Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15]S(C3C=CC(C)=CC=3)(=O)=O)=[C:11]([C:26]3[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:36][CH:37]([CH3:42])[CH2:38][CH2:39][CH2:40]O.N>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([O:15][CH2:40][CH2:39][CH2:38][CH:37]([CH3:42])[CH3:36])=[C:11]([C:26]3[CH:27]=[CH:28][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:30][CH:31]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(-c3ccc(S(C)(=O)=O)cc3)cnn(-c3ccc(F)cc3)c2=O)cc1
Reactant: CC(C)CCCO
Agent: N
Product: CC(C)CCCOc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(-c2ccc(F)cc2)c1=O

Procedure:
The title compound was prepared according to the method of Example 335, starting with 2-(4-fluorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone in place of 2-(3-chlorophenyl)-4-tosyloxy-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone and substituting 4-methyl-1-pentanol in place of isobutanol (yield: 0.128 g, 85%). mp 123–125° C. 1H NMR (300 MHz, DMSO d6) δ 0.74 (d, J=6 Hz, 6H), 1.03 (m, 2H), 1.39 (m, 1H), 1.54 (m, 2H), 3.28 (s, 3H), 4.39 (t, J=6 Hz, 2H), 7.37 (m, 2H), 7.66 (m, 2H), 7.91 (m, 2H), 8.07 (m, 2H), 8.18 (s, 1H). MS (DCI/NH3) m/z 445 (M+H)+. Anal. calc. for C23H25FN2O4S: C, 62.14; H, 5.67; N, 6.30. Found: C, 62.28; H, 5.59; N, 6.25.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[C:11](=[S:13])=[S:12].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[C:3]([C:5](=[C:11]([S:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[S:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)CC#N
Reactant: S=C=S
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)=C(SCc1ccccc1)SCc1ccccc1
Temperature: 10 °C
Reaction time: 0.17 h
Yield: 82 %

Procedure:
Under nitrogen atmosphere, sodium hydride (60%, 6.77 g) was added to dimethylformamide (75 mL). Thereto was added dropwise a solution of ethyl cyanoacetate (9.57 g) in dimethylformamide (15 mL) under cooling (internal temperature: ca. 10° C.) over a period of 15 minutes, and the mixture was stirred at room temperature for 10 minutes. Thereto was added dropwise a solution of carbon disulfide (5.09 mL) in dimethylformamide (12 mL) under cooling (internal temperature ≦10° C.) over a period of 20 minutes. The mixture was stirred at room temperature overnight, and thereto was added dropwise a solution of benzyl bromide (20.1 mL) in dimethylformamide (23 mL) under cooling (internal temperature ≦25° C.). The mixture was stirred at 70° C. for 7 hours and at room temperature overnight. The reaction mixture was poured in ice-water, and the mixture was stirred. The precipitates were collected by filtration and recrystallized from hot ethanol. The resultant crystals were washed with cold ethanol to give ethyl 2-cyano-3,3-bis(benzylthio)acrylate (25.63 g, yield: 82%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([CH3:27])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21](O)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH:29]1[CH2:33][C:32](=[O:34])[NH:31][CH2:30]1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C>ClCCl.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([CH3:27])[O:16][N:15]=[C:14]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([N:29]4[CH2:33][C:32](=[O:34])[NH:31][CH2:30]4)=[O:22])=[C:19]([CH3:26])[CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: O=C1CNCN1
Reactant: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(C(F)(F)F)c3)C2)ccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc(C2=NOC(C)(c3cc(Cl)cc(C(F)(F)F)c3)C2)ccc1C(=O)N1CNC(=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of 4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-2-methylbenzoic acid (100 mg, 0.25 mmol, 1.00 equiv) in dichloromethane (5 mL), imidazolidin-4-one hydrochloride (27.05 mg, 0.22 mmol, 1.00 equiv), HOBt (32.92 mg, 0.24 mmol, 1.10 equiv), triethylamine (33.59 mg, 0.33 mmol, 2.10 equiv), EDCI (63.85 mg, 0.33 mmol, 1.50 equiv). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 20 mL of water. The resulting solution was extracted with 3×10 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1). This resulted in 80 mg (68%) of 1-[(4-[5-[3-chloro-5-(trifluoromethyl)phenyl]-5-methyl-4,5-dihydro-1,2-oxazol-3-yl]-2-methylphenyl)carbonyl]imidazolidin-4-one as a white solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH2:2][CH2:3][CH3:4].[CH2:7]([C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:27])/[CH:21]=[CH:22]/[CH2:23][CH2:24][CH2:25][CH3:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:28]N1C(=O)CCC1=O>C1COCC1.CSC>[CH2:7]([C@@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:27])[C@H:21]([Br:28])[CH:22]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:23][CH2:24][CH2:25][CH3:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCCC/C=C/C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reactant: CCCC[Mg]Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCC(CCCC)[C@@H](Br)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -15 °C
Reaction time: 0.33 h

