Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])[S:5][CH:6]=1.[Cu](C#N)[C:17]#[N:18].N>CN(C)C=O.CCOCC>[Si:9]([O:8][CH2:7][C:4]1[S:5][CH:6]=[C:2]([C:17]#[N:18])[CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)cs1
Reactant: N#C[Cu]C#N
Agent: N
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1cc(C#N)cs1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of [(4-bromo-2-thienyl)methoxy]t-butyldimethylsilane (9.0 g, 29 mmol) [reference literature: J. Med. Chem., vol. 45, 5005 (2002)] in N,N-dimethylformamide (20 ml) was added copper cyanide (4.7 g, 53 mmol) with stirring, and the resulting mixture was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was diluted with ether (80 ml), and after adding a 28% aqueous solution of ammonia (50 ml), the resulting mixture was stirred at room temperature for 1 hour. After stirring, the reaction mixture was extracted with ether, and the extract was washed successively with water and a saturated aqueous solution of sodium chloride and dried over sodium sulfate. After filtration, the filtrate was evaporated in vacuo, and the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:50 to 1:4) as the eluent to afford the title compound (4.3 g) in a yield of 58% as a colourless oily product.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28]([O:30]CC)=O)[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:43][N:44]1[C:48]([CH2:49][NH2:50])=[CH:47][CH:46]=[N:45]1>>[CH3:41][C@@H:39]1[CH2:40][N:35]([C:21]2[C:20]([CH2:19][OH:18])=[CH:33][C:24]3[C:25]([C:28]([NH:50][CH2:49][C:48]4[N:44]([CH3:43])[N:45]=[CH:46][CH:47]=4)=[O:30])=[N:26][O:27][C:23]=3[C:22]=2[F:34])[CH2:36][C@H:37]([CH3:42])[O:38]1
Reactant: Cn1nccc1CN
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)NCc4ccnn4C)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and (1-methyl-1H-pyrazol-5-yl)methanamine
Reaction SMILES: [OH:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH:4]([O:24][CH3:25])[N:5]([C:15]([CH3:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:6]2=[O:14].C(N(CC)CC)C.[CH3:33][S:34](Cl)(=[O:36])=[O:35]>ClCCl>[CH3:33][S:34]([O:1][C:2]1[C:10]([CH:11]=[O:12])=[CH:9][C:8]([I:13])=[C:7]2[C:3]=1[CH:4]([O:24][CH3:25])[N:5]([C:15]([CH3:16])([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:23])[C:6]2=[O:14])(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COC1c2c(O)c(C=O)cc(I)c2C(=O)N1C(C)(C)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1c2c(OS(C)(=O)=O)c(C=O)cc(I)c2C(=O)N1C(C)(C)c1ccccc1
Yield: 100 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-formyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (325 mg, 0.720 mmol) was dissolved in dichloromethane (10 mL), and the solution was treated with triethylamine (0.401 mL, 2.88 mmol) and methanesulfonyl chloride (0.111 mL, 1.43 mmol), followed by purification by flash column chromatography (hexane/ethyl acetate=95/5 to 80/20) to obtain 4-methanesulfonyloxy-5-formyl-3-methoxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (381 mg, yield 58%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:13][C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4].[H-].[Na+].Br[CH2:17][C:18]1[CH:22]=[C:21]([C:23]2[S:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[O:20][N:19]=1>CN(C=O)C.O>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[S:24][C:25]([Cl:28])=[CH:26][CH:27]=3)[O:20][N:19]=2)[C:8]2=[N:9][CH:10]=[CH:11][CH:12]=[C:7]2[N:6]=1)=[O:4]
Reactant: COC(=O)c1nc2cccnc2[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1nc2cccnc2n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
