Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.O(C(C)(C)C)[Na].Br[CH2:28][CH2:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[ClH:37]>COCCOC>[ClH:37].[O:30]([CH2:29][CH2:28][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCOc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2O)CC1
Agent: CC(C)(C)O[Na]
Agent: Cl
Solvent: COCCOC
Product: c1ccc(OCCOc2ccccc2N2CCNCC2)cc1
Temperature: 55 °C
Reaction time: 0.08 h

Procedure:
The product from Step 1 above (0.55 g, 2.0 mmol) was added to a stirred solution of NaO-t-Bu (0.55 g, 2.0 mmol) in DME (5 mL). After 5 min, β-bromophenetole (0.56 g, 2.8 mmol) was added, and the reaction was stirred at 55° C. for 15 h. 2 M HCl was added, and the reaction mixture was stirred for another 3 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between 2 M NaOH/CHCl3. The aqueous phase was extracted with CHCl3 (×3). The combined organic layers were dried (MgSO4), concentrated, and the residue was purified by chromatography on silica gel using CHCl3/MeOH/NH4OH (90:10:0.4) as eluent to give the free base of the title compound. The free base was treated with HCl/ether, and the resulting hydrochloride salt was dried (80° C., 1 mmHg) to afford 0.254 g (35%) of the title compound as a light brown semi-solid material that solidified upon standing. Anal. (C18H22N2O2.HCl. H2O) H, N; C: calc, 61.27; found, 61.9.
Reaction SMILES: [O:1]=[O+][O-].[OH:4][CH:5]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:16]([CH3:27])[C:15]1=[O:28])/[CH:6]=C/C1C=CC=CC=1>CO.ClCCl>[OH:4][CH:5]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH:16]([CH3:27])[C:15]1=[O:28])[CH:6]=[O:1]
Reactant: CC1C(=O)C(C(O)/C=C/c2ccccc2)CCN1C(=O)OC(C)(C)C
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CC1C(=O)C(C(O)C=O)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ozone gas was bubbled into a solution of 0.450 g (1.30 mmol) of tert-butyl 4-[(2E)-1-hydroxyl-3-phenylprop-2-enyl]-2-methyl-3-oxopiperidine-1-carboxylate (Step D) in 10 mL of methanol and 10 mL of dichloromethane at −78° C. until the solution turned blue. The reaction was quenched with dimethyl sulfide, warmed to ambient temperature, and stirred for 1 h. The mixture was concentrated in vacuo and purified by flash chromatography on a Biotage® system (silica gel, eluting with 20% ethyl acetate/hexane to 60% ethyl acetate/hexane), affording the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[S:10][C:11]([NH:41]C(=O)OC(C)(C)C)=[C:12]([C:14](=[O:40])[NH:15][C:16]2[CH:17]=[N:18][N:19]([CH3:39])[C:20]=2[N:21]2[CH2:27][CH2:26][CH:25]([O:28]CC3C=CC(OC)=CC=3)[CH:24]([OH:38])[CH2:23][CH2:22]2)[N:13]=1.[H][H].C(O)(C(F)(F)F)=O>CO.C(Cl)Cl.[Pd]>[NH2:41][C:11]1[S:10][C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[F:8])=[N:13][C:12]=1[C:14]([NH:15][C:16]1[CH:17]=[N:18][N:19]([CH3:39])[C:20]=1[N:21]1[CH2:22][CH2:23][C@@H:24]([OH:38])[C@H:25]([OH:28])[CH2:26][CH2:27]1)=[O:40]
Reactant: COc1ccc(COC2CCN(c3c(NC(=O)c4nc(-c5c(F)cccc5F)sc4NC(=O)OC(C)(C)C)cnn3C)CCC2O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1ncc(NC(=O)c2nc(-c3c(F)cccc3F)sc2N)c1N1CC[C@@H](O)[C@H](O)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a solution of tert-butyl N-(2-(2,6-difluorophenyl)-4-((5-(4-hydroxy-5-((4-methoxyphenyl)methoxy)azepan-1-yl)-1-methyl-pyrazol-4-yl)carbamoyl)thiazol-5-yl)carbamate (0.50 g, 0.73 mmol) in MeOH (25 mL) was added 10% Pd/C (0.20 g). The mixture was stirred under a 50 psi atmosphere of hydrogen at room temperature for 18 hr. The reaction mixture was filtered through Celite® and the filtrate concentrated under reduced pressure to give a colourless solid. The crude solid was dissolved in DCM (10 mL) and TFA (10 mL) was added. The reaction mixture was stirred at room temperature for 18 hr, concentrated under reduced pressure and the crude residue was dissolved in a 1/1 mixture of MeOH/2 M aqueous NaOH (40 mL) and heated at 50° C. for 18 hr. The reaction mixture was concentrated under reduced pressure, diluted with water (30 mL) and extracted with DCM (50 mL) and EtOAc (2×50 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via preparative HPLC gave 490 as a pale yellow solid (86 mg, 25% over two steps). 1H NMR (400 MHz, d6-DMSO) δ 8.72-8.63 (m, 1H), 7.61-7.45 (m, 4H), 7.31-7.23 (m, 2H), 4.57 (s, 2H), 3.63 (s, 3H), 3.52 (d, J=6.5 Hz, 2H), 3.20-3.05 (m, 4H), 1.94-1.86 (m, 2H), 1.74-1.64 (m, 2H). LCMS (ES+) m/z 465 (M+1)
Reaction SMILES: O1CCOCC1.O.C([O:14][C@@H:15]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][CH2:18][NH:17][CH2:16]1)(=O)C(C)(C)C.O.[OH-].[Li+]>C(OCC)(=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C@@H:15]([OH:14])[CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)O[C@H]1CNCC=C1c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: O[C@H]1CNCC=C1c1ccc(F)cc1
Yield: 74 %

