Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]1(=O)OCC[O:15]1>>[CH2:4]([CH:3]1[O:13][C:14](=[O:15])[NH:1][CH2:2]1)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCC(O)CN
Reactant: O=C1OCCO1
Product: CCCCCCCCCC1CNC(=O)O1
Yield: 81.1 %

Procedure:
13.8 g of racemic 1-amino-2-undecanol (obtained from reaction of decanal with nitromethane in presence of KF followed bysilylation of nitroalcohol and reduction with LAH) and 6.5 g of ethylene carbonate were heated at approximately 110° C. for 48 hours. The progress of the reaction was followed by tlc. The reaction mixture was worked up as under Example 1 to give 12.74 g (81%) of solid, m.p. 83°-85° C.
Reaction SMILES: [CH:1]([N:4]([CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25])[C:5]([C:7]1[N:8]=[C:9]([N:12]2[CH2:15][CH:14](OS(C)(=O)=O)[CH2:13]2)[S:10][CH:11]=1)=[O:6])([CH3:3])[CH3:2].[C:37]([O-:40])(=[S:39])[CH3:38].[K+]>CN(C)C=O>[C:37]([S:39][CH:14]1[CH2:15][N:12]([C:9]2[S:10][CH:11]=[C:7]([C:5](=[O:6])[N:4]([CH:1]([CH3:2])[CH3:3])[CH2:21][CH2:22][NH:23][C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[N:8]=2)[CH2:13]1)(=[O:40])[CH3:38]
Reactant: CC(C)N(CCNC(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N(CCNC(=O)OCc3ccc([N+](=O)[O-])cc3)C(C)C)cs2)C1
Temperature: 90 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
A solution of 1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (776 mg, 1.43 mmol) (obtained as described in Reference Example 60(4)) in dimethylformamide (23 ml) was added potassium thioacetate (982 mg, 8.60 mmol) at room temperature. The mixture was stirred in an oil bath (90° C.) for 4 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane:ethyl acetate (1:2) as the eluant to afford 3-acetylthio-1-(4-{N-isopropyl-N-[2-(p-nitrobenzyloxycarbonylamino)ethyl]-carbamoyl}-1,3-thiazol-2-yl)azetidine (746 mg, yield 46%) as a pale brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[N+:16]([O-])=O)(=[O:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[O:14][CH3:15])=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:16])(=[O:3])[CH3:2]
Reactant: COc1c(C(C)=O)cnc2c([N+](=O)[O-])cccc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1c(C(C)=O)cnc2c(N)cccc12
Yield: 87 %

Procedure:
A mixture of 3-acetyl-4-methoxy-8-nitroquinoline (230 mg), ammonium chloride (30 mg) and iron (313 mg) in ethanol (3 ml) and water (0.8 ml) was refluxed for 2 hours. Insoluble material was filtered off and the filtrate was concentrated in vacuo. The residue was dissolved in ethyl acetate, and the solution was washed with saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo to give 3-acetyl-8-amino-4-methoxyquinoline (175.7 mg).
Reaction SMILES: [N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:44]=[CH:43][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[N:19](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:18]3=[O:42])=[CH:14][CH:13]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12>FC(F)(F)C(O)=O>[N:1]1[C:2]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:16][CH:17]3[S:21][C:20](=[O:22])[NH:19][C:18]3=[O:42])=[CH:43][CH:44]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1SC(Cc2ccc(OCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(OCc3cn4ccccc4n3)cc2)S1
Yield: 45 %

