Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][CH2:9][CH2:10][C@@H:11]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:28]([CH3:30])[CH3:29])=[CH:21][CH:20]=2)[CH2:12][C:13]([O:15][CH3:16])=[O:14])C1C=CC=CC=1.[H][H]>CCOC(C)=O.[Pd]>[OH:8][CH2:9][CH2:10][C@@H:11]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([O:26][Si:27]([CH:34]([CH3:36])[CH3:35])([CH:28]([CH3:30])[CH3:29])[CH:31]([CH3:33])[CH3:32])=[CH:21][CH:20]=2)[CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: [H][H]
Reactant: COC(=O)C[C@@H](CCOCc1ccccc1)c1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)C[C@@H](CCO)c1cc2cc(O[Si](C(C)C)(C(C)C)C(C)C)ccc2[nH]1
Yield: 92 %

Procedure:
To a solution of (R)-methyl 5-(benzyloxy)-3-(5-(triisopropylsilyloxy)-1H-indol-2-yl)pentanoate (52.5 g, 103 mmol in EtOAc (150 mL) was added 10% Pd/C (wet, 15 g) and placed in a Parr shaker under 45 psi of hydrogen for 2.5 h (dropped 10 psi during the 2.5 h). The mixture was filtered through celite and concentrated to give (R)-methyl 5-hydroxy-3-(5-(triisopropylsilyloxy)-1H-indol-2-yl)pentanoate (47.6 g, 93 mmol, 92% yield) as a viscous yellow oil. Exact mass calculated for C23H37NO4Si: 419.2, found: LCMS m/z=420.3, [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.11 (d, J=7.2 Hz, 18 H), 1.27 (m, 3 H), 1.97 (m, 2 H), 2.75 (m, 2 H), 3.49 (m, 1 H), 3.69 (m, 5 H), 6.13 (d, J=2.0 Hz, 1 H), 6.73 (dd, J1=8.6, J2=2.3 Hz, 1 H), 6.99 (d, J=2.3 Hz, 1 H), 7.21 (d, J=8.6 Hz, 1 H), 8.58 (bs, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]([O:18][CH2:19][CH2:20][C:21]#[N:22])(=[O:17])[CH2:13][C:14]([CH3:16])=[O:15]>CC(O)C.N1CCCCC1.C(O)(=O)C>[C:21]([CH2:20][CH2:19][O:18][C:12](=[O:17])[C:13](=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[C:14](=[O:15])[CH3:16])#[N:22]
Reactant: CC(=O)CC(=O)OCCC#N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.9 %

Procedure:
A suspension of 4-nitrobenzaldehyde (5.00 g, 33.0 mmol), 2-cyanoethyl acetoacetate (5.13 g, 33.0 mmol), piperidine (140 mg, 1.65 mmol) and acetic acid (99 mg, 1.7 mmol) in 150 ml of 2-propanol was stirred at r.t. for 48 hrs. Reaction mixture was filtered, the solid collected was dried in air to give 2-[(4-nitrophenyl)methylene]-3-oxobutanoic acid 2-cyanoethyl ester as a white powder (6.08 g, 64%). A solution of 2-[(4-nitrophenyl)methylene)-3-oxobutanoic acid 2-cyanoethyl ester (4.29 g, 14.9 mmol) and 3-amino-N-methylcrotonamide (2.55 g, 22.3 mmol) in 50 ml of EtOH was refluxed for 36 hrs. After solvent was removed, the residue was dissolved in 250 ml of CHCl3 washed with water (2×100 ml) and dried over Na2SO4. After filtration and removal of solvent, 3-(2-cyanoethoxy) carbonyl-1,4-dihydro-2,6-dimethyl-5-(N-methyl) carboxamido-4-(4-nitrophenyl) pyridine was obtain as a yellow powder (7.96 g, 63%). The solution of 3-(2-cyanoethoxy) carbonyl-1,4-dihydro-2,6-dimethyl-5-(N-methyl) carboxamido-4-(4-nitrophenyl) pyridine (2.00 g, 5.20 mmol) in 40 ml acetone was treated with 40 ml 1N KOH solution at 0° C. for 45 min. The acetone was removed in vacuo and aqueous layer was acidified to pH=3 by 2N hydrochloric acid, the yellow precipitation was collected by filtration, washed with 10 ml of cold water and dried in vacuo. 1.53 g (89% yield) of 1,4-dihydro-2,6-dimethyl-5-(N-methyl)carboxamido-4-(4-nitrophenyl)pyridine-3-carboxylic acid was obtained as a yellow powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[C:2]=1[NH2:8].Cl[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.[OH-].[NH4+]>ClC(Cl)Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][C:4]2[CH:5]=[CH:6][N:1]=[C:2]([NH2:8])[C:3]=2[NH2:7])=[CH:12][CH:13]=1
Reactant: Nc1cccnc1N
Reactant: Fc1ccc(CCl)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Nc1nccc(Cc2ccc(F)cc2)c1N
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture of 3 parts of 2,3-pyridinediamine and 4 parts of 1-(chloromethyl)-4-fluorobenzene was stirred overnight at 120° C. Trichloromethane and a dilute ammonium hydroxide solution were added and the product was extracted. The organic phase was washed with water, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The second fraction was collected and the eluent was evaporated, yielding 1.8 parts of N3 -[(4-fluorophenyl)methyl]-2,3-pyridinediamine as a residue (intermediate 18).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12].C(O)(=O)C.[Br:18]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[Br:18][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([F:1])[CH:3]=1)[NH:9][C:8](=[O:11])[C:7]2([CH3:13])[CH3:12]
Reactant: BrBr
Reactant: CC1(C)C(=O)Nc2c(F)cccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC1(C)C(=O)Nc2c(F)cc(Br)cc21
Reaction time: 24 h
Yield: 81.9 %