Procedure:
To a 1,4-dioxane (4.5 mL)-water (2.5 mL) solution of the crude product of (R)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-yl pivalate synthesized in Reference Synthesis Example 132, lithium hydroxide monohydrate (229 mg, 5.45 mmol) was added and the resultant mixture was stirred at 115° C. for 3 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=49/1→7/3) to obtain the title compound (640 mg, two step yield 74%).
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:17]2[C:21]([OH:23])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[N+:38]([C:41]1[CH:48]=[CH:47][C:44]([CH2:45]Br)=[CH:43][CH:42]=1)([O-:40])=[O:39].Cl>CN(C)C=O>[O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:19](=[O:20])[N:18]2[CH:13]1[S:14][CH2:15][N:16]([S:24]([C:27]([F:28])([F:29])[F:30])(=[O:25])=[O:26])[CH:17]2[C:21]([O:23][CH2:45][C:44]1[CH:47]=[CH:48][C:41]([N+:38]([O-:40])=[O:39])=[CH:42][CH:43]=1)=[O:22])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)O
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)NC1C(=O)N2C1SCN(S(=O)(=O)C(F)(F)F)C2C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 46.6 %

Procedure:
To a solution of 7 -phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylic acid (547 mg.) in N,N-dimethylformamide (4 ml.) were added triethylamine (160 μl) and 4-nitrobenzyl bromide (276 mg.) at 0° C., and the mixture was stirred at room temperature for 18.5 hours. The reaction mixture was poured into a chilled dilute hydrochloric acid and then extracted with ethyl acetate (50 ml.). The extract was washed with water (×3), a dilute aqueous solution of sodium bicarbonate (×2), water and an aqueous solution of sodium chloride, successively. Drying over magnesium sulfate and removal of the solvent gave a residue (610 mg.), which was chromatographed on silica gel (9.5 g.) with a mixed solvent of benzene and ethyl acetate (10:1 to 5:1 by volume) to give an amorphous solid (328 mg.) of 4-nitrobenzyl 7-phenoxyacetamido-8-oxo-3-trifluoromethanesulfonyl-5-thia-1,3-diazabicyclo[4,2,0]octane-2-carboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][N:14]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:13]1=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH:35]1[CH:36]=[CH:37]C2N(O)N=[N:41][C:39]=2[CH:40]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[CH3:21][C@H:17]([N:14]1[CH2:15][CH2:16][C@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:13]1=[O:22])[C:18](=[O:20])[N:41]1[CH2:37][CH2:36][CH2:35][CH2:40][CH2:39]1
Reactant: On1nnc2ccccc21
Reactant: C[C@@H](C(=O)O)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1CCNCC1
Product: C[C@@H](C(=O)N1CCCCC1)N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.8 %