Procedure:
A procedure similar to that described in Example 1 was repeated, except that 3.0 g of 5-{4-(imidazo-[1,2-a]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 21) were reacted with 30 ml of trifluoroacetic acid for 1 hour. At the end of this time, the reaction mixture was freed from trifluoroacetic acid by distillation under reduced pressure. An aqueous solution of potassium carbonate and ethyl acetate were added to the residue, and the resulting precipitated insoluble material was collected by filtration, dried over anhydrous sodium sulfate and recrystallized from ethanol, to give 0.8 g of the title compound, melting at 197°-202° C.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C:26]2[O:30][C:29]([CH:31]=[O:32])=[CH:28][CH:27]=2)[CH:23]=[CH:24][CH:25]=1.[Cl-].[NH4+]>O1CCCC1>[OH:32][CH:31]([C:29]1[O:30][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C:19]([F:34])([F:18])[F:33])[CH:21]=2)=[CH:27][CH:28]=1)[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(O)c2ccc(-c3cccc(C(F)(F)F)c3)o2)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Ethyl 4-iodobenzoate (0.55 g) was dissolved in tetrahydrofuran (5 mL), and the mixture was cooled to −40° C. Isopropylmagnesium chloride (2M tetrahydrofuran solution, 1.0 mL) was added dropwise, and the mixture was stirred at the same temperature for 30 min to prepare Grignard reagent. A solution of the compound (0.40 g) obtained in Example 222a in tetrahydrofuran (5 mL) was cooled to −40° C., and the prepared Grignard reagent solution was added. After stirring at −40° C. for 30 min, saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.26 g) as an oil.
Reaction SMILES: [C:1]([O:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C=O.Cl.[CH2:20](Cl)[Cl:21]>[Cl-].[Zn+2].[Cl-]>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[CH:16]=[CH:15][C:14]([CH2:20][Cl:21])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC1CCC(c2ccccc2)CC1
Reactant: ClCCl
Agent: C=O
Agent: Cl
Agent: [Cl-]
Product: CC(=O)O[C@H]1CC[C@H](c2ccc(CCl)cc2)CC1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
A solution of 24.3 g (0.11 mol) of O-acetyl-4-phenylcyclohexanol in 1300 ml of methylene chloride is combined with 26.0 g (0.86 mol) of paraformaldehyde and 26.0 g (0.19 mol) of zinc chloride. Hydrogen chloride is introduced into this suspension, with stirring, for 2.5 hours, whilst the temperature rises to about 30° C. and a substantially homogeneous solution is formed. The mixture is then allowed to react for 15 hours at ambient temperature and the reaction mixture is then hydrolysed with stirring in about 1.5 liters of ice water. The organic phase is separated off, the aqueous phase is extracted with methylene chloride again and the two organic phases are combined. They are washed until neutral, dried and evaporated in vacuo. The yellow oil remaining is crystallised by trituration with diisopropylether and the solid product is recrystallised from diisopropylether. White crystals are obtained, melting point 87-89° C. Yield: 12.7 g (43% of theory). C15H19ClO2 (266.77) Calculated: C 67.53 H 7.18 Cl 13.29 Found: 67.68 7.29 13.11
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1)[C:5]([OH:7])=[O:6].C(O)(=O)C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+].[OH-].[K+].[N:34]1([C:38]([C:40]2[CH:45]=[N:44][C:43](Cl)=[CH:42][N:41]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC.CC1CCCO1.O>[N:34]1([C:38]([C:40]2[N:41]=[CH:42][C:43]([O:1][C:2]3[CH:3]=[C:4]([CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=3)[C:5]([OH:7])=[O:6])=[N:44][CH:45]=2)=[O:39])[CH2:37][CH2:36][CH2:35]1
Reactant: COC[C@H](C)Oc1cc(O)cc(C(=O)O)c1
Reactant: O=C(c1cnc(Cl)cn1)N1CCC1
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C(O)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC1CCCO1
Product: COC[C@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Temperature: 50 °C

