Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[CH3:12][N:13]([CH3:19])[CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:16]1[CH2:17][CH2:18][CH:14]([N:13]([CH3:19])[CH3:12])[CH2:15]1
Reactant: CN(C)C1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-chloro-1-fluoro-4-nitrobenzene (4.79 g), dimethylpyrrolidin-3-ylamine (2.60 g), potassium carbonate (3.82 g) and DMF (35 mL) was stirred at room temperature for 4 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was extracted with hydrochloric acid (2 M), and the extract was basified with sodium hydroxide solution (2M). Extraction with ethyl acetate afforded an organic phase which was dried and concentrated. The product with the molecular weight of 269.73 (C12H16ClN3O2) was obtained in this way; MS (ESI): 270 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=1.[F:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][C:27](O)=[CH:26][CH:25]=1)=[O:23]>>[F:19][C:20]1[CH:34]=[CH:33][CH:32]=[CH:31][C:21]=1[C:22]([C:24]1[CH:29]=[CH:28][C:27]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([O:17][CH3:18])[C:14]([OH:16])=[O:15])=[CH:8][CH:7]=2)=[CH:26][CH:25]=1)=[O:23]
Reactant: CO[C@@H](Cc1ccc(OCCCO)cc1)C(=O)O
Reactant: O=C(c1ccc(O)cc1)c1ccccc1F
Product: CO[C@@H](Cc1ccc(OCCCOc2ccc(C(=O)c3ccccc3F)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Hydroxy-propoxy)-phenyl]-2-methoxy-propionic acid linked to Wang's Resin (Example 94, Step D) via Mitsunobu coupling with 2-fluoro-4′-hydroxybenzophenone and cleavage from the resin (Standard Procedure G) gave an oily solid (7%). 1H-NMR (200.15 MHz, CDCl3): δ 7.81 (dd, 2H, J=8.8, 1.3), 7.54–7.45 (m, 2H), 7.28–7.09 (m, 4H), 6.94 (d, 2H, J=8.6), 6.83 (d, 2H, J=8.6), 4.24 (t, 2H, J=6.2), 4.14 (t, 2H, J=6.2), 3.98 (dd, 1H, J=7.0, 4.6), 3.40 (s, 3H), 3.09 (dd, 1H, J=14.2, 4.6), 2.96 (dd, 1H, J=14.2, 7.0), 2.28 (q, 2H, J=6.2).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][C@@H:26]3[CH3:31])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:31][C@H:26]1[CH2:27][O:28][CH2:29][CH2:30][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: C[C@H]1COCCN1c1nnc2ccc(F)cn12
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1COCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 56.3 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 187 mg, 4.68 mmol) in DMF (6.0 mL) was added Intermediate A (191 mg, 1.17 mmol) and the reaction stirred for 20 min. Intermediate 139b (276 mg, 1.17 mmol) was added in DMF (2.00 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH. The product was eluted with 2M NH3 in MeOH. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (250 mg, 56%). LCMS (Method 4): Rt 1.83, m/z 380 [MH+].
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[CH2:3][O:4][C:5]([CH3:8])([CH3:7])[CH3:6]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:9]([NH:11][C@H:12]([C:17]([NH:19][C@H:20]([C:25]([O:27][CH3:28])=[O:26])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:18])[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[CH2:3][O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](COC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)COC(C)(C)C

Procedure:
A solution of 6.3 g of Z-Ser(tBu)-Asn-Leu-OMe in 600 ml of methanol is hydrogenated in the presence of 1.2 g of palladium carbon (10% Pd). After 11/4 hours the catalyst is suctioned off and the filtrate evaporated to dryness at 30° C. bath temperature under vacuum. The resulting crystalline tripeptide derivative reveals in the thin-layer chromatogram on silica gel plates in chloroform+methanol (90:10) an Rf value of 0.11.
Reaction SMILES: [NH2:1][CH:2]1[C:7]([C:8](=[O:13])[C:9]([F:12])([F:11])[CH3:10])=[CH:6][CH:5]=[CH:4][N:3]1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.S(=O)(=O)(O)O>CCOC(C)=O.CCCCCC>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]2[NH:3][C:2]3[N:1]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8]([OH:13])([C:9]([F:11])([F:12])[CH3:10])[C:19]=2[CH:18]=1
Reactant: CC(F)(F)C(=O)C1=CC=CN(c2ccc(Cl)cc2)C1N
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(F)(F)C1(O)c2cc(Cl)ccc2Nc2ncccc21
Temperature: 25 °C
Reaction time: 47.5 h
Yield: 91.1 %