Procedure:
7-Fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.1 g, 22.9 mmol) was dissolved in dichloromethane (100 mL) and acetic acid (2 mL) at room temperature. Bromine (1.2 mL, 23 mmol) was added and the solution allowed to stir for 24 hours. The reaction mixture was poured into sodium thiosulfate solution, extracted with diethyl ether, dried (MgSO4), evaporated and the crude product triturated with hexane to give 5-bromo-7-fluoro-3,3-dimethyl-1,3-dihydro-2H-indol-2-one (4.84 g, 82%): HRMS: calc'd for C10H9BrFNO, 256.9852; found (ESI, [M−H]−), 255.9781.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:18]3[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=3[S:11][CH:10]=2)O1.Br[C:28]([C:30]([F:33])([F:32])[F:31])=[CH2:29].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:31][C:30]([F:33])([F:32])[C:28]([C:9]1[C:18]2[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:13][C:12]=2[S:11][CH:10]=1)=[CH2:29]
Reactant: C=C(Br)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(B3OC(C)(C)C(C)(C)O3)csc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(c1csc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 50.9 %

Procedure:
A mixture of tert-butyl 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (300 mg), 2-bromo-3,3,3-trifluoropropene (0.2 ml), tetrakis(triphenylphosphine)palladium(0) (25.5 mg), saturated aqueous sodium carbonate solution (7 ml) and dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give the title compound (140 mg, 50.9%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1.[CH:16]12[CH2:22][CH:19]([CH2:20][CH2:21]1)[CH2:18][CH:17]2[NH2:23].C(N(CC)C(C)C)(C)C.Cl>O.O1CCOCC1>[C@H:16]12[CH2:22][C@H:19]([CH2:20][CH2:21]1)[CH2:18][C@H:17]2[NH:23][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][N:3]=1
Reactant: NC1CC2CCC1C2
Reactant: COC(=O)c1cnc(Cl)nc1C(F)(F)F
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N[C@@H]2C[C@H]3CC[C@@H]2C3)nc1C(F)(F)F
Reaction time: 19 h
Yield: 99.2 %

Procedure:
To a mixture of methyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (4.0 g), rac-(1R,2R,4S)-bicyclo[2.2.1]heptan-2-amine (3.7 g), and 1,4-dioxane (60 mL) was added N,N-diisopropyl ethylamine (4.3 mL) at room temperature, and the mixture was stirred at the same temperature for 19 hours. To the reaction mixture were added water and 1 M hydrochloric acid, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure to obtain methyl rac-2-[(1R,2R,4S)-bicyclo[2.2.1]hept-2-ylamino]-4-(trifluoromethyl)pyrimidine-5-carboxylate (5.2 g) as a yellowish white solid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH:10]=[N:11][OH:12])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][C:20](=[O:28])[C:21]([CH2:23][C:24]([O:26][CH3:27])=[O:25])=[CH2:22].Cl[O-].[Na+]>O1CCCC1.O>[CH3:18][O:19][C:20]([C:21]1([CH2:23][C:24]([O:26][CH3:27])=[O:25])[O:12][N:11]=[C:10]([C:9]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[CH2:22]1)=[O:28]
Reactant: COc1ccc(C=NO)cc1OC1CCCC1
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CC1(C(=O)OC)CC(c2ccc(OC)c(OC3CCCC3)c2)=NO1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a solution of the compound obtained from step b above (1 eq) in tetrahydrofuran, was added dimethylitaconate (2 eq). The reaction mixture was stirred at 60° C. for 0.5 hours followed by the addition of sodium hypochlorite solution. The resulting reaction mixture was stirred at 60-70° C. for 5-6 hours. Tetrahydrofuran was removed under reduced pressure. The residue thus obtained was diluted with water, extracted with ethyl acetate, washed with saturated sodium chloride solution and water. The reaction mixture was dried over anhydrous sodium sulphate and concentrated under reduced pressure to furnish the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH3:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].CCCCCC.C(OCC)(=O)C>[Pd].C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH3:26])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:17][CH:18]=1)[CH2:7]2
Reactant: [H][H]
Reactant: CC#Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Yield: 68.6 %

