Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4].[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:27](=[O:29])[CH3:28])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH3:26])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(O)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccc(OC(C)=O)cc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
3-Butyryl-4-(4-hydroxy-2-methylphenylamino)-8-methoxyquinoline (1.75 g, 5 mmol) was dissolved in a mixture of acetic anhydride (10 ml) and pyridine (10 ml), stirred for 18 hours at room temperature, then the solvent evaporated, the product dissolved in dichloromethane and washed with aqueous sodium bicarbonate. Dryinq, evaporation, and recrystallisation from ethyl acetate/petroleum ether gave 3-butyryl-4-(4-acetoxy-2-methylphenylamino)-8-methoxyquinoline (1.55 g, 79%), m.p. 167°-169°.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[N:7][C:8]=1[CH3:9].I.[O-]S([O-])=O.[Na+].[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[N:7][C:8]=1[CH3:9]
Reactant: COc1ccc(C(=O)O)nc1C
Agent: I
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1nc(C(=O)O)ccc1O

Procedure:
A mixture of 5-methoxy-6-methyl-pyridine-2-carboxylic acid (53 mg, 0.32 mmol) and hydrogen iodide (2.06 mL of 57% w/v, 9.20 mmol) was heated at reflux for 4 hours. The reaction was cooled to room temperature before water (3 mL) was added. Na2SO3 was added to decolorize the reaction. The aqueous layer was decanted and the pH was adjusted to 3-4 using 2 M HCl. The product was extracted using ethyl acetate (7×5 mL). The organic layer was dried over sodium sulfate, filtered and the solvent was evaporated under reduced pressure to yield 5-hydroxy-6-methylpicolinic acid. ESI-MS m/z calc. 153.0, found 154.1 (M+1)+; Retention time: 0.21 minutes (3 min run).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]([CH2:9][C@H:10]([CH2:14][NH:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:11](=[O:13])[CH3:12])[CH3:8])=[O:6])[CH:2]=[CH2:3].C(N1CCCCC1)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@H:46]1[NH:49][C:48](=[O:50])[C@@H:47]1[C@H:51]([O:53][Si:54]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:56])[CH3:55])[CH3:52])(=O)C.Cl>ClCCl.O.C(OCC)(=O)C.[Br-].[Zn+2].[Br-]>[CH2:1]([O:4][C:5]([N:7]([CH2:9][C@H:10]([CH2:14][NH:15][C:16]([O:18][CH2:19][CH:20]=[CH2:21])=[O:17])[C:11](=[O:13])[CH2:12][C@H:46]1[NH:49][C:48](=[O:50])[C@@H:47]1[C@H:51]([O:53][Si:54]([C:57]([CH3:58])([CH3:60])[CH3:59])([CH3:56])[CH3:55])[CH3:52])[CH3:8])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)NC[C@@H](CN(C)C(=O)OCC=C)C(C)=O
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCN1CCCCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C=CCOC(=O)NC[C@@H](CN(C)C(=O)OCC=C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.5 %

Procedure:
