Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH:3]([CH3:5])[CH3:4].[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][S:16]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([N:15]([CH2:2][CH:3]([CH3:5])[CH3:4])[S:16]([CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:18])=[O:17])[CH3:14])=[CH:9][CH:8]=1
Reactant: C[C@H](NS(=O)(=O)Cc1ccccc1)c1ccc(Br)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)CN([C@@H](C)c1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Yield: 12 %

Procedure:
1-Bromo-2-methylpropane (34.7 g, 255.0 mmol) was added into a solution of (S)—N-(1-(4-bromophenyl)ethyl)(phenyl)methanesulfonamide (30.0 g, 85.0 mmol) and K2CO3 (35.2 g, 255.0 mmol) in CH3CN (500 mL) dropwise at 0° C. The mixture was then stirred at reflux for 48 h before it was cooled to ambient temperature. The mixture was filtered and the filtrate was concentrated in vacuo to remove the solvent. The residue was dissolved with DCM (100 mL) and washed with water (100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give a residue which was purified on silica gel chromatography (petroleum ether:ethyl acetate=10:1) to provide (S)—N-(1-(4-bromophenyl)ethyl)-N-isobutyl(phenyl)methanesulfonamide (4.2 g, 12% yield) as colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 0.71 (d, 3H), 0.77 (d, 3H), 1.48 (d, 3H), 1.60-1.66 (m, 1H), 2.77-2.83 (m, 2H), 4.11-4.22 (m, 2H), 4.94-4.96 (m, 2H), 7.24-7.48 (m, 9H); >99% ee value (Chiral-HPLC, 214 nm).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=2)[NH:4][CH:3]=1.Cl[C:21]1[N:26]=[N:25][C:24]([O:27][C@@H:28]2[CH:33]3[CH2:34][CH2:35][N:30]([CH2:31][CH2:32]3)[CH2:29]2)=[CH:23][CH:22]=1.N>>[N:30]12[CH2:31][CH2:32][CH:33]([CH2:34][CH2:35]1)[C@@H:28]([O:27][C:24]1[N:25]=[N:26][C:21]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[NH:4][CH:3]=[C:2]4[CH3:1])=[CH:22][CH:23]=1)[CH2:29]2
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: Cc1c[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: N
Product: Cc1c[nH]c2ccc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)cc12

Procedure:
The product of Example 10A (240 mg, 1 mmol) coupled with the product of Example 9A (250 mg, 1 mmol) according to the procedure in Example 8A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm) as solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.64 (m, 1H), 1.69-1.92 (m, 2H), 2.01-2.14 (m, 1H), 2.29-2.35 (m, 1H), 2.37 (s, 3H), 2.81-3.04 (m, 5H), 3.43-3.55 (m, 1H), 5.27-5.34 (m, 1H), 7.06 (d, J=1.4 Hz, 1H), 7.24 (d, J=9.2 Hz, 1H), 7.44 (dd, J=8.5, 0.7 Hz, 1H), 7.71 (dd, J=8.8, 2.0, Hz, 1H), 8.07-8.12 (m, 2H) ppm. MS (DCI/NH3): m/z 335 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:14][C@H:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[NH:20][C:21](=[O:33])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]3[N:32]=[CH:31][CH:30]=[N:29]3)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=2)[CH2:3][CH2:2]1.ClC1C(N[C@H]2CCC[C@@H]2NC(=O)C2C=CC=CC=2N2N=CC=N2)=NC=C(C(F)(F)F)N=1.CC1(C)C(C)(C)OB(C(C)=C)O1.[H][H]>CO.[Pd]>[CH3:3][CH:1]([C:4]1[C:5]([NH:14][C@H:15]2[CH2:19][CH2:18][CH2:17][C@@H:16]2[NH:20][C:21](=[O:33])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:28]2[N:32]=[CH:31][CH:30]=[N:29]2)=[N:6][CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[N:9]=1)[CH3:2]
Reactant: [H][H]
Reactant: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1)c1ccccc1-n1nccn1
Agent: [Pd]
Agent: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl)c1ccccc1-n1nccn1
Solvent: CO
Product: CC(C)c1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ccccc1-n1nccn1

