Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[O:33])=[C:30]([O:36][CH3:37])[CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[O-]S(C(F)(F)F)(=O)=O.C([B+]CCCC)CCC>C(N(CC)CC)C>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:32]([C:31]1[CH:34]=[CH:35][C:28]([O:27][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:29][C:30]=1[O:36][CH3:37])[OH:33])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: COc1cc(OCc2ccccc2)ccc1C=O
Agent: CCCC[B+]CCCC
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCN(CC)CC
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(OCc2ccccc2)cc1OC

Procedure:
In analogy to the procedure described in example 1 a], (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one (for the preparation of (S)-4-benzyl-3-ethoxyacetyl-oxazolidin-2-one see: D. Haigh, H. C. Birrell, B. C. C. Cantello, D. S. Eggleston, R. C. Haltiwanger, R. M. Hindley, A. Ramaswamy, N. C. Stevens, Tetrahedron: Asymmetry 1999, 10, 1353-1367) was reacted with 4-benzyloxy-2-methoxy-benzaldehyde in the presence of triethylamine and di-n-butylboron triflate to give (S)-4-benzyl-3-[(2S,3R)-3-(4-benzyloxy-2-methoxy-phenyl)-2-ethoxy-3-hydroxy-propionyl]-oxazolidin-2-one as light yellow solid. According to 1H-NMR spectroscopy, one of the four isomers is strongly predominating. The configuration was tentatively assigned as 2S,3R according to D. Haigh et al., Tetrahedron: Asymmetry 1999, 10, 1353-1367.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][N:10]=1)=O)(C)(C)C.Cl.[OH-].[Na+]>O>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([B:15]([OH:17])[OH:16])=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(B(O)O)cn1
Temperature: 10 °C
Reaction time: 12 h
Yield: 89.5 %

Procedure:
To a mixture of [2-[(tert-butoxycarbonyl)amino]pyrimidin-5-yl]boronic acid 12 (40.0 kg, 49 wt % by HPLC, 82.0 mol) in water (245 kg) was added concentrated hydrochloric acid (39.6 L) while maintaining the temperature below 30° C. The reaction mixture was stirred for 12 h and was then cooled to 10° C. The pH of the mixture was adjusted to 6.5 by addition of 50% aqueous sodium hydroxide solution while maintaining the temperature below 15° C. and the mixture was then stirred for 1 h. Water (69.0 kg) was added and the mixture was aged for 30 min. The resulting slurry was filtered and the cake was dried under vacuum at 50° C. to afford 2-aminopyrimidin-5-ylboronic acid III (10.2 kg, 90% yield). 1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 2H), 7.97 (s, 2H), 6.74 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14](/[CH:18]=[CH:19]/[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:25])=[CH:5][CH:4]=1.[N+](=[CH2:30])=[N-]>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]4[CH2:30][CH:19]4[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:25])=[CH:5][CH:4]=1
Reactant: CCOC(=O)/C=C/c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Reactant: C=[N+]=[N-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C1CC1c1ccc2c(ccc(=O)n2Cc2ccc(OC)cc2)c1
Temperature: -10 °C
Reaction time: 12 h
Yield: 42.1 %

Procedure:
To a stirred solution of (E)-ethyl 3-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)acrylate (1.2 g, 3.21 mmol) in diethyl ether (50 mL) was added palladium (II) acetate (0.031 g, 0.138 mmol). The reaction mixture was cooled to −10° C., and a cold solution of diazomethane (1.351 g, 32.1 mmol) in ether (generated from aqueous KOH (8 g, 143 mmol) and 1-methyl-1-nitrosourea (4 g, 38.8 mmol) at −15° C.) was added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was filtered through celite, diluted with diethyl ether, and washed with water and saturated NaCl solution. The organic layer was dried over sodium sulfate, concentrated, and purified by flash chromatography on silica gel column using 15% ethyl acetate in hexane to give ethyl 2-(1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinolin-6-yl)cyclopropanecarboxylate as a yellow gum (510 mg, 57%). 1H NMR 400 MHz, CDCl3: δ 1.29 (t, J=4.80 Hz, 3H), 1.31 (d, J=4.80 Hz, 1H), 1.62 (d, J=4.80 Hz, 1H), 1.84-1.89 (m, 1H), 2.51-2.56 (m, 1H), 3.76 (d, J=2.80 Hz, 3H), 3.98 (q, J=174.00 Hz, 2H), 5.47 (s, 2H), 6.77-6.83 (m, 3H), 7.13-7.28 (m, 5H), 7.66 (d, J=9.60 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:10]2C=C(C(O)=O)[N:12]=[C:11]2[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])[CH:7]=[CH:8][CH:9]=1)[CH3:2].C(OC1C=C(N2C=C(C(OCC)=O)N=C2C2C=CC(C)=CC=2F)C=CC=1)C.[OH-].[Na+].Cl>O1CCCC1.O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][C:19]=2[F:25])=[NH:12])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1cccc(-n2cc(C(=O)O)nc2-c2ccc(C)cc2F)c1
Agent: CCOC(=O)c1cn(-c2cccc(OCC)c2)c(-c2ccc(C)cc2F)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1cccc(NC(=N)c2ccc(C)cc2F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2.2 mL (4.4 mmol) of 2.0 M (in tetrahydrofuran) sodium bis(trimethylsilyl)amide in 10 mL of tetrahydrofuran at ambient temperature was added 0.52 mL (4.0 mmol) of 3-ethoxyaniline and the resulting solution was stirred for 20 min. To this reaction mixture was added 0.54 g (4.0 mmol) of 4-fluoro-4-methylbenzonitrile. The resulting mixture was stirred at ambient temperature for 3 hrs and then poured into brine (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a pale green solid, which was used without further purification. LC/MS 273.2 (M+1). Step B: Ethel 1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylate. To a mixture of the compound from Step A and 0.80 g (9.5 mmol) of sodium bicarbonate in 10 mL of 1,4-dioxane was added 0.60 mL (4.8 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as a viscous yellow oil. LC/MS 369.2 (M+1). Step C: 1-(3-Ethoxyphenyl)-2-(2-fluoro-4-methyl-phenyl)-1H-imidazole-4-carboxylic acid. To a solution of 0.81 g (2.2 mmol) of ethyl 1-(3-ethoxyphenyl)-2-(2-fluoro-4-methylphenyl)-1H-imidazole-4-carboxylate in 10 mL of tetrahydrofuran, 5 mL of water and 5 mL of methanol was added 1.0 mL (5.0 mmol) of 5.0 M NaOH solution. The reaction mixture was stirred at ambient temperature overnight. Hydrochloric acid (2.0 M) was then added to neutralize the reaction mixture. After removal of the organic solvents in vacuo, dichloromethane (20 mL) was added and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 mL), and the combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound as a yellow foam. LC/MS 341.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([NH2:14])[CH3:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:14][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: CCNS(=O)(=O)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 26.7 %

Procedure:
Following general procedure A, 4-Bromobenzene sulfonyl chloride (0.40 g, 1.56 mmol) and ethylamine (5 mL, [2.0M], 10 mmol) were stirred together for 16 hours. 4-bromo-N-ethylbenzenesulfonamide (0.11 g) was provided after purification. MS (ESI) m/z 264. HPLC purity 100.0% at 210-370 nm, 8.1 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[NH2:4].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)[C:19](O)=O)=[CH:14][CH:13]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([C:19]2[O:1][N:2]=[C:3]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:4]=2)[N:22]2[C:30]3[C:25](=[C:26]([NH:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH:27]=[CH:28][CH:29]=3)[CH:24]=[CH:23]2)=[CH:14][CH:13]=1
Reactant: CS(=O)(=O)Nc1cccc2c1ccn2C(C(=O)O)c1ccc(Cl)cc1
Reactant: NC(=NO)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)Nc1cccc2c1ccn2C(c1ccc(Cl)cc1)c1nc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N′-Hydroxybenzenecarboximidamide (49 mg, 0.36 mmol) was added to a stirred solution of compound 6a (90 mg, 0.24 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (91 mg, 0.48 mmol), 1-hydroxybenzotriazole (44 mg, 0.29 mmol) and N,N,-diisopropylethylamine (50 μL, 0.29 mmol) in DMF (2.4 mL). The reaction was allowed to stir at rt for 2 h, at which time, the reaction was partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated to a crude oil that was dissolved in toluene (2.0 mL). The resulting mixture was heated to 100° C. for 1 h, at which time, the reaction was concentrated in vacuo, and the resulting crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (CH3CN/H2O as eluent, 0.05% TFA as modifier), followed by lyophilization of the purified fractions to afford the title compound 63. m/z (ES) 479 (MH)+; IP=C rating.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[CH:22]([N-]C(C)C)(C)C.[Li+]>C1COCC1.C(OCC)(=O)C.O>[CH3:22][C:14]1([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C)CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-Methyl-4-ethoxycarbonyl-piperidine was prepared by alkylation of 1-(benzyloxycarbonyl)-4-ethoxycarbonyl-piperidine (J.Med.Chem 1994, 37, p 368)-2.6 g (10 mmol) 1. in 25 ml dry THF at -70° C., under argon, treated with 7 ml lithium di-isopropylamide solution (2M). Stirred 1.5 hours then a solution of 1.5 equivalents of alkyl halide in 5 ml of THF added dropwise. Reaction allowed to warm to ambient temperature over several hours, diluted with ethyl acetate and water. Aqueous layer extracted twice with ethyl acetate, organic solution washed with brine and dried. Evaporated to give the liquid product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N+:11]([O-:18])[CH:12]=[C:13]([CH:17]=1)[C:14]([OH:16])=O.[CH3:19][C:20]1[N:24]=[C:23]([C@H:25]([NH2:27])[CH3:26])[O:22][N:21]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[N+:11]([O-:18])[CH:12]=[C:13]([CH:17]=1)[C:14]([NH:27][C@@H:25]([C:23]1[O:22][N:21]=[C:20]([CH3:19])[N:24]=1)[CH3:26])=[O:16]
Reactant: Cc1ccc(-c2cc(C(=O)O)c[n+]([O-])c2)c(F)c1
Reactant: Cc1noc([C@@H](C)N)n1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2cc(C(=O)N[C@H](C)c3nc(C)no3)c[n+]([O-])c2)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.4 %