To a solution of (2S)-1-(N-allyloxycarbonyl-N-methylamino)-2-(allyloxycarbonylaminomethyl)butan-3-one (14.59 g) in dichloromethane (110 ml) were added N-ethylpiperidine (13.5 ml) and trimethylsilyl trifluoromethanesulfonate (18.9 ml) at -10° C. and the resulting mixture was stirred at ambient temperature for 1 hour. To a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-2-azetidinone (21.1 g) in dichloromethane (140 ml) were added N-ethylpiperidine (10.1 ml) and trimethylsilyl trifluoromethanesulfonate (14.2 ml) at -20° C. and the mixture was stirred at 0° C. for 1 hour. To a mixture of the latter solution and zinc bromide (44.05 g) was added the former solution at 0° C. and the resulting mixture was allowed to stir at ambient temperature for 2 hours. The reaction mixture was diluted with a mixture of water (800 ml) and ethyl acetate (800 ml). After adjusting pH to 0.7 with hydrochloric acid (6N), the mixture was allowed to stir at ambient temperature for 2 hours. The separated organic layer was washed in turn with water and brine. After adjusting pH to 7 with aqueous sodium hydrogen carbonate, the organic layer was washed with brine, dried over magnesium sulfate. Evaporation of the solvent gave a residue which was chromatographed on silica gel (1.5 l) eluting with a mixture of n-hexane and ethyl acetate (9:1-2:8, V/V) to give (3S,4R)-4-[(3S)-4-(N-allyloxycarbonyl-N-methylamino)-3-(allyloxycarbonylaminomethyl)-2-oxobutyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (19.42 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[CH:18]1([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:37]=[CH:36][C:32]([C:33]([O-])=[O:34])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH2:20][CH2:19]1>>[CH:18]1([C:21]([NH:17][C:14]2[CH:15]=[CH:16][C:11]([N:7]3[C:8]4[C:4](=[CH:3][C:2]([NH:1][C:33](=[O:34])[C:32]5[CH:36]=[CH:37][C:29]([N:26]6[CH2:27][CH2:28][N:23]([C:21]([CH:18]7[CH2:19][CH2:20]7)=[O:22])[CH2:24][CH2:25]6)=[CH:30][CH:31]=5)=[CH:10][CH:9]=4)[CH:5]=[N:6]3)=[CH:12][CH:13]=2)=[O:22])[CH2:20][CH2:19]1
Reactant: O=C([O-])c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Product: O=C(Nc1ccc2c(cnn2-c2ccc(NC(=O)C3CC3)cc2)c1)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1

Procedure:
Compound 488 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-(4-cyclopropanecarbonylpiperazino)benzoate. [M+H]+ calcd for C32H32N6O3: 549.25; found: 549.16.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:30][NH:31][O:32][CH3:33]>C1COCC1.CCOC(C)=O>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[N:31]([O:32][CH3:33])[CH3:30])[CH2:12][CH2:13]1)=[O:2])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
N-BOC-piperidine-4-carboxylic acid (3.00 g, 13.08 mmol) was dissolved in THF and CDI (4.00 g, 24.7 mmol) was added in portions. The mixture was stirred for 2 h and N,O-dimethylhydroxylamine hydrochloride (4.00 g, 41 mmol) was added and stirring continued for 12 hours. The mixture was diluted with EtOAc and extracted 3 times with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified Biotage® to provide the title compound. 1H NMR (CD2Cl2) δ 4.12 (d,2H), 3.71 (s, 3H), 3.15 (s, 3H), 2.83 (m, 1H), 2.76 (t, 2H), 1.70 (dd, 2H), 1.59 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH3:26])#[CH:18]>>[CH3:26][O:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:17]#[C:18][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Reactant: C#Cc1ccccc1OC
Product: COc1ccccc1C#Cc1ccnc2[nH]c(=O)c3ccccc3c12
Yield: 72 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 160 using Compound 83 (100 mg, 0.43 mmol) and 1-ethynyl-2-methoxy-benzene (86 mg, 0.65 mmol) to provide 164 (101 mg, 71% yield) as a white solid. LC-MS (M+H=327, obsd.=327).