Procedure:
To a solution of (2S)-2-((3S)-3-{[(benzyloxy)carbonyl]amino}-2-oxopyrrolidin-1-yl)propanoic acid (3.1 g) in DCM (30 ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.6 g), HOBT (3.2 g) and triethylamine (2.5 ml) and the mixture was stirred at room temperature for 5 min. Piperidine (2.9 ml) was added and the resultant mixture stirred at room temperature for 72 h. The mixture was washed with potassium carbonate (2M), dried (over magnesium sulphate) and concentrated under reduced pressure. The residue was purified using Biotage™ chromatography (silica, eluting with cyclohexane:ethyl acetate 3:1 and then ethyl acetate) to give the title compound (2.6 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:11]([N:12]2[C:16]([C:17]([OH:19])=O)=[CH:15][N:14]=[CH:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:20])[O:3]1.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>ClCCl>[CH2:33]([NH:40][C:17]([C:16]1[N:12]([CH:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4](=[O:20])[O:3][C:2]2([CH3:21])[CH3:1])[CH:13]=[N:14][CH:15]=1)=[O:19])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)O
Reactant: NCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccccc2C1n1cncc1C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
3-(3,3-Dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid (0.100 g, 0.349 mmol) (Example 23) is dissolved in dichloromethane (2 mL). Catalytic amount of dimethylformamide (0.002 mL, 0.0262 mmol) is added to the reaction mixture and cooled to 0° C. Oxalyl chloride (0.076 mL, 0.874 mmol) is added and the cooling bath is removed. The mixture is stirred at room temperature for 2 h and then concentrated in vacuo. The residue obtained is redissolved in dichloromethane and benzylamine (0.114 mL, 1.04 mmol) is added. Reaction mixture is stirred at room temperature for 1 h. The mixture is washed with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The combined organic phase is dried over Na2SO4 and concentrated in vacuo. The residue is purified by silica gel chromatography (dichlormethane-methanol, 19:1) to give 3-(3,3-dimethyl-1-oxo-isochroman-4-yl)-3H-imidazole-4-carboxylic acid benzylamide; MS (ESI) m/z 376.0 (M+H); 1H NMR (400 MHz, MeOD) δ ppm 1.24 (s, 3 H), 1.53 (s, 3 H), 4.62 (s, 2 H), 6.98 (s, 1 H), 7.26-7.35 (m, 1 H), 7.35-7.46 (m, 5 H), 7.57 (d, J=7.6 Hz, 1 H), 7.64-7.73 (m, 2 H), 7.74-7.84 (m, 1 H), 8.26 (dd, J=7.8, 1.5 Hz, 1 H).
Reaction SMILES: N1C=CC=C[CH:2]=1.Cl.[CH2:8]([C:11]1[N:15]2[CH2:16][CH2:17][CH2:18][N:19]=[C:14]2[S:13][C:12]=1[C:20]([Cl:22])=[O:21])[CH2:9][CH3:10].[CH2:23]([NH2:41])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]C.CNC1C=NC=C(NC)C=1>CN(C)C=O>[ClH:22].[CH2:32]([CH:31]([CH3:2])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]/[CH:24]=[CH:23]\[NH:41][C:20]([C:12]1[S:13][C:14]2=[N:19][CH2:18][CH2:17][CH2:16][N:15]2[C:11]=1[CH2:8][CH2:9][CH3:10])=[O:21])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: c1ccncc1
Reactant: CCCCCCCC/C=C\CCCCCCCCN
Reactant: CCCC1=C(C(=O)Cl)SC2=NCCCN21
Agent: CNc1cncc(NC)c1
Agent: Cl
Solvent: CN(C)C=O
Product: CCCCCCCCC(C)CCCCCC/C=C\NC(=O)C1=C(CCC)N2CCCN=C2S1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
In the mixture of 30 ml of pyridine and 3 ml of dimethylformamide was suspended 849 mg of 3-propyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonylchloride hydrochloride (described in Example 13). To the suspension were added 807 mg of oleyl amine and 36 mg of 3,5-dimethylaminopyridine, followed by stirring at 70° C. for 20 hours. The reaction mixture was concentrated and to the concentrate was added saturated sodium hydrogencarbonate aqueous solution. The mixture was extracted with chloroform. The extract was washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and treated with active carbon. The solvent was removed under reduced pressure. The residue was dissolved in ethanol and to the solution was added saturated hydrogenchloride diethylether solution, followed by stirring at room temperature. After removing the solvent, the residue was purified by silica gel column chromatography (silica gel: 150 g) using a mixed solvent of chloroform and methanol (20:1 by volume). The purified substance was added to saturated hydrogenchloride diethylether solution, followed by stirring at room temperature. The solvent was removed under reduced pressure. The residue was crystallized from hexane-diethylether to obtain 203 mg of the titled compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[N:3]=1.CC(C)([O-:15])C.[K+].Cl>C(O)(C)(C)C>[F:9][C:8]([F:11])([F:10])[C:4]1[N:3]=[C:2]([OH:15])[CH:7]=[CH:6][CH:5]=1
Reactant: FC(F)(F)c1cccc(Cl)n1
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Product: Oc1cccc(C(F)(F)F)n1
Yield: 62.2 %

