Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1>C(N(CC)CC)C>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][N:2]([NH:1][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([F:18])=[CH:20][CH:21]=2)[CH2:7][CH2:6]1)=[O:9])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Product: O=C(NN1CCN(C(=O)OCc2ccccc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.5 %

Procedure:
Crude 1-amino-4-benzyloxycarbonylpiperazine (433 g) and triethylamine (254 ml) were dissolved in dry methylene chloride(1.81) and to this solution was added dropwise p-fluorobenzoyl chloride (225 g) under cooling in an ice-bath at 8~25° C. for a period of 20 minutes. The reaction mixture was stirred for 1 hour at ambient temperature and then the resultant crystal was collected by filtration and washed with methylene chloride (300 ml), diisopropyl ether (500 ml) and water (1.51) successively to give N-(4-benzyloxycarbonyl-1-piperazinyl)-4-fluorobenzamide (327 g) as a white powder.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:14])[O:13][CH2:12][CH2:11][CH2:10]1>>[OH:8][CH:1]([CH:10]1[CH2:11][CH2:12][O:13][C:9]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCCO1
Reactant: O=Cc1ccccc1
Product: O=C1OCCC1C(O)c1ccccc1

Procedure:
Benzaldehyde is reacted with γ-butyrolactone to produce 2-(1-hydroxy-1-phenylmethyl)-γ-butyrolactone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:30])([CH3:29])[C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.O1CCOCC1.O.[OH-].[Li+].Cl>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]3[CH2:14][CH2:15][CH2:16][C:11]3=[C:10]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:24]([CH3:30])([CH3:29])[C:25]([OH:27])=[O:26])=[CH:22][CH:23]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C(=O)O)c1ccc(Cc2cc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 50 °C
Reaction time: 6.5 h
Yield: 423.2 %

Procedure:
An 250-mL round bottom flask was charged with methyl 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoate (0.200 g, 0.47 mmol), dioxane (15 ml) and water (10 ml). To this solution was then added lithium hydroxide monohydrate (0.060 g, 1.43 mmol). The resulting mixture was stirred at 50° C. for 6.5 h. The cooled reaction mixture was treated with 2N aqueous HCl until pH˜5. The volatile materials were removed under reduced pressure to afford impure 2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoic acid hydrochloride (0.44 g, >100%). A sample (0.112 g) was purified by preparative HPLC (water/acetonitrile with 0.05% TFA) and converted into HCl salt to afford the title compound (0.035 g, 16%) as a white solid. MW=432.38. M.p. 182-184° C. 1H NMR (DMSO-d6, 500 MHz) δ 12.23 (br s, 1H), 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.88 (br s, 1H), 7.58-7.53 (m, 2H); 7.29-7.24 (m, 4H), 4.04 (s, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.43 (s, 6H); APCI MS m/z 406 [M+H]+.
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4](/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[O:3]1.[OH-].[K+]>CO>[B:4](/[CH:9]=[CH:10]/[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([OH:5])[OH:3]
Reactant: COC(=O)CC/C=C/B1OC(C)(C)C(C)(C)O1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC/C=C/B(O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
Methyl (E)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pent-4-enoate (2.0 g, 8.33 mmol) was dissolved in MeOH (100 ml), a 0.8 M aqueous potassium hydroxide solution (52.1 ml, 41.6 mmol) was added and the mixture was stirred at room temperature overnight. MeOH was removed by concentration under reduced pressure, and 3 M hydrochloric acid was then added until the pH was 3. This aqueous solution was washed with tert-butyl methyl ether and then concentrated under reduced pressure. The resulting residue was purified by column chromatography (10 mM aqueous ammonium acetate solution:methanol). Obtained fractions were concentrated under reduced pressure, and the resulting solid was washed with tert-butyl methyl ether again to afford the title compound (674.6 mg, 56.3%).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:51])[NH:7][C@@H:8]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:18]3[CH:31]=[CH:30][S:29][C:19]=3[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:13][C@H:12]1[C:32]([NH:34][C@@H:35]([CH2:44][CH2:45][CH3:46])[CH:36]([OH:43])[C:37]([NH:39][CH:40]1[CH2:42][CH2:41]1)=[O:38])=[O:33])=[O:10])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl>[C:1]([NH:5][C:6](=[O:51])[NH:7][C@@H:8]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:9]([N:11]1[CH2:15][C@H:14]([O:16][C:17]2[C:18]3[CH:31]=[CH:30][S:29][C:19]=3[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:22]=2)[CH2:13][C@H:12]1[C:32]([NH:34][C@@H:35]([CH2:44][CH2:45][CH3:46])[C:36](=[O:43])[C:37]([NH:39][CH:40]1[CH2:41][CH2:42]1)=[O:38])=[O:33])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2nc(-c3ccccn3)nc3sccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)C(O)C(=O)NC1CC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2nc(-c3ccccn3)nc3sccc23)CN1C(=O)[C@@H](NC(=O)NC(C)(C)C)C(C)(C)C)C(=O)C(=O)NC1CC1