100 mg (0.56 mmol) 3H-Imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester were dissolved in 3 mL DMF. 22.6 mg (0.56 mmol) sodium hydride (60% in mineral oil) were added and the mixture was stirred 30 minutes at room temperature. 157.2 mg (0.56 mmol) 3-Bromomethyl-5-(5-Chloro-thiophen-2-yl)-isoxazole were added and the resulting mixture was stirred for 1 h at 80° C. The reaction mixture was cooled to room temperature and after the addition of a few drops of water concentrated under reduced pressure. HPLC-MS-analysis showed the presence of another isomer (ratio of isomers≈7:1). Final purification by preparative RP-HPLC (CH3CN/H2O gradient+0.05% formic acid) gave pure 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-3H-imidazo[4,5-b]pyridine-2-carboxylic acid methyl ester as a brown amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][NH:6][CH2:7][CH2:8][C:9]([NH2:11])=[O:10].[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH:25]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:27]=[C:28]([Cl:30])[CH:29]=1)[CH2:19][N:20]1[CH:24]=[CH:23][N:22]=[C:21]1[CH2:25][N:6]([CH2:5][C:4]1[CH:12]=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=1)[CH2:7][CH2:8][C:9]([NH2:11])=[O:10]
Reactant: NC(=O)CCNCc1cccc(F)c1
Reactant: O=Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)CCN(Cc1cccc(F)c1)Cc1nccn1Cc1cc(Cl)cc(Cl)c1
Yield: 40 %

Procedure:
To a mixture of 3-(3-Fluoro-benzylamino)-propionamide (98 mg, 0.5 mmol), 1-(3,5-dichloro-benzyl)-1H-imidazole-2-carbaldehyde, (see Example 2) (102 mg, 0.4 mmol) and CH2Cl2 (2 mL) was added NaBH(OAc)3 (119 mg, 0.56 mmol). The mixture was stirred at ambient temperature for 3 h before addition of saturated NaHCO3 (8 mL). The mixture was extracted with CH2Cl2 (2×15 mL) and the combined CH2Cl2 extracts dried over Na2SO4. Volatiles were removed in vacuo and the residue purified by column chromatography (silica gel, 20:1 CH2Cl2/MeOH) to provide the title compound (71 mg, 40%) as colorless, viscous oil: ESI MS m/z 435 [C21H21Cl2FN4O+H]+.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]([OH:8])=[O:7])[C@H:3]([CH3:5])[OH:4].C([O-])(O)=O.[Na+].[CH2:14]([O:21][C:22](N1C=CC=CC1=O)=[O:23])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O.C1COCC1>[OH:4][C@@H:3]([CH3:5])[C@@H:2]([NH:1][C:22]([O:21][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:23])[C:6]([OH:8])=[O:7]
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Reactant: CCCCCCCOC(=O)n1ccccc1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCOC(=O)N[C@@H](C(=O)O)[C@H](C)O
Reaction time: 15 h
Yield: 91.8 %

Procedure:
To a stirred mixture of D-threonine (0.15 g, 1.25 mmol) and NaHCO3 (0.158 g, 1.89 mmol) in H2O (3.5 mL), the crude mixture containing heptyl-2-pyridyl-carbonate and heptyl-2-oxopyridine-1-carboxylate (0.45 g, 1.89 mmol) in THF (3.5 mL) was added. After 15 h at rt, the crude mixture was rotary evaporated to remove the organics and subsequently extracted with Et2O (3×5 mL). The aqueous phase was acidified with 2.0 M HCl solution to pH 2-3 and subsequently extracted with EtOAc (3×10 mL). The organic fraction was dried over Na2SO4, filtered and concentrated to dryness to afford the title compound (0.3 g, 91%) as transparent oil, which was used in the next step without further purification. 1H NMR (DMSO-d6) δ 0.86 (t, J=6.8 Hz, 3H), 1.08 (d, J=6.4 Hz, 3H), 1.18-1.36 (m, 8H), 1.46-1.61 (m, 2H), 3.87-4.01 (m, 3H), 4.01-4.14 (m, 1H), 6.67 (d, J=9.0 Hz, 1H) 12.20 (br s, 1H).