Procedure:
Method JJ: 2-Amino-N-(4-chlorophenyl)-3-(2,2-difluoropropionyl)pyridine (35) (190 mg, 0.640 mmol) was treated with conc. sulfuric acid (1 mL). The resulting red homogeneous solution was stirred at room temperature for 47.5 h. The reaction was quenched with saturated aqueous Na2CO3 (15 mL), and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. Flash chromatography (50% EtOAc-hexane) provided 37 (173 mg, 91% yield) as an off-white solid (m.p. 188-190° C.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:15]=[C:14]([OH:16])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:23](Br)[CH:24]=[CH2:25]>CC(C)=O>[CH2:25]([O:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:15]=1)[CH:24]=[CH2:23]
Reactant: C=CCBr
Reactant: CCOC(=O)c1cc(O)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OCC)nc2ccccc12

Procedure:
A well-stirred mixture of 65.1 parts of ethyl-4-hydroxy-quinoline-2-carboxylate, 42 parts of anhydrous potassium carbonate, 38.4 parts of allyl bromide and 800 parts of acetone was boiled under reflux for 24 hours. The cooled reaction mixture was filtered to remove inorganic salts and acetone was removed by evaporation under reduced pressure. A solution of the residual brown oil in ether (360 parts) was washed successively with N-sodium hydroxide solution (3 portions each comprising 50 parts) and water (4 portions each of 100 parts), then dried over magnesium sulphate and evaporated to remove solvent. The resultant viscous oil crystallised on cooling and the crystals were recrystallised from light petroleum (60°-80°C) to yield 57.1 parts of ethyl 4-allyloxyquinoline-2-carboxylate as pale yellow needles, m.pt. 71°-72°C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7].[OH-].[Na+].[H][H]>[Pd]>[F:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1ccc(F)cc1F
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCc1ccc(F)cc1F
Temperature: 100 °C
Yield: 85 %

Procedure:
The procedure was as in Example 5, but the 2,4-difluorocinnamic acid obtained was not isolated. The aqueous-acidic product suspension obtained was rendered alkaline using sodium hydroxide solution and treated with 2 g of Pd/C (5% strength) at 50° C. with further stirring and heated to 100° C. It was then pressurized to 5 bar of hydrogen. After constant pressure had been achieved, it was cooled to room temperature, the pressure was released and the palladium catalyst was filtered off. The alkaline product solution was acidified with sulfuric acid and the product precipitate was isolated by filtration. After drying in vacuo, 95.0 g of 3-(2,4-difluorophenyl)propionic acid (85% of theory) were obtained.
Reaction SMILES: [C:1]1(=[O:6])O[CH2:4][CH2:3][CH2:2]1.[CH3:7][C@@H:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(OCC)(=O)C>[CH3:7][C@@H:8]([N:15]1[CH2:4][CH2:3][CH2:2][C:1]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCO1
Reactant: C[C@@H](N)c1ccccc1
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N1CCCC1=O
Temperature: 180 °C
Reaction time: 48 h