Procedure:
A slurry of copper bromide(I) dimethyl sulfide complex (5.132 g, 24.967 mmol) in THF (60 mL) and dimethyl sulfide (30 mL) as a co-solvent was cooled to −40° C. and n-butyl magnesium chloride (25 mL, 49.93 mmol) was added dropwise for 10 min and stirred for 20 min while warming to −15° C. The black slurry was cooled to −40° C. and (4R)-4-benzyl-3-[(E)-2-heptenoyl]-1,3-oxazolidin-2-one (6 g, 20.80 mmol) was added dropwise over 10 min as a solution in THF (20 mL) at −40° C. The reaction was let warm up to 25° C. overnight (20 h). N-Bromosuccinimide (7.407 g, 41.61 mmol) was added portionwise to a cold −78° C. solution of the black slurry. It was allowed to warm to 0° C. and was stirred for an additional 3 h. The reaction was quenched with a 1:1 solution of saturated ammonium carbonate and 0.5 N potassium bisulfate. The black slurry became greenish to blue. A precipitate formed (light blue). It was filtered. The mother liquor was diluted with ethyl acetate (150 mL) and the organic was dried over MgSO4, filtered, concentrated to obtain (4R)-4-benzyl-3-[(2R)-2-bromo-3-butylheptanoyl]-1,3-oxazolidin-2-one as a crude semi-solid (green) (8.49 g, 96.15%). Mass Spectrum (−ESI): 423 (M−H)−.
Reaction SMILES: [NH2:1][C@H:2]([C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1)[C:3]([N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[C:23]4[C:28](=[CH:29][CH:30]=3)[CH:27]=[C:26]([C:31]3[NH:35][C:34]([C@@H:36]5[CH2:40][CH2:39][CH2:38][N:37]5[C:41](=[O:51])[C@@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[CH:43]([CH3:45])[CH3:44])=[N:33][CH:32]=3)[CH:25]=[CH:24]4)=[CH:17][CH:16]=2)=[CH:13][N:14]=1)=[O:4].[O:58]1[CH2:62][CH2:61][CH2:60][C@H:59]1[C:63](O)=[O:64].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:45][CH:43]([CH3:44])[C@H:42]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:41](=[O:51])[N:37]1[CH2:38][CH2:39][CH2:40][C@H:36]1[C:34]1[NH:35][C:31]([C:26]2[CH:25]=[CH:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([C:18]4[CH:17]=[CH:16][C:15]([C:12]5[NH:11][C:10]([C@@H:6]6[CH2:7][CH2:8][CH2:9][N:5]6[C:3](=[O:4])[C@@H:2]([C:52]6[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=6)[NH:1][C:63]([C@H:59]6[CH2:60][CH2:61][CH2:62][O:58]6)=[O:64])=[N:14][CH:13]=5)=[CH:20][CH:19]=4)[CH:22]=3)[CH:27]=2)=[CH:32][N:33]=1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](N)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Reactant: O=C(O)[C@@H]1CCCO1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)[C@H]6CCCO6)c6ccccc6)[nH]5)cc4)ccc3c2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 13.8 %