Reaction SMILES: C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C[Si](C)(C)[O:15][CH2:16][CH2:17][O:18][Si](C)(C)C.O=[C:26]1[CH2:31][CH2:30][CH2:29][CH:28]([C:32]([O:34][CH3:35])=[O:33])[CH2:27]1>ClCCl>[O:15]1[C:26]2([CH2:31][CH2:30][CH2:29][CH:28]([C:32]([O:34][CH3:35])=[O:33])[CH2:27]2)[O:18][CH2:17][CH2:16]1
Reactant: COC(=O)C1CCCC(=O)C1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CCCC2(C1)OCCO2
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of trimethylsilyltrifluoromethanesulfonate (0.034 mL) in dry dichloromethane (5 mL) was added 1,2-bis(trimethylsiloxy)ethane (4.55 mL) followed by methyl 3-oxocyclohexanecarboxylate (2.9 g). The reaction mixture was stirred for 3 hours at −78° C. The reaction mixture was quenched with dry pyridine (0.5 mL), poured into saturated aqueous NaHCO3, and extracted with ether. The ether layer was dried over Na2CO3/Na2SO4. The reaction mixture was concentrated and purified by flash chromatography on silica with 5 to 30% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([N:20]1[CH2:25][CH2:24][N:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH2:22][CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Clc1ccc2ccnc(Cl)c2c1
Solvent: O
Product: Clc1ccc2ccnc(N3CCN(Cc4ccccc4)CC3)c2c1
Temperature: 150 °C
Reaction time: 3 h
Yield: 70.8 %

Procedure:
A mixture of 3.96 g 1,7-dichloroisoquinoline and 10.50 g of benzylpiperazine was stirred at 150° C. for 3 hours. To the residue water was added, followed by extraction with chloroform, washing with saturated aqueous sodium hydrogencarbonate solution and drying over anhydrous magnesium sulfate. Distilling the solvent off under reduced pressure, the residue was purified on silica gel column chromatography (ethyl acetate) to provide 4.78 g (71%) of 1-(4-benzylpiperazin-1-yl)-7-chloroisoquinoline.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:24][O:23][C:20]1[CH:19]=[CH:18][C:17]([C:16]([NH:15][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[NH2:8])=[O:25])=[CH:22][CH:21]=1
Reactant: COc1ccc(C(=O)Nc2cnccc2NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)Nc2cnccc2N)cc1
Reaction time: 6.5 h
Yield: 76.3 %

Procedure:
A solution of N4-(tert-butyloxycarbonyl)-N3-(4-methoxybenzoyl)-3,4-pyridinediamine (600 mg, 1.75 mmol) in methylene chloride (8 mL) was treated with trifluoroacetic acid (1.35 mL, 17.5 mmol). After 6.5 h, the mixture was concentrated and the residue dissolved in water and treated with 5 N aqueous sodium hydroxide. The resulting precipitate was collected by filtration yielding 325 mg (76%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:15][C:14]=3[I:28])=[O:9])=[CH:4][CH:3]=1.[C:31]([O-])([O-])=O.[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[C:14]([I:28])[CH:15]=[C:16]([CH2:21][CH:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[CH:17]=3)[N:12]([CH3:31])[CH:11]=2)=[O:9])=[CH:29][CH:30]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2c(I)cc(CC3CCOCC3)cc2c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(CC3CCOCC3)cc(I)c21
Temperature: 25 °C
Reaction time: 120 h
Yield: 48.1 %

Procedure:
To a mixture of N-(4-chlorobenzyl)-4-hydroxy-8-iodo-6-(tetrahydro-2H-pyran-4-ylmethyl)-3-quinolinecarboxamide (0.075 g) and K2CO3 (0.077 g) in 5 mL DMF is added methyl iodide (2.4 g) and the mixture is stirred at room temperature for 5 days. The mixture is then poured into water and the resulting solid collected. The crude product is chromatographed (Biotage flash 40S, eluent CH2Cl2 then 1% MeOH/CH2Cl2). Fractions homogeneous by TLC are combined and concentrated. The resulting solid is recrystallized from CH2Cl2/hexanes to yield 0.037 g (48%) of the desired product as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:8].[N:26]([CH2:29][C:30](Cl)=[O:31])=[N+:27]=[N-:28]>O1CCCC1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[N:26]([CH2:29][C:30]([NH:1][C:2]1[CH2:3][C@@H:4]2[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:5]2[C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)=[O:8])=[O:31])=[N+:27]=[N-:28]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(N)C[C@H]12
Reactant: [N-]=[N+]=NCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(NC(=O)CN=[N+]=[N-])C[C@H]12
Temperature: 0 °C
Reaction time: 4 h

Procedure:
A solution of p-nitrobenzyl (5R,6S)-2-amino-6-[(R)-1-hydroxyethyl]carbapen-2-em-3-carboxylate (35 mg, 0.1 mmol) in anhydrous tetrahydrofuran (2 ml) is cooled to -25° C. and treated with 4-dimethylaminopyridine (15.9 mg, 0.13 mmol) and, dropwise over 5 minutes, with a solution of 2-azidoacetyl chloride (14.3 mg, 0.12 mmol) in tetrahydrofuran (0.5 ml). The resulting mixture is stirred under a nitrogen atmosphere at 0° C. for 4 hours. The mixture is diluted with ethyl acetate, washed with pH 3 phosphate buffer, water, 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated under vacuum. The residue is chromatographed on a silica gel thin layer preparative plate to afford the title compound.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1Br)([CH3:3])[CH3:2].C([Li])CCC.[C:19](=[O:21])=[O:20]>Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[C:19]([OH:21])=[O:20])([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(C(C)C)c1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Product: CC(C)c1cccc(C(C)C)c1C(=O)O
Temperature: -29 °C
Reaction time: 1 h

Procedure:
2,6-Diisopropylbromobenzene (21.58 g, 0.0895 mol) was cooled to -23° C. under nitrogen and 2.5M n-butyl lithium in hexanes (36 mL) was added dropwise as the temperature further cooled to -29° C. When the addition was complete, the reaction mixture was warmed to 0° C. and was stirred 1 hour at zero and was then poured onto a large excess of crushed dry ice. The mixture was stirred with a glass rod. When the dry ice had sublimed, hydrochloric acid (1N, 200 mL) was added and the mixture was extracted with ethyl ether, the ether washed with brine, dried (magnesium sulfate), filtered, and concentrated to a yellow oil. The oil was taken up in ether (200 mL), the ether solution extracted with sodium hydroxide solution (1N, 200 mL), the layers separated, the aqueous layer made acidic with 1.5N hydrochloric acid, brine added, and the aqueous layer extracted with ether (200 mL). The ether layer was washed with brine (50 mL), dried (magnesium sulfate), filtered and concentrated to an oil which solidified on standing, 13.42 g, 72.7%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]=[C:20]([C:25]([C:27]1[N:28]=[CH:29][N:30](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:31]=1)=[O:26])[CH:19]=[CH:18]2.O>CCOCC.CCCCCC.C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[NH:30]1[CH:31]=[C:27]([C:25]([C:20]2[CH:19]=[CH:18][C:17]3[C:22](=[CH:23][CH:24]=[C:15]([O:14][CH3:13])[CH:16]=3)[CH:21]=2)([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:26])[N:28]=[CH:29]1
Reactant: COc1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Reactant: Brc1cccnc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc2cc(C(O)(c3cccnc3)c3c[nH]cn3)ccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
