Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][C:13]([O:16][C:17](=[O:30])[N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:19][CH2:20][OH:21])([CH3:15])[CH3:14].FC1C=C(C=CC=1)CNCCO.C(N(CC)CC)C>ClCCl>[C:13]([O:16][C:17]([N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)[CH2:19][CH2:20][O:21][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])=[O:30])([CH3:12])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CCO)Cc1cccc(F)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: OCCNCc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add p-toluenesulfonyl-chloride (0.71 g, 3.71 mmol), portionwise, to a mixture of (3-fluoro-benzyl)-(2-hydroxy-ethyl)-carbamic acid dimethyl-ethyl ester (1 g, 3.71 mmol, prepared from 2-(3-fluoro-benzylamino)-ethanol by methods as are known in the art), triethylamine (0.751 g, 7.4 mmol) and dichloromethane (6 mL). Stir the resulting suspension vigorously overnight at room temperature. Add water (10 mL), separate the organic layer, and extract the aqueous layer with dichloromethane (5 mL), twice. Combine the organic layers and wash with citric acid (5 mL, 20% in water), dry with sodium sulfate and evaporate the solvent to give the final, desired compound. The final compound may be purified by chromatography.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C(O[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15])C>C(O)C>[CH2:17]([O:16][C:14](=[O:15])[C:13](=[CH:12][NH:6][C:5]1[CH:7]=[CH:8][C:2]([I:1])=[CH:3][CH:4]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:18]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccc(I)cc1
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(I)cc1)C(=O)OCC
Temperature: 90 °C
Reaction time: 10 h
Yield: 90490 %

Procedure:
A mixture of 4-iodoaniline (50 g, 0.23 mol) and diethyl ethoxymethylenemalonate (50.3 g, 0.23 mmol) was stirred at 90° C. for 10 hours. 150 mL of ethanol was added and the mixture was refluxed for 3 h. After cooling, the solid was collected, washed with hexane and dried over the oven to obtain 2-[(4-iodo-phenylamino)-methylene]-malonic acid diethyl ester (81 g, 91%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[NH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:17]=3[NH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccncc23)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cc2[nH]cc(C3CCNCC3)c2cn1
Yield: 158.1 %