Procedure:
3-Hydroxy-5-[(1S)-2-methoxy-1-methylethoxy]benzoic acid (5.00 g, 22.10 mmol) and tetra n-butyl phosphonium chloride (6.53 g, 22.1 mmol) were suspended in 2-methyltetrahydrofuran (25 ml, 5 vol rel. to the benzoic acid) and 22 mL water at ambient temperature under nitrogen. Solid potassium carbonate (27.98 g, 202.4 mmol) was charged portionwise with vigorous mechanical stirring. At the end of addition KOH liquor (2.46 g 50% wt/wt in water, 22.1 mmol) was added before the biphasic slurry was heated to 50° C. Once the temperature had stabilised, 2-(azetidin-1-ylcarbonyl)-5-chloropyrazine (4.586 g, 23.21 mmol) was charged portionwise over 40 minutes and the mixtures was stirred over night under nitrogen at 50° C. The phases were split and the lower aqueous phase was run off 25 ml of toluene and 50 mL water were added to the remaining dark red organic phase. The pH of the aqueous phase was then adjusted to 7.0 using conc. hydrochloric acid. The jacket temperature was adjusted to 20° C. and the phases were separated again (the lower aqueous phase was run off and retained; the upper organic phase was discarded). The aqueous phase was washed with more toluene (25 mL). After phase separation the toluene phase was removed again. The pH of the retained aqueous phase was adjusted to 2.1 using 5M hydrochloric acid solution (7.1 mL). Isopropyl acetate (34.9 g) was charged and the jacket temperature was raised to 80° C. Equilibration was performed with the jacket temperature set to 80° C. After phase split the lower aqueous phase was run off again and back-extracted with more isopropyl acetate (17.4 g). The organic phases were combined and homogenised at 80° C. before being washed with water (10 mL). The organic phase was dried by azeotropic distillation under slight vacuum at constant batch volume (batch partially crystallised). The suspension was cooled to 0° C. over 13.5 h and the batch was isolated by filtration followed by a cake-wash with isopropyl acetate (17.4 g). After drying at 40° C. in a vacuum oven overnight 5.25 g at 96% strength (59% corrected yield) of the desired product was obtained as white solid.
Reaction SMILES: [Li+].[BH4-].CO.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([N:28](COCC[Si](C)(C)C)[S:29]([CH3:32])(=[O:31])=[O:30])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20]2)([CH2:17][CH3:18])[C:13](OC)=O)=[CH:8][CH:7]=1>C1COCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([N:19]2[C:27]3[C:22](=[C:23]([NH:28][S:29]([CH3:32])(=[O:30])=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH:21]=[N:20]2)([CH:13]2[CH2:8][CH:9]2[C:12]#[N:19])[CH2:17][CH3:18])=[CH:10][CH:11]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ncc2c(N(COCC[Si](C)(C)C)S(C)(=O)=O)cccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(c1ccc(Cl)cc1)(C1CC1C#N)n1ncc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of LiBH4 (120 mg, 5.43 mmol) in THF (5 mL) was added MeOH (174 mg, 5.43 mmol) and a solution of methyl 2-(4-chlorophenyl)-2-(4-(N-((2-(trimethylsilyl)ethoxy)methyl)methylsulfonamido)-1H-indazol-1-yl)butanoate (600 mg, 1.09 mmol) in THF (8 mL) followed. The mixture was stirred at room temperature for 2 h. The solution was quenched with saturated NH4Cl solution, and extracted with ethyl acetate (30 mL). The organic layer was washed with brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by silica gel chromatography (PE/EA=3/1) to afford the title compound as a pale yellow solid. LC/MS m/z=524.2 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH2:23][OH:24])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>ClCCl>[CH:1]1([N:4]([CH2:12][C:13]2[CH:14]=[C:15]([CH:23]=[O:24])[CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc(CO)cc2cccnc12)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N(Cc1cc(C=O)cc2cccnc12)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 1,1-dimethylethyl cyclopropyl{[6-(hydroxymethyl)-8-quinolinyl]methyl}carbamate (1 eq.) from the previous step and sodium bicarbonate (1.1 eq.) in dichloromethane (0.1 M) was added DMP (1.1 eq.) at 0° C. The resulting mixture was stirred at RT for 2 h before it was quenched with sat. aq. NaHSO3 and then extracted with Et2O. The combined organic extracts were washed further with 1 N aq. NaOH, water and brine, dried over Na2SO4, and filtered. Concentration of the filtrate in vacuo afforded the crude title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:13]=3)[C:8]=2[C:7](C2C(C)=C(N3C(=O)CC(C(O)=O)C3)C=CC=2)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].CNC.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(Cl)Cl.CN(C=O)C>[OH:20][C:17]([C:12]1[CH:13]=[C:14]2[C:9]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[C:16]=3[NH:15]2)=[CH:10][CH:11]=1)([CH3:18])[CH3:19]
Reactant: Cc1c(-c2ccc(C(N)=O)c3[nH]c4cc(C(C)(C)O)ccc4c23)cccc1N1CC(C(=O)O)CC1=O
Agent: CNC
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cccc12
Reaction time: 8 h
Yield: 29.5 %

