Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([CH3:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.C([Li])CCC.[C:21](=[O:23])=[O:22]>C1COCC1.O>[CH3:15][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[C:4](=[CH:3][C:2]([CH3:1])=[CH:14][CH:13]=3)[CH:5]([C:21]([OH:23])=[O:22])[C:6]=2[CH:7]=1
Reactant: Cc1ccc2c(c1)Cc1cc(C)ccc1-2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc2c(c1)C(C(=O)O)c1cc(C)ccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.9 %

Procedure:
A solution of 2,7-dimethylfluorene (5.0 g, 25.7 mmol) in THF (100 mL) at -78° C. was charged with butyl lithium (16.8 mL, 26.0 mmol). The reaction mixture was stirred for 15 min, then CO2 gaseous (5g, 113.6 mmol) was introduced with cannula over a period of 15 min at -78° C. The reaction mixture Was Warmed up to room temperature and stirred overnight, diluted with water (150 mL). The layers were separated, the water layer was washed with ethyl acetate (5×20 mL), then acidified with conc. HCl. The precipitate formed was collected, washed with water and dried to give 4.4 g of 2,7-dimethyl-9-fluorenecarboxylic acid (72.4%).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[C:19]([CH3:24])=[N:20][O:21][C:22]=3[CH3:23])[CH:16]=2)[NH:11][C:10]1=[O:25])(=O)=O.C(N(CC)CC)C.[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1.O>C1COCC1>[CH3:24][C:19]1[C:18]([C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10](=[O:25])[C:9]3([CH2:8][CH2:7][CH2:6][N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:22]([CH3:23])[O:21][N:20]=1
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(CCCOS(C)(=O)=O)(c1ccccc1)C(=O)N2
Reactant: C1COCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: Cc1noc(C)c1-c1ccc2c(c1)C(CCCN1CCOCC1)(c1ccccc1)C(=O)N2
Temperature: 80 °C
Yield: 89.2 %

Procedure:
A mixture of compound 5-(3,5-dimethylisoxazol-4-yl)-3-(3-hydroxypropyl)-3-phenylindolin-2-one (0.72 g, 2.0 mmol), DIPEA (1.05 mL, 6.0 mmol), MsCl (250 mg, 2.2 mmol) in CH2Cl2 (20 mL) was stirred at 0° C. then gradually raised to RT overnight. The contents were diluted with CH2Cl2, washed with water (2×10 mL), and concentrated. The crude was purified with flash chromatography to afford compound 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (575 mg, 65.3%). 1H NMR (400 MHz, DMSO-d6): δH 10.73 (s, 1H), 7.24-7.38 (m, 7H), 7.02 (d, J=8.0 Hz, 1H), 4.13-4.16 (m, 2H), 3.12 (s, 3H), 2.37 (s, 3H), 2.30-2.34 (m, 2H), 2.20 (s, 3H), 1.30-1.48 (m, 2H). To a stirred solution of 3-(5-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-phenylindolin-3-yl)propyl methanesulfonate (440 mg, 1.0 mmol) in dry THF (10 mL) was successively added triethylamine (280 μl, 2.0 mmol) and morpholine (174 mg, 2.0 mmol) at room temperature. The reaction mixture was heated at 80° C. for 15 h and then water (10 mL) was added. The aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were dried over sodium sulfate and filtered. After concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (eluent: CH2Cl2/MeOH: 95/5) to afford compound (385 mg, 89.3%) as a white solid. 1H NMR (400 MHz, CDCl3): δH 7.88 (s, 1H), 7.28-7.39 (m, 5H), 7.14-7.16 (m, 1H), 7.08 (s, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.76 (m, 4H), 2.45-2.55 (m, 5H), 2.37-2.39 (m, 4H), 2.22-2.29 (m, 5H), 1.54-1.55 (m, 2H). MS (ESI) m/e [M+1]+ 432.0.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11]C)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2.B(Br)(Br)Br>C(Cl)Cl>[F:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:13])[NH:6]2
Reactant: COc1ccc2[nH]c(C)cc2c1F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(F)c(O)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a solution of 4-fluoro-5-methoxy-2-methylindole (709 mg, 3.95 mmol) in methylene chloride (9 in) cooled at −30° C. was added a solution of boron tribromide (2.18 g, 8.7 mmol) in methylene chloride (1 ml). After stirring for 1 hour at ambient temperature, the mixture was poured onto water and was diluted with methylene chloride. The pH of the aqueous layer was adjusted to 6. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate/petroleum ether (3/7) to give 4-fluoro-5-hydroxy-2-methylindole (461 mg, 70%).
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=3)[N:8]3[CH2:21][CH2:22][N:23]=[C:7]3[C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl[CH2:25][CH2:26][CH2:27][S:28]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)(=[O:30])=[O:29]>>[N:31]1([S:28]([CH2:27][CH2:26][CH2:25][O:1][C:2]2[C:11]3[N:10]=[C:9]([NH:12][C:13](=[O:20])[C:14]4[CH:19]=[CH:18][CH:17]=[N:16][CH:15]=4)[N:8]4[CH2:21][CH2:22][N:23]=[C:7]4[C:6]=3[CH:5]=[CH:4][CH:3]=2)(=[O:30])=[O:29])[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: O=S(=O)(CCCCl)N1CCOCC1
Reactant: O=C(NC1=Nc2c(O)cccc2C2=NCCN12)c1cccnc1
Product: O=C(NC1=Nc2c(OCCCS(=O)(=O)N3CCOCC3)cccc2C2=NCCN12)c1cccnc1