Procedure:
2-Chloro-6-trifluoromethylpyridine (5.0 g, 27.6 mmol) was dissolved in tert-butyl alcohol (135 mL). Potassium tert-butoxide (25.0 g, 220 mmol) was added and the mixture was refluxed under nitrogen for 20 h. After cooling, cold 3N HCl was carefully added to the flask until the pH was approximately 1-2. The resulting solution was extracted several times with methylene chloride. The organic layers were dried (MgSO4) and evaporated. This residue was then treated with trifluoroacetic acid 1.5 mL) at 80° C. for 2 h. The solution was neutralized with aqueous sodium bicarbonate and extracted several times with methylene chloride. The organic layer was dried (MgSO4), filtered and evaporated in-vacuo. The residue was recrystallized from methylene chloride and hexane to give 6-trifluoromethyl-2-pyridinol (2.8 g, 62% yield) as a white solid, mp=117° C. -118 ° C. Anal. Calcd. for C6H4NOF3 : C, 44.19; H, 2.47; N, 8.59
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=[O:5].[H-].[Na+].[CH:18]([Si:21](Cl)([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])([CH3:20])[CH3:19]>CN(C=O)C>[CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[C:14]2[C:9](=[N:10][CH:11]=[CH:12][CH:13]=2)[N:8]([Si:21]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:18]([CH3:20])[CH3:19])[CH:7]=1)=[O:5]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: CON(C)C(=O)c1c[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Reaction time: 0.08 h
Yield: 92 %

Procedure:
A solution of N-Methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-3-carboxamide (300 mg, 1.46 mmol) in DMF (5 mL) was cooled to in an ice bath and sodium hydride (73 mg of 60% dispersion, 1.83 mmol) added in one portion. The mixture was stirred for 5 minutes then triisopropylsilyl chloride (353 mg, 1.83 mmol) added dropwise. The reaction was then stirred for 14 hrs during which time the temperature reached rt. The reaction was then quenched by pouring into a mixture of ice and 25% ammonium chloride solution (50 mL). The resulting mixture was then extracted with EtOAc (2×20 mL) and the combined extracts washed with water (10 mL) and brine (10 mL) then dried over magnesium sulfate. Subsequent filtration and concentration afforded a yellow oil. This crude oil was considered sufficiently pure to carry forward directly. Yield=92%
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[O:22]1[CH:26]=[CH:25][CH:24]=[C:23]1[C:27](Cl)=[O:28].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:27]([C:23]2[O:22][CH:26]=[CH:25][CH:24]=2)=[O:28])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccco1
Yield: 81.3 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), 2-furancarbonyl chloride (1.05 g) and pyridine (626 mg) were added thereto, the mixture was refluxed for 2 hours. Water (100 ml) was added to the reaction mixture, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collected by filtration, to thereby obtain 2.15 g of the titled compound (Yield: 77,4%).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.BrC1C=C(C#N)[CH:31]=[N:32]C=1>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([C:31]#[N:32])[CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Reactant: N#Cc1cncc(Br)c1
Product: Cc1ccc(Nc2cncc(C#N)c2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) in accordance with the general method of example 20 using 5-Bromo-3-cyanopyridine instead of 3-Bromo-4-methylpyridine to yield the final compound as an off-white solid, MS (ISP): m/e=405.4 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:6][CH:5]=[N:4][C:3]=1[C:7]([OH:9])=O.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN1CCCC1=O>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:3]5[N:4]=[CH:5][S:6][C:2]=5[CH3:1])=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1scnc1C(=O)O
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1scnc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 47.3 %