3-Bromopyridine (0.92 ml) was dissolved in ether (20 ml), and the solution was cooled at −78° C. To the solution was slowly added dropwise a solution of n-butyllithium in hexane (1.6 M 5.9 ml), the mixture was stirred for 20 min at −78° C. To the reaction mixture was slowly added a solution of (6-methoxynaphthalen-2-yl)-(1-trityl-1H-imidazol-4-yl)ketone (1.0 g) in THF (8 ml), and the mixture was stirred for 30 min at −78° C. To the reaction mixture was added water, and mixture was diluted with 2% citric acid (50 ml). The dilution was extracted with ethyl acetate, washed with saturated aqueous solution of sodium chloride, dried and concentrated. The residue was recrystallized from a mixed solution of ethyl acetate and diethyl ether to give the titled compound (0.98 g) as a pale yellow powder.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([N:18]=[C:19]=[O:20])=[O:17])[C:3]1=[O:25].[NH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([CH3:12])[CH:10]=2)[CH:5]=[C:4]([C:13]2[CH:14]=[C:15]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:16]([NH:18][C:19](=[O:20])[NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:17])[C:3]1=[O:25]
Reactant: Cc1cc2c(cn1)cc(-c1cc(C(=O)N=C=O)ccc1C)c(=O)n2C
Reactant: Nc1ccccc1
Solvent: ClCCl
Product: Cc1cc2c(cn1)cc(-c1cc(C(=O)NC(=O)Nc3ccccc3)ccc1C)c(=O)n2C

Procedure:
3-(1,7-Dimethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-methylbenzoyl isocyanate 31 (10 mg, 0.03 mmol) is suspended in DCM at rt with aniline (3 mg, 0.3 mmol) for 1 h. Solvent is removed and the residue is purified by preparative LC/MS to give the desired product N1. 1H NMR (400 MHz, DMSO-d6) δ 11 (s, 1H), 10.8 (s, 1H), 8.99 (s, 1H), 8.1 (s, 1H), 8.01 (d, J=8 Hz, 1H), 7.95 (s, 1H), 7.69 (s, 1H), 7.59 (s, 1H), 7.57 (s, 1H), 7.48 (d, J=7.9 Hz, 1H), 7.36 (m, 2H), 7.12 (t, J=7 Hz, 1H), 2.7 (s, 3H), 2.51 (s, 3H), 2.25 (s, 3H); LC/MS (M+1, m/z): 427.2.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([OH:21])[CH2:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)Cl.CCOC(C)=O>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:26]([O:28][CH3:29])=[O:27])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19](=[O:21])[CH2:18][C:17]4[CH:22]=[CH:23][CH:24]=[CH:25][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(O)Cc1ccccc1-3
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution (0.05 M) of methyl 13-cyclohexyl-6-hydroxy-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate in DCM was treated with DMP (1.3 eq) at 0° C. and left warming to RT and then stirred for 2 h under nitrogen. The solution was then diluted with EtOAc and washed with satd. NaHCO3, water, brine, dried over Na2SO4 and evaporated in vacuo to afford methyl 13-cyclohexyl-6-oxo-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate. The crude material was dissolved in 1,2-DCE (0.05 M), 2-dimethylamino-ethylamine was added and the pH adjusted to 6 with AcOH and the solution left stirring for 30 min. NaBH(OAc)3 was added and the solution was left stirring at RT overnight. After diluting with EtOAc, the organic phase was washed with NaOH (1N), water, brine, dried over Na2SO4 and evaporated in vacuo to afford methyl 13-cyclohexyl-6-{[2-(dimethylamino)ethyl]amino}-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate. Hydrolysis of the foregoing methyl ester was done with 1M aqueous KOH (6 eq) in dioxane (0.IM) at 60 ° C.; the reaction was complete in 2 h, and the title compound was obtained in 31% yield after RP-HPLC purification and lyophilisation (Conditions: Column: Waters X-TERRA MS C18, 10 micron, 19×150 mm; Gradient: A: H2O+0.1% TFA; B: MeCN+0.1% TFA; 75% A isocratic for 3 min, linear to 20% A in 12 min).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:36])=[C:23]([C:25]4[N:26]=[C:27]([CH3:35])[C:28]5[C:33]([CH:34]=4)=[CH:32][CH:31]=[CH:30][CH:29]=5)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.[ClH:43]>>[ClH:43].[ClH:43].[ClH:43].[CH3:35][C:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:34]=[C:25]([C:23]2[C:22]([NH2:36])=[N:21][CH:20]=[C:19]([C:17]3[CH:16]=[N:15][N:14]([CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[CH:18]=3)[CH:24]=2)[N:26]=1
Reactant: Cc1nc(-c2cc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)cnc2N)cc2ccccc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc(-c2cc(-c3cnn(C4CCNCC4)c3)cnc2N)cc2ccccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 4-{4-[6-Amino-5-(1-methylisoquinolin-3-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (36.8 mg, 0.0759 mmol) in 1,4-dioxane (1.0 mL, 13 mmol) was added 4.0 M of HCl in 1,4-dioxane (1.0 mL, 4.0 mmol), and the mixture was stirred at ambient temperature for 1.5 h. Almost immediately a pale yellow solid precipitated. The solid was filtered off, washed with MTBE, and dried in vacuo, giving the title compound as pale yellow solid. 1H NMR (400 MHz, DMSO-d6): δ=14.7 (very brs, 1H), 9.33-9.23 (brm, 1H), 9.21-9.08 (brm, 1H), 8.82 (d, J=1.8 Hz, 1H), 8.8 (very brs, 2H), 8.59 (s, 1H), 8.50 (s, 1H), 8.48 (d, J=1.8 Hz, 1H), 8.38 (d, J=8.4 Hz, 1H), 8.14 (s, 1H), 8.13 (d, J=8.0 Hz, 1H), 7.95 (dd, J=7.2, 7.2 Hz, 1H), 7.84 (dd, J=7.8, 7.8 Hz, 1H), 4.58-4.49 (mc, 1H), 3.39 (brd, J=12.6 Hz, 2H), 3.11 (brq, J=11.4 Hz, 2H), 3.07 (s, 3H), 2.30-2.13 (m, 4H). MS(ES+): m/z=385.15 (53) [MH+], 302.12 (100) [MH+-piperidine]. HPLC: tR=1.88 min (polar—5 min, ZQ3).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].[F:10][C:11]1[CH:12]=[C:13]([N:30]2[CH2:34][C@H:33]([CH2:35][N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[O:32][C:31]2=[O:41])[CH:14]=[CH:15][C:16]=1[C:17]1[CH:18]=[N:19][C:20]([C:23]2[CH2:27][C@@H:26]([CH2:28]O)[O:25][N:24]=2)=[CH:21][CH:22]=1.CN(C=O)C.C(N=C=NC(C)C)(C)C>CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:10][C:11]1[CH:12]=[C:13]([N:30]2[CH2:34][C@H:33]([CH2:35][N:36]3[CH:40]=[CH:39][N:38]=[N:37]3)[O:32][C:31]2=[O:41])[CH:14]=[CH:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH2:27][C@@H:26]([CH2:28][O:8][C:7]([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)=[O:9])[O:25][N:24]=2)=[N:19][CH:18]=1
Reactant: O=C1O[C@@H](Cn2ccnn2)CN1c1ccc(-c2ccc(C3=NO[C@H](CO)C3)nc2)c(F)c1
Reactant: O=C(O)c1cnccn1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OC[C@@H]1CC(c2ccc(-c3ccc(N4C[C@H](Cn5ccnn5)OC4=O)cc3F)cn2)=NO1)c1cnccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Pyrazine-2-carboxylic acid (118 mg, 0.95 mMol), (5R)-3-(3-fluoro-4-{6-[(5S)-5-(hydroxymethyl)-4,5-dihydroisoxazol-3-yl]pyridin-3-yl}phenyl)-5-(1H-1,2,3-triazol-1-ylmethyl)-1,3-oxazolidin-2-one (Example 1: 200 mg, 0.46 mMol), 4-(dimethylamino)pyridine (5 mg, 0.041 mmol) and DMF (2 ml) were combined and warmed to give a clear solution. The solution was allowed to cool to room temperature, and then diisopropylcarbodiimide (0.15 ml, 0.96 mmol) was added. The mixture was stirred for 18 hours, ethyl acetate was added, followed by washing with saturated NaCl. The organic layer was dried over sodium sulfate, evaporated, triturated with 1:5 ether:hexane, dissolved in 1:1 acetonitrile:methanol, adsorbed on silica gel and purified by chromatography (silica gel; elution with 1 to 10% methanol in dichloromethane). The product containing fractions were pooled and evaporated to give the title compound as a white solid, 159 mg.