Procedure:
A mixture of 7-chloro-5-propynyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.082 g, 0.19 mmol) and 10% palladium on carbon (20 mg) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using combinations 3:1 hexane-ethyl acetate afforded 7-Chloro-5-propyl-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.050 g, 69%). 1H NMR (300 MHz, CDCl3): δ (ppm) 0.94 (t, 3H), 1.64 (m, 2H), 2.63 (t, 2H), 4.20 (s, 2H), 4.78 (s, 2H), 7.09 (s, 1H), 7.14-7.38 (m, 5H). GC-MS: m/z 383 (M)+, 354 (M−29)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Reactant: O=C1NCCO1
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCOC4=O)cc3)CC2)c(C)c1
Yield: 57.5 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using [4-(2,4-dimethylphenyl)piperazin-1-yl](4-iodophenyl)methanone (7.7 g) described in Preparation Example 8 and oxazolidin-2-one (1.6 g), the title compound (4 g) was obtained.
Reaction SMILES: ClC(Cl)(Cl)C([C:5]1[N:9]2[C:10]([CH2:14][N:15]([C:30]([O:32]C(C)(C)C)=O)[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:29])[C:22]([F:28])([F:27])[C:23]([F:26])([F:25])[F:24])=[CH:11][CH:12]=[CH:13][C:8]2=[N:7][CH:6]=1)=O.Cl>C(O)C>[F:28][C:22]([F:27])([C:23]([F:26])([F:24])[F:25])[C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:15]1[CH2:14][C:10]2[N:9]3[C:5](=[CH:6][N:7]=[C:8]3[CH:13]=[CH:12][CH:11]=2)[C:30]1=[O:32])=[O:29]
Reactant: CC(C)(C)OC(=O)N(CCCCNC(=O)C(F)(F)C(F)(F)F)Cc1cccc2ncc(C(=O)C(Cl)(Cl)Cl)n12
Agent: Cl
Solvent: CCO
Product: O=C1c2cnc3cccc(n23)CN1CCCCNC(=O)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.9 %

Procedure:
To a solution of 5.00 g (8.2 mmol) of 3-trichloro acetyl-5-(N-tert-butoxycarbonyl-N-(4-pentafluoropropion amidobutan-1-yl)aminomethyl]imidazo[1,2-a]pyridine in 100 ml of ethanol was added 3.4 ml (41.0 mmol) of 12N hydrochloric acid. The mixture was stirred for one hour at room temperature. The solvent and an excess volume of hydrochloric acid were distilled off under reduced pressure. The residue was dissolved in a mixture of 50 ml of purified water and 50 ml of ethanol. The solution was neutralized with 2N aqueous solution of sodium hydroxide. This solution was extracted with 150 ml of dichloromethane. The organic layer was washed with 150 ml of a saturated aqueous saline solution, dried over magnesium sulfate, and distilled off the solvent under reduced pressure. The residue was purified by silica gel column chromatography (eluent; dichloromethane:methanol=20:1) to afford 2.11 g of the desired compound (66.1%, a pale yellow solid).
Reaction SMILES: [CH2:1]=[C:2]([CH2:5][CH3:6])[CH:3]=[O:4].[CH2:7]([O:9][C:10](=[O:14])[CH2:11][N+:12]#[C-:13])[CH3:8]>>[CH2:7]([O:9][C:10]([CH:11]1[CH:3]([C:2]([CH2:5][CH3:6])=[CH2:1])[O:4][CH:13]=[N:12]1)=[O:14])[CH3:8]
Reactant: C=C(C=O)CC
Reactant: [C-]#[N+]CC(=O)OCC
Product: C=C(CC)C1OC=NC1C(=O)OCC

