Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=O)[CH2:8]2)=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]#[C:19][CH3:20].O1CCCC1>C(N(CC)CC)C>[Cl:1][C:2]1[S:6][C:5]([CH:7]2[CH2:8][C:9]3[N:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:10]=3[C:11](=[O:13])[CH2:12]2)=[CH:4][CH:3]=1
Reactant: O=C1CC(=O)CC(c2ccc(Cl)s2)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccc(Cl)s1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a mixture of 5-(5-chloro-2-thienyl)cyclohexane-1,3-dione (2.2 g), 1-amino-2-butyne hydrochloride (1.0 g) and tetