Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:30][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C@H:11]([C:13]3[N:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:17](=[O:25])[C:16]4=[C:26]([CH3:29])[CH:27]=[CH:28][N:15]4[N:14]=3)[CH3:12])[C:4]=2[CH:3]=1.[C:31](=O)([O-])[O-].[K+].[K+].CB1OB(C)OB(C)O1.[Cl-].[NH4+]>CN(C)C=O.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>[CH3:29][C:26]1[CH:27]=[CH:28][N:15]2[C:16]=1[C:17](=[O:25])[N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]([C@@H:11]([NH:10][C:9]1[C:4]3[CH:3]=[C:2]([CH3:31])[S:30][C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:12])=[N:14]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4sc(Br)cc34)n(-c3ccccc3)c(=O)c12
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: Cc1cc2c(N[C@@H](C)c3nn4ccc(C)c4c(=O)n3-c3ccccc3)ncnc2s1
Temperature: 130 °C
Reaction time: 2 h

Procedure:
(S)-2-(1-((6-Bromothieno[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mmol) was dissolved in 3 mL dimethylformamide. Potassium carbonate (287 mg, 2.08 mmol), tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.01 mmol) and trimethylboroxine (130 μl, 0.93 mmol) were added under argon conditions. The reaction mixture was stirred at 130° C. for 2 h. The crude was poured into 25 mL saturated ammonium chloride solution and extracted twice with ethyl acetate. The organics were dried over magnesium sulphate, filtered and evaporated under reduced pressure. The residue was purified using SP1® Purification System by reverse phase to obtain 26 mg (60% yield) of a yellow solid as a title compound. Purity 100%.
Reaction SMILES: [CH3:1][C:2]1([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][C:4](=C)[CH2:3]1.O.CC1C=CC=C(C)N=1.C(OI(C1C=CC=CC=1)OC(=O)C)(=[O:29])C>C1COCC1.O=[Os](=O)(=O)=O>[CH3:1][C:2]1([NH:7][C:8](=[O:17])[O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][C:4](=[O:29])[CH2:3]1
Reactant: CC(=O)OI(OC(C)=O)c1ccccc1
Reactant: C=C1CC(C)(NC(=O)OCc2ccccc2)C1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Solvent: O
Product: CC1(NC(=O)OCc2ccccc2)CC(=O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
Crude benzyl (1-methyl-3-methylidenecyclobutyl)carbamate (20.6 mmol) was dissolved in THF (10 mL), then water (0.100 mL), 2,6-dimethylpyridine (0.400 mL, 3.4 mmol), OsO4 (2.5% wt in 2-methyl-2-propanol, 0.340 mL, 0.027 mmol), and PhI(OAc)2 (1.0 g, 3.07 mmol) were added and the reaction mixture was stirred at rt for 3 hrs. The reaction was quenched with sat. sodium thiosulfate (20 mL) and extracted with EtOAc (two×30 mL). The combined organics were washed with sat. aqueous copper sulfate (three×50 mL), dried over MgSO4 and concentrated. The residue was purified via flash chromatography (eluting with 10%-20% EtOAc/heptanes) to give the title compound (558 mg, 12% yield) as a colorless oil. 1H NMR (400 MHz, chloroform-d) δ ppm 7.31-7.47 (m, 5H) 5.12 (s, 3H) 3.36-3.64 (m, 2H) 2.96-3.12 (m, 2H) 1.63 (s, 3H)); m/z (APCI+) for C13H15NO3 234.20 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH2:12][CH2:11][CH2:10][CH:9]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC.[Pt]=O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: Brc1cnccc1C1=CCCC1
Agent: O=[Pt]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Brc1cnccc1C1CCCC1
Reaction time: 8 h
Yield: 69.7 %