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([OH:15])[C:5]1=[O:16])[CH:2]=[CH2:3].[CH3:17][N:18]([CH3:22])[CH2:19][CH2:20]Cl.Cl>C(OCC)(=O)C>[CH2:1]([N:4]1[CH2:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:6]([O:15][CH2:20][CH2:19][N:18]([CH3:22])[CH3:17])[C:5]1=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCN1CC(c2ccccc2)=C(O)C1=O
Reactant: CN(C)CCCl
Agent: Cl
Solvent: CCOC(C)=O
Product: C=CCN1CC(c2ccccc2)=C(OCCN(C)C)C1=O

Procedure:
In a manner analogous to that described in Example 1, 30.6 g. 1-allyl-3-hydroxy-4-phenyl-3-pyrrolin-2-one are reacted with 23.0 g. β-dimethylaminoethyl chloride. The base obtained is reacted with gaseous hydrogen chloride in ethyl acetate. There is obtained 15.0 g. (45.5% of theory) 1-allyl-3-(β-dimethylaminoethoxy)-4-phenyl-3-pyrrolin-2-one hydrochloride: m.p. 115°-117° C., after recrystallization from methyl ethyl ketone.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](Br)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](/B(O)O)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH2:1]([O:8][C:9]1[C:10]([NH:16][C:17]2[S:18][CH:19]=[C:20]([CH3:22])[N:21]=2)=[N:11][CH:12]=[C:13](/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: OB(O)/C=C/c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1csc(Nc2ncc(/C=C/c3ccccc3)cc2OCc2ccccc2)n1
Temperature: 80 °C
Yield: 98.6 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.300 g, 0.797 mmol), (E)-styrylboronic acid (0.142 g, 0.957 mmol), Pd(PPh3)4 (0.0461 g, 0.0399 mmol), and sodium carbonate (0.254 g, 2.39 mmol) were added to DME (10 mL) and water (5 mL) and heated at 80° C. for 18 hours. An additional 0.5 eq of (E)-styrylboronic acid, Pd(PPh3)4, and 2M sodium carbonate were added and the reaction was heated at 80° C. for an additional 6 hrs. The reaction mixture was cooled and partitioned between water and dichloromethane. The layers were separated, dried, filtered, and concentrated to provide the title compound (0.314 g, 98.6% yield). 1H NMR (CDCl3) δ 8.03 (d, 1H), 7.63 (d, 2H), 7.49 (m, 2H), 7.39 (m, 5H), 7.32 (m, 2H), 6.98 (s, 2H), 6.39 (s, 1H), 5.42 (s, 2H), 2.46 (s, 3H). Mass spectrum (apci) m/z=400.0 (M+H).
Reaction SMILES: C1OC2C(C3C4OCOC=4C=CC=3P(C3C=CC=CC=3)C3C=CC=CC=3)=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2O1.O(C(C)(C)C)[Na].C1(C)C=CC=CC=1.[O:58]=[C:59]1[CH2:66][C:63]([CH3:65])([CH3:64])[CH2:62][C:61]([CH3:67])=[CH:60]1>[Cu].CC(O)(C)C>[CH3:64][C:63]1([CH3:65])[CH2:62][CH:61]([CH3:67])[CH2:60][C:59](=[O:58])[CH2:66]1
Reactant: CC1=CC(=O)CC(C)(C)C1
Agent: [Cu]
Agent: CC(C)(C)O[Na]
Agent: c1ccc(P(c2ccccc2)c2ccc3c(c2-c2c(P(c4ccccc4)c4ccccc4)ccc4c2OCO4)OCO3)cc1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: CC1CC(=O)CC(C)(C)C1
Temperature: 50 °C
Reaction time: 17 h
Yield: 18 %

Procedure:
Into a 100-mL stainless-steel autoclave was put 22.6 mmol (0.03 mmol; Cu reduced) of the chiral copper complex [CuBr((S)-SEGPHOS)]n obtained in the same manner as described in Example 1, 18.3 mg (0.03 mmol) of (S)-SEGPHOS and 28.8 mg (0.30 mmol) of NaO-t-Bu, followed by replacing with nitrogen in the autoclave, and then 2 mL of a mixed solvent of toluene and t-BuOH in a ratio of 3:1, and isophorone 1 (0.15 mL, 1 mmol) were added. The reaction was carried out with stirring under a hydrogen pressure of 5.0 MPa at 50° C. for 17 hours. The reaction mixture was analyzed by using GC. The results indicated that the products shown in the scheme A, that is, 3,3,5-trimethylcyclohexanone 2 was obtained in a yield of 18% (optical purity 93% ee), 3,3,5-trimethylcyclohexanol 3 was obtained in a yield of 61% (dr: 93/7, optical purity of main diastereomer: 95% ee), and 3,3,5-trimethyl-2-cyclohexenol 4 was obtained in a trace amount, respectively.