Procedure:
The starting material is manufactured as follows: Reaction of 2-methylene-butyraldehyde with isocyanoacetic acid ethyl ester in a manner analogous to that described in Example 1 yields 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester. A solution of 16 g of 5-(buten-2-yl)-2-oxazoline-4-carboxylic acid ethyl ester in 100 ml of ethanol/water (1:1) is heated at the boil, under reflux, for 15 hours. The whole is concentrated by evaporation in vacuo, the residue is taken up in 200 ml of dichloromethane, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation to yield 2-formylamino-3-hydroxy-4-ethyl-4-pentenoic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:25]([OH:29])=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1.[H-].[Na+]>CN(C=O)C>[CH3:18][C:19]1[CH:28]=[N:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[O:29][C:2]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[N:5]=[CH:4][N:3]=2)[N:20]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Cc1cnc2c(O)cccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cnc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cccc2n1

Procedure:
The title compound was prepared analogous to the procedure in Example 29 using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.20 g, 0.77 mmol), 2-methyl-quinoxalin-5-ol (0.14 g, 0.85 mmol, J. Med. Chem, 1988, 41, 4062.) DMF (3 mL), and a 60% dispersion of sodium hydride in mineral oil (0.040 g, 1.0 mmol, Aldrich). Purification by flash chromatography (0→75% EtOAc/hexanes) gave the title compound as an ivory powder. Mp: 135–141° C., MS (ESI, pos. ion) m/z: 383 (M+1).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[Br:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12](Br)[N:11]=1.CC(C)([O-])C.[Na+]>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].C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Br:9][C:10]1[N:11]=[C:12]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH:13]=[C:14]([CH3:16])[CH:15]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: Cc1cc(Br)nc(Br)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: Cc1cc(Br)nc(NC(=O)OC(C)(C)C)c1
Temperature: 70 °C
Yield: 81.6 %

Procedure:
Into a flask were added tert-butyl carbamate (5.6 g, 47.8 mmol) and 2,6-dibromo-4-methyl-pyridine (12 g, 47.8 mmol) followed by degassed 2-MeTHF (120 mL). Solid sodium tert-butoxide (4.6 g, 47.8 mmol) was then added followed by tris(dibenzylideneacetone)dipalladium(0) (1.1 g, 1.2 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene (1.1 g, 2.4 mmol), and the solution evacuated and refilled with nitrogen 3 times. The solution was heated to 70° C. for 4 h and then cooled to rt. The mixture was treated with water (20 mL) and EtOAc (100 mL) and filtered through Celite®. The organic solution was washed with brine (100 mL) and then concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography to afford tert-butyl (6-bromo-4-methylpyridin-2-yl)carbamate (11.2 g, 82%) as a white solid. MS ESI calcd for C11H15BrN2O2 [M+H]+ 287, found 287. 1H NMR (600 MHz, CDCl3) δ 7.70 (s, 1H), 7.13 (s, 1H), 6.95 (s, 1H), 2.29 (s, 3H), 1.49 (s, 9H) ppm.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15](=[O:16])[CH:14]=[N:13][C:12]3[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[N:20][C:11]2=3)[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CO>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:12]2[N:13]=[CH:14][C:15](=[O:16])[N:10]([CH2:9][CH2:8][N:5]3[CH2:4][CH2:3][CH:2]([NH:1][CH2:34][C:32]4[CH:31]=[CH:30][C:27]5[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=5[N:33]=4)[CH2:7][CH2:6]3)[C:11]=2[N:20]=1
Reactant: COc1ccc2ncc(=O)n(CCN3CCC(N)CC3)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc2ncc(=O)n(CCN3CCC(NCc4ccc5c(n4)NC(=O)CO5)CC3)c2n1
Reaction time: 24 h
Yield: 52 %