Procedure:
4-(1H-Pyrrolo[3,2-c]pyridin-3-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 6.6 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 2.1 g (100%) of a white solid as a TFA salt. MS (electrospray): exact mass calculated for C12H15N3, 201.13; m/z found, 202.1 [M++H]. 1H NMR (CDCl3, 400 MHz): 9.4 (br s, 1H), 8.96 (s, 1H), 8.26 (d, J=5.87 Hz, 1H), 7.24 (s, 1H), 6.99 (s, 1H), 3.22-3.16 (m, 2H), 3.05-2.95 (m, 1H), 2.86-2.77 (m, 2H), 2.05 (d, J=12.72 Hz, 2H), 1.89 (br s, 1H), 1.75-1.63 (m, 2H).
Reaction SMILES: C([C@H]1COC(C2C=CC=C(C3OC[C@H](C(C)C)N=3)N=2)=N1)(C)C.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][CH:56]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:46]=[CH:45][C:43](=[O:44])[NH:42][C:40]3=[O:41])[C@H:36]([OH:47])[C@@H:35]2[OH:48])=[CH:27][CH:26]=1.[C:63]1([N:69]=[C:70]=[O:71])[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1.COC1C=CC(C(C2C=CC(OC)=CC=2)(C2C=CC=CC=2)OC[C@H]2O[C@@H](N3C=CC(=O)NC3=O)[C@H](OC(=O)NC3C=CC=CC=3)[C@@H]2O)=CC=1>C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Cu+2].C1COCC1>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]([C:55]2[CH:56]=[CH:57][C:58]([O:61][CH3:62])=[CH:59][CH:60]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[O:32][CH2:33][C@H:34]2[O:38][C@@H:37]([N:39]3[CH:46]=[CH:45][C:43](=[O:44])[NH:42][C:40]3=[O:41])[C@H:36]([OH:47])[C@@H:35]2[O:48][C:70](=[O:71])[NH:69][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C=Nc1ccccc1
Agent: [Cu+2]
Agent: CC(C)[C@H]1COC(c2cccc(C3=N[C@@H](C(C)C)CO3)n2)=N1
Agent: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](OC(=O)Nc3ccccc3)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2OC(=O)Nc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The THF solution (2 ml) containing 2,6-bis[(4S)-isopropyl-2-oxazoline-2-yl]pyridine (0.04 mmol, 12.2 mg) and Cu(OTf)2 (II) (0.04 mmol, 14.8 mg) was stirred for two hours at room temperature. After the reaction mixture was cooled to 0° C., the THF solution of 5′-O-[bis(4-methoxyphenyl)phenylmethyl]uridine (0.4 mmol, 218.6 mg) and the THF solution of phenyl isocyanate (0.4 mmol, 47.7 mg) were added thereto. After the mixture was continuously stirred for 19 hours at 0° C., the mixture was analyzed with high-performance liquid chromatography. As a result, it was found that 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-2′-O-phenylcarbamoyl-uridine and 5′-O-[bis(4-methoxyphenyl)phenylmethyl]-3′-O-phenylcarbamoyl-uridine were produced at the ratio of 84:14, and the transformation ratio of the reaction was 76%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]([CH3:10])=[C:5]([C:7]([OH:9])=O)[N:6]=1.C(Cl)(=O)C(Cl)=O.C(N(C(C)C)CC)(C)C.[Cl:32][C:33]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:34]=1[NH2:35]>C(Cl)(Cl)Cl.ClCCl>[Cl:32][C:33]1[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:34]=1[NH:35][C:7]([C:5]1[N:6]=[C:2]([CH3:1])[N:3]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:4]=1[CH3:10])=[O:9]
Reactant: Nc1cccc(Cl)c1Cl
Reactant: Cc1nc(C(=O)O)c(C)n1-c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1nc(C(=O)Nc2cccc(Cl)c2Cl)c(C)n1-c1ccccc1
Yield: 36 %

Procedure:
Part A: To a magnetically stirred suspension of 2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxylic acid (0.4 gram, 1.85 mmol) in CHCl3 (4 ml) was added oxalyl chloride (0.34 gram, 2.685 mmol) and the resulting mixture was reacted at 58° C. for 2 hours and subsequently concentrated in vacuo. The resulting residue was taken up in dichloromethane and diisopropylethylamine (0.28 gram, 2.148 mmol) was subsequently added. A solution of 2,3-dichloroaniline (0.35 gram, 2.146 mmol) in dichloromethane (5 ml) was slowly added to the resulting mixture and the resulting mixture was reacted for 2 hours at room temperature and subsequently concentrated in vacuo. The resulting residue was purified by flash chromatography (dichloromethane) to give N-(2,3-dichlorophenyl)-2,5-dimethyl-1-phenyl-1H-imidazole-4-carboxamide (0.24 gram, 36% yield). Melting point: 127-129° C.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].C(C1SC(C2SC(NC(=O)C)=NC=2C)=CC=1)=O.OB(O)[C:31]1[S:35][C:34]([C:36]([OH:38])=[O:37])=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.CN(C=O)C>[C:8]([NH:7][C:5]1[S:6][C:2]([C:31]2[S:35][C:34]([C:36]([OH:38])=[O:37])=[CH:33][CH:32]=2)=[C:3]([CH3:11])[N:4]=1)(=[O:10])[CH3:9]
Reactant: O=C(O)c1ccc(B(O)O)s1
Reactant: CC(=O)Nc1nc(C)c(I)s1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)Nc1nc(C)c(-c2ccc(C=O)s2)s1
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)s2)s1
Temperature: 150 °C

Procedure:
N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide, Intermediate 1 (550 mg; 1.95 mmol; 1 eq.), 5-(dihydroxyboryl)-2-thiophenecarboxylic acid (335.3 mg; 1.95 mmol; 1 eq.), cesium carbonate (1397.5 mg; 4.29 mmol; 2.20 eq.), Pd(dppf)Cl2 (57.1 mg; 0.08 mmol; 0.04 eq.) are put in a microwave reactor, followed by DMF (8 ml) and water (4 ml). The reaction mixture is flushed with argon and is heated under microwave action for 10 min at 150° C. It is filtered through a paper filter, diluted with HCl 1N solution (10 ml) and the desired product is extracted with EtOAc. Combined organic layer is dried over MgSO4, filtered and evaporated. The crude product is purified by preparative HPLC, affording Compound (4) as white-off solid (125 mg; 22.7%). 1H NMR (DMSO-d6) δ 2.14 (s, 3H), 2.44 (s, 3H), 7.21 (d, J=3.8 Hz, 1H), 7.67 (d, J=3.8 Hz, 1H), 12.30 (s, 1H), 13.15 (br s, 1H). M−(ESI): 281; M+(ESI): 283. HPLC, Rt: 2.54 min (purity: 99.9%).
Reaction SMILES: [Cl:1][C:2]1[C:6]([N+:7]([O-])=O)=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1.C(O)C.O.[Cl-].[NH4+]>[Fe].C(OCC)(=O)C>[Cl:1][C:2]1[C:6]([NH2:7])=[CH:5][N:4]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cn(-c2cccnc2)nc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Nc1cn(-c2cccnc2)nc1Cl
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
In a 250 mL 3-neck round bottom flask was added 3-(3-chloro-4-nitro-1H-pyrazol-1-yl)pyridine (5.00 g, 21.8 mmol), ethanol (80 mL), water (40 mL), and ammonium chloride (5.84 g, 109 mmol). The suspension was stirred under nitrogen stream for 5 minutes then iron powder (4.87 g, 87.2 mmol) added. The reaction mixture was heated to reflux (˜80° C.) and held there for 4 hours. After 4 hours a reaction aliquot taken showed by HPLC analysis the reaction had gone to full conversion. Ethyl acetate (120 mL) and Celite® (10 g) were added to the reaction mixture and let stir for 10 minutes. The black colored suspension was then filtered via a Celite® pad and the pad rinsed with ethyl acetate (80 mL). The reaction mixture was washed with saturated sodium bicarbonate (30 mL) and the organic layer was assayed. The assay gave (4.19 g, 99%) of product. The organic solvent was removed in vacuo to give a brown colored crude solid that was used without further purification.
Reaction SMILES: S(=O)(=O)(O)O.[F:6][C:7]([F:23])([F:22])[C:8]1[CH:9]=[C:10]([CH2:18][C:19]([OH:21])=[O:20])[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.[CH3:24]O>>[F:6][C:7]([F:22])([F:23])[C:8]1[CH:9]=[C:10]([CH2:18][C:19]([O:21][CH3:24])=[O:20])[CH:11]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:13]=1
Reactant: CO
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 93 %

Procedure:
Sulfuric acid (conc., 1 mL) was added to a solution of 3,5-bis(trifluoromethyl)benzeneacetic acid (50.0 g, 0.18 mol) in methanol (400 mL) and the mixture was stirred at room temperature for 1 week. The solvent was evaporated and ethyl acetate (100 mL) and aqueous sodium hydrogen carbonate (saturated, 600 mL) were added. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×300 mL). The combined organic fractions were washed with brine, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound (49.0 g, 93%). 1H NMR (400 MHz, CDCl3) δ 7.80 (1H, s), 7.75 (2H, s), 3.77 (2H, s), and 3.75 (3H, s).
Reaction SMILES: [CH2:1]([S:4][CH:5]1[NH:8][C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3].Br[CH2:13][C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:1]([S:4][CH:5]1[N:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:7](=[O:9])[CH:6]1[CH2:10][CH3:11])[CH:2]=[CH2:3]
Reactant: COC(=O)CBr
Reactant: C=CCSC1NC(=O)C1CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCSC1C(CC)C(=O)N1CC(=O)OC
Reaction time: 18 h