Procedure:
According the the procedure of J. Am. Chem. Soc., 74, 1952 (1959), combine butyrolactone (8.6 g, 100 mmol) and (R)-α-methylbenzylamine (15.0 g, 123 mmol) and heat to 180° C. After 48 hours, heat to 210° C. After 6 hours, cool the reaction mixture and evaporate in vacuo using a short path distillation apparatus to obtain a residue: bp 110° C. at 0.5 mm Hg. Chromatograph the residue on silica gel eluting with ethyl acetate to give the title compound: Rf=0.45 (silica gel, ethyl acetate).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:38])[N:14]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:15]2=[O:20].[Cl:39][CH2:40][C:41](Cl)=[O:42]>>[Cl:39][CH2:40][C:41]([NH:9][CH2:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[C:13](=[O:38])[N:14]([CH:21]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH2:36][CH3:37])[CH:28]=1)[CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[C:15]2=[O:20])=[O:42]
Reactant: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CN)c3C2=O)ccc1OC
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOc1cc(C(CS(C)(=O)=O)N2C(=O)c3cccc(CNC(=O)CCl)c3C2=O)ccc1OC
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
Triethylamine (0.52 g, 5.11 mmol) was added to a stirred suspension of 4-(aminomethyl)-2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindoline-1,3-dione hydrochloride (1.0 g, 2.13 mmol). The clear solution was cooled in an ice bath to 5° C. Chloroacetyl chloride (0.30 g, 2.56 mmol) was added keeping the temperature between 5-9° C. The mixture was stirred at 5° C. for 30 min and then warmed to room temperature for 2 hours. The mixture was washed with water (2×30 mL), brine (30 mL) and dried over magnesium sulfate. The solvent was removed in vacuo and the residue was purified by chromatography (silica gel, methylene chloride:ethyl acetate 7:3) to give 2-chloro-N-({2-[1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-1,3-dioxoisoindolin-4-yl}methyl)acetamide (1.0 g, 92%): 1H NMR (CDCl3) δ 7.84-7.65 (m, 4H), 7.14-7.12 (m, 2H), 6.86 (d, J=8.9 Hz, 1H), 5.94-5.88 (dd, J=4.6, 10.3 Hz, 1H), 4.79 (d, J=6.5 Hz, 2H), 4.61-4.51 (dd, J=10.4, 14.4 Hz, 1H), 4.10 (q, J=7.2 Hz, 2H), 4.02 (s, 2H), 3.85 (s, 3H), 3.80-3.72 (dd, J=4.6, 14.4 Hz, 1H), 2.86 (s, 3H), 1.47 (t, J=7.0 Hz, 3H).
Reaction SMILES: Cl[C:2]1C=[C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]=2[Cl:24])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]=1.COS(OC)(=O)=O.C(N(CC)CC)C.CC(O)=O.[CH3:43][CH2:44][OH:45]>C(Cl)(Cl)Cl>[Cl:24][C:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:22]=[CH:23][C:14]=1[NH:13][C:11]1[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:3]([CH3:2])[C:44](=[O:45])[CH:43]=1
Reactant: CCOC(=O)c1cnc(Cl)cc1Nc1ccc2ccccc2c1Cl
Reactant: CCO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C)c(=O)cc1Nc1ccc2ccccc2c1Cl
Yield: 71 %

Procedure:
Ethyl 6-chloro-4-[(1-chloro-2-naphthyl)amino]nicotinate was dissolved in CHCl3 and reacted with Me2SO4, followed by triethylamine, AcOH and EtOH as described for example 33, step B. Purification by flash chromatography on silica gel (50% EtOAc/Hexane) afforded ethyl 4-[(1-chloro-2-naphthyl)amino]-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylate (71%). 1H NMR [400 MHz, (CD3)2SO] δ 9.73 (s, 1H), 8.59 (s, 1H), 8.18 (d, J=8.4 Hz, 1H), 8.02 (t, J=8.4 Hz, 2H), 7.75-7.69 (m, 2H), 7.64-7.59 (m, 1H), 5.59 (s, 1H), 4.34 (q, J=7.1 Hz, 2H), 3.45 (s, 3H), 1.35 (t, J=7.1 Hz, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.[F:33][C:34]([F:41])([F:40])[C:35]1[CH:39]=[CH:38][NH:37][N:36]=1.CN[C@@H]1CCCC[C@@H]1NC.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.[Cu]I>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([N:37]2[CH:38]=[CH:39][C:35]([C:34]([F:41])([F:40])[F:33])=[N:36]2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])[C:6]=12
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Reactant: FC(F)(F)c1cc[nH]n1
Agent: [Cu]I
Agent: CN[C@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cnc(-n2ccc(C(F)(F)F)n2)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Temperature: 100 °C

Procedure:
A mixture of 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (100 mg, 0.204 mmol), 3-(trifluoromethyl)-1H-pyrazole (55.4 mg, 0.407 mmol), (1R,2S)—N1,N2-dimethylcyclohexane-1,2-diamine (5.79 mg, 0.041 mmol), copper(I) iodide (19.38 mg, 0.102 mmol) and potassium carbonate (84 mg, 0.611 mmol) in dioxane (1 mL) was heated up at 100° C. for 36 hours. LCMS indicated desired product was formed. The reaction mixture was filtered and the clear solution was dissolved in methanol and purified by prep. HPLC to give 1-(4-methoxy-7-(3-(trifluoromethyl)-1H-pyrazol-1-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione as white solid (37 mg, 32%). LCMS: m/e 547.05 (M+H)+, 2.17 min (method 9). 1H NMR (500 MHz, MeOD) δ ppm 2.85-3.09 (m, 2H) 3.74-3.99 (m, 5H) 4.84 (s, 1H) 5.04 (s, 1H) 6.94 (d, J=2.44 Hz, 1H) 7.36-7.67 (m, 3H) 7.80-7.88 (m, 1H) 7.97-8.16 (m, 2H) 8.31-8.40 (m, 1H) 8.52-8.67 (m, 1H) 8.79 (s, 1H) 8.84-8.96 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([O:22]CC)=[O:21])[C:8]2=[O:25])=[C:4]([F:28])[CH:3]=1.[OH-].[Na+:30]>C(O)C>[Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][C:12]([Cl:18])=[CH:13][CH:14]=3)[N:9]([CH2:19][C:20]([O-:22])=[O:21])[C:8]2=[O:25])=[C:4]([F:28])[CH:3]=1.[Na+:30]
Reactant: CCOC(=O)Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C([O-])Cn1c(=O)n(Cc2ccc(Br)cc2F)c(=O)c2ccc(Cl)cc21
Temperature: 0 °C