Procedure:
The procedure used for the preparation of Example 1 was used to prepare the title compound from N-(7-hydroxy-2,3-dihydroimidazo[1,2-c]quinazolin-5-yl)nicotinamide (Intermediate C) and 4-[(3-chloropropyl)sulfonyl]morpholine (Intermediate E). High vacuum drying at 60° C. gave the title compound (42 mg, 34%): HPLC MS RT=1.82 min, MH+=499.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.26-2.31 (2H, m), 3.13-3.24 (4H, m), 3.37-3.43 (2H, m), 3.60-3.63 (4H, m), 4.27-4.34 (2H, m), 4.43 (2H, t), 4.58-4.65 (2H, m), 7.58 (1H, t), 7.73 (1H, d), 7.84 (1H, d), 7.94 (1H, dd), 8.86 (1H, d), 8.98 (1H, dd), 9.46 (1H, d).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12](NCC(OCC=C)=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25]CC)C>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:23][NH2:25])[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOC(=O)CN[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Reactant: CCNCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CN)CC1
Reaction time: 0.08 h

Procedure:
To an Ar filled flask containing 5 g (4.33 mmol) of tetrakis(triphenylphosphine) palladium (Aldrich) and 15.92 g (50.96 mmol) of trans-4-t-butoxycarbonylaminocyclohexyl-(allyloxycarbonyl)methylamine was added 220 mL of dry THF. After the solids had dissolved, the solution was stirred for 5 min. and 50 mL (483 mmol) of diethylamine (Aldrich) was added in one portion. The solution was stirred at ambient temperature overnight. The solvents were removed by rotovap, and the residue partitioned between ice-cold 0.5M aq HCl and ethyl acetate. The organic layer was extracted with cold 0.5M aq HCl, and the combined aqueous layers washed with ethyl acetate, basified with aq NaOH and extracted with 3 x ethyl acetate. The combined organic layers were washed with water, brine, dried over Na2SO4 and solvents removed to give an oil that was chromatographed on 250 g of fine SiO2 using 90:10:1 chloroform-methanol-ammonium hydroxide to give 7.9 g (56%) of the title compound as a colorless semi-solid: NMR (CDCl3) d 0.5-1.5 (m, 4H), 1.8-1.3 (m, 1H), 1.44 (s, 9H), 1.81 (dm, J=10.3, 2H), 2.03 (din, J=10.3, 2H), 2.53 (d, J=6.6, 2H), 3.37 (br s, 1H), 4.44 (br s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:15]3[CH:16]=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=3)[N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[C:4]=2[CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][N:35]=1.O>CC(O)(C)C.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[C:9]([C:15]4[CH:16]=[N:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:19]=4)[N:10]([S:11]([CH3:14])(=[O:13])=[O:12])[C:4]=3[CH:3]=2)=[N:35][CH:36]=1
Reactant: Nc1ccc(F)cn1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Cl)cc3n2S(C)(=O)=O)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(F)cn4)cc3n2S(C)(=O)=O)cn1
Temperature: 80 °C
Yield: 36.7 %