Procedure:
Prepared according to the procedure for N-[(1S,2S)-2-{ [3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Example 109) from N-[(1S,2S)-2-{[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]-2-(2H-1,2,3-triazol-2-yl)benzamide (Intermediate 29; 170 mg, 0.38 mmol) and 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (CAS number 126726-62-3; 190 mg, 1.13 mmol) except this was then dissolved in methanol (1.4 ml) and to this was then added palladium on carbon (10% wt, 50% wet) (15 mg, 0.014 mmol) and the resulting mixture was stirred under a balloon of hydrogen gas for 2 hours. The reaction was filtered through diatomaceous earth (commercially sold under the trade mark “Celite”) and concentrated in vacuo to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([CH:13]=[O:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]1[CH2:19]OC[CH2:16]1.[CH:20]1([Mg]Br)[CH2:22][CH2:21]1>[NH4+].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([CH:16]2[CH2:15][CH2:19]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([C@H:13]([CH:20]2[CH2:22][CH2:21]2)[OH:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](C=O)C1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@@H](O)C2CC2)C1
Product: CC(C)(C)OC(=O)N1CC[C@H]([C@H](O)C2CC2)C1
Temperature: -78 °C

Procedure:
(S)-3-Formyl-pyrrolidine-1-carboxylic acid t-butyl ester (1.0 g, 5 mmol) and THF (10 mL, 100 mmol) were combined under nitrogen, and the resulting solution was cooled to −78° C. 0.5M Cyclopropylmagnesium bromide in THF (15 mL, 7.5 mmol) was then added dropwise over 10 minutes. The mixture was allowed to warm to room temperature slowly overnight. Then aqueous saturated NH4Cl (30 mL) was added dropwise to quench the reaction. The resulting mixture was extracted with EtOAc (2×30 mL), and the combined organic layers were washed with saturated aqueous NaHCO3 (1×30 mL) and saturated aqueous NaCl (1×30 mL), then dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC (15-55% MeCN:H2O+0.05% TFA over 80 minutes) on a 2″ column to yield (S)-3-((R)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (520 mg, 2nd eluting peak) and (S)-3-((S)-cyclopropylhydroxymethyl)pyrrolidine-1-carboxylic acid t-butyl ester (418 mg, 1st eluting peak). The lyophilized solids were dissolved in EtOAc and washed with saturated aqueous NH4CO3, the organics were separated, dried over Na2SO4 and the solvent was removed under reduced pressure.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([NH2:11])=[N:9][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:7][N:6]=1)=[O:4].[OH-].[Na+:19].[ClH:20].C1(C)C=CC=CC=1>C1COCC1>[NH2:11][C:10]1[C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=[C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])[N:9]=1.[Cl-:20].[Na+:19]
Reactant: COC(=O)c1ncc(OCC(F)(F)F)nc1N
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(OCC(F)(F)F)cnc1C(=O)O
Product: [Cl-]
Temperature: 25 °C

Procedure:
To a solution of 3-amino-5-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid methyl ester (400 mg, 1.59 mmol) in 20 ml THF was added 2.5 ml (2.5 mmol) 1N sodium hydroxide and the mixture was stirred at room temperature over night. To the mixture were added (2.39 ml, 2.39 mmol) 1N HCl after stirring for 5 min toluene was added and the solvents were evaporated to provide the title compound together with sodium chloride as an off-white solid. The mixture was used for coupling reactions without further purification.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][C@@H:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[CH2:19]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:34][N:31]1[CH2:30][CH2:29][N:28]([C:24]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:25]=2[CH2:26][CH2:27][C@@H:18]([NH:17][C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=2)[CH2:19]3)[CH2:33][CH2:32]1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: CN1CCN(c2cccc3c2CC[C@@H](N)C3)CC1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CCN(c2cccc3c2CC[C@@H](NC(=O)c2cccc(Oc4ccccc4)c2)C3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3-Phenoxybenzoic acid (1.0 g, 4.7 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 30 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (70 mg, 0.30 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-5-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (70 mg, 0.28 mmol) and triethylamine (55 μL, 0.42 mmol) in methylene chloride (25 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 45 mg (36%) of the title compound as a solid foam: [α]21D +24° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 441 (18, M+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]2([CH3:17])[CH3:16])#[CH:2].[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:18][O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:2]#[C:1][C:3]2[CH:4]=[C:5]3[C:10](=[C:11]([OH:13])[CH:12]=2)[O:9][C:8]([CH3:15])([CH3:14])[CH2:7][C:6]3([CH3:17])[CH3:16])=[CH:26][CH:27]=1
Reactant: C#Cc1cc(O)c2c(c1)C(C)(C)CC(C)(C)O2
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC(=O)Cc1ccc(C#Cc2cc(O)c3c(c2)C(C)(C)CC(C)(C)O3)cc1

