead of 5-bromo-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidin-4-amine. LC-MS: (M+1=495, obsd.=495).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.CN(C=O)C.C(N(CC)CC)C.[CH2:21]([O:23][SiH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[CH3:22]>CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:24]([O:28][CH2:29][CH3:30])([O:25][CH2:26][CH3:27])[O:23][CH2:21][CH3:22])=[CH:4][CH:3]=1
Reactant: CCO[SiH](OCC)OCC
Reactant: Brc1ccc(I)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO[Si](OCC)(OCC)c1ccc(Br)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
[Rh(cod)(MeCN)2]BF4 (22.0 mg, 0.0600 mmol, 0.0300 equiv) and 1-bromo-4-iodobenzene (563 mg, 2.00 mmol, 1.00 equiv) were charged in 20 mL vial capped with a rubber septum. The vial was evacuated and backfilled with nitrogen. To this vial, DMF (8 mL), triethylamine (0.830 mL, 6.00 mmol, 3.00 equiv) and triethoxysilane (0.730 mL, 4.00 mmol, 2.00 equiv) were added. The reaction mixture was stirred at 80° C. for 2 h, then cooled to 23° C. The mixture was diluted with ether (100 mL) and washed three times with water (3×40 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Kugelrohr distillation to give 508 mg of the title compound as a colorless oil (80% yield). Rf=0.63 (hexanes). NMR Spectroscopy: 1H NMR (500 MHz, CDCl3, 23° C., δ): 7.53−7.52 (m, 4H), 3.85 (q, J=7.0 Hz, 6H), 1.24 (t, J=7.0 Hz, 9H). 13C NMR (125 MHz, CDCl3, 23° C., δ): 136.34, 131.04, 129.86, 125.33, 58.77, 18.16.
Reaction SMILES: F.F.F.C(N(CC)CC)C.[C:11]([NH:14][CH2:15][CH2:16][CH2:17][S:18]([O:21][CH2:22][C:23]([CH3:45])([CH3:44])[C@@H:24]([O:36][Si](C)(C)C(C)(C)C)[C:25]([O:27][CH2:28][C:29]1[O:30][C:31](=[O:35])[O:32][C:33]=1[CH3:34])=[O:26])(=[O:20])=[O:19])(=[O:13])[CH3:12]>O1CCCC1>[C:11]([NH:14][CH2:15][CH2:16][CH2:17][S:18]([O:21][CH2:22][C:23]([CH3:45])([CH3:44])[C@@H:24]([OH:36])[C:25]([O:27][CH2:28][C:29]1[O:30][C:31](=[O:35])[O:32][C:33]=1[CH3:34])=[O:26])(=[O:19])=[O:20])(=[O:13])[CH3:12]
Reactant: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)OCc1oc(=O)oc1C
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCCCS(=O)(=O)OCC(C)(C)[C@@H](O)C(=O)OCc1oc(=O)oc1C
Temperature: 55 °C
Reaction time: 8 h
Yield: 8.1 %

Procedure:
Following the general procedure for the cleavage of silyl ethers with triethylamine trihydrofluoride of Description 20, a mixture of (5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl (2R)-4-{[(3-acetylamino)propyl]sulfonyloxy}-3,3-dimethyl-2-(1,1,2,22-tetramethyl-1-silapropoxy)butanoate (48a) (100 mg, 0.18 mmol) and triethylamine trihydrofluoride (Et3N.3HF) 150 μL (149 mg, 0.93 mmol) in 2 mL of tetrahydrofuran (THF) was stirred overnight at ca. 50-60° C. (oil bath). After work-up and further purification by mass-guided preparative HPLC and lyophilization of the solvents, 6.2 mg (8.1% yield) of the title compound (48) was obtained as a colorless, viscous oil. 1H NMR (400 MHz, CDCl3): δ=1.03 (s, 3H), 1.11 (s, 3H), 2.01 (s, 3H), 2.04-2.11 (m, 2H), 2.22 (s, 3H), 3.10-3.23 (m, 2H), 3.31-3.46 (m, 2H), 4.00 (d, J=9.2 Hz, 1H), 4.07-4.10 (m, 2H), 4.93 (d, J=14.0 Hz, 1H), 5.03 (d, J=13.6 Hz, 1H), 5.86-5.88 (br. m, 1H) ppm. MS (ESI) m/z 424.01 (M+H)+, 446.01 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Li+].[OH-].[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[NH:21][CH:20]([CH2:22][C:23]([O:25]C)=[O:24])[C:19](=[O:27])[N:18]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:17][C:16]=2[CH:36]=1)=[O:11]>O1CCOCC1.O>[NH:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH2:8][NH:9][C:10]([C:12]1[CH:13]=[CH:14][C:15]2[NH:21][CH:20]([CH2:22][C:23]([OH:25])=[O:24])[C:19](=[O:27])[N:18]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:17][C:16]=2[CH:36]=1)=[O:11]
Reactant: COC(=O)CC1Nc2ccc(C(=O)NCc3ncc[nH]3)cc2CN(CCc2ccccc2)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CC1Nc2ccc(C(=O)NCc3ncc[nH]3)cc2CN(CCc2ccccc2)C1=O
Temperature: 65 °C
Yield: 76.6 %