Procedure:
Pd2(dba)3 (9.0 mg, 0.01 mmol) was added to a mixture of tert-butyl 4-(6-chloro-1-(methylsulfonyl)-1H-pyrrolo[3,2-c]pyridin-2-yl)-1H-pyrazole-1-carboxylate (15) (39 mg, 0.098 mmol), cesium carbonate (128 mg, 0.393 mmol), 2-amino-5-fluoropyridine (22 mg, 0.197 mmol) and di-tBuX-Phos (16.7 mg, 0.039 mmol) in t-BuOH containing water (3%) (1.1 mL). The reaction mixture was heated at 80° C. for 1.5 hr under microwave irradiation. It was then diluted with EtOAc and washed with water. The organic extracts were dried over MgSO4, filtered and concentrated under vacuum. The residue was then purified by prep TLC (DCM/MeOH, 95/5) to afford 17 mg of title compound mixed with some 2-amino-5-fluoropyridine. This mixture was used in the next step without further purification. 1H NMR (500 MHz, CDCl3) 1.70 (s, 9H), 2.97 (s, 3H), 6.72 (d, J=0.9 Hz), 7.37-7.41 (m, 1H), 7.52-7.56 (m, 1H), 7.62 (br s, 1H), 7.95 (m, 1H), 8.17-8.19 (m, 1H), 8.26 (s, 1H), 8.38 (s, 1H), 8.54 (d, J=0.9 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1Cl)=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]>O1CCOCC1>[C:11]([C:16]1[CH:17]=[N:18][C:19]2[C:24]([C:25]=1[NH:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10])=[CH:23][CH:22]=[CH:21][C:20]=2[O:27][CH3:28])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1c(C)cc(O)cc1C

Procedure:
4-Amino-3,5-dimethylphenol (1.8 g, 1.3 mmol) and 3-butyryl-4-chloro-8-methoxyquinoline (2.6 g, 10 mmol) were heated together under reflux in 1,4-dioxan (50 ml) for 2 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, sodium hydrogen carbonate solution and brine, dried and evaporated to a yellow solid which on recrystallisation from ethanol, followed by methanol, afforded 3-butyryl-4-(4-hydroxy-2,6-dimethylphenylamino)-8-methoxyquinoline as yellow crystals, m.p. 247°-8°.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.C(N(CC)CC)C.[NH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[OH:33]>CC#N>[OH:33][C@@H:29]1[CH2:30][CH2:31][CH2:32][C@H:28]1[NH:27][C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: Cn1c(Cl)nc2ncn(Cc3ccccc3)c2c1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2ncn(Cc3ccccc3)c2c1=O

Procedure:
Heat at reflux for 2 days a mixture of 2-chloro-1-methyl-7-(phenylmethyl)purin-6-one (3.14 g=11.4 mmol), triethylamine (1.7 g=16.8 mmol), and (±)-trans-2-aminocyclopentanol (4.04 g=39.9 mmol) in CH3CN (150 ml). Collect the precipitate, wash with water, and dry to give the title compound, a solid, FAB MS: M+1=340.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[NH:15][C:16]([C:18]2[N:19]=[C:20]([C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[S:21][C:22]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:17])[CH2:4][CH2:3]1.I[CH2:40][C:41]1([CH3:45])[CH2:44][O:43][CH2:42]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.C1COCC1>[F:38][C:32]1[CH:33]=[CH:34][CH:35]=[C:36]([F:37])[C:31]=1[C:20]1[S:21][C:22]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[C:18]([C:16](=[O:17])[NH:15][C:10]2[CH:11]=[N:12][N:13]([CH3:14])[C:9]=2[N:5]2[CH2:6][CH2:7][CH2:8][C@@H:2]([NH:1][CH2:40][C:41]3([CH3:45])[CH2:44][O:43][CH2:42]3)[CH2:3][CH2:4]2)[N:19]=1
Reactant: CC1(CI)COC1
Reactant: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NCC2(C)COC2)CC1
Temperature: 65 °C
Yield: 108.3 %

Procedure:
To a solution of (S)-tert-butyl (4-((5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)carbamoyl)-2-(2,6-difluorophenyl)thiazol-5-yl)carbamate (103 mg, 0.19 mmol) in acetonitrile (2 mL) and THF (2 mL) was added 3-(iodomethyl)-3-methyl-oxetane (78 mg, 0.38 mmol) and potassium carbonate (130 mg, 0.94 mmol). The mixture was heated at 65° C. for 3 days. After cooling to room temperature, water (20 mL) was added and the mixture extracted with DCM (50 mL×3). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0 to 15% methanol/DCM) gave tert-butyl N-[2-(2,6-difluorophenyl)-4-[[1-methyl-5-[(4R)-4-[(3-methyloxetan-3-yl)methylamino]azepan-1-yl]pyrazol-4-yl]carbamoyl]thiazol-5-yl]carbamate (130 mg, quantitative). This solid (130 mg, 0.21 mmol) was stirred with TFA (3 mL) and DCM (3 mL) at room temperature for 1 h. The solvent was removed under reduced pressure, basified with saturated NaHCO3, and extracted with ethyl acetate (3×). The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure and the residue purified by preparative HPLC to afford 334 (55.7 mg, 51%). 1H NMR (400 MHz, DMSO) δ 8.66 (s, 1H), 8.18 (s, 1H), 7.56 (s, 1H), 7.55-7.41 (m, 3H), 7.26 (t, J=8.7 Hz, 2H), 4.28 (d, J=5.6 Hz, 2H), 4.12 (d, J=5.5 Hz, 2H), 3.65 (s, 3H), 3.23-3.00 (m, 4H), 2.83-2.70 (m, 1H), 2.70-2.58 (m, 2H), 1.99-1.77 (m, 3H), 1.68-1.51 (m, 3H), 1.17 (s, 3H). LCMS (ES+) m/z 532 (M+1)
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13](Br)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)[N:12]([S:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)(=[O:18])=[O:17])[CH:11]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(Cc1cc(Br)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C
Reactant: OB(O)c1ccc(F)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+]
Product: CN(Cc1cc(-c2ccc(F)cc2)n(S(=O)(=O)c2cccnc2)c1)C(=O)OC(C)(C)C

