Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:9](NC(=O)[C@H]([C@H](CC)C)N)C1C=CC=CC=1.C(N(CC)CC)C.BrC(C(C)(C)C)C([O-])=O>C1COCC1>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[C@H:6]([CH2:7][CH3:8])[CH3:9]
Reactant: CC[C@H](C)[C@H](N)C(=O)NCc1ccccc1
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC(C)(C)C(Br)C(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@H](N)C(=O)O
Yield: 254.1 %

Procedure:
Using the procedure described in Example 5, treatment of a solution of L-proline-L-isoleucine benzylamide (66 mg, 0.21 mmol), with triethylamine (147 uL, 1.05 mmol, 5.0 eq), and alpha-bromo-tert-butylacetate (68 uL, 0.42 mmol, 2 eq) in THF (5 mL), provided 70 mg (77%) of L-isoleucine, N-[1-(2-(carbo-tert-butoxymethylene)-2-oxoethyl)-L-proline] benzylamide.
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Reactant: COCCCN
Product: COCCCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(3-methoxy-propyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 3-methoxy-propylamine in an analogous manner to Example 1396. Product isolated as a white solid (21 mg, 36%). m.p.=154-156° C.; LCMS (m/e) 539 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.25 (s, 1H), 8.69 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.47-7.40 (m, 1H), 7.36 (s, 1H), 7.30-7.23 (m, 1H), 7.15-7.00 (m, 3H), 6.93 (s, 1H), 3.65-3.58 (m, 4H), 3.56 (t, 2H, J=5.7 Hz), 3.41 (s, 3H), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.82-2.69 (m, 6H), 1.97-1.88 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:21][C:22]([NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)=[O:23].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[C:3]([CH3:19])=[C:4]([N:8]([S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:10])=[O:11])[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CNC(=O)CBr)cc1
Reactant: Cc1c(Cl)cccc1NS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(CNC(=O)CN(c2cccc(Cl)c2C)S(=O)(=O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
449 mg of N-(3-chloro-2-methylphenyl)-4-fluorobenzenesulfonamide was dissolved in 3.00 mL of DMF, and 387 mg of 2-bromo-N-(4-methoxybenzyl)acetamide and 207 mg of potassium carbonate were added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to obtain a product, which was crystallized from hexane/ethyl acetate to obtain 466 mg of N2-(3-chloro-2-methylphenyl)-N-(4-methoxybenzyl)-N2-[(4-fluorophenyl)sulfonyl]glycinamide.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].C(N(CC)CC)C.Cl.[F:16][C:17]([F:51])([F:50])[C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:21]=[C:20]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]3[CH:41]=[C:42]([S:46](Cl)(=[O:48])=[O:47])[CH:43]=[CH:44][CH:45]=3)[CH:35]=2)[N:19]=1>C1COCC1>[OH:4][CH2:3][CH2:2][N:1]([CH2:5][CH2:6][OH:7])[S:46]([C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:36]2[CH:35]=[C:34]([C:20]3[N:19]=[C:18]([C:17]([F:16])([F:50])[F:51])[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:31])[F:32])=[CH:26][CH:25]=4)[N:21]=3)[CH:39]=[CH:38][N:37]=2)[CH:41]=1)(=[O:47])=[O:48]
Reactant: OCCNCCO
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1)N(CCO)CCO
Temperature: 0 °C
Yield: 57.6 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of diethanolamine (0.114 g, 1.08 mmol), triethylamine (0.11 ml, 0.76 mmol) and THF (2 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example 1.1) (0.21 g, 0.36 mmol) in THF (3 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/hexane) and crystallization (diethyl ether/hexane) yielded the title compound as a white solid (0.127 g, 57%). MS (ISP) 613.2 [(M+H)+]; mp 186° C.
Reaction SMILES: C([Si](C)(C)[N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[F:15])[CH:8]=[CH:7]1)(C)(C)C.Cl[C:19]1[CH:24]=[CH:23][N:22]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:20]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>>[F:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:14]=1[NH:6][CH:7]=[C:8]2[C:23]1[CH:24]=[CH:19][N:20]=[C:21]([NH:25][CH:26]2[CH2:31][C:30]([CH3:33])([CH3:32])[NH:29][C:28]([CH3:35])([CH3:34])[CH2:27]2)[N:22]=1
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cccc(F)c21
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC1(C)CC(Nc2nccc(-c3c[nH]c4c(F)cccc34)n2)CC(C)(C)N1