Procedure:
LiOH (16 mg, 0.38 mmol) was added at RT to a solution of methyl (±)-7-[[[(2-imidazolyl)methyl]amino]carbonyl]-3-oxo-4-(2-phenylethyl)-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (98 mg, 0.21 mmol) in dioxane (3 mL) and H2O (3 mL). The reaction mixture was heated at 65° C. for 3 h then the organic solvent was removed in vacuo. The aqueous residue was acidified with 1M HCl solution (0.38 mL) to obtain a white solid which was filtered, dissolved in hot methanol, and precipitated with ether. The thus obtained white solid was collected to yield the title compound (72 mg, 78%). 1H NMR (DMSO-d6, 400 MHz) δ 2.59 (dd, J=16.2, 5.0 Hz, 1H), 2.77 (dd, J=7.7, 6.8 Hz, 2H), 2.92 (dd, J=16.5, 8.8 Hz, 1H), 3.63-3.75 (m, 2H), 3.79 (d, J=16.5 Hz, 1H), 4.61 (s, 2H), 5.13 (dd, J=8.8, 5.0 Hz, 1H), 5.45 (d, J=16.5 Hz, 1H), 6.57 (d, J=8.6 Hz, 1H), 7.07 (s, 2H), 7.10-7.19 (m, 5H), 7.41 (s, 1H), 7.54 (d, J=8.4 Hz, 1H). MS (ES) m/e 448 (M+H)+. Anal. Calcd. for C24H25N5O4.H2O: C, 61.92; H, 5.85; N, 15.04. Found: C, 61.69; H, 5.60; N, 14.86.
Reaction SMILES: [CH2:1]([N:3]1[C:7](B2OC(C)(C)C(C)(C)O2)=[CH:6][CH:5]=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[CH:25]=[C:26]([C:30]([O:32][CH3:33])=[O:31])[O:27][C:28]=1[Cl:29]>COCCOC.O.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:29][C:28]1[O:27][C:26]([C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=1[C:7]1[N:3]([CH2:1][CH3:2])[N:4]=[CH:5][CH:6]=1
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)o1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: ClCCl
Product: CCn1nccc1-c1cc(C(=O)OC)oc1Cl
Temperature: 75 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
To a 100 mL sealed flask was added 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2.61 g, 11.74 mmol), potassium carbonate (3.25 g, 23.48 mmol), methyl 4-bromo-5-chloro-2-furancarboxylate (1.85 g, 8.33 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.16 g, 0.31 mmol) in 1,2-Dimethoxyethane (DME) (30 mL) and H2O (5 mL). After stirring for 2 h at 75° C., the reaction solution was diluted with DCM (100 mL) and washed with H2O. The organic layer was dried Na2SO4, filtered and concentrated. The residue was purified on silica gel [EtOAc/hexanes, 10-30%] to give the product (0.8 g, 50.1%) as an off-white solid: LC-MS (ES) m/z 255 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][CH:21]1[C:25]1[NH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[C:32](C(OC)=O)[CH:31]=2)=[CH:28][N:29]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)(O)[O-].[Na+]>O.CCOC(C)=O.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>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:25]1[NH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:33]3[CH:32]=[CH:31][C:30]([C:27]4[NH:26][C:25]([CH:21]5[CH2:22][CH2:23][CH2:24][N:20]5[C:18]([O:17][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:19])=[N:29][CH:28]=4)=[CH:35][CH:34]=3)=[CH:32][CH:31]=2)=[CH:28][N:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1
Reactant: COC(=O)c1cc(-c2cnc(C3CCCN3C(=O)OC(C)(C)C)[nH]2)ccc1B1OC(C)(C)C(C)(C)O1
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: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCCN5C(=O)OC(C)(C)C)[nH]4)cc3)cc2)[nH]1
Temperature: 80 °C
Yield: 105 %