Procedure:
By a similar operation as in Reference Example 79 and using tert-butyl{[5-bromo-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]methyl}methylcarbamate (300 mg), (4-fluorophenyl)boronic acid (195 mg), tetrakis(triphenylphosphine)palladium (40 mg) and sodium carbonate (222 mg), the title compound was obtained as a pale-yellow oil (yield 293 mg, 94%).
Reaction SMILES: [CH2:1]([C@H:8]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9]([NH:11][CH2:12][CH2:13][CH:14](OCC)[O:15]CC)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCCC1>[CH2:1]([C@H:8]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH:14]=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 93.7 %

Procedure:
By using an analogous procedure to that described for Reference Example 14, 1-benzyl-2-[(3,3-diethoxypropyl)amino]-2-oxoethylcarbamate (2.37 g, 5.54 mmol, obtained from Reference Example 21) in tetrahydrofuran (11 ml) was reacted with 0.5 N hydrochloric acid (11 ml) for 45 minutes at room temperature, to provide benzyl (1S)-1-benzyl-2-oxo-2-[(3-oxopropyl)amino]ethylcarbamate (1.84 g, 94%) as a white solid.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][C:13](=[O:35])[C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C@H:18]4[C:28](=[CH:29][CH2:30]3)[C@:26]3([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]3)[CH2:20][CH2:19]4)[CH2:16][C@H:15]2[CH3:34])(=O)=O)=CC=1.[CH:36]1([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:53][CH2:52][CH2:51][CH2:50]3)[CH:45]=[C:44]([N:54]3[CH2:59][CH2:58][NH:57][CH2:56][CH2:55]3)[N:43]=2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([NH:41][C:42]2[N:47]=[C:46]([NH:48][CH:49]3[CH2:50][CH2:51][CH2:52][CH2:53]3)[CH:45]=[C:44]([N:54]3[CH2:59][CH2:58][N:57]([CH2:12][C:13](=[O:35])[C@@H:14]4[C@:31]5([CH3:32])[C@H:17]([C@H:18]6[C:28](=[CH:29][CH2:30]5)[C@:26]5([CH3:27])[C:21](=[CH:22][C:23](=[O:33])[CH:24]=[CH:25]5)[CH2:20][CH2:19]6)[CH2:16][C@H:15]4[CH3:34])[CH2:56][CH2:55]3)[N:43]=2)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: c1c(NC2CCCC2)nc(NC2CCCC2)nc1N1CCNCC1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)COS(=O)(=O)c1ccc(Br)cc1
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@H]1C(=O)CN1CCN(c2cc(NC3CCCC3)nc(NC3CCCC3)n2)CC1
Yield: 73.1 %