Procedure:
The title compound was prepared as described in Example 215, starting from 1-(tert-butyl-dimethyl-silanyl)-7-fluoro-1H-indole (prepared by TBDMS protection of 7-fluoro-1H-indole) and (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine, followed by in situ cleavage of the TBDMS protecting group with catalytic amounts of TBAF. Yield: 810 mg (81%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([OH:10])=[O:9])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].S(OCC)(O[CH2:25][CH3:26])(=O)=O>CN(C=O)C>[C:1]([NH:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[Cl:14])[C:8]([O:10][CH2:25][CH3:26])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(C(=O)O)ccc1Cl
Reactant: CCOS(=O)(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
120 g (562 mmol) of 3-acetamido-4-chlorobenzoic acid were dissolved in 77 ml of DMF and stirred with 93.16 g (674 mmol) of potassium carbonate at 60° C. for 30 min. The mixture was then cooled, admixed with 91 g (590 mmol) of diethyl sulfate, and left with stirring at RT for 7 h. The batch was concentrated, the residue was stirred with 2 l of water, and the precipitated crystals were isolated by filtration with suction. They were washed with water and dried in a vacuum cabinet at 70° C. for 3 h.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:15]=[CH:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2>C(O)C.[Pd]>[CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([CH:14]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:15][CH2:16][C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCCCCC(C=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Pd]
Solvent: CCO
Product: CCCCCC(CCc1ccc(C(=O)O)cc1)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reaction time: 6 h
Yield: 69.7 %

Procedure:
200 mg of (RS)-4-[3-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-oct-1-enyl]-benzoic acid were dissolved in 20 ml of absolute ethanol and 60 mg of 30% Pd on carbon were added. The reaction flask was purged from the oxygen by vacuum and hydrogen filling (two times). The mixture was subjected to atmospheric H2 pressure for 6 hours. The reaction mixture was filtered on a pad of Celite and concentrated in vacuo. The product was purified by preparative tic (SiO2, 5% methanol/methylene chloride), giving 140 mg of the titled compound as a white solid. 1H NMR (CDCl3): 7.99 (d, J=8.3 Hz, 2H), 7.21 (d, J=8.1 Hz, 1H), 7.19 (d, J=8.3 Hz, 2H), 7.02 (d, J=1.8 Hz, 1H), 6.89 (dd, J=8.1, 1.8 Hz, 1H), 2.60-2.35 (m, 3H), 2.05-1.80 (m, 2H), 1.68 (s, 4H), 1.60-1.45 (m, 2H), 1.28 (s, 3H), 1.27 (s, 9H), 1.30-1.10 (m, 6H), 0.82 (t, J=6.7 Hz, 3H).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8](O)([C:15]3[C:23](O)=[CH:22][C:18]4[O:19][CH2:20][O:21][C:17]=4[CH:16]=3)[C:7]2=[O:26])[CH2:3][CH2:2]1.O1C2C=CC(C3(O)C4C(=CC=CC=4)N(CCCCC)C3=O)=CC=2OC1>>[O:19]1[C:18]2[CH:22]=[CH:23][C:15]([CH:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:6]([CH2:5][CH2:4][CH2:1][CH2:2][CH3:3])[C:7]3=[O:26])=[CH:16][C:17]=2[O:21][CH2:20]1
Reactant: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Agent: CCCCCN1C(=O)C(O)(c2ccc3c(c2)OCO3)c2ccccc21
Product: CCCCCN1C(=O)C(c2ccc3c(c2)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 3-(1,3-benzodioxol-5-yl)-3-hydroxy-1-pentyl-1,3-dihydro-2H-indol-2-one, the title compound was obtained (90%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.30 (td, 1H), 7.14 (d, 1H), 7.03 (td, 1H), 6.89 (d, 1H), 6.75 (d, 1H), 6.67 (dd, 1H), 6.57 (d, 1H), 5.90 (s, 2H), 4.50 (s, 1H), 3.81-3.62 (m, 2H), 1.76-1.62 (m, 2H), 1.41-1.28 (m, 4H), 0.88 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 176.8, 148.1, 147.2, 143.5, 130.0, 129.4, 128.4, 125.1, 122.9, 122.0, 108.7, 108.6, 101.1, 51.9, 40.4, 29.0, 27.1, 22.3, 14.0.
Reaction SMILES: C([Mg]Cl)(C)C.[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10](Br)=[CH:9][N:8]=1.N1(C=O)CC[O:18][CH2:17]C1.O>C1COCC1>[Br:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH:17]=[O:18])=[CH:9][N:8]=1
Reactant: Cc1cc(Br)cnc1Br
Reactant: O=CN1CCOCC1
Agent: CC(C)[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C=O)cnc1Br
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Under an argon atmosphere, a solution of 2 M isopropylmagnesium chloride in THF (5.5 ml) was cooled to −78° C., and a solution of 2,5-dibromo-3-methylpyridine (2.5 g) in THF (10 ml) was added dropwise. After stirring at the same temperature for 30 minutes, a solution of morpholine-4-carboaldehyde (1.26 g) in THF (5 ml) was added dropwise thereto, followed by elevating the temperature to 0° C. over 30 minutes, followed by stirring at 0° C. for 2 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over Na2SO4 and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/EtOAc) to obtain 6-bromo-5-methyl nicotine aldehyde (1.42 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]([CH3:15])[NH:8][CH2:7][CH2:6]2.[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26](O)=[O:27])([O-:18])=[O:17]>>[N+:16]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][C:26]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:9]1[CH3:15])=[O:27])([O-:18])=[O:17]
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Reactant: COc1cc2c(cc1OC)C(C)NCC2
Product: COc1cc2c(cc1OC)C(C)N(C(=O)Cc1ccccc1[N+](=O)[O-])CC2
Yield: 72.1 %