Procedure:
Platinum oxide (20 mg) was added to a mixture of 3-bromo-4-cyclopent-1-enyl-pyridine (I-34b: 140 mg, 0.622 mmol) in toluene (5 mL) and stirred overnight under hydrogen atmosphere. The reaction was monitored by TLC (20% ethyl acetate in hexane). The reaction mixture was filtered through celite pad and washed with toluene and concentrated to afford crude product. Purification by column chromatography (8% ethyl acetate in hexane) afforded 98 mg of the product (71% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][O:9][CH2:10][CH:11]2[CH2:14][C:13]([F:16])([F:15])[CH2:12]2)[CH:5]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1)[NH2:27].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:15][C:13]1([F:16])[CH2:14][CH:11]([CH2:10][O:9][CH2:8][C:6]2[CH:5]=[C:4]([C:17]([O:19][CH2:20][CH3:21])=[CH2:18])[N:3]=[C:2]([NH:27][C:26]3[CH:28]=[CH:29][C:30]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)=[C:24]([O:23][CH3:22])[CH:25]=3)[N:7]=2)[CH2:12]1
Reactant: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Cl)n1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: C=C(OCC)c1cc(COCC2CC(F)(F)C2)nc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)n1
Temperature: 120 °C
Yield: 26.1 %

Procedure:
A mixture of 2-chloro-4-(((3,3-difluorocyclobutyl)methoxy)methyl)-6-(1-ethoxyvinyl)pyrimidine (0.048 g, 0.15 mmol), 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)aniline (0.031 g, 0.15 mmol), cesium carbonate (0.098 g, 0.30 mmol), palladium (II) acetate (5 mg, 0.02 mmol) and (2-biphenylyl)dicyclohexylphosphine (8 mg, 0.02 mmol) in dioxane (2 mL) was heated under argon at 120° C. for 90 minutes in micro wave reactor. The mixture was filtered through a short silica and was eluted with EtOAc. The residue was purified by preparative HPLC to give the title compound (0.019 g, 26.0%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([N:14]1[C:18](=[O:19])[CH:17]=[C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])[NH:15]1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:12]([N:14]1[C:18]([O:19][C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[CH:17][C:16]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[C:23]#[N:24])=[N:15]1)[CH3:13]
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: CCn1[nH]c(-c2cccc(C#N)c2)cc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 160 °C
Reaction time: 16 h
Yield: 43.8 %

Procedure:
1-fluoro-4-(trifluoromethyl)benzene (22.9 mL, 180 mmol, 6.00 equiv) was added to a mixture of 3-(1-ethyl-5-oxo-2,5-dihydro-1H-pyrazol-3-yl)benzonitrile (6.40 g, 30.0 mmol, 1 equiv) and potassium carbonate (12.4 g, 90.0 mmol, 3.00 equiv) in dimethyl sulfoxide (60 mL) in a high pressure reaction vessel. The vessel was sealed, and the reaction mixture was heated to 160° C. After stirring for 16 hours, the high pressure vessel was cooled to 22° C. and the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 50% ethyl acetate-hexanes) to afford 3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}benzonitrile (4.70 g, 44%) as a white solid. Calcd (M+1)+: 357.1. Found: 358.0.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([NH2:23])[N:17]=3)[CH2:11]2)=[N:3][CH:2]=1.S(=O)(=O)(O)O.[N:30]([O-])=O.[Na+].C([O-])(O)=O.[Na+]>O>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([N:10]2[CH2:14][CH2:13][C@@H:12]([N:15]([CH3:24])[C:16]3[N:17]=[C:18]4[NH:23][N:30]=[N:22][C:19]4=[CH:20][CH:21]=3)[CH2:11]2)=[N:3][CH:2]=1
Reactant: O=N[O-]
Reactant: CN(c1ccc(N)c(N)n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CN(c1ccc2nn[nH]c2n1)[C@@H]1CCN(c2ncnc3[nH]ccc23)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of (R)—N2-(1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrrolidin-3-yl)-N2-methylpyridine-2,5,6-triamine (50 mg, 0.15 mmol,) in water (0.6 mL) was added concentrated sulfuric acid (23 uL). The mixture was stirred at room temperature for 1 h. It was cooled to 0° C. and aqueous sodium nitrite (17 mg, 0.25 mmol, in 0.1 mL of water) was added. The reaction mixture was stirred at 0° C. for 1 h. It was then neutralized till pH equal to 5 with aqueous NaHCO3 (10%) and extracted with EtOAc (3×10 mL). The combined extracts were washed with brine (2×10 mL), concentrated, and the residue was purified by chromatography to give the title compound. MS (m/z): 336 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[N:15]=[N:16][C:17]([Cl:19])=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23]>C(Cl)Cl>[F:20][C:21]([F:26])([F:25])[C:22]([OH:24])=[O:23].[Cl:19][C:17]1[N:16]=[N:15][C:12]2[CH2:13][CH2:14][NH:8][CH2:9][CH2:10][C:11]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)nnc2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1cc2c(nn1)CCNCC2