Procedure:
To a 0° C. solution of methyl (S)-1-((S)-2-(5-(6-(4-(2-((S)-1-((R)-2-amino-2-phenylacetyl) pyrrolidin-2-yl)-1H-imidazol-5-yl)phenyl)naphthalen-2-yl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (70 mg, 0.08 mmol) in DMF (1 mL) was added (S)-tetrahydrofuran-2-carboxylic acid (10 mg, 0.09 mmol), PyBOP (52 mg, 0.10 mmol), HOBT (14 mg, 0.10 mmol), and N-methylmorpholine (40 mg, 0.4 mmol) successively. The solution was warmed to rt and allowed to stir for 2 h. The mixture was diluted with EtOAc, washed with 1N HCl, sat. NaHCO3, and brine, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (9.5 mg). LCMS-ESI+: calc'd for C50H54N8O6: 863.01 (M+); Found: 863.31 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([OH:20])=O)=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[C:22]([S:41][CH2:42][CH2:43][NH2:44])([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([NH:44][CH2:43][CH2:42][S:41][C:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:20])=[CH:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)c1cc2cccc(OCc3ccccc3)c2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1)c1cc2cccc(OCc3ccccc3)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a mixture of 7-(benzyloxy)-1H-indole-2-carboxylic acid (0.80 g), 2-(tritylthio)ethylamine hydrochloride (1.07 g), 1H-1,2,3-benzotriazol-1-ol (0.49 g), triethylamine (0.50 mL) and N,N-dimethylformamide (15 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.69 g) at 0° C., and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography and the title compound (1.60 g, yield 94%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (2:3, volume ratio). melting point 156-157° C.
Reaction SMILES: [Na].[CH:2](=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH:11](Cl)[C:12]([O:14][CH3:15])=[O:13].[NH2:17][C:18]([NH2:20])=O>CO.CCOCC.C(OCC)(=O)C>[NH2:20][C:18]1[O:9][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:11]([C:12]([O:14][CH3:15])=[O:13])[N:17]=1
Reactant: NC(N)=O
Reactant: O=Cc1ccccc1
Reactant: COC(=O)C(Cl)Cl
Agent: [Na]
Solvent: CCOCC
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(N)oc1-c1ccccc1
Reaction time: 1.5 h
Yield: 19.2 %

Procedure:
A solution of 3 g (0.13 gram atom) of sodium in 50 ml of methanol were added dropwise at 0°-5° within 20 minutes to a solution, cooled to 0°, of 16.1 g (152 mmol) of benzaldehyde and 20.0 g (140 mmol) of methyl dichloroacetate in 50 ml of ether. Thereafter, the reaction mixture was stirred at 0°-5° for a further 1.5 hours, then diluted with 100 ml of ethyl acetate and extracted with saturated sodium chloride solution. The organic phase was dried over magnesium sulfate and evaporated. The residue was dissolved in 50 mo of methanol and heated to reflux for 14 hours with 6.72 g (112 mmol) of urea. The reaction mixture was evaporated under reduced pressure, partitioned between methylene chloride and water, adjusted to pH 9 with conc. sodium hydroxide solution and extracted. The alkaline, aqueous phases were further extracted with methylene chloride. The organic phases were combined and washed twice with saturated sodium chloride solution, dried and evaporated. The residue was purified by medium pressure chromatography on 1 kg of silica gel. Elution with methylene chloride as well as methylene chloride/methanol 9:1 yield 8.4 g of an oil which crystallized from a mixture of methylene chloride, ether and hexane. In this manner there were obtained 4.7 g (35%) of methyl 2-amino-5-phenyl-4-oxazolecarboxylate as light yellowish crystals which were processed without further purification.
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6]/[C:7](=[CH:9]/[CH2:10][OH:11])/[CH3:8])[CH3:3].[OH:12][CH2:13]/[CH:14]=[C:15](/[CH3:22])\[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20].[C:23]1(=O)[O:28][C:26](=[O:27])[CH2:25][CH2:24]1>O>[C:23]([O:12][CH2:13]/[CH:14]=[C:15](/[CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])\[CH3:22])(=[O:28])[CH2:24][CH2:25][C:26]([O:11][CH2:10]/[CH:9]=[C:7](/[CH2:6][CH2:5][CH:4]=[C:2]([CH3:1])[CH3:3])\[CH3:8])=[O:27]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: CC(C)=CCC/C(C)=C\CO
Reactant: O=C1CCC(=O)O1
Solvent: O
Product: CC(C)=CCC/C(C)=C/COC(=O)CCC(=O)OC/C=C(\C)CCC=C(C)C
Temperature: 25 °C