Reaction SMILES: CC(C)([O-])C.[K+].CCOCC.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][C:21]2=[O:24])=[CH:16][CH:15]=1.[N:25](OCCC(C)C)=[O:26]>C(O)C.C(O)(C)(C)C>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[N:25][OH:26])[C:21]2=[O:24])=[CH:16][CH:15]=1
Reactant: CC(C)CCON=O
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc2c(c1)C(=O)C(=NO)CC2
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of potassium tert-butoxide (11.5 gm, 0.1 m), ether (400 ml), tert-butanol (15 ml) and absolute ethanol (15 ml) was refluxed for 1/2 hour to insure complete solution of the potassium tert-butoxide. To the hot solution was added 7-methoxy-1-tetralone (17.6 gms, 0.1 m) and the reaction mixture turned from yellow to dark brown. To this refluxing solution was added isopentyl nitrite (19 ml). During this addition external heating was not necessary because of the exothermic nature of the reaction. The reaction mixture was refluxed for 1/2 hour during which time the walls of the flask became coated with a brown solid. After cooling in an ice-bath, the solvent was removed by decantation. To the solid was added aqueous hydrogen chloride (1 N, 200 ml). After stirring 1/2 hour, the brown solid was filtered to yield 10 gms (50%) of product.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]CBr)([CH3:11])([CH3:10])[CH3:9].[CH3:24][C:25]1[C:34]([CH3:35])=[CH:33][C:28]2[N:29]=[C:30]([SH:32])[NH:31][C:27]=2[CH:26]=1.O>CN(C)C=O>[C:8]([O:12][C:13](=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][S:32][C:30]1[NH:31][C:27]2[CH:26]=[C:25]([CH3:24])[C:34]([CH3:35])=[CH:33][C:28]=2[N:29]=1)([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)c1ccccc1CCBr
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1cc2nc(SCc3ccccc3C(=O)OC(C)(C)C)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.2 %

Procedure:
Triethylamine (276 μl, 1.98 mmol) and 2-(bromoethyl)benzoic acid t-butyl ester (538 mg, 1.99 mmol) were added to 5,6-dimethylbenzimidazole-2-thiol (236 mg, 1.32 mmol) in 2 ml of dimethylformamide, which was then stirred at 80° C. for 3 hours. After the reaction was complete, water was added, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous sodium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 2-((5,6-dimethylbenzimidazole-2-ylthio)methyl)benzoic acid t-butyl ester (288 mg, yield 59%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Reactant: BrCCCCC1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [CH:1]1([C:5]2[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=2)[CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])[CH2:4][CH2:3][CH2:2]1.[ClH:17].[CH3:18][C:19](=[CH2:21])[CH3:20].OS(O)(=O)=O.Cl>O1CCOCC1>[CH:1]1([C:5]2[CH:6]=[C:7]([CH:14]=[CH:15][CH:16]=2)[CH2:8][C@@H:9]([C:11]([O:13][C:19]([CH3:21])([CH3:20])[CH3:18])=[O:12])[NH2:10])[CH2:2][CH2:3][CH2:4]1.[ClH:17]
Reactant: C=C(C)C
Reactant: N[C@@H](Cc1cccc(C2CCC2)c1)C(=O)O
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1cccc(C2CCC2)c1
Yield: 81 %

Procedure:
According to example 54, 0.65 g of 3-cyclobutyl-L-phenylalanine·HCl was treated with 25 mL of isobutylene in 25 mL of 1,4-dioxane in the presence of 0.5 mL of conc. H2SO4. Work-up in the usual manner followed by acidification of the free amine with ethereal HCl afforded 0.64 g (81%) of tert-butyl 3-cyclobutyl-L-phenylalaninate·HCl as a white powder, m.p. 173-174° C.