Procedure:
Following General Procedure B and using 6-ethynyl-8-hydroxy-2,2,4,4-tetramethyl-chroman (Intermediate 19, 0.035 g, 0.15 mmol), 4-iodo phenyl acetic acid methyl ester (0.060 g, 0.23 mmol), triethyl amine (3 mL), copper(I)iodide (0.020 g, 0.1 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.07 g, 0.1 mmol) followed by flash column chromatography over silica gel (230-400 mesh), and preparative normal phase HPLC using 10% ethyl acetate in hexane as the mobile phase, the title compound was obtained (0.015 g, 25%).
Reaction SMILES: ClCCl.[NH2:4][CH2:5][C:6]1([CH2:10][NH2:11])[CH2:9][O:8][CH2:7]1.[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O>[NH2:4][CH2:5][C:6]1([CH2:10][NH:11][C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:9][O:8][CH2:7]1
Reactant: NCC1(CN)COC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NCC1(CNC(c2ccccc2)(c2ccccc2)c2ccccc2)COC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 51.4 %

Procedure:
A dichloromethane suspension (3.0 ml) of C-(3-aminomethyloxetan-3-yl)methylamine (411 mg, 3.54 mmol) prepared according to the method described in J. Org. Chem., (1985),50(17), 3211; and Japanese Patent Application Kokai Publication No. (JP-A) S61-69784 (unexamined, published Japanese patent application) was cooled to 0° C., and a dichloromethane solution (3.0 ml) of triphenylmethyl chloride (246 mg, 0.88 mmol) was added thereto. The mixture was stirred at 0° C. for 30 minutes, and then at room temperature for one hour. A saturated aqueous sodium bicarbonate solution (1.0 ml) and water (15 ml) were added to the solution. The mixture was extracted three times with dichloromethane (20 ml). The organic layers were combined together, and dried over anhydrous sodium sulfate. After the inorganic salt was removed by filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: dichloromethane:methanol=20:1) to yield (3-aminomethyloxetan-3-ylmethyl)tritylamine (162 mg) as a white amorphous material.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[C:19]([CH2:21][NH:22][C:23](=O)[O:24]C(C)(C)C)[CH:18]=[CH:17][N:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[C:41](Cl)(=O)[C:42](C)([CH3:44])[CH3:43].O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13]([C:15]3[CH:20]=[C:19]([CH2:21][NH:22][C:23](=[O:24])[C:42]([CH3:44])([CH3:43])[CH3:41])[CH:18]=[CH:17][N:16]=3)=[O:14])[CH2:9][CH2:8]2)=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccnc(C(=O)N2CCC(Oc3ccc(Cl)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.2 %