Procedure:
(2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((3S)-1-(cyclopropylamino)-2-hydroxy-1-oxohexan-3-yl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-2-carboxamide (61) (1 mmol) was oxidized with Dess-Martin periodinane (1.2 mmol) in dry dichloromethane, to provide (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-N-((S)-1-(cyclopropylamino)-1,2-dioxohexan-3-yl)-4-(2-(pyridin-2-yl)thieno[2,3-d]pyrimidin-4-yloxy)pyrrolidine-2-carboxamide (62) after aqueous/organic work up and purification of the crude product using silica gel chromatography.
Reaction SMILES: B(Br)(Br)Br.[NH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15]C)[CH:13]=2)[C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([O:24]C)=[CH:20][CH:19]=1.[OH-].[NH4+]>ClCCl>[NH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[C:8](=[O:17])[C:7]=1[C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1
Reactant: COc1ccc(C2=C(N)c3cc(OC)ccc3C2=O)cc1
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: NC1=C(c2ccc(O)cc2)C(=O)c2ccc(O)cc21
Reaction time: 1 h
Yield: 55.9 %

Procedure:
Boron tribromide (0.5 mL, 5.3 mmol) was added dropwise into a cold (−78° C.) mixture of 3-Amino-5-methoxy-2-(4-methoxyphenyl)-1H-inden-1-one (250 mg, 0.89 mmol), and dichloromethane (2.0 mL). The reaction mixture was allowed to come gradually to room temperature and stirred for 1 hour. The mixture was poured onto ice containing ammonium hydroxide (1 mL) and extracted with ethyl acetate. The organic extracts were washed with brine and were dried over MgSO4. Evaporation and flash chromatography (5%-10% ETOH/dichloromethane) gave (126 mg, 56% yield) of the product as a purple solid: mp 260-265° C.;
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O>C1COCC1>[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: Cn1ccnc1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cn1ccnc1N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -70 °C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
n-Butyllithium (1.6M in hexane, 20.76 mL, 33.22 mmol) was added dropwise to 1-methyl-1H-imidazole (CAS no. 616-47-7) (3 g, 36.54 mmol), in THF (10 mL) cooled to −70° C. over a period of 10 minutes under nitrogen. The resulting solution was stirred at −70° C. for 10 minutes. di-tert-Butyl diazene-1,2-dicarboxylate (CAS no. 870-50-8) (7.65 g, 33.22 mmol) in THF (6 ml) added dropwise over 10 minutes, not allowing the solution to rise above −65° C. After the addition was complete the solution was allowed to warm to ambient temperature overnight. Water (20 mL) added at RT. The THF was removed under vacuum. Extracted with EtOAc (2×40 mL). The organic extracts were combined, washed with brine (15 mL), dried over MgSO4 and reduced to give crude product. The crude product was purified by flash silica chromatography eluting with 20 to 100% EtOAc in isohexane to afford the product (6.17 g, 59.5%). m/z (ESI+) (M+H)+=313; HPLC tR=1.36 min.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19](=[O:25])[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)[CH2:10]2.[Cl-].[NH4+].CCOCC>C1COCC1.N#N>[N:9]12[CH2:16][CH2:15][CH:12]([CH2:13][CH2:14]1)[C@@H:11]([O:17][C:18](=[O:26])[C:19]([C:20]1[O:21][CH:22]=[CH:23][CH:24]=1)([OH:25])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:10]2
Reactant: Br[Mg]c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(=O)c1ccco1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O[C@H]1CN2CCC1CC2)C(O)(c1ccccc1)c1ccco1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Phenylmagnesium bromide, 0.0057 mol (5.7 ml of a solution 1M in THF), was added to a solution of 1.3 g (0.0052 mol) of oxofuran-2-ylacetic acid 1-azabicyclo[2.2.2]oct-3(R)-yl ester (intermediate I-4-e-) dissolved in 15 ml of THF, at −70° C. in N2 atmosphere. The mixture was stirred at this temperature for 10 minutes, and then warmed to room temperature. After 1 hour, the reaction mixture was treated with a saturated solution of ammonium chloride and extracted three times with ethyl acetate. The organic phases were combined, washed with water and dried over Na2SO4. After removal of the solvent, the solid obtained was treated with ether and filtered to yield 0.67 g (40%) of a product whose structure was confirmed by 1H-NMR. This compound was also prepared as is described in Example I-1a (Method c). The diastereomers were separated by crystallization from acetonitrile and distinguished by 1H-NMR.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C.[Cl-].[Na+].O>[CH2:17]([O:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Br:1])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Oc1cc(F)c(Cl)cc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1cc(OCc2ccccc2)c(Br)cc1Cl
Reaction time: 0.08 h