Procedure:
A solution of 1-(3-(1-carbamoyl-7-(2-hydroxypropan-2-yl)-9H-carbazol-4-yl)-2-methylphenyl)-5-oxopyrrolidine-3-carboxylic acid (Intermediate 81-27, 49 mg, 0.101 mmol), dimethylamine (2 M in THF, 0.252 mL, 0.505 mmol), EDC (38.7 mg, 0.202 mmol) and HOBT (30.9 mg, 0.202 mmol) in THF (2 mL) was stirred at rt overnight. Additional dimethylamine (2 M in THF, 0.252 mL, 0.505 mmol), EDC (38.7 mg, 0.202 mmol) and HOBT (30.9 mg, 0.202 mmol) were added along with DMF (0.5 mL) and the mixture was again stirred overnight. The mixture was diluted with DCM, washed with NaHCO3 (aq), dried and concentrated. The residue was purified by preparative HPLC, and the appropriate effluent fractions were made basic with 1 M aqueous sodium hydroxide and extracted twice with DCM. The organic phase was washed with water, dried and concentrated. The residue was purified by column chromatography (eluting with DCM-methanol-ammonia) to provide 4-(3-4-(dimethylcarbamoyl)-2-oxopyrrolidin-1-yl)-2-methylphenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide as a white solid (8 mg, 15%). 1H NMR (400 MHz, methanol-d4) δ 7.91 (1H, d, J=7.7 Hz), 7.73 (1H, d, J=1.1 Hz), 7.40-7.49 (2H, m), 7.33 (1H, dd, J=6.5, 2.3 Hz), 7.07 (1H, ddd, J=8.5, 1.4, 1.3 Hz), 7.01 (1H, d, J=7.9 Hz), 6.94 (1H, br. s.), 3.84-4.13 (3H, m), 3.13 (3H, 2 s), 2.97 (3H, 2 s), 2.85-2.94 (1H, m), 2.74-2.83 (1H, m), 1.93 (3H, s), 1.57 (6H, 2 s). Mass spectrum m/z 495.1 (M+H—H2O)+.
Reaction SMILES: [Si](I)(C)(C)C.C[C@:7]([NH:35]C(OC(C)(C)C)=O)([CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[C:8]([O-:10])=[O:9].[C:43](=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:43][O:10][C:8](=[O:9])[C@@H:7]([NH2:35])[CH2:11][S:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@](C)(CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1)C(=O)[O-]
Reactant: O=C([O-])O
Agent: C[Si](C)(C)I
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@@H](N)CSCc1ccc(-c2ccc(-n3ccc4ccccc43)cc2)cc1
Reaction time: 0.17 h
Yield: 95 %

Procedure:
TMSI (1.56 mL, 10.63 mmol) was added dropwise to a stirred solution of (2R)-methyl-tert-butoxycarbonylamino-3-(4′-indol-1-ylbiphen-4-ylmethylsulfanyl)-propionate (4.47 g, 8.66 mmol) in anhydrous methylene chloride (50 mL). The reaction was stirred for 10 mins. and then poured into 1N sodium bicarbonate solution (50 mL), extracted with ethyl acetate (3×50 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. Purification of the product by flash column chromatography, using 5% methanol in methylene chloride as eluent, afforded the title compound as a yellow oil (3.43 g, 95%):. Rf=0.65 (10% methanol in dichloromethane). 1H NMR (DMSO-d6, 300 MHz): δ 7.86 (2H, d, J=8 Hz, Ar—H), 7.64-7.72 (6H, m, Ar—H), 7.61 (1H, d, J=8 Hz, , Ar—H), 7.42 (1H, d, J=8 Hz, Ar—H), 7.21 (1H, td, J=7, 2 Hz, Ar—H), 7.14 (1H, td, J=7, 2 Hz, Ar—H), 6.72 (1H, d, J=3.5 Hz, Ar—H), 3.80 (2H, s, PhCH2), 3.62 (3H, s, OMe), 3.56 (1H, t, J=6.5 Hz, CHN), 2.68 (1H, dd, J=6.5, 3 Hz, CHHCHN), 2.63 (1H, dd, J=6.5, 3 Hz, CHHCHN), 2.04 (2H, br s, NH2).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=4)[NH2:25])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH:38]1([C:41](Cl)=[O:42])[CH2:40][CH2:39]1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:23]=[C:24]([NH:25][C:41]([CH:38]5[CH2:40][CH2:39]5)=[O:42])[CH:26]=[CH:27][CH:28]=4)=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(OCCCOc2ncnc3scc(-c4ccc(F)cc4)c23)c1)C1CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 103.6 %