Procedure:
A solution of 4-[2-(4-amino-1-piperidinyl)ethyl]-6-(methyloxy)pyrido[2,3-b]pyrazin-3(4H)-one (50 mg, 0.1648 mmoles) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e)) (29.4 mg, 0.1648 mmoles) in anhydrous DCM (5 ml) and anhydrous MeOH (0.5 ml) was stirred at rt for 5 mins. Sodium triacetoxyborohydride (104.7 mg, 0.494 mmoles) was added and the mixture was stirred, under argon, for 24 h. The reaction was treated with sat. aq. NaHCO3 solution (2 ml) and 9:1 DCM:MeOH (5 ml). The layers were separated and the aqueous layer was washed with 9:1 DCM:MeOH (10 ml) and 5:1 DCM:MeOH (2×20 ml). The organic extracts were combined, passed through a hydrophobic frit and evaporated to an orange gum. Purification on a 10 g silica column eluted with an 80:20 DCM:MeOH elution gave the product as a yellow gum (39.8 mg, 52%).
Reaction SMILES: C(S(N1CCC(C2[C:20]3[C:15](=[C:16]([C:33](N)=O)[CH:17]=C(C4SC(CNCC(C)CC)=CC=4)C=3)[NH:14]C=2)CC1)(=O)=O)C.[CH:36]([C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)=O.C[C@@H](N)C(C)C.[BH3-]C#N.[Na+]>>[CH3:20][C@@H:15]([NH:14][CH2:36][C:38]1[S:42][C:41]([B:43]([OH:45])[OH:44])=[CH:40][CH:39]=1)[CH:16]([CH3:33])[CH3:17]
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: CCC(C)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: CC(C)[C@@H](C)N
Agent: [BH3-]C#N
Agent: [Na+]
Product: CC(C)[C@@H](C)NCc1ccc(B(O)O)s1

Procedure:
Following the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[(2-methylbutyl)amino]methyl}-2-thienyl)-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1R)-1,2-dimethylpropyl]amine (28 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1R)-1,2-dimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (4 mg, 0.003 mmol) to give 20.5 mg of the title compound (30%).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:3][NH:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[NH:17]1[C:21](=[O:22])[CH2:20][CH2:19][C@H:18]1[C:23](O)=[O:24].O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH3:15][CH:14]([CH3:16])[CH2:13][CH:2]([NH:1][C:23]([CH:18]1[CH2:19][CH2:20][C:21](=[O:22])[NH:17]1)=[O:24])[CH2:3][NH:4][CH2:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7]
Reactant: CC(C)C[C@H](N)CNCC(=O)OC(C)(C)C
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CC(CNCC(=O)OC(C)(C)C)NC(=O)C1CCC(=O)N1
Reaction time: 0.5 h

Procedure:
A solution of 1.54 g of (S)-N-(2-amino-4-methylpentyl)glycine, 1,1-dimethylethyl ester, 890 mg of L-pyroglutamic acid, and 904 mg of hydroxybenzotriazole, hydrate in 30 ml of N,N-dimethylformamide is cooled in ice and treated dropwise with a solution of 1.4 g of N,N'-dicyclohexylcarbodiimide in 5 ml of N,N-dimethylformamide. After stirring at 0° for 0.5 hours, the mixture is kept at room temperature overnight. The mixture is filtered and the solvent distilled off under high vacuum. The residue is taken up in ethyl acetate and the ethyl acetate washed two times with water. The water is adjusted to pH 6 and lyophilized. The residue is chromatographed on 95 g of silica gel eluting with chloroform/methanol, (94:6). Combining the appropriate fractions gives 1.2 g of [S-(R*,R*)]-N-[4-methyl-2-[[(5-oxo-2-pyrrolidinyl]carbonyl)amino]pentyl]glycine, 1,1-dimethylethyl ester. The product is homogeneous by thin layer chromatography.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].Cl[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]([Cl:27])[N:18]=1>CN1C(=O)CCC1.O>[Cl:27][C:19]1[N:18]=[C:17]([O:1][C@H:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)[C:26]2[C:21]([CH:20]=1)=[CH:22][CH:23]=[CH:24][CH:25]=2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Reactant: Clc1cc2ccccc2c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Oc2nc(Cl)cc3ccccc23)C1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 300.3 %

Procedure:
To (S)-tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1.134 g, 6.06 mmol) in NMP (10 mL) at 0° C. was added NaH (60%) (202 mg, 5.05 mmol). The mixture was stirred for 5 minutes and 1,3-dichloroisoquinoline (1.000 g, 5.05 mmol) was added. The reaction mixture was stirred at RT for 5 minutes and then heated at 135° C. for 30 minutes in a microwave reactor. The mixture was diluted with water (400 mL) and extracted with EtOAc (3×125 mL). The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica column chromatography eluting with a gradient of 25-50% EtOAc in hexane to give the title compound (5.29 g, 75%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.40 (d, J=14.16 Hz, 9H), 2.12-2.34 (m, 2H), 3.42-3.58 (m, 3H), 3.69 (td, J=12.33, 4.64 Hz, 1H), 5.63-5.76 (m, 1H), 7.59 (s, 1H), 7.64 (ddd, J=8.30, 7.08, 1.22 Hz, 1H), 7.81 (td, J=7.57, 1.46 Hz, 1H), 7.87-7.92 (m, 1H), 8.11-8.19 (m, 1H); ESI-MS m/z [M+H-tert-butyl]+ 293.5.