Procedure:
2-Bromo-4-chloro-5-fluoro-phenol (1 eq) was taken up in DMF. Caesium Carbonate (2.5 eq) was added and the solution was stirred for 5 minutes. Benzyl bromide (1.05 eq) was added and all was stirred at room temperature for 3 hours under nitrogen. The reaction mixture was diluted with brine and extracted into diethyl ether. The organic phase was washed several time with brine, dried over MgSO4, filtered and concentrated in vacuo, to give 1-benzyloxy-2-bromo-4-chloro-5-fluoro-benzene as an oil, which solidified on standing.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([NH:12][CH2:13][CH2:14][NH2:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:5]([C@H:4]1[NH:12][CH2:13][CH2:14][NH:15][C:3]1=[O:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NCCN[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.5 %

Procedure:
(2R)-2-(2-Aminoethylamino)-3-phenylpropionic acid methyl ester (0.67 g; 1.49 mmol) and triethylamine (1 ml) were dissolved in methylene chloride (10 ml) and stirred for 48 hours at room temperature. The reaction mixture was evaporated and the residue was chromatographed on silica (2.5×30 cm) using a 7% solution of ammonia in ethanol/methylene chloride (1:9) as eluent to afford 0.18 g of (3R)-3-benzylpiperazin-2-one.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:23][CH2:24][C:25]([F:28])([F:27])[F:26])([O-:9])=[O:8].O>C(Cl)Cl.CS(C)=O>[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)=[CH:12][C:11]=1[O:23][CH2:24][C:25]([F:28])([F:26])[F:27])([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1ccc(N2CCC(O)CC2)cc1OCC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=C1CCN(c2ccc([N+](=O)[O-])c(OCC(F)(F)F)c2)CC1
Temperature: 25 °C
Yield: 89.7 %