Procedure:
Using the procedures described in Example 3 hereinabove, 9.4 g of 1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline is reacted with 8.0 g 2-nitrophenylacetic acid to give 11.8 g N-(2-nitrophenylacetyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline. This amide is reduced with borane in THF to produce 13.2 g of N-(2-nitrophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline hydrochloride. Reduction of the nitro function by catalytic hydrogenation over palladium provides, after recrystallization from ethanol/ether and drying under vacuum, 9.6 g N-(2-aminophenethyl)-1,2,3,4-tetrahydro-6,7-dimethoxy-1-methylisoquinoline dihydrochloride, m.p. 229°-230°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:28]([CH3:33])([CH3:32])[C:29]([NH2:31])=O)[CH:8]=[C:9]([C:11]2[N:12]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:13]([CH3:20])=[C:14]([S:16](=[O:19])(=[O:18])[NH2:17])[CH:15]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>C1COCC1>[NH2:31][CH2:29][C:28]([C:7]1[CH:8]=[C:9]([C:11]2[N:12]([CH2:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:13]([CH3:20])=[C:14]([S:16]([NH2:17])(=[O:19])=[O:18])[CH:15]=2)[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)([CH3:32])[CH3:33]
Reactant: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)C(N)=O)c2)n1CC1CCCCC1
Solvent: C1CCOC1
Product: Cc1c(S(N)(=O)=O)cc(-c2cc(C(C)(C)C)cc(C(C)(C)CN)c2)n1CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
To a solution of compound 47 (330 mg, 0.70 mol) in dry THF (5 mL) was added a solution of BH3 in THF (1M, 7 mL, 7 mmol) dropwise under cooling with an ice-bath. After the addition, the mixture was stirred at rt overnight, slowly diluted MeOH (5 mL), concentrated and purified by CC (DCM/MeOH=10/1) to give compound 48 (280 mg, 87%) as a white solid. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.64-0.67 (2H, m), 0.89-0.96 (3H, m), 1.21-1.35 (20H, m), 1.46 (3H, d, J=8.0 Hz), 2.44 (3H, s), 3.03 (2H, s), 3.78 (3H, d, J=6.8 Hz), 6.31 (1H, s), 6.93 (2H, s), 7.18 (1H, s), 7.24 (1H, s), 7.37 (1H, s). MS Calcd.: 459; MS Found: 460, (M+1).
Reaction SMILES: [C:1]1([S:7]([CH2:9][F:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[CH3:18].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[H+].[B-:35]([F:39])([F:38])([F:37])[F:36]>C(OCC)C>[F:36][B-:35]([F:39])([F:38])[F:37].[CH3:11][C:12]1[CH:13]=[C:14]([S+:7]([CH2:9][F:10])[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:15]=[CH:16][C:17]=1[CH3:18]
Reactant: Cc1ccccc1C
Reactant: O=S(CF)c1ccccc1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: Cc1ccc([S+](CF)c2ccccc2)cc1C

Procedure:
Monofluoromethyl phenyl sulfoxide (645 mg, 4.08 mmol) of example 2 was dissolved in dry diethyl ether (15 ml) under argon atmosphere. O-xylene (0.54 ml, 1.1 eq) was added to the previous solution and then the mixture was cooled to a temperature below −50° C. After stabilizing the temperature, trifluoromethanesulfonic anhydride (0.68 mL, 1.0 eq) was added slowly maintaining the same temperature. The mixture was stirred until the reaction was complete. HBF4 solution (54%, 1.12 mL, 2 eq) was added and the resulting suspension was stirred for 30 minutes. The precipitate tetrafluoroborate salt was isolated by filtration, washed with diethyl ether at 0° C. and dried. The desired product was obtained as a slightly yellow oily solid (1.729 g).
Reaction SMILES: C[O:2][C:3]([CH:5]([OH:23])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[C@H:8]([OH:21])[C@@H:7]1[OH:22])=O.O.[NH2:25][NH2:26]>CO>[C@@H:9]1([N:11]2[C:20]3[N:19]=[CH:18][N:17]=[C:15]([NH2:16])[C:14]=3[N:13]=[CH:12]2)[O:10][C@H:6]([CH:5]([C:3]([NH:25][NH2:26])=[O:2])[OH:23])[C@@H:7]([OH:22])[C@H:8]1[OH:21]
Reactant: COC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: NN
Solvent: CO
Solvent: O
Product: NNC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 93 %

Procedure:
5 g of adenosine-5'-carboxylic acid methyl ester are suspended in 150 ml of methanol mixed with 20 ml of hydrazine hydrate and heated to the boil. The ester thereby goes into solution, while, almost simultaneously, the hydrazide precipitates out in the form of a fine crystalline material. After standing overnight, it is filtered off with suction, washed with methanol and dried. There are obtained 4.4 g of adenosine-5'-carboxylic acid hydrazide, which melts, with decomposition, at 270°-272° C. The yield is 93% of theory. The compound can be readily recrystallized from hot water.
Reaction SMILES: CON(C)[C:4](=[O:15])[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH3:6].[CH2:17]([Mg]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[O:15]=[C:4]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C@@H:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:12])[CH3:13])[CH3:6]
Reactant: CON(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: Cl[Mg]Cc1ccccc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccc1

Procedure:
Prepared as described in Example 6 from (S)-tert-butyl 1-(methoxy(methyl)amino)-1-oxopropan-2-ylcarbamate (600 mg, 2.58 mmol) and benzylmagnesium chloride (2.0 M in THF, 3.87 mL, 7.75 mmol). Yield 653 mg (96%).
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[C:11]3[C:15]([CH:16]=[C:17](B4OC(C)(C)CC(C)(C)O4)[CH:18]=2)=[N:14][N:13](C2CCCCO2)[CH:12]=3)=[O:8])[N:6]=1.Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].CC#N>O1CCOCC1.O.Cl[Pd]C1C=CC=CC=1C1C=CC=CC=1N(C)C.[C@H]12C[C@H](CC1)CC2PC1C[C@H]2C[C@@H]1CC2>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:18]=[C:17]([C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH:16]=[C:15]3[C:11]=2[CH:12]=[N:13][NH:14]3)=[O:8])[N:6]=1
Reactant: Brc1cccnc1
Reactant: Cc1nc(C(=O)Nc2cc(B3OC(C)(C)CC(C)(C)O3)cc3nn(C4CCCCO4)cc23)cs1
Agent: CN(C)c1ccccc1-c1ccccc1[Pd]Cl
Agent: C1C[C@@H]2C[C@H]1CC2PC1C[C@@H]2CC[C@H]1C2
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: Cc1nc(C(=O)Nc2cc(-c3cccnc3)cc3[nH]ncc23)cs1
Reaction time: 1 h
Yield: 11.9 %