Procedure:
21-(4-Bromobenzenesulfonyloxy)-16α-methyl-pregna-1,4,9(11)-triene-3,20-dione is reacted with 2,4-bis(cyclopentylamino)-6-(1-piperazinyl)pyrimidine according to the method of Example 6 to obtain the title compound in a yield of 73.1%, m.p.:180°-185° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[C:32]1([CH:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:29])([F:31])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([C:21]([N:41]4[CH2:40][CH2:39][CH:38]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH2:43][CH2:42]4)=[O:22])[CH:24]=[CH:25][CH:26]=3)=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: c1ccc(C2CCNCC2)cc1
Product: O=C(c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1)N1CCC(c2ccccc2)CC1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-phenylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=590.98 (M+H+); retention time=1.03 minutes.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=[O:31])[CH:27]=[C:26]([Cl:41])[C:5]=1[C:6]([NH:8][C@H:9]([C:22]([O:24]C)=[O:23])[CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[C:15]([F:20])[CH:14]=1)=[O:7]>CO>[Cl:3][C:4]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([OH:40])[CH:35]=2)=[O:31])[CH:27]=[C:26]([Cl:41])[C:5]=1[C:6]([NH:8][C@H:9]([C:22]([OH:24])=[O:23])[CH2:10][NH:11][C:12](=[O:21])[C:13]1[CH:14]=[C:15]([F:20])[CH:16]=[C:17]([F:19])[CH:18]=1)=[O:7]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(F)cc(F)c1)NC(=O)c1c(Cl)cc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1cc(Cl)c(C(=O)N[C@@H](CNC(=O)c2cc(F)cc(F)c2)C(=O)O)c(Cl)c1
Reaction time: 8 h
Yield: 39.3 %

Procedure:
An aqueous solution of sodium hydroxide (1 M; 0.386 Ml, 0.386 mmol) was added to a solution of N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl)amino)-carbonyl)benzoyl)-3-[(3,5-difluorobenzoyl)amino]-L-alanine, methyl ester (112 mg, 0.193 mmol) in methanol (2 Ml). The solution was allowed to stir overnight and then concentrated. The residue was purified by HPLC and lyophilized to give N-[2,6-dichloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-3-[(3,5-difluorobenzoyl)amino]-L-alanine (43 mg, 39%) as a white solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]([O:15][CH2:16][CH:17]3[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]3)=[N:11][CH:12]=[CH:13][CH:14]=2)O1.Br[C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:38]=[CH:39][C:40]([NH2:43])=[N:41][CH:42]=2)=[C:33]([F:44])[CH:32]=1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:34]2[CH:35]=[CH:36][C:31]([C:9]3[C:10]([O:15][CH2:16][CH:17]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18]4)=[N:11][CH:12]=[CH:13][CH:14]=3)=[CH:32][C:33]=2[F:44])=[N:38][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ncccc2B2OC(C)(C)C(C)(C)O2)C1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Product: CC(C)(C)OC(=O)N1CCC(COc2ncccc2-c2ccc(-c3cnc(N)cn3)c(F)c2)C1

Procedure:
The title compound was prepared using methods analogous to those described in Example 369 using tert-butyl 3-(((3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-yl)oxy)methyl)pyrrolidine-1-carboxylate and 5-(4-bromo-2-fluorophenyl)pyrazin-2-amine in Step B. MS (ESI): mass calcd. for C25H28FN5O3, 465.22; m/z found, 466.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.63-8.58 (m, 1H), 8.18-8.09 (m, 2H), 8.03-7.94 (m, 1H), 7.73-7.64 (m, 1H), 7.48-7.36 (m, 2H), 7.05-6.96 (m, 1H), 4.70 (s, 2H), 4.47-4.22 (m, 2H), 3.68-3.26 (m, 3H), 3.25-3.09 (m, 1H), 2.77-2.60 (m, 1H), 2.14-1.98 (m, 1H), 1.84-1.68 (m, 1H), 1.44 (s, 9H).
Reaction SMILES: [OH:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:12]=[CH:11][CH:10]=1.[CH3:29][C:30]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:31]=1[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C(Cl)Cl>[CH3:29][C:30]1[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:31]=1[CH2:32][O:1][C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([N:15]2[C:19]([C:20]([F:23])([F:22])[F:21])=[C:18]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:17]=[N:16]2)[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1ccc(CO)c(C)c1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3O)n2)c1C(F)(F)F
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cccc(I)c3OCc3ccc(C)cc3C)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the title compound from Example 15 Step A (200 mg, 0.397 mmol), 2,4-dimethylbenzyl alcohol (81.0 mg, 0.596 mmol), and triphenylphosphine (156 mg, 0.596 mmol) in DCM (2 mL) was added diisopropyl azodicarboxylate (0.114 mL, 0.596 mmol), and the resulting mixture was stirred at ambient temperature. After 18 h, the reaction mixture was concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20% EtOAc in hexanes, then 20 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 594.8 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.17 (s, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.92 (d, J=7.5 Hz, 1H), 7.85-7.81 (m, 2H), 7.60 (d, J=7.5 Hz, 1H), 7.13 (d, J=7.5 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.95-6.92 (m, 2H), 4.69 (s, 2H), 4.41 (q, J=7.0 Hz, 2H), 2.30 (s, 3H), 2.17 (s, 3H), 1.43 (t, J=7.0 Hz, 3H).