Procedure:
Oxalyl chloride (4.3 mL, 2.0M in DCM, 8.6 mmol) in 40 mL of DCM was cooled to −78° C. with stirring. DMSO (1.2 mL, 17 mmol) was added dropwise via addition funnel at such a rate so as to maintain the internal reaction temperature below −70° C. After ten min, 1-{4-nitro-3-[(2,2,2-trifluoroethyl)oxy]phenyl}-4-piperidinol (1.83 g, 5.71 mmol) in 8 mL of DMSO and 20 mL of DCM was added dropwise via addition funnel at such a rate so as to maintain the internal reaction temperature below −70° C. The addition funnel was rinsed with 10 mL of DCM, and the reaction was stirred for 1 h. TEA (4.0 mL, 29 mmol) was added dropwise via addition funnel, and the reaction was allowed to warm to rt. The reaction was poured into H2O, and the layers were separated. The aqueous layer was poured into saturated NaHCO3 (aqueous) and extracted with EtOAc. The DCM layer was washed with H2O and brine. The combined organic layers was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was triturated with 2:1 diethyl ether/EtOAc, filtered, and washed with diethyl ether. The yellow solid was collected to afford 1.63 g (90%) of the title compound of step C. 1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J=9.2 Hz, 1H), 6.70 (dd, J=9.5, 2.6 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 4.94 (q, J=8.8 Hz, 2H), 3.82 (t, J=6.0 Hz, 4H), 3.02-3.13 (m, 2H), 1.16 (t, J=7.3 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([OH:18])=O)[CH:12]=2)[CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl.[CH3:68][O:69][C:70](=[O:74])[CH2:71][CH2:72][NH2:73].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:22]=[CH:21][C:20]([C:23]([NH:25][C:26]2[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=2[F:33])=[O:24])=[CH:19][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:73][CH2:72][CH2:71][C:70]([O:69][CH3:68])=[O:74])=[O:18])[CH:12]=2)[CH:6]=1
Reactant: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)c2)c1
Reactant: COC(=O)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrole-3-carboxylic acid (100 mg, 0.22 mmol) in 10 ml of anhydrous DMF were added HATU (100 mg, 0.26 mmol) and N,N-diisopropylethylamine (85 mg, 0.66 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of β-alanine methyl ester hydrochloride (46 mg, 0.33 mmol). The mixture was stirred for another 5 minutes and poured into 100 ml of water. 2M HCl was added dropwise with vigorous stirring until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate as white solid. Yield: 110 mg, 92%.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16](=[O:42])[NH:17][CH2:18][C:19]3[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:21](=[O:37])[C:22]4[C:27]([C:28]=3[O:29][CH2:30][CH2:31][CH2:32][CH3:33])=[CH:26][C:25]([C:34]([NH2:36])=[S:35])=[CH:24][CH:23]=4)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:44][C:45](=O)[C:46]([O:48][CH2:49][CH3:50])=[O:47].O>C(O)C>[CH2:30]([O:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:34]3[S:35][CH:44]=[C:45]([C:46]([O:48][CH2:49][CH3:50])=[O:47])[N:36]=3)[CH:26]=2)[C:21](=[O:37])[N:20]([CH2:38][CH:39]([CH3:41])[CH3:40])[C:19]=1[CH2:18][NH:17][C:16]([O:15][CH2:14][CH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:42])[CH2:31][CH2:32][CH3:33]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(C(N)=S)cc12
Solvent: CCO
Solvent: O
Product: CCCCOc1c(CNC(=O)OCC2c3ccccc3-c3ccccc32)n(CC(C)C)c(=O)c2ccc(-c3nc(C(=O)OCC)cs3)cc12
Yield: 88.3 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl[6-(aminocarbothioyl)-4-butoxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.29 g, 0.5 mmol) and ethyl bromopyruvate (0.19 g, 1 mmol) in ethanol (10 ml) was refluxed under heating for 1 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-diisopropyl ether to give ethyl 2-[4-butoxy-3-[[[(9H-fluoren-9-ylmethoxy)carbony]amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]-1,3-thiazole-4-carboxylate (0.30 g, 90.9%) as crystals.
Reaction SMILES: Cl[C:2]([CH:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9]([O:11][CH2:12][CH:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2)=[O:10])=[O:3].[NH2:26][C:27]1[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:28]=1[C:29]([NH2:31])=[O:30].CCN(CC)CC>C1COCC1.O>[Br:36][C:34]1[CH:33]=[CH:32][C:28]([C:29](=[O:30])[NH2:31])=[C:27]([NH:26][C:2]([CH:4]2[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([O:11][CH2:12][CH:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])=[O:3])[CH:35]=1
Reactant: O=C(Cl)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: NC(=O)c1ccc(Br)cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: NC(=O)c1ccc(Br)cc1NC(=O)C1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21