Procedure:
0.15 g (0.53 mmol) 3-chloro-5,6,8,9-tetrahydro-1,2,7-triaza-benzocycloheptene-7-carboxylic acid tert-butyl ester (CAS: 1251001-53-2), 0.4 mL trifluoroacetic acid and 2 mL DCM were stirred at RT for 4 hours. The reaction was concentrated to dryness. Yield: 0.16 g (quantitativ). ESI-MS: m/z=184/186 (M+H)+; Rt(HPLC): 0.41 min (Method K).
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:13]2[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[N+]=[N-].[Cl:21][C:22]1[CH:23]=[C:24]([CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39])[C:25](ON1C(=O)CCC1=O)=[O:26]>[Pd].CO.C1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([NH:1][CH2:4][C:5]2[C:13]3[N:12]=[CH:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:9]=3[CH:8]=[CH:7][CH:6]=2)=[O:26])[CH:35]=[CH:36][C:37]=1[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)(C)OC(=O)n1cnc2c(CN=[N+]=[N-])cccc21
Reactant: COC(=O)c1ccc(C(=O)ON2C(=O)CCC2=O)cc1Cl
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)NCc2cccc3c2ncn3C(=O)OC(C)(C)C)cc1Cl
Reaction time: 1.75 h
Yield: 66.3 %

Procedure:
A mixture of 4-(azidomethyl)benzimidazole-1-carboxylic acid, 1,1-dimethylethyl ester (Example 13; 1.40, 5.1 mmol), 1-[[3-chloro-4-(methoxycarbonyl)benzoyl]oxy]-2,5-pyrrolidinedione (Example 5; 1.62 g, 5.2 mmol), and 10% palladium on charcoal (210 mg) in methanol (40 mL) and benzene (2 mL) was hydrogenated at atmospheric pressure for 105 min and then filtered through Celite. Tlc indicated that the reaction was not complete so more 10% palladium on charcoal (210 mg) was added and the mixture was hydrogenated at atmospheric pressure for 3 h and then shaken at 50 psi of hydrogen for 3 h. The reaction mixture was allowed to stand under hydrogen for 12 h, then filtered through Celite, evaporated, and chromatographed (20-100% ethyl acetate/hexanes) to give 2-chloro-4-[[[[1-[(1,1-dimethylethoxy)carbonyl]benzimidazol-4-yl]methyl]amino]carbonyl]benzoic acid, methyl ester (1.50 g, 66%). A solution of the ester (1.45 g, 3.3 mmol) in methanol (15 mL) and 3 M lithium hydroxide solution (5.5 mL) was stirred at room temperature overnight. A white solid was filtered off and discarded. The filtrate was evaporated to dryness. Water and 1 M HCl (16.6 mL) were added, and the mixture was filtered and washed with water to give 2-chloro-4-[[[(benzimidazol-4-yl)methyl]amino]carbonyl]-benzoic acid (925 mg, 86%).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([O:18]CC)=O)=[CH:13][C:14](=[O:15])[C:3]1=2.[NH3:21]>C(O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]2[O:11][C:12]([C:16]([NH2:21])=[O:18])=[CH:13][C:14](=[O:15])[C:3]1=2
Reactant: N
Reactant: CCOC(=O)c1cc(=O)c2c(o1)c1ccccc1n2C
Solvent: CCO
Product: Cn1c2ccccc2c2oc(C(N)=O)cc(=O)c21
Temperature: 25 °C