Procedure:
Synthesis (c): A mixture of geraniol and nerol (approximately 70:30 by weight) in the amount of 94.86 g (0.615 mol) and succinic anhydride in theamount of 20.51 g (0.205 mol) are combined at room temperature. The mixtureis heated to 140° C. for 6 h while water is removed using an argon sparge. After cooling to room temperature, the mixture is placed in a Kugelrohr oven and concentrated at 80°-85 ° C. for 5.5 h. Purity of the product is determined by thin layer chromatography and the structure confirmed by 13C and 1H NMR.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C@H:9]([OH:10])[CH2:8][CH2:7][CH2:6]1)=[O:3].N1C=CC=CC=1.[Cl:17][C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[Cl:17][C:18]([O:10][C@@H:9]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:4][C:2](=[O:3])[CH3:1])=[O:20]
Reactant: CC(=O)O[C@@H]1CCC[C@H]1O
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)O[C@@H]1CCC[C@H]1OC(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of (1R,2R)-trans-2-acetoxy-1-cyclopentanol (1.0 g, 6.9 mmol) in dichloromethane (25 mL) at 0° C. under nitrogen atmosphere was added pyridine (0.88 mL, 10.4 mmol) followed by a solution of triphosgene (1.03 g, 3.5 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at 0° C. for 30 min. to provide the corresponding 2(R)-acetoxycyclopent-1(R)-yl chloroformate which was carried to next step without further purification.
Reaction SMILES: C[Si](Cl)(C)C.[C:6]([C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)#N.O.C(=O)([O-])[O-:18].[Na+].[Na+].[CH2:23]([OH:25])[CH3:24]>>[CH2:23]([O:25][C:6]([C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[CH:10][N:9]=1)=[O:18])[CH3:24]
Reactant: N#Cc1cc(CO)ccn1
Reactant: CCO
Reactant: O=C([O-])[O-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc(CO)ccn1
Yield: 16 %

Procedure:
Trimethylsilyl chloride (0.4 mL, 3.0 mmol) was added to a solution of 2-cyanopyridine-4-methanol (200 mg, 1.5 mmol, Reference compound No. 11-1) in ethanol (3 mL) at 50° C. under a nitrogen atmosphere, then the mixture was stirred for 12 hours. The mixture was allowed to stand, and a little water and sodium carbonate (160 mg, 1.5 mmol) were added thereto. The solution was dried over anhydrous magnesium sulfate, then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 43 mg of the title reference compound as a white solid. (Yield 16%)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Cl[CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:17]([N:18]([CH2:21][CH3:22])[CH2:19][CH2:20][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:16]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCN(CC)CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 140 °C
Reaction time: 1.5 h
Yield: 13.6 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (500 mg, 2.5 mmol) in DMF (10 mL) was added (2-chloroethyl)diethylamine (Compound 175B, 0.6 g, 4 mmol) and K2CO3 (1.38 g, 10 mmol). The reaction mixture was stirred at 140° C. for 1.5 h in a microwave reactor, then concentrated, residue was purified by HPLC to afford 100 mg of the title compound (yield: 12%). 1H NMR (DMSO-d6, 400 MHz): δ=1.1-1.2 (m, 9H), 1.25 (s, 12H), 2.72 (s, 0.5H), 2.75 (s, 1H), 3.00-3.10 (s, 4H), 3.1-3.2 (m, 2H), 3.44 (s, 3H), 4.58-4.59 (br, 3H), 7.74 (s, 1H), 7.82 (s, 0.5H), 8.05 (s, 0.5H), 8.09 (s, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][NH:27]5)[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C([O:42][CH2:43][C:44](Cl)=[O:45])(=O)C.[OH-].[Na+]>C(Cl)Cl.CO>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([N:13]3[C:22](=[O:23])[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][N:27]5[C:43](=[O:42])[CH2:44][OH:45])[CH:20]=4)[N:15]=[CH:14]3)[CH:7]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3)cc2c1=O
Reactant: CC(=O)OCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2ccc(OC[C@@H]3CCCN3C(=O)CO)cc2c1=O
Reaction time: 1 h

Procedure:
N-Cyclopropyl-4-methyl-3-[4-oxo-6-[(2S)-pyrrolidin-2-ylmethoxy]quinazolin-3(4H)-yl]benzamide (0.20 g), triethylamine (0.133 ml), and acetoxyacetyl chloride (0.077 ml) were stirred in methylene chloride (2 ml) under argon at room temperature for 30 minutes. A solution of 2N NaOH (2 ml) and methanol (2 ml) was added to the reaction mixture and stirring continued for 1 hour at room temperature. The reaction mixture was diluted with methylene chloride and washed with brine, dried (magnesium sulfate) and concentrated. Purification by column chromatography on a silica column eluting with 5% methanol/ethyl acetate to give the title compound (0.113 g) as a white foam solid; NMR Spectrum: (DMSOd6) 0.56 (m, 2H), 0.70 (m, 2H), 1.83-2.10 (m, 4H), 2.14 (s, 3H), 2.86 (m, 1H), 3.40 (m, 2H), 4.05 (m, 3H), 4.25 (m, 1H), 4.32 (m, 1H), 4.52 (t, 1H), 7.53 (m, 2H), 7.60 (s, 1H), 7.74 (d, 1H), 7.84 (s, 1H), 7.91 (d, 1M, 8.19 (s, 1H), 8.43 (d, 1H); Mass Spectrum: M+H+ 477.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[NH2:11][CH:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.C(OCC)C>[Cl:8][C:7]1[C:2]([NH:11][C@H:12]2[CH2:13][CH2:14][C@@H:15]([C:18]([OH:24])([CH3:23])[C:19]([F:21])([F:22])[F:20])[CH2:16][CH2:17]2)=[N:3][CH:4]=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: CCc1ncnc(Cl)c1Cl
Reactant: CC(O)(C1CCC(N)CC1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(O)C(F)(F)F)CC2)c1Cl
Yield: 39.5 %