Procedure:
To a solution of 5-(2-fluoro-4-methylphenyl)nicotinic acid 1-oxide (22.6 mg, 0.09 mmol) in DMF (0.5 mL) were added hydrochloride salt of (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine (23.8 mg, 0.12 mmol), EDC (26.3 mg, 0.14 mmol), HOBT (15.4 mg, 0.10 mmol) and diisopropylethylamine (64 μL, 0.37 mmol). The mixture was stirred at ambient temperature. After 72 h, the mixture was purified by reverse chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) to give the title compound (18.4 mg). HRMS 357.1367 (M+1). 1H NMR (400 MHz, CDCl3): δ 9.02 (s, 1H); 8.73 (d, J=7.6 Hz, 1H); 8.53 (s, 1H); 7.98 (s, 1H); 7.32 (t, J=8.0 Hz, 1H); 7.08 (d, J=8.0 Hz, 1H); 7.02 (d, J=11.8 Hz, 1H); 5.60-5.51 (m, 1H); 2.42 (s, 3H); 2.29 (s, 3H); 1.80 (d, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[Br:10]>C1(C)C=CC=CC=1.O=[Mn]=O>[NH2:1][C:2]1[C:3]([Br:10])=[CH:4][C:5]([CH:8]=[O:9])=[CH:6][N:7]=1
Reactant: Nc1ncc(CO)cc1Br
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: Nc1ncc(C=O)cc1Br
Temperature: 80 °C
Reaction time: 2 h
Yield: 95.7 %

Procedure:
To a suspension of compound A of Example 5 (1.9 g, 9.36 mmol) in toluene (20 mL) was added activated MnO2 (2.2 g, 25.6 mmol) and the mixture was heated to 80° C. with vigorous stirring. After 2 h, the mixture was cooled to RT and filtered. The filtrate was concentrated in vacuo to obtain 6-amino-5-bromonicotinaldehyde as a solid (1.8 g, 96%). LC/MS; (M+H)+=203, 201 (1:1 ratio). 1H NMR (CD3OD, 300 MHz) δ 9.59 (s, 1H), 8.34 (s, 1H), 8.03 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[CH2:6][S:7](Cl)(=[O:9])=[O:8].[CH3:16][NH:17][CH2:18][C:19]#[N:20].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:16][N:17]([CH2:18][C:19]#[N:20])[S:7]([CH2:6][C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:4]=1)(=[O:9])=[O:8]
Reactant: CNCC#N
Reactant: O=S(=O)(Cl)Cc1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(CC#N)S(=O)(=O)Cc1cccc(C(F)(F)F)c1
Temperature: 70 °C