Procedure:
A suspension of 11.0 g (40.7 mmole) of ethyl 4,5-dihydro-5-methyl-4-oxopyrano[3,2-b]indole-2-carboxylate in 500 ml ethanol was stirred in ice while gaseous ammonia was added until the reaction mixture temperature reached 20° C. (ca. 10 min). The ice bath was removed, and stirring at room temperature was continued for a total of 24 hr. The light yellow solid was filtered and washed with a little cold ethanol. Recrystallization from 50% aqueous DMF gave light yellow needles of mp >295° C.
Reaction SMILES: S1C2C=CC=CC=2N=C1S[S:11][C@H:12]1[N:15]([CH:16]([C:33]([CH3:35])=[CH2:34])[C:17]([O:19][CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[C:14](=[O:36])[C@H:13]1[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.O.[C:49]1([CH3:58])[CH:54]=[CH:53][C:52]([S:55]([O-:57])=[O:56])=[CH:51][CH:50]=1.[Na+]>CC(C)=O.O.[N+]([O-])([O-])=O.[Ag+]>[C:49]1([CH3:58])[CH:54]=[CH:53][C:52]([S:55]([S:11][C@H:12]2[N:15]([CH:16]([C:33]([CH3:35])=[CH2:34])[C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)=[O:18])[C:14](=[O:36])[C@H:13]2[NH:37][C:38](=[O:47])[CH2:39][O:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)(=[O:57])=[O:56])=[CH:51][CH:50]=1
Reactant: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SSc1nc2ccccc2s1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)C(C(=O)OC(c1ccccc1)c1ccccc1)N1C(=O)[C@@H](NC(=O)COc2ccccc2)[C@H]1SS(=O)(=O)c1ccc(C)cc1
Yield: 74.1 %

Procedure:
To a solution of diphenylmethyl 2-[(3R,4R)-4-[(benzothiazol-2-yl)dithio]-3-phenoxyacetamido-2-oxo-azetidin-1-yl]-3-methyl-3-butenoate (XIIIa. 12.12 g, 0.0182 mole) in acetone (325 mL) and water (37 mL), silver nitrate (3.86 g, 0.0227 mole) was added all at once. A freshly prepared solution of sodium p-toluenesulfinate hydrate (4.05 g; 0.0227 mole) in acetone (255 mL) and water (37 mL) was added dropwise over 1 h, while the reaction mixture was protected from light. After an additional 1h period at room temperature, Celite (5 g) was added and the mixture was diluted with acetone (500 mL) and then was filtered. The filtrate was evaporated to a small volume, and the crude product was extracted into ether (3×250 mL). The ether phase was dried with magnesium sulfate and concentrated to afford a crude product. Flash chromatography (SiO2, eluting with 40% ethyl acetate in hexane) gave 9.05 g (73.5%) of the title compound as a white solid.
Reaction SMILES: C1COCC1.[C:6]1([C@H:16]([N:18]([CH2:26][C@@H:27]2[C@@H:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH2:30][NH:29][CH2:28]2)[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[CH:8][CH:7]=1.[CH:38]1[N:42]=[CH:41][N:40]([C:43](N2C=NC=C2)=[O:44])[CH:39]=1>C(N(CC)CC)C>[N:40]1([C:43]([N:29]2[CH2:30][C@H:31]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:27]([CH2:26][N:18]([C@@H:16]([C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=[CH:8][CH:7]=3)[CH3:17])[C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:24])[CH3:22])[CH2:28]2)=[O:44])[CH:39]=[CH:38][N:42]=[CH:41]1
Reactant: C[C@H](c1cccc2ccccc12)N(C[C@H]1CNC[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(C(=O)n2ccnc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 107.4 %