Procedure:
A solution of (9H-fluoren-9-yl)methyl 2-(chlorocarbonyl)pyrrolidine-1-carboxylate (600 mg, 1.8 mmol), 2-amino-4-bromobenzamide (400 mg, 1.8 mmol), and Et3N (2 mL) in THF was stirred at room temperature. The reaction was monitored by TLC. After diluting with H2O (50 mL), the mixture was extracted with ethyl acetate (3×100 mL). The organic layers were dried over Na2SO4 and concentrated to give yellow residue, which was purified by column chromatography. MS (ESI): 534, 536 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[C:20]4[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=4)[N:14]=[C:13]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[C:12]=3[CH3:28])[CH2:9][C:8]([CH3:30])([CH3:29])[C:5]2=[N:6][CH:7]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:65]1[CH2:70][CH2:69][O:68][CH2:67][CH2:66]1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:29][C:8]1([CH3:30])[C:5]2=[N:6][CH:7]=[C:2]([N:65]3[CH2:70][CH2:69][O:68][CH2:67][CH2:66]3)[CH:3]=[C:4]2[N:10]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([F:21])=[CH:18][CH:19]=3)[N:14]=[C:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:12]=2[CH3:28])[CH2:9]1
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(Br)cc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure N using 4-(6-bromo-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (75 mg, 0.162 mmol), Pd2dba3 (3.8 mg, 0.016 mmol), XPhos (15.4 mg, 0.032 mmol), morpholine (1.6.9 mL, 0.194 mmol) and sodium tert-butoxide (31.1 mg, 0.324 mmol) in toluene (6 mL). After purification 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-7-fluoro-3-methyl-2-(2-pyridinyl)quinoline was obtained as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.70-8.77 (1H, m), 7.75-7.96 (4H, m), 7.60 (1H, d, J=2.7 Hz), 7.41 (1H, ddd, J=7.1, 5.0, 1.6 Hz), 7.30 (1H, ddd, J=9.1, 8.1, 2.7 Hz), 5.83 (1H, d, J=2.3 Hz), 3.82 (2H, s), 3.69-3.77 (4H, m), 2.91-3.06 (4H, m), 2.38 (3H, s), 1.57-1.64 (3H, m), 1.50-1.56 (3H, m). Mass Spectrum (ESI) m/e=470 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][NH:12][CH2:11]1)(C(C)(C)C)(C)C.O[CH:22]([CH2:35][CH:36]1[CH2:39][CH2:38][CH2:37]1)[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:24]>>[OH:8][CH2:9][C@@H:10]1[C@@H:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:13][N:12]([C@@H:22]([CH2:35][CH:36]2[CH2:39][CH2:38][CH2:37]2)[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)=[O:24])[CH2:11]1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1ccccc1
Reactant: COc1ccc(COC(=O)C(O)CC2CCC2)cc1
Product: COc1ccc(COC(=O)[C@H](CC2CCC2)N2C[C@H](CO)[C@@H](c3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 3-(R)-(t-butyldimethylsilyloxymethyl)-4-(S)-phenyl pyrrolidine (from EXAMPLE 1, Step E) and (R/S)-2-hydroxy-3-(cyclobutyl)propanoic acid (from EXAMPLE 92, Step A) using procedures analogous to those described in EXAMPLE 1, Steps G an H. The diastereomers were separated by HPLC in the second step using the following conditions: Chiralpak AD 2×25 cm column, 17:3 v/v hexanes/iPrOH, 9.0 mL/min, 220 nm) to provide the title compound.
Reaction SMILES: C([Sn](CC)(CC)[C:4]1[S:5][CH:6]=[CH:7][N:8]=1)C.[CH3:13][O:14][N:15]=[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1Br)[C:17]([O:19][CH3:20])=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.[Pd](Cl)Cl>[CH3:13][O:14][N:15]=[C:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:4]1[S:5][CH:6]=[CH:7][N:8]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: CON=C(C(=O)OC)c1ccccc1Br
Reactant: CC[Sn](CC)(CC)c1nccs1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CON=C(C(=O)OC)c1ccccc1-c1nccs1

Procedure:
Under a nitrogen blanket, 1.7 g of 2-triethylstannylthiazole is added to a mixture of 1.4 g (5.19 mmol) of the bromo compound (Compound E), 100 mg of palladium(II) chloride and 310 mg of triphenylphosphine in 30 ml of tetrahydrofuran, and the whole is refluxed for 2 hours. The mixture is then filtered and evaporated down. After chromatography on silica gel using cyclohexane/ethyl acetate there remains 700 mg (49%) of compound 1, Tab. I, as an oil.