Procedure:
A solution of ethyl 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]-acetate (69 g) and 1N aqueous sodium hydroxide (191 ml) in ethanol (350 ml) was stirred at 60° C. for 3 hours. After cooling to 0° C., the precipitates were collected by filtration, washed with water, and dried over phosphorus pentoxide. Recrystallization from water (360 ml) gave sodium 2-[3-(4-bromo-2-fluorobenzyl)-7-chloro-1,2,3,4-tetrahydro-2,4-dioxoquinazolin-1-yl]acetate (39.2 g).
Reaction SMILES: [CH:1]1([C:7]2[O:8][C:9]([CH3:14])=[C:10]([CH3:13])[N+:11]=2[O-])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=P(Cl)(Cl)[Cl:17]>C(Cl)Cl>[Cl:17][CH2:13][C:10]1[N:11]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:8][C:9]=1[CH3:14]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(C2CCCCC2)[n+]([O-])c1C
Solvent: ClCCl
Product: Cc1oc(C2CCCCC2)nc1CCl

Procedure:
25.1 g of the above prepared 2-cyclohexyl-4,5-dimethyl-oxazole 3-oxide (˜88.8 mmol) was dissolved in 325 ml of CH2Cl2 and treated dropwise with 9.755 ml of POCl3 (1.2 eq.). The reaction mixture was refluxed over night and then quenched by carefully pouring onto crashed ice/3N NaOH. Separation of the layers, additional extraction of the aqueous phase with CH2Cl2, washing with Na2CO3 and water, drying of the combined organic phase over sodium sulfate, evaporation of the solvents, and, finally, flash chromatography (SiO2, hexane/AcOEt=9/1) afforded 4.12 g of the title compound as yellowish oil, exhibiting in the 1H-NMR the typical signal at 4.46 ppm (2H). The other, unstable regioisomer was not isolated.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([O:21]C)=[O:20])=[CH:14][C:13]=3[N:12]=[C:11]([NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]=2[N:43]=1)[CH3:4]>C1COCC1.CO>[CH2:3]([O:5][CH2:6][C:7]1[N:8]([CH2:44][C:45]([OH:48])([CH3:47])[CH3:46])[C:9]2[C:18]3[CH:17]=[CH:16][C:15]([C:19]([OH:21])=[O:20])=[CH:14][C:13]=3[N:12]=[C:11]([NH:23][C:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:10]=2[N:43]=1)[CH3:4]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)OC)ccc3c2n1CC(C)(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3cc(C(=O)O)ccc3c2n1CC(C)(C)O
Temperature: 25 °C
Reaction time: 120 h
Yield: 94.6 %

Procedure:
Sodium hydroxide solution (1 N, 3.51 ml) was added to methyl 2-(ethoxymethyl)-1-(2-hydroxy-2-methylpropyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinoline-7-carboxylate (540 mg, 878 μmol) dissolved in THF (6.21 mL) and methanol (621 μL). The reaction mixture was stirred for 120 hours at room temperature and concentrated in vacuo. The residue was partitioned between ethyl acetate (30 mL) and cold 1M HCl solution (5 mL). The aqueous layer was extracted with ethyl acetate (2×50 mL). Organic layers were washed with water (20 mL) and brine (20 mL), combined, dried with MgSO4, and concentrated in vacuo to obtain the title compound (0.499 g, 94%) as white solid; LC-MS (UV peak area, ESI) 99%, 601.3 (MH+).
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22](I)=[CH:21][N:20](COCC[Si](C)(C)C)[C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4].[CH3:32][N:33]1[C:37]([Sn](CCCC)(CCCC)CCCC)=[CH:36][C:35]([C:51]([F:54])([F:53])[F:52])=[N:34]1.[F-].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].CN(C=O)C>[OH:1][CH:2]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:15]=[C:16]3[C:22]([C:37]4[N:33]([CH3:32])[N:34]=[C:35]([C:51]([F:54])([F:53])[F:52])[CH:36]=4)=[CH:21][NH:20][C:17]3=[N:18][CH:19]=2)[CH:13]=1)[C:3]([N:5]([CH3:7])[CH3:6])=[O:4]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(F)(F)F)nn1C
Reactant: CN(C)C(=O)C(O)c1cncc(-c2cnc3c(c2)c(I)cn3COCC[Si](C)(C)C)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(O)c1cncc(-c2cnc3[nH]cc(-c4cc(C(F)(F)F)nn4C)c3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.4 %