Procedure:
A 10 ml THF solution of 940 mg of tert-butyl [(1R)-1-(1-naphthyl)ethyl]{[(3R,4S)-4-phenylpyrrolidin-3-yl]methyl}carbamate was mixed with 0.3 ml of triethylamine and 3.54 g of CDI and stirred at room temperature for 2Hours. The reaction solution was concentrated under a reduced pressure and diluted with ethyl acetate. This was washed with 1 M hydrochloric acid and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. By evaporating the solvent under a reduced pressure, 1.23 g of tert-butyl {[(3R,4S)-1-(1H-imidazol-1-ylcarbonyl)-4-phenylpyrrolidin-3-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate was obtained as a pale yellow amorphous substance. EP: 525.
Reaction SMILES: [SH:1][CH:2]([CH2:5][SH:6])[CH2:3][OH:4].[C:7]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.B(F)(F)F.CCOCC>C(Cl)Cl>[SH:6][CH2:5][CH:2]1[CH2:3][O:4][C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[S:1]1
Reactant: COC(=O)CCC(=O)c1ccccc1
Reactant: OCC(S)CS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CCC1(c2ccccc2)OCC(CS)S1

Procedure:
The title compound was prepared according to the procedure of Example 1 using 2,3-dimercapto-1-propanol (2.3 g, 0.019 mol), methyl 3-benzoylpropionate from Example 67 (3.7 g, 0.019 mol) and boron trifluoride etherate (0.5 ml) in methylene chloride (50 ml). The crude product was chromatographed on silica gel using 1% acetone/toluene as eluent to give 1.0 g (31%) of product.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:26])[CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40].CN(C)CCNC>C1COCC1>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@H:15]([CH2:16][CH2:17][O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCOCc1ccccc1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: CNCCN(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@@H](CCOCc1ccccc1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 116.3 %

Procedure:
To a solution of (S)-4-benzyl-3-(4-(benzyloxy)butanoyl)oxazolidin-2-one (170 g, 482 mmol) in THF (1.0 L) at −78° C. was added LiHMDS (1.0 M in THF, 530 mL, 530 mmol) over 10 minutes via cannula. After stirring for 1 h at −78° C. tert-butyl bromoacetate (82.0 mL, 554 mmol) was added slowly over 45 min via syringe pump. The mixture was slowly allowed to warm to room temperature overnight. The reaction mixture was quenched with sat. ammonium chloride (300 mL) and stirred for 10 min, diluted further with H2O (500 mL), and extracted with MTBE (1.0 L). The organic layer was isolated, treated with N,N,N′-trimethylethylenediamine (5 mL) and shaken for 2 min in order to remove excess tert-butyl bromoacetate. The mixture was washed with 1 N HCl (2×750 mL), and brine (1.0 L). The organics were dried over MgSO4, filtered, and concentrated to give 262 g of crude (R)-tert-butyl 3-((S)-4-benzyl-2-oxooxazolidine-3-carbonyl)-5-(benzyloxy)pentanoate.
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][OH:13])=[CH:10][CH:9]=1.C1OCCOCCOCCOCCOCCOC1.Cl[C:35]1[N:36]=[N:37][CH:38]=[C:39]2[C:43]([CH3:44])=[C:42]([CH3:45])[N:41]([CH2:46][CH:47]=[CH2:48])[C:40]=12>O1CCCC1>[F:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][O:13][C:35]2[N:36]=[N:37][CH:38]=[C:39]3[C:43]([CH3:44])=[C:42]([CH3:45])[N:41]([CH:46]=[CH:47][CH3:48])[C:40]=23)=[CH:10][CH:9]=1
Reactant: OCc1ccc(F)cc1
Reactant: C=CCn1c(C)c(C)c2cnnc(Cl)c21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC=Cn1c(C)c(C)c2cnnc(OCc3ccc(F)cc3)c21
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 39.3 %