Procedure:
Using 5-methyl-1,3-thiazole-4-carboxylic acid (143 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (107 mg, yield 47%) was obtained.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][C:15]1[N:16]=[C:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[O:18][C:19]=1[CH3:20])C=O)[CH:2]=[CH2:3].[Cl-].C([O:35][C:36]([CH:38]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[O:39][CH2:40][CH3:41])=[O:37])C1C=CC=CC=1.[Cl-].[CH2:62](OC(C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)OC)=O)C1C=CC=CC=1>>[CH2:40]([O:39][CH:38]([CH2:62][C:6]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:18][C:19]=2[CH3:20])=[C:4]([CH2:1][CH2:2][CH3:3])[CH:5]=1)[C:36]([OH:35])=[O:37])[CH3:41]
Reactant: COC(C(=O)OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(C(=O)OCc1ccccc1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCc1cc(C=O)ccc1OCCc1nc(-c2ccccc2)oc1C
Agent: [Cl-]
Product: CCCc1cc(CC(OCC)C(=O)O)ccc1OCCc1nc(-c2ccccc2)oc1C

Procedure:
In analogy to the procedures described in examples 114 b], c] and d], 3-allyl-4-hydroxy-benzaldehyde was reacted with methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester [PCT Int. Appl. (2000) WO0008002] to give 3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde. Treatment of 3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-benzaldehyde with (benzyloxycarbonyl-ethoxy-methyl)-triphenyl-phosphonium chloride (prepared in analogy to the procedure described for the synthesis of (benzyloxycarbonyl-methoxy-methyl)-triphenyl-phosphonium chloride in example 114 a]) then gave 3-{3-allyl-4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-phenyl}-2(Z,E)-ethoxy-acrylic acid benzyl ester, which was hydrogenated to yield [rac]-2-ethoxy-3-{4-[2-(5-methyl-2-phenyl-oxazol-4-yl)-ethoxy]-3-propyl-phenyl}-propionic acid as colorless solid.
Reaction SMILES: Br.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][C:9]([CH3:13])=[CH:10][CH:11]=2)[C:6](=[O:14])[N:5]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[C:4]1=[O:21].[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[C:26](Cl)=[N:25][N:24]=1.[I-].[K+]>>[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH3:36])=[C:30]([O:33][CH3:34])[CH:31]=2)[C:26]([N:18]2[CH2:19][CH2:20][CH:15]([N:5]3[C:6](=[O:14])[C:7]4[C:12](=[CH:11][CH:10]=[C:9]([CH3:13])[CH:8]=4)[N:3]([CH3:2])[C:4]3=[O:21])[CH2:16][CH2:17]2)=[N:25][N:24]=1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCNCC1)c(=O)n2C
Reactant: COc1cc2c(Cl)nnc(Cl)c2cc1OC
Agent: Br
Agent: [I-]
Agent: [K+]
Product: COc1cc2c(Cl)nnc(N3CCC(n4c(=O)c5cc(C)ccc5n(C)c4=O)CC3)c2cc1OC
Yield: 49 %

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 354.0 mg (1.0 mmol) of 1,2,3,4-tetrahydro-1,6-dimethyl-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide (Compound v) obtained in Example 41 was used, 1,4-dichloro-6,7-dimethoxyphthalazine was used in place of 4-chloro-6,7-dimethoxyquinazoline, and a catalytic amount of potassium iodide was added. As a result, 243.7 mg (yield: 49%) of Compound 76 was obtained as white crystals.
Reaction SMILES: [CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:28]=[CH:27][C:26]([N:29]5[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]5)=[CH:25][CH:24]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:51]=[CH:50][C:48]([CH3:49])=[CH:47][CH:46]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([N:9]1[CH:13]=[C:12]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([C:23]4[CH:24]=[CH:25][C:26]([N:29]5[CH2:30][CH2:31][NH:32][CH2:33][CH2:34]5)=[CH:27][CH:28]=4)[CH:21]=3)[N:16]([S:42]([C:45]3[CH:46]=[CH:47][C:48]([CH3:49])=[CH:50][CH:51]=3)(=[O:44])=[O:43])[CH:15]=2)[CH:11]=[N:10]1)[CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(CCc4ccccc4)c3)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Yield: 102.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl 4-(4-(3-(1-phenethyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (200 mg, 0.284 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 175 mg (86.2% yield) of the titled compound. MS: m/z=603.2 (M+1).