Procedure:
A mixture of 3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)aniline (10 mg, 0.025 mmol), diisopropylethylamine (13 mg, 0.10 mmol), and dichloromethane (2 mL) was treated with cyclopropanecarbonyl chloride (30 mg, 0.028 mmol) and stirred at room temperature for 6 hours. The solvent was removed in vacuo and the remaining residue was dissolved in ethyl acetate (25 mL), washed with aqueous sodium bicarbonate solution (2×20 mL), and the organic fraction was separated and concentrated. The product was purified by column chromatography over silica gel using 1% methanol and 0.01% ammonia in 1:1 ethyl acetate/hexanes to give 12 mg (quantitative yield) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]oxy}propoxy)phenyl]cyclopropanecarboxamide as a yellow gum. MS [M+H] 464.0,
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[CH3:2].ClC1C=C([N+]([O-])=O)C=CC=1.N1CCCCC1>C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:32])[C:5]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=2)[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][C:6]=1[NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=1)[CH3:2]
Reactant: CCOC(=O)C1=CC(Nc2cccc(Cl)c2)C(C(=O)OCC)C=C1Nc1cccc(Cl)c1
Agent: O=[N+]([O-])c1cccc(Cl)c1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Nc2cccc(Cl)c2)c(C(=O)OCC)cc1Nc1cccc(Cl)c1

Procedure:
20 parts of 2,5-bis-(m-chloroanilino)-dihydroterephthalic acid diethyl ester are oxidized by heating for three hours to 125° to 130° C. with 40 parts of m-chloronitrobenzene, with addition of 2 parts of glacial acetic acid and 0.6 part of piperidine. The 2,5-bis-(m-chloroanilino)-terephthalic acid diethyl ester is obtained having a content of chlorine of 14.7% (calculated: 15.0%).
Reaction SMILES: CO.C[O-].[Na+].C(O)(=O)C.[CH:10]([NH2:12])=[NH:11].Cl.[F:14][C:15]([CH3:25])([CH3:24])[C:16](=O)[CH2:17][C:18](OCC)=[O:19]>CO>[F:14][C:15]([C:16]1[N:12]=[CH:10][NH:11][C:18](=[O:19])[CH:17]=1)([CH3:25])[CH3:24]
Reactant: CCOC(=O)CC(=O)C(C)(C)F
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(F)c1cc(=O)[nH]cn1
Temperature: 50 °C
Reaction time: 6 h
Yield: 40.9 %

Procedure:
To a solution in which 5.52 g of ethyl 4-fluoro-4-methyl-3-oxopentanoate had been dissolved in 20 ml of methanol were added 11.6 g of a 28 % sodium methoxide methanol solution and 4.0 g of formamidine acetate, and the mixture was stirred at 50° C. for 6 hours. The mixture was cooled to 10° C. or lower, and 7.1 g of conc. hydrochloric acid was added to the reaction mixture and the reaction mixture was concentrated under reduced pressure. To the concentrated solution was added 100 ml of acetone, and the resulting mixture was stirred at 60° C. for 30 minutes and then, insolubles were removed by filtration. The filtrate was concentrated under reduced pressure and the concentrated solution was recrystallized from 20 ml of acetone to obtain 2.0 g of 6-(1-fluoro-1-methylethyl)-4-pyrimidone (isolated yield: 64.0%).
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32](Br)[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2]
Reactant: COc1ccc(Br)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A rt suspension of tert-butyl(S)-1-((3S,4S)-5-acetyl-1-(5-bromo-2-methoxybenzyl)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (24 mg, 37.4 μmol), phenylboronic acid (6.83 mg, 56.0 μmol), and sodium bicarbonate (7.84 mg, 93.4 μmol) in 1,4-dioxane (280 μl) was sparged with Ar for 5 min, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (3.05 mg, 3.74 μmol) was added. The reaction was sparged with Ar for an additional minute, then sealed and stirred at 80° C. for 2 h, then cooled to rt, diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (18 mg, 75%) as a white solid. MS m/z 662 (MNa)+.