Procedure:
To a vigorously stirred solution of 2.34 g of 4-allylthio-3-ethylazetidin-2-one in 20 ml of dimethylformamide were added 1.37 ml of methyl bromoacetate and 4.16 g of finely ground potassium carbonate. After 18 hours, the mixture was poured into 75 ml of water, was extracted into ethyl acetate (5×20 ml) and the combined organic extracts were washed with water (6×15 ml), dried over MgSO4 and evaporated in vacuo to dryness. Chromatography over silica gel, eluting with hexane-ethyl acetate mixtures, afforded the title compound as a yellow oil (3 g).
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[Cl:6][C:7]1([C:10]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:11][C:12]#[CH:13])[CH2:9][CH2:8]1.N.C(I)C>CCCCCC.O1CCCC1>[Cl:6][C:7]1([C:10]([OH:20])([CH2:14][N:15]2[CH:19]=[N:18][CH:17]=[N:16]2)[CH2:11][C:12]#[C:13][CH2:1][CH3:2])[CH2:8][CH2:9]1
Reactant: C#CCC(O)(Cn1cncn1)C1(Cl)CC1
Reactant: [Li]CCCC
Agent: N
Solvent: CCI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC#CCC(O)(Cn1cncn1)C1(Cl)CC1
Reaction time: 1 h

Procedure:
89.7 ml (021 mol) of n-butyllithium in hexane are added at -40° C., with stirring and under a nitrogen atmosphere, to a solution of 22.5 g (0.1 mol) of 4-(1-chlorocyclopropyl)4hydroxy-5-(1,2,4-triazol-1-yl)1-pentine in 350 ml of liquid ammonia. After the end of the addition, stirring is continued initially at from -30° C. to -40° C. for 1 hour, and then a solution of 17.2 g (0.11 mol) of ethyl iodide in 20 ml of absolute tetrahydrofuran is added dropwise. The reaction mixture is subsequently stirred under ammonia reflux. For working up, the ammonia is evaporated off, ethyl acetate and water are added to the residue, and the organic phase is separated off, dried over sodium sulphate and concentrated under reduced pressure. This gives 25 g of a product which consists to the extent of 85.3% of 6-(1-chlorocyclopropyl)-6-hydroxy-7-(1,2,4-triazol-1-yl)-3-heptine. Recrystallization from ethanol gives 6-(1-chlorocyclopropyl)-6-hydroxy-7-(1,2,4triazol-1-yl)3-heptine in the form of a solid of melting point 83°-84° C. ##STR63##
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([CH:10]=[O:11])=[C:8]([I:12])[CH:7]=[CH:6][N:5]=1>O1CCCC1>[F:3][C:4]1[C:9]([CH2:10][OH:11])=[C:8]([I:12])[CH:7]=[CH:6][N:5]=1
Reactant: O=Cc1c(I)ccnc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OCc1c(I)ccnc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.72 g (19.2 mmol) of sodium borohydride is added to a solution of 4 g (16 mmol) of 2-fluoro-4-iodo-3-pyridinecarbaldehyde (described in J.O.C., 1993, 58, pp.7832) in 100 ml of tetrahydrofuran. The mixture is stirred at room temperature for 4 hours and then hydrolysed. The reaction mixture is extracted with ethyl acetate. The organic phases are dried and concentrated to yield the expected product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)(=[O:26])=[O:25]>>[CH3:23][S:24]([N:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1)(=[O:26])=[O:25]
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: CS(=O)(=O)N1CCNCC1
Product: CS(=O)(=O)N1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 1-(methylsulfonyl)piperazine (1.2 equiv) to give 200 (M+1 460.0)
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([OH:19])[CH:14]=[CH:15][C:16]=3[O:17][CH3:18])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Cl:20][C:21]([O-])=[O:22]>>[Cl:20][C:21]([O:19][C:13]1[CH:14]=[CH:15][C:16]([O:17][CH3:18])=[C:11]([C:1]23[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]2)[CH2:8]3)[CH:12]=1)=[O:22]
Reactant: COc1ccc(O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: O=C([O-])Cl
Product: COc1ccc(OC(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2

Procedure:
In a manner similar to Example 17(a), starting with 6.45 g (25 mmol) of 3-(1-adamantyl)-4-methoxyphenol, 5 g (62%) of the expected chloroformate, melting point 87°-89° C., are obtained.
Reaction SMILES: ClC(Cl)(Cl)C(OC1[O:41][C@@H:40]([CH3:42])[C@@H:29]([O:30][CH2:31][C:32]2C=CC(OC)=CC=2)[C@@H:18](OCC2C=CC(OC)=CC=2)[C@@H]1OCC1C=CC(OC)=CC=1)=N.[CH3:45][O:46][C:47]1[CH:82]=[CH:81][C:50]([CH2:51][O:52][C@H:53]2[C@H:59]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[C@H:58]([O:70][CH2:71][C:72]3[CH:77]=[CH:76][C:75]([O:78][CH3:79])=[CH:74][CH:73]=3)[C@H:57]([CH3:80])[O:56][CH:54]2[OH:55])=[CH:49][CH:48]=1.ClC(Cl)(Cl)C#N.[H-].[Na+].CC1C(=O)C(O)=C(C)O1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(OCC)C>[CH3:45][O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:51][O:52][C@H:53]2[C@H:59]([O:60][CH2:61][C:62]3[CH:67]=[CH:66][C:65]([O:68][CH3:69])=[CH:64][CH:63]=3)[C@H:58]([O:70][CH2:71][C:72]3[CH:73]=[CH:74][C:75]([O:78][CH3:79])=[CH:76][CH:77]=3)[C@H:57]([CH3:80])[O:56][C@H:54]2[O:55][C:42]2[C:40](=[O:41])[CH:29]([CH3:18])[O:30][C:31]=2[CH3:32])=[CH:81][CH:82]=1
Reactant: COc1ccc(CO[C@@H]2[C@H](OCc3ccc(OC)cc3)[C@H](C)OC(O)[C@H]2OCc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CO[C@@H]2[C@H](OCc3ccc(OC)cc3)[C@H](C)OC(OC(=N)C(Cl)(Cl)Cl)[C@H]2OCc2ccc(OC)cc2)cc1
Agent: CC1=C(O)C(=O)C(C)O1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [H-]
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COc1ccc(CO[C@H]2[C@H](OCc3ccc(OC)cc3)[C@H](OC3=C(C)OC(C)C3=O)O[C@@H](C)[C@H]2OCc2ccc(OC)cc2)cc1
Reaction time: 1 h

Procedure:
The solution of 2,3,4-tri-O-(4-methoxybenzyl)-L-fucopyranose trichloroacetimidate (a/β mixture, prepared from 85 mmol of 2,3,4-tri-O-(4-methoxybenzyl)-L-fucopyranose and trichloroacetonitrile in the presence of NaH in quantitative yield) in diethyl ether (100 ml) was added to a mixture of 2,5-dimethyl-4-hydroxy-3-oxo-(2H)-furan (85 mmol) and TMS-triflate (1.2 ml) in diethyl ether (200 ml) at −14° C. After 3 hours the cooling bath was removed and the stirring continued for 1 hour. The reaction mixture was diluted with ethyl acetate and extracted with sat. NaHCO3-solution (3×150 ml) and brine (150 ml). The organic phase was dried over Na2SO4 and evaporated. The resulting syrup was purified by column chromatography yielding 23.27 g of 2,5-dimethyl-3-oxo-(2H)-furan-4-yl 2,3,4-tri-O-(4-methoxybenzyl)-α-L-fucopyranoside as a thick yellow syrup in a 1:1 mixture of diastereoisomers. Selected NMR chemical shifts in CDCl3: anomeric protons: 5.32 and 5.57 ppm, J1,2=3.4 Hz; anomeric carbons: 113.81 and 113.95 Hz.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[N:13]([C@@H](C3C=CC=CC=3)CO)[C:12](=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>[Pd].C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[CH2:9][CH2:10][CH2:11][CH2:12][NH:13]2)=[CH:6][CH:7]=1
Reactant: O=C1CCC[C@H](c2ccc(F)cc2)N1[C@H](CO)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc([C@H]2CCCCN2)cc1
Yield: 92.3 %