Procedure:
2-Methyl-N-[2-(tetrahydro-2H-pyran-2-yl)-6-(4,4,6,6-tetramethyl-1,3,2-dioxaborinan-2-yl)-2H-indazol-4-yl]-1,3-thiazole-4-carboxamide (53 mg, 0.11 mmol) was dissolved in 1,4-Dioxane (0.4 ml) and added to 3-bromopyridine (16 mg, 0.1 mmol) in a microwave vessel. 1,4-Dioxane (0.4 ml) was added, followed by chloro[2′-(dimethylamino)-2-biphenylyl]palladium-(1R,4S)-bicyclo[2.2.1]hept-2-yl[(1S,4R)-bicyclo[2.2.1]hept-2-yl]phosphane (1:1) (Solvias catalyst, 2 mg, 0.004 mmol, (heaped microspatula) available from ABCR) and a solution of potassium triphosphate (0.2 g, 0.1 mmol) in water (0.2 ml). The vessel was sealed and heated in CEM Discover using initial 150 W to 110° C. for 20 min. After cooling the solution was loaded onto a C18 SPE cartridge (pre-conditioned with MeCN/0.1% TFA) and flushed through with a further 3 ml MeCN/0.1% TFA. Solvent was removed by blowdown under a stream of nitrogen. The residue was dissolved in MeOH (0.5 ml) and loaded onto a SCX-2 SPE cartridge (1 g) pre-conditioned with MeOH. The material was left on the column for 1 hr then eluted with 2M ammonia/MeOH and evaporated to dryness. The sample was purified by MDAP (Method C) to afford the title compound (4 mg).
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:46])[CH2:30][NH:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:36][CH:35]=2)=[O:33])[CH2:25][CH2:24]1)=[O:22])(C)(C)C>C(Cl)Cl>[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29](=[O:46])[CH2:30][NH:31][C:32]([C:34]2[CH:39]=[CH:38][C:37]([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:36][CH:35]=2)=[O:33])[CH2:25][CH2:24]1)=[O:22]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccccc1C(=O)N1CCN(C(=O)CNC(=O)c2ccc(-c3ccccc3)cc2)CC1
Reaction time: 4 h
Yield: 41.1 %

Procedure:
Trifluoroacetic acid (0.6 mL) was added to a stirred cold (0-5° C.) solution of [2-(4-{2-[(Biphenyl-4-carbonyl)-amino]-acetyl}-piperazine-1-carbonyl)-phenyl]-carbamic acid tert-butyl ester (90 mg, 0.165 mmol) in DCM (4 mL). Stirring was continued at same temperature for 4 hr. The mixture was quenched with DIPEA (1.1 ml) and cold water was then added and the product was extracted with DCM and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using neutral alumina and 100% EtOAc as eluent) to afford 30 mg (40.8% yield) of biphenyl-4-carboxylic acid {2-[4-(2-amino-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.48%. 1H NMR (CDCl3): δ 7.9 (d, 2H), 7.68 (d, 2H), 7.62 (d, 2H), 7.5-7.4 (t, 3H), 7.4 (m, 1H), 7.3 (s, 1H), 7.2 (d, 1H), 7.08 (dd, 1H), 6.8-6.7 (m, 2H), 4.4 (s, 1H), 4.3 (d, 2H), 3.7 (d, 6H), 3.56 (t, 2H), 3.3 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].O[C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:15])([F:14])[S:3]([O:6][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]2[C:26]=1[CH2:25][N:24]([C:27]([O:29][C@H:30]1[CH2:34][N:33]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:32]([C:42]([O:44][CH3:45])=[O:43])[CH2:31]1)=[O:28])[CH2:23][CH2:22]2)(=[O:5])=[O:4]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(O)c3C2)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](OC(=O)N2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3C2)CN1C(=O)OC(C)(C)C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
Trifluoromethanesulfonic anhydride (1.76 g, 6.24 mmol) was added to a stirred, 0° C. mixture of 1-tert-butyl 2-methyl (2S,4R)-4-{[(8-hydroxy-3,4-dihydroisoquinolin-2(1H)-yl)carbonyl]oxy}pyrrolidine-1,2-dicarboxylate (1.81 g, 4.30 mmol) and Et3N (1.31 g, 12.90 mmol) in DCM (20 mL) and stirred for 18 h. The resulting mixture was poured into saturated aqueous NaHCO3 and extracted into dichloromethane. The organic layer was washed with 10% citric acid solution, dried over Na2SO4 and concentrated to red oil. The oil was purified by column chromatography on silica gel (gradient elution, 10 to 70% EtOAc in hexanes) to give a yellow oil, 1-tert-butyl 2-methyl (2S,4R)-4-({[8-{[(trifluoro methyl)sulfonyl]oxy}-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}oxy)pyrrolidine-1,2-dicarboxylate (1.65 g, 69.4% yield). LRMS (ESI) m/z 453.2 [((M-Boc)+H)+; calcd for C17H20F3N2O7S: 453.4].