Reaction SMILES: [CH:1]([C:4]1([CH3:20])[C:8](=[O:9])[NH:7][C:6]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[N:5]1)([CH3:3])[CH3:2].CN(C)CCN(C)C.C([Li])CCC.CN([CH:37]=[O:38])C>CCOCC.CCCCCC.O.C(O)C.C(O)(=O)C>[CH:1]([C:4]1([CH3:20])[C:8](=[O:9])[NH:7][C:6]([C:10]2[C:19]([CH:37]=[O:38])=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)C1(C)N=C(c2ccc3ccccc3n2)NC1=O
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CC(C)C1(C)N=C(c2nc3ccccc3cc2C=O)NC1=O
Temperature: -63 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To a mixture of 4-isopropyl-4-methyl-2-(2-quinolyl)-2-imidazolin-5-one (3 g, 0.0112 mol) in ether (150 ml) is added tetramethylethylenediamine (3.4 g, 0.00225 mol). n-Butyllithium (17 ml, 0.027 mol) in hexane is added dropwise to the reaction mixture cooled to -63° C. An intense red color is generated and after the addition the mixture was maintained at -10° to -20° C. for 21/2 hours. Dry DMF (5 ml) was added at -10° C. and the mixture is allowed to attain room temperature, while stirring overnight. The mixture is diluted with water (75 ml) and is neutralized with acetic acid. A pale yellow solid 2.57 g (78%) is obtained with mp 226°-227° C. after crystallization* from 95% ethanol. Anal. calcd. for C17H17N3O2 : C, 69.13; H, 5.80; N, 14.23. Found: C, 68.98; H, 5.88; N, 14.25. The oxime of this aldehyde, prepared in the usual way, has mp 255°-257° C.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:41][C@H:42]3[CH2:46][CH2:45][C:44](=[O:47])[CH2:43]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([O:26][CH2:27][C:28]([O:31]CC4C=CC(OC)=CC=4)([CH3:30])[CH3:29])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.ClCCl>O>[CH:1]1([C:4]2[CH:5]=[C:6]([C@@H:16]([CH2:41][C@H:42]3[CH2:46][CH2:45][C:44](=[O:47])[CH2:43]3)[C:17]([NH:19][C:20]3[CH:25]=[N:24][C:23]([O:26][CH2:27][C:28]([OH:31])([CH3:29])[CH3:30])=[CH:22][N:21]=3)=[O:18])[CH:7]=[CH:8][C:9]=2[S:10]([CH:13]2[CH2:15][CH2:14]2)(=[O:12])=[O:11])[CH2:3][CH2:2]1
Reactant: COc1ccc(COC(C)(C)COc2cnc(NC(=O)[C@H](C[C@H]3CCC(=O)C3)c3ccc(S(=O)(=O)C4CC4)c(C4CC4)c3)cn2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Product: CC(C)(O)COc1cnc(NC(=O)[C@H](C[C@H]2CCC(=O)C2)c2ccc(S(=O)(=O)C3CC3)c(C3CC3)c2)cn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a solution of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-3-[(1R)-3-oxocyclopentyl]propanoic acid (99 mg) in dichloromethane (2.0 mL) were added oxalyl chloride (27 μL) and DMF (3 μL) under ice-cooling, followed by stirring for 10 minutes. Thereafter, pyridine (28 μL) and 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-amide (53 mg) were added thereto under ice-cooling, followed by stirring for 20 minutes. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1-1:1) to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide (82 mg) as a white amorphous substance. A mixture of (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-(5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazin-2-yl)-3-[(1R)-3-oxocyclopentyl]propanamide (82 mg), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (56 mg), dichloromethane (7.5 mL), and water (0.38 mL) was stirred at room temperature for 10 minutes. To the reaction