Procedure:
1.3 g (7.2 mmol) of 4,5-dichloro-6-ethylpyrimidine, 2.7 g (7.2 mmol) of 1-amino-4(2-hydroxy-1,1,1-trifluoro-2-propyl)cyclohexane and 1.5 g (17.1 mmol) of potassium carbonate were stirred in 10 ml of dimethylformamide at from 80° to 90° C. for 6 hours. The solvent was stripped off and the residue was taken up in water/diethyl ether, and the organic phase was washed with water, dried and concentrated. For purification it was chromatographed on silica gel (ethyl acetate). 1.0 g of product was obtained as colorless crystals. m.p.: 119to 121° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6](=[CH:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:7](=[O:9])[CH3:8].[CH2:15]=[CH:16][CH:17]=[CH:18]C.[C:20]1(C)C=CC=CC=1>>[C:7]([C:6]1([CH3:5])[CH2:14][CH2:13][CH2:12][C:11]([CH2:15][CH2:16][CH2:17][CH3:18])=[C:10]1[CH3:20])(=[O:9])[CH3:8]
Reactant: CCCCC=C(C)C(C)=O
Reactant: C=CC=CC
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC1=C(C)C(C)(C(C)=O)CCC1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
Into a 1-liter flask equipped with stirrer, thermometer, and reflux condenser is added a mixture of 150 ml anhydrous toluene and 13.4 grams of aluminum chloride. While maintaining the reaction temperature at 10° C. over a period of 10 minutes, 128 grams (0.91 moles) of 3-methyl-oct-3-ene-2-one is added to the reaction mass. Over a period of 1 hour, 250 grams (1.47 moles) of a 40% solution of piperylene in toluene is added to the reaction mass while maintaining the reaction mass at 10° C. The reaction mass is stirred at a temperature of about 10° C. for a period of 2 hours. The reaction mass is then distilled on a spinning band column yielding the following fractions:
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6]N=1)[CH3:3].C1(CC[CH:18]([OH:20])C)C=CC=CC=1.C1C2C3[NH+]([O-:30])C(C2)CC1C3>>[CH3:18][O:20][C:4]1[CH:9]=[CH:8][C:7]([CH2:6][OH:30])=[CH:3][CH:2]=1
Reactant: CC(O)CCc1ccccc1
Reactant: CC(O)c1ccccn1
Reactant: [O-][NH+]1C2CC3CC(C2)C1C3
Product: COc1ccc(CO)cc1

Procedure:
2-(1-Hydroxyethyl)pyridine (76.8 mg, 0.624 mmol) was oxidized in the same manner as that described in Example 8, (a) (except that Nor-AZADO was used at 3 mol %, and the reaction was performed at room temperature) to obtain the objective compound (66.0 mg; yield, 87.4%). The spectrum data were found to be the same as those obtained in Example 6, (h).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[S:10]1[C:14]2=[N:15][C:16]3[C:22](=[O:23])[O:21][C:19](=[O:20])[C:17]=3[CH:18]=[C:13]2[CH:12]=[CH:11]1.N#N>C1COCC1>[C:3]([C:2]([NH:1][C:22]([C:16]1[N:15]=[C:14]2[S:10][CH:11]=[CH:12][C:13]2=[CH:18][C:17]=1[C:19]([OH:21])=[O:20])=[O:23])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: O=C1OC(=O)c2nc3sccc3cc21
Reactant: CC(C)C(C)(N)C(N)=O
Agent: N#N
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2sccc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
2-Amino-2,3-dimethylbutyramide (9.84 g, 0.076 mol) is added to a stirred suspension of thieno-[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (14.8 g, 0.072 mol) in THF under an inert atmosphere of N2 at room temperature. The dark solution is stirred at room temperature overnight and the resulting solid filtered off, washed with THF and air dried to give 17.35 g (72%) of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]thieno[2,3-b]pyridine-5-carboxylic acid.