Procedure:
1.62 g (0.014 mole) of potassium tert-butoxide was added to a solution of 1.02 g (0.0081 mole) of 4-fluorobenzyl alcohol and 0.12 g (0.00045 mole) of 18-crown-6 in 10 ml of tetrahydrofuran and the resulting mixture was stirred at room temperature for 25 minutes. A solution of 0.60 g (0.0027 mole) of 7-chloro-1-(2-propenyl)-2,3-dimethylpyrrolo[2,3-d]pyridazine in 5 ml of tetrahydrofuran was added dropwise to the mixture and stirred at room temperature for 10 hours. After completion of the reaction, the reaction mixture was poured into ice-water and the aqueous mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel using a 2:3 mixture of ethyl acetate and hexane as an eluent to give 0.33 g of 7-(4-fluorobenzyloxy)-2,3-dimethyl-1-(1-propenyl)pyrrolo[2,3-d]pyridazine (trans) as a pale yellow powder.
Reaction SMILES: [OH:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:1][N:2]=[C:3]([CH3:13])[C:4](=[N:10][O:11][CH3:12])[C:5]([N:7]([CH3:8])[CH3:9])=[O:6])=[CH:17][CH:16]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CON=C(C(=O)N(C)C)C(C)=NO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CON=C(C(=O)N(C)C)C(C)=NOCc1ccc(C)cc1
Yield: 96.5 %

Procedure:
To a solution of 600 mg (3.2 mmol) of 3-hydroxyimino-2-methoxyimino-N,N-dimethylbutyramide in 20 ml of acetone, 500 mg (3.5 mmol) of 4-methylbenzylchloride and 660 mg (4.8 mmol) of potassium carbonate were added and the mixture was heated under reflux for 16 hours. The reaction mixture was combined with 30 ml of water and extracted three times with 30 ml of diethylether. After washing with water and a saturated aqueous sodium chloride, the mixture was dried over with anhydrous magnesium sulfate and then the solvent was distilled off. The residue thus obtained was purified by a column chromatography on a silica gel (n-hexane/ethyl acetate) to obtain 900 mg (yield: 96%) of 3-(4-methylbenzyloxyimino)-2-methoxyimino-N,N-dimethylbutyramide as a colorless crystal.
Reaction SMILES: [OH-].[K+].[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([CH2:25][C:26]([O:28]C)=[O:27])=[CH:20][C:19]=3[F:30])=[CH:14][CH:13]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4].Cl>C(O)(C)(C)C>[C:3]([C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([F:24])=[CH:22][C:21]([CH2:25][C:26]([OH:28])=[O:27])=[CH:20][C:19]=3[F:30])=[CH:16][CH:17]=2)[C:9]([CH3:31])=[N:8][C:7]=1[CH3:32])(=[O:5])[NH2:4]
Reactant: COC(=O)Cc1cc(F)c(-c2ccc(-c3nc(C(N)=O)c(C)nc3C)cc2)c(F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: Cc1nc(C)c(-c2ccc(-c3c(F)cc(CC(=O)O)cc3F)cc2)nc1C(N)=O
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 56.9 %

Procedure:
Powdered potassium hydroxide (0.039 g, 0.70 mmol) was added in one portion to methyl 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetate (Intermediate 24-1; 0.096 g, 0.23 mmol) in tert-butanol (2.00 mL) at 40° C. under nitrogen. The resulting suspension was stirred at 40° C. for 20 minutes. A thick precipitate formed so the reaction was quenched with aq 1M HCl (1.4 mL, 1.40 mmol) and the resulting solution stirred for a further 20 minutes before being evaporated to dryness. The resulting solid was partitioned between water (5 mL) and EtOAc (15 mL). The organic layer was separated and the aqueous re-extracted with EtOAc (2×5 mL). The combined organics were washed with brine (15 mL), dried over MgSO4 and evaporated in vacuo to give product. The crude product was purified by preparative HPLC (Waters—Xbridge Prep C18 5 μm), using decreasingly polar mixtures of water (containing 0.1% formic acid) and {MeOH(3):MeCN(1)} as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(4′-(6-carbamoyl-3,5-dimethylpyrazin-2-yl)-2,6-difluorobiphenyl-4-yl)acetic acid (0.052 g, 56.0%) as a colourless solid.