mixture was added water, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=80:20). The obtained residue was sonicated with diethyl ether and the resulting precipitate was collected by filtration to obtain (2R)-2-[3-cyclopropyl-4-(cyclopropylsulfonyl)phenyl]-N-[5-(2-hydroxy-2-methylpropoxy)pyrazin-2-yl]-3-[(1R)-3-oxocyclopentyl]propanamide (52 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10](C=C)[N:9]2[C:16](=[O:21])[CH2:17][CH2:18][CH:19]=[CH2:20])=[CH:4][CH:3]=1>C(Cl)Cl.CC1C=C(C)C(N2[CH-]N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1.C1C=CC(C=[Ru](Cl)Cl)=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[N:9]3[C:16](=[O:21])[CH2:17][CH2:18][CH:19]=[CH:20][C@@H:10]3[CH2:11][CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)N1[C@H](C=C)CCC[C@@H]1c1ccc(F)cc1
Agent: Cl[Ru](Cl)=Cc1ccccc1
Agent: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Agent: Cc1cc(C)c(N2[CH-]N(c3c(C)cc(C)cc3C)CC2)c(C)c1
Solvent: ClCCl
Product: O=C1CCC=C[C@@H]2CCC[C@H](c3ccc(F)cc3)N12
Temperature: 25 °C
Yield: 52.7 %

Procedure:
A solution of 1-[(2R*,6S*)-2-(4-fluorophenyl)-6-vinylpiperidin-1-yl]-4-penten-1-one (307 mg) and tricyclohexylphosphine[1,3-bis(2,4,6-trimethylphenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium (IV) dichloride (64 mg) in methylene chloride (150 mL) was heated under reflux for 25 hours. The reaction solution was left to cool to room temperature and then concentrated. The residue was purified by silica gel column chromatography (elution solvent: heptane:ethyl acetate=4:1->ethyl acetate) to obtain 146 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:59])([CH3:58])[CH3:57])[C:4]2[C@@H:5]([N:27]([CH2:39][CH2:40][C:41]([C:43]3[C:48]([F:49])=[CH:47][CH:46]=[C:45]([Cl:50])[C:44]=3[F:51])=O)[C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH2:6][CH2:7][CH2:8][C@@H:9]([CH3:26])[C:10](=[O:25])[NH:11][C:12]3[C:17]([C:18]=1[N:19]=2)=[CH:16][CH:15]=[C:14]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH:13]=3.C[O-].[Na+]>CO>[Br:1][C:2]1[N:3]([CH2:52][O:53][CH2:54][CH2:55][Si:56]([CH3:58])([CH3:57])[CH3:59])[C:4]2[C@@H:5]([N:27]3[C:28](=[O:38])[CH:29]=[C:41]([C:43]4[C:48]([F:49])=[CH:47][CH:46]=[C:45]([Cl:50])[C:44]=4[F:51])[CH2:40][CH2:39]3)[CH2:6][CH2:7][CH2:8][C@@H:9]([CH3:26])[C:10](=[O:25])[NH:11][C:12]3[C:17]([C:18]=1[N:19]=2)=[CH:16][CH:15]=[C:14]([NH:20][C:21](=[O:24])[O:22][CH3:23])[CH:13]=3
Reactant: CCOP(=O)(CC(=O)N(CCC(=O)c1c(F)ccc(Cl)c1F)[C@H]1CCC[C@@H](C)C(=O)Nc2cc(NC(=O)OC)ccc2-c2nc1n(COCC[Si](C)(C)C)c2Br)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)Nc1ccc2c(c1)NC(=O)[C@H](C)CCC[C@H](N1CCC(c3c(F)ccc(Cl)c3F)=CC1=O)c1nc-2c(Br)n1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.9 %

Procedure:
To the solution of 227B (1.35 g, 1.27 mmol) in MeOH (36.3 ml) at 0° C. was added sodium methoxide (25% wt in MeOH) (1.454 ml, 6.36 mmol). The reaction was warmed to RT. After 1 h, the reaction mixture was concentrated. The residue dissolved in EtOAc, washed twice with 1.5 dipotassium phosphate solution (aq.), brine, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by normal phase column chromatography to give 227C (765 mg, 76%) as a tan solid. MS (ESI) m/z: 792/794 (M+H)+, bromine isotope.