Procedure:
To a stirred solution of (4-(aminomethyl)pyridin-2-yl)(4-(4-chlorophenoxy)piperidin-1-yl)methanone (25 mg, 0.072 mmol. Example 321), N,N-diisopropylethylamine (0.038 mL, 0.22 mmol) in dichloromethane (1 mL) was added pivaloyl chloride (0.011 mL, 0.087 mmol) at room temperature. After stirring at room temperature for 2 hours, the mixture was poured into water (3 mL). This was extracted with ethyl acetate (4 mL) and washed with water (3 mL). The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica-gel column chromatography (NH-gel, eluting with ethyl acetate) and then preparative LC-MS to give 14.0 mg (45% yield) of the title compound.
Reaction SMILES: O[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].N1C=CC=CC=1.P(Br)(Br)[Br:18].Cl>CCOCC>[Br:18][CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: BrP(Br)Br
Reactant: O=C(O)CCCC#CCO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(O)CCCC#CCBr
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 7-hydroxy-5-heptynoic acid (88.2 g), described in Example 78, in anhydrous ether (300 ml) and pyridine (12 ml) is added dropwise phosphorus tribromide (67.5 g) at 10° C. The solution is stirred at room temperature for 30 min. then cooled to 5° C and 10% HCl (120 ml) is added slowly. The organic layer is washed with water and 10% sodium carbonate, dried (Na2SO4) and concentrated. The residue is distilled under reduced pressure to give 7-bromo-5-heptynoic acid, b.p. 146° C, 0.8 mm.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]([CH2:21][OH:22])([C:18]([OH:20])=O)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:47][C:48]1[CH:49]=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH2:52].CCN(C(C)C)C(C)C>CN(C=O)C>[F:47][C:48]1[C:49]([CH3:23])=[C:50]([CH:53]=[CH:54][CH:55]=1)[CH2:51][NH:52][C:18]([C:15]1([CH2:21][OH:22])[CH2:14][CH2:13][N:12]([C:10](=[O:11])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])[CH2:17][CH2:16]1)=[O:20]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(CO)(C(=O)O)CC1
Reactant: NCc1cccc(F)c1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(F)cccc1CNC(=O)C1(CO)CCN(C(=O)CNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 111.6 %

Procedure:
To a solution of crude 1-(2-(tert-butoxycarbonylamino)acetyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid (120 mg, ˜0.379 mmol, 1.0 equiv) in DMF (30 mL) were added HBTU (144 mg, 0.379 mmol, 1.0 equiv.), 2-methyl, 3-fluorobenzylamine (53 mg, 0.379 mmol, 1.0 equiv.) and DIEA (132 μL, 0.758 mmol, 2.0 equiv.). The reaction mixture was stirred overnight at rt. The mixture was partitioned between EtOAc and H2O. The organic layer was washed by 1 N HCl, Saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated to dryness to give tert-butyl 2-(4-(3-fluoro-2-methylbenzylcarbamoyl)-4-(hydroxymethyl)piperidin-1-yl)-2-oxoethylcarbamate (185 mg), which was used without further purification. LRMS (M+H+) m/z 439.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=2)[NH2:32])[CH2:24][CH2:23]1)(=[O:21])[CH3:20].C(N(CC)C(C)C)(C)C>CS(C)=O>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:30]=[C:31]([NH:32][C:2]3[N:7]=[C:6]([N:8]4[CH:12]=[CH:11][N:10]=[C:9]4[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[CH:5]=[CH:4][N:3]=3)[CH:33]=[CH:34][CH:35]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CC(=O)N1CCN(Cc2cccc(N)c2)CC1
Reactant: Clc1nccc(-n2ccnc2-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)N1CCN(Cc2cccc(Nc3nccc(-n4ccnc4-c4ccccc4)n3)c2)CC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
2-Chloro-4-(2-phenyl-1H-imidazol-1-yl)pyrimidine (56 mg, 0.22 mmol) and 3-[(4-acetylpiperazin-1-yl)methyl]aniline (142 mg, 0.61 mmol) were mixed and heated neat to 100° C. After 2 hours the reaction was heated to 120° C. for 1 hour then to 140° C. for 1 hour. N,N-di-iso-propylethylamine (0.076 ml, 0.44 mol) was added and the reaction was heated for an additional 1.5 hours. The reaction was cooled, diluted with DMSO and directly purified by reverse phase HPLC (5-100% CH3CN/H2O+0.1% TFA) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ 8.29 (d, J=5.2 Hz, 1H), 7.67 (d, J=1.5 Hz, 1H), 7.52 (m, 3H), 7.41 (m, 4H), 7.25 (m, 2H), 7.02 (d, J=7.8 Hz, 1H), 6.30 (d, J=5.1 Hz, 1H), 3.63 (t, J=5.5 Hz, 2H), 3.52 (s, 2H), 3.47 (m, 2H), 2.45 (m, 4H), 2.08 (s, 3H).
Reaction SMILES: Cl.CO[C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[CH2:15]([CH2:17][NH2:18])[OH:16].CO.[CH3:21][C:22]([CH3:24])=O>>[CH2:7]([C@@H:5]1[NH:6][C:22]([CH3:24])([CH3:21])[N:18]([CH2:17][CH2:15][OH:16])[C:4]1=[O:14])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: NCCO
Reactant: CC(C)=O
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Solvent: CO
Product: CC1(C)N[C@@H](Cc2ccccc2)C(=O)N1CCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
(S)-phenylalanine methyl ester hydrochloride (21.5 g, 100 mmol) was added to ethanolamine (48 mL, 800 mmol), and the resulting mixture was stirred at room temperature for 24 h. The excess ethanolamine was removed by distillation until the N-(2-hydroxylethyl) amide product was obtained as a white solid. Dry MeOH (200 mL) and dry acetone (40 mL) were added to this residue. The resulting solution was stirred at 60° C. for 24 h, cooled to room temperature, and then concentrated in vacuo. Compound 6 was obtained as a white solid in 55% overall yield (13.6 g, 55 mmol) after silica gel chromatography (2:1 of EtOAc:Hex). 1H NMR (CDCl3): δ 7.2-7.34 (m, 5H), 3.85 (t, 1H), 3.60-3.70 (m, 2H), 3.42 (m, 1H), 3.14 (m, 2H), 3.09 (d, 2H), 1.28 (s, 3H), 1.13 (s, 3H). Elemental analysis for C14H20N2O2 (6)—calculated: C 67.71, H 8.12, N 11.28%; observed: C 67.12, H 7.99, N 11.52%.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:21][O:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18].[Na+].[Cl-]>CN(C)C=O.C1COCC1>[CH2:1]([O:5][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16](=[CH:21][O:22][CH3:23])[C:17]([O:19][CH3:20])=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: COC=C(C(=O)OC)c1ccccc1CBr
Reactant: CCCCO
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOCc1ccccc1C(=COC)C(=O)OC
Temperature: 0 °C