Procedure:
To the solution of 245-{4-bromo-3-[(tert-butoxycarbonyl-methyl-amino)-methyl]-phenyl}-1H-imidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (142 mg, 0.27 mmol) and 2-{5-[3-Methoxycarbonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (125 mg, 0.25 mmol) in 1,2-dimethoxyether (2.3 ml) and water (0.7 ml) was added sodium bicarbonate (63 mg, 0.75 mmol), followed by Pd(PPh3)4 (12 mg) and PdCl2(dppf)CH2Cl2 (12 mg). The mixture was heated at 80° C. for 20 hours. The mixture was diluted with EtOAc, and was washed with water and brine, and was dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave 4,4′-bis-[2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-3H-imidazol-4-yl]-biphenyl-2-[(tert-butoxycarbonyl-methyl-amino)-2′-carboxylic acid dimethyl ester (82 mg). m/z: 826 (M+H)+, 413.6 (M+2H)+/2.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][S:17]([N:20]2[CH2:36][CH2:35][C:23]3([N:27]=[C:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[NH:25][C:24]3=[O:34])[CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:11][CH:10]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:28]1([C:26]2[NH:25][C:24](=[O:34])[C:23]3([CH2:22][CH2:21][N:20]([S:17]([CH2:16][CH2:15][C:12]4[CH:13]=[CH:14][C:9]([NH:8][C:5](=[O:7])[CH3:6])=[CH:10][CH:11]=4)(=[O:18])=[O:19])[CH2:36][CH2:35]3)[N:27]=2)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CCS(=O)(=O)N2CCC3(CC2)N=C(C2CCCCC2)NC3=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.3 %

Procedure:
Acetic anhydride (45 mg, 0.44 mmol) was added to a solution of 8-[2-(4-amino-phenyl)-ethanesulfonyl]-2-cyclohexyl-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (92 mg, 0.22 mmol) in CH2Cl2 (5 mL). Triethylamine (55 mg, 0.5 mmol) was then added on an ice bath, and the mixture was stirred at room temperature for one hour. The reaction mixture was diluted with dichloromethane, and the organic layer was then sequentially washed with water and saturated brine and dried over Na2SO4. The organic layer was concentrated under reduced pressure, and the resulting residue was then purified by P-TLC to give N-{4-[2-(2-cyclohexyl-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl)-ethyl]-phenyl}-acetamide (55 mg, 54.3%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1>O>[CH3:22][C:12]1[CH:17]=[CH:16][C:15]([S:18]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Clc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 55 °C
Reaction time: 3 h

Procedure:
To 150 ml of chlorobenzene, 100.1 g (0.75 mol) of aluminum chloride was added, and further 143 g (0.75 mol) of p-toluenesulfonyl chloride was added dropwise over 1 hour. After stirred for 3 hours at 55° C., the reaction mixture was poured into 1.5 liter of water, and then the obtained crystal was filtered off and washed with n-hexane to obtain 140 g of the intended 4-methyl-4'-chlorodiphenylsulfone. NMR (heavy chloroform): δ7.9-7.8 (m, 4H), 7.5 (m, 2H), 7.3 (d, 2H), 2.4 (s, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][N:20]=[CH:19]2.C(O)(=O)C.C(=O)([O-])O.[Na+]>CO>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc(CN2CCC(Nc3ccc4[nH]ncc4c3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
1-Benzyl-4-piperidone (635 mg), 5-aminoindazole (532 mg), and acetic acid (0.20 ml) were dissolved in methanol (10 ml), and a borane-pyridine complex (0.51 ml) was added dropwise to the solution at room temperature. The reaction mixture was stirred at room temperature for 18 hr. A saturated aqueous sodium hydrogencarbonate solution (10 ml) was then added thereto, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel [chloroform/methanol] to give the title compound (1.00 g, yield 82%).