Procedure:
In this example 36.1 g of 3-trifluoromethylbenzylsulfonyl chloride was added cautiously to a solution containing 29.8 g of the hydrochloride salt of methylaminoacetonitrile and 38.7 g of potassium carbonate in 130 ml of water at room temperature. The reaction mixture was maintained at about 70° C. for about four hours. The mixture was allowed to cool and then extracted with ethyl ether. The ethyl ether extract was dried over magnesium sulfate and evaporated to dryness. The residue was vacuum filtered through silica gel using 3% vol. tetrahydrofuran: chloroform as eluent. 29 g of the title compound was obtained as a waxy white solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([O:30][CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:5]2[C:10]([C:11]3[CH:20]=[C:19]([F:21])[C:14]4[N:15]=[C:16]([CH3:18])[O:17][C:13]=4[CH:12]=3)=[CH:9][N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:6]=2[N:7]=1.[NH2:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([NH:43][CH3:44])=[O:42])=[CH:39][C:38]=1[O:47][CH3:48].CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=C(OC)C=CC=2OC)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1>O1CCOCC1>[CH:31]1([O:30][C:4]2[C:5]3[C:10]([C:11]4[CH:20]=[C:19]([F:21])[C:14]5[N:15]=[C:16]([CH3:18])[O:17][C:13]=5[CH:12]=4)=[CH:9][N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[C:6]=3[N:7]=[C:2]([NH:36][C:37]3[CH:46]=[CH:45][C:40]([C:41]([NH:43][CH3:44])=[O:42])=[CH:39][C:38]=3[O:47][CH3:48])[N:3]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CNC(=O)c1ccc(N)c(OC)c1
Reactant: Cc1nc2c(F)cc(-c3cn(COCC[Si](C)(C)C)c4nc(Cl)nc(OC5CCCC5)c34)cc2o1
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: COc1ccc(OC)c(P(C2CCCCC2)C2CCCCC2)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(Nc2nc(OC3CCCC3)c3c(-c4cc(F)c5nc(C)oc5c4)cn(COCC[Si](C)(C)C)c3n2)c(OC)c1
Temperature: 110 °C
Yield: 63 %

Procedure:
A mixture of 6-(2-chloro-4-(cyclopentyloxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluoro-2-methylbenzo[d]oxazole (1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1.2 equiv), brettphos (0.15 equiv), cesium carbonate (3 equiv), and dicyclohexyl(2′,6′-diisopropoxy-[1,1′-biphenyl]-2-yl)phosphine (0.15 equiv) in 1,4-dioxane (0.2 M) was purged with nitrogen and sealed. The reaction mixture was heated to 110° C. for 2 h. The reaction was filtered and solvents were removed under reduced pressure. The reaction mixture was purified using silica gel chromatography (0 to 100% ethyl acetate in hexane) to give the title compound (63% yield). MS (ESI) m/z 661.5 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][OH:24])[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]([CH2:21][CH2:22][CH2:23][O:24][C:35]3[CH:36]=[CH:37][C:32]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:33][CH:34]=3)[C:17]([CH3:20])=[CH:18][CH:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cc2ccccc2)cc1
Reactant: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCO
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccc(OCc3ccccc3)cc2)n1CCCOc1ccc(Cc2ccccc2)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 79.6 %