Procedure:
7.4 g of n-butanol are dissolved in 50 ml of dimethylformamide, and 2.4 g of sodium hydride are added. The solution is slightly heated until everything has reacted. This solution is gradually added dropwise at -20° C. to 28.4 g of methyl α-(2-bromomethylphenyl)-β-methoxyacrylate in 150 ml of THF. Once the bromomethyl compound is no longer detectable by thin layer chromatography, 100 g of ice and 100 ml of saturated NaCl solution are added. Extraction with methylene chloride gives 23 g of an oil which is chromatographed. 10 g of a resin are obtained after elution with ethyl acetate/hexane.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[C:6]([CH2:9][C:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[O:11])=[N:7][O:8][C:4]=2[CH:3]=1.[CH:27]1([NH:30][C:31](=[O:48])[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[CH2:29][CH2:28]1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(C)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>[CH:27]1([NH:30][C:31]([C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([C:2]3[CH:26]=[CH:25][C:5]4[C:6]([CH2:9][C:10]([N:12]5[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]5)=[O:11])=[N:7][O:8][C:4]=4[CH:3]=3)[CH:33]=2)=[O:48])[CH2:28][CH2:29]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2noc3cc(Br)ccc23)CC1
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: CC(C)O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(CC(=O)N3CCN(C(=O)OC(C)(C)C)CC3)noc2c1
Yield: 58.1 %

Procedure:
A mixture of 1,1-dimethylethyl 4-[(6-bromo-1,2-benzisoxazol-3-yl)acetyl]-1-piperazinecarboxylate (Intermediate 33) (0.045 g) N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5) (0.03 g) and 2M aqueous sodium carbonate (0.65 ml) in isopropanol (2.5 ml) under nitrogen was treated with tetrakis(triphenylphosphine)palladium(0) (1 mg) then stirred at reflux for 18 h. On cooling the mixture was absorbed onto silica (Merck 7734) and applied to a Varian Bond-Elut SPE cartridge (silica, 5 g). Sequential elution with dichloromethane, chloroform, ether, ethyl acetate, acetonitrile and acetone yielded the title compound as a white solid (0.03 g).