Procedure:
A mixture of 2-hydroxy-2-{5-[3-iodo-1(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-3-yl}-N,N-dimethyl-acetamide (194 mg, 0.4 mmol), 1-methyl-5(tributylstannyl)3-(trifluoromethyl)-1H-pyrazole (186 mg, 0.4 mmol), CuI (7 mg, 0.04 mmol), CsF (107 mg, 0.7 mmol), dichlorobis(benzonitrile)palladium (II) (7 mg, 0.02 mmol), tri-t-butylphosphine 10% w/v in hexanes (10 μl, 0.04 mmol) and DMF were stirred at 100° C. under nitrogen overnight. The mixture was allowed to cool to room temperature and then extracted with ethyl acetate (2X). The combined organic layers were extracted with brine, dried with Na2SO4, decanted, and concentrated to dryness. The material was purified using silica gel chromatography and a gradient of ethyl acetate and hexane. The purified product was treated with dichloromethane/trifluoroacetate acid (1 ml/1 ml) at room temperature for 2 hours. The solvents were removed under vacuum and the crude was stirred in dichloromethane/ethylenediamine (1 ml/1 ml) for 2 hours at room temperature. Again the solvents was removed under vacuum and the crude was dissolved in DMSO, filtered and purified by reverse phase HPLC, lyophilized afforded 2-hydroxy-N,N-dimethyl-2-{5-[3-(2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl]-pyridin-3-yl}-acetamide (13.2 mg, 8% yield). 1H NMR (500 MHz, DMSO-d6) δ 2.80 (s, 3H), 2.94 (s, 3H), 5.56 (s, 1H), 5.80 (s, 1H), 7.08 (s, 1H), 7.98 (s, 1H), 8.04 (t, 1H), 8.26 (d, 1H), 8.50 (d, 1H), 8.58 (d, 1H), 8.88 (d, 1H), 12.40 (s, 1H). MS: m/z 445.0 (M+H+).
Reaction SMILES: [C:1]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][C:8]1[NH:9][C:10](=[O:19])[C:11]([OH:18])=[C:12]([C:14](OC)=[O:15])[N:13]=1.[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][C:14]([C:12]2[N:13]=[C:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:9][C:10](=[O:19])[C:11]=2[OH:18])=[O:15])=[CH:29][CH:28]=1
Reactant: COC(=O)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Reactant: NCc1ccc(F)cc1
Product: O=C(NCc1ccc(F)cc1)c1nc(Cc2ccccc2-c2ccccc2)[nH]c(=O)c1O
Yield: 17.9 %

Procedure:
The synthesis performed as in Example 21 using methyl 2-(biphenyl-2-ylmethyl)-5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.070 g, 208 μmol) and 4-fluorobenzylamine (0.5 ml; 4.38 mmol) to provide the title compound as an off-white solid (0.016 g; 18%). LCMS: m/z=430 (MH+).
Reaction SMILES: [CH3:1][C:2]([N:9]([CH3:11])[NH2:10])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH2:12]([N:19]=[C:20]=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([NH:10][N:9]([C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH3:11])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C)(C)N(C)N
Reactant: O=C=NCc1ccccc1
Product: CCOC(=O)C(C)(C)N(C)NC(=O)NCc1ccccc1
Yield: 56.8 %

Procedure:
According to the procedure described in the synthesis method of Compound V-1, ethyl 2-methyl-2-(1-methylhydrazinyl)propanoate (10.27 g, 77.8 mmol) was reacted with benzyl isocyanate (15.53 g, 116.7 mmol) to obtain the title compound (12.97 g, 57%).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[CH3:31][C@H:32]([N:39]=[C:40]=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:40]([NH:39][C@H:32]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH3:31])=[O:41])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1)c1ccccc1
Reaction time: 18 h

Procedure:
A solution of 40 mg (0.11 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 29.8 μl (0.21 mmol) of triethylamine and 31.5 mg (0.21 mmol) of (S)-(−)-α-methylbenzyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of methanol and 1 N hydrochloric acid (2:1), again concentrated and dried under high vacuum. 315 mg (62.7% of theory) of the title compound are obtained.