Procedure:
To a solution of 3-[2-(4-benzyloxyphenyl)-5-methyl-1H-pyrrol-1-yl]propan-1-ol (1.00 g, 3.11 mmol), 4-benzylphenol (572 mg, 3.11 mmol) and triphenylphosphine (1.22 g, 4.67 mmol) in toluene (2 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.18 g, 4.67 mmol) and the mixture was stirred at 80° C. for 12 hours. The reaction solution was poured into water and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=30:1) to give the object compound as an oily substance. 1.21 g (yield: 79.6%)
Reaction SMILES: Br[CH:2]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[N:10][C:8]=2[N:9]=1)[CH3:3].[CH3:22][NH2:23]>C(O)C>[F:21][C:18]1[CH:19]=[CH:20][C:15]([N:5]2[C:6](=[O:14])[C:7]3[CH:13]=[CH:12][CH:11]=[N:10][C:8]=3[N:9]=[C:4]2[CH:2]([NH:23][CH3:22])[CH3:3])=[CH:16][CH:17]=1
Reactant: CC(Br)c1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Reactant: CN
Solvent: CCO
Product: CNC(C)c1nc2ncccc2c(=O)n1-c1ccc(F)cc1
Temperature: 40 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
A suspension of the bromide (18) (80 mg, 0.23 mmol) and 8.03M solution of methylamine in ethanol (0.64 mL) was heated to 40° C. for 3 h, and stirred at ambient temperature overnight. The resulting suspension was concentrated to dryness under reduced pressure, and the resulting light brown solid was taken up in dichloromethane and filtered through a silica-gel plug to give the title amine (19) (57 mg, 83%) as a beige solid (The crude material was directly taken through the next step without further purification).
Reaction SMILES: [OH:1][C@H:2]([C:4]1[CH:5]=[CH:6][C:7]2[CH:23]=[CH:22][C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:15]=[C:10]3[C:9](=[O:24])[C:8]=2[CH:25]=1)[CH3:3].[H-].[Na+].[CH3:28]I.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[CH3:28][O:1][C@H:2]([C:4]1[CH:5]=[CH:6][C:7]2[CH:23]=[CH:22][C:11]3=[N:12][CH:13]=[C:14]([C:16]4[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=4)[CH:15]=[C:10]3[C:9](=[O:24])[C:8]=2[CH:25]=1)[CH3:3]
Reactant: C[C@H](O)c1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CO[C@@H](C)c1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one (7 mg, 0.02 mmol) was dissolved in 1 mL of tetrahydrofuran. Sodium hydride (10 mg of 60% dispersion in oil) was added and the reaction was stirred at room temperature for 2 hours. Methyl iodide (26 μL, 0.42 mmol) was added and the reaction was stirred an additional 3 hours. The reaction was then poured into a mixture of ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, concentrated in vacuo, and purified via reverse phase HPLC (10-100% acetonitrile/water gradient, 0.05% trifluoroacetic acid modifier) to afford the title compound. 1H NMR and LRMS data matched 7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-5-one.
Reaction SMILES: [CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[C:15]([N+:16]([O-])=O)=[CH:14][C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[C:12]([O:35][CH3:36])[CH:11]=3)[CH2:6][CH2:7]2)[CH2:3]1.[NH4+].[Cl-].C(O)C>[Fe].O>[CH3:1][N:2]1[CH2:9][C@@H:8]2[C@@H:4]([N:5]([C:10]3[CH:11]=[C:12]([O:35][CH3:36])[C:13]([NH:19][C:20]4[N:25]=[C:24]([C:26]5[CH:27]=[N:28][N:29]6[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=56)[CH:23]=[CH:22][N:21]=4)=[CH:14][C:15]=3[NH2:16])[CH2:6][CH2:7]2)[CH2:3]1
Reactant: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H]3CN(C)C[C@@H]32)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
A mixture of N-[4-[(3aR,6aR)-5-methyl-2,3,3a,4,6,6a-hexahydropyrrolo[3,4-b]pyrrol-1-yl]-2-methoxy-5-nitrophenyl]-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 161, 190 mg, 0.39 mmol), iron (131 mg, 2.34 mmol), NH4Cl (14.62 mg, 0.27 mmol), ethanol (6 mL) and water (2 mL) was heated at reflux for 4 h and then stirred at r.t. overnight. Part-purification was achieved by ion exchange chromatography, using an SCX column and eluting with 7N methanolic ammonia. Appropriate fractions were then concentrated in vacuo onto silica. Purification by FCC, eluting with 0-5% 7N methanolic ammonia in CH2Cl2 provided impure material. The fractions containing desired product were combined and further purified by FCC, eluting with 0-2.5% 7N methanolic ammonia in CH2Cl2 to give the title compound (100 mg, 56%); m/z: ES+ MH+ 457.21.
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20]>>[NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([NH:17][CH2:18][C:19]([NH:21][C@H:22]([C:27]([NH:29][C@H:30]([C:32]([O:34][CH2:35][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)=[O:33])[CH3:31])=[O:28])[CH2:23][CH:24]([CH3:26])[CH3:25])=[O:20])=[O:9])[CH2:3][CH:4]([CH3:5])[CH3:6]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)CN)C(=O)N[C@@H](C)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)OCc1ccccc1

Procedure:
Boc-Leu-Gly-Leu-Ala-OBzl was prepared by coupling Boc-Leu-OH (2.62 g, 10.5 mmoles) to H-Gly-Leu-Ala-OBzl using the mixed anhydride procedure described in Example 2. The resulting product was crystallized from ethyl acetate:hexane to yield 2.7 g (mp 95°-96°) in the first crop.