Procedure:
(R)-6-(4-Fluoro-phenyl)-1-((S)-2-hydroxy-1-phenyl-ethyl)-piperidin-2-one (650 mg, 1.94 mmol) and palladium on charcoal (0.2 g) in ethanol (25 mL) were stirred under an atmosphere of hydrogen for 20 hours. The reaction mixture was filtered through Celite® then evaporated and the material dissolved in methanol and purified on a 10 g SCX-2 cartridge, eluting with 2 N ammonium hydroxide in methanol. The ammoniacal fractions were evaporated to yield the title compound (0.321 g), which was used in the synthesis of EE-46. LCMS m/z 180.11 [M+H]+ R.T.=1.3-1.6 min (Analytical Method 6).
Reaction SMILES: [H-].[Na+].[C:3]([O:11]CC)(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C=C1OC(=O)C1.Cl.[O:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[OH:21][C:25]1[CH:24]=[C:23]([CH3:22])[O:11][C:3](=[O:10])[C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: C1CCOC1
Reactant: CCOC(=O)CC(=O)OCC
Agent: C=C1CC(=O)O1
Agent: Cl
Agent: [H-]
Product: CCOC(=O)c1c(O)cc(C)oc1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
8 g of sodium hydride (ca. 60% in oil) was suspended in 200 ml of tetrahydrofuran, and 32 g of diethyl malonate was added dropwise with cooling on ice, and then stirred for 1 hour at room temperature. A solution of 14 g of a diketene in 30 ml of tetrahydrofuran was added dropwise to the reaction mixture with cooling on ice, and then the reaction mixture was stirred for 16 hours at room temperature. Subsequently, 1% hydrochloric acid was poured into the reaction mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chrolide, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to a silica gel column chromatography to obtain 9.5 g of ethyl 4-hydroxy-6-methyl-2-oxo-2H-pyrane-3-carboxylate (Compound No. 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][C:28]([OH:30])=O)[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:41]([NH:44][CH:45]([CH3:47])[CH3:46])([CH3:43])[CH3:42].Cl.CN(C)CCCN=C=NCC.CN(C1C=CC=CN=1)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:31])=[C:24]([CH2:27][C:28](=[O:30])[N:44]([CH:45]([CH3:47])[CH3:46])[CH:41]([CH3:43])[CH3:42])[CH:25]=2)[NH:20][C:19](=[O:32])[C:18]=1[C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[C:35]([CH3:40])[CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CC(=O)O)c(Cl)cc3[nH]c2=O)c1
Reactant: CC(C)NC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(C)cc(-c2c(OCCC3CCCCN3C(=O)OC(C)(C)C)c3cc(CC(=O)N(C(C)C)C(C)C)c(Cl)cc3[nH]c2=O)c1
Temperature: 25 °C
Reaction time: 42 h

Procedure:
To a solution of 2-{2-[6-carboxymethyl-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (57 mg in 0.50 mL methylene chloride) was added 0.042 mL diisopropylamine followed by 98 mg 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) and 6.1 mg dimethylaminopyridine, and the mixture stirred at room temperature. After 42 hours, the mixture was diluted with methylene chloride and washed with water and brine. The organics were dried over sodium sulfate and the concentrate purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 97:2:1) to give the title compound (41 mg).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:28])[CH3:27])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)#[N:31].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:37]=[C:32]([CH:33]=[CH:34][CH:35]=3)[C:30]#[N:31])[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:25][CH2:24][CH:23]([N:26]([CH3:27])[CH3:28])[CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CN(C)C1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)C1
Reactant: N#Cc1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)C1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2cccc(C#N)c2)C1
Yield: 40 %

Procedure:
The title compound was synthesized in analogy to example 66, from (RS)-(4,4-difluoro-piperidin-1-yl)-[5-(3-dimethylamino-pyrrolidine-1-carbonyl)-1H-indol-2-yl]-methanone (example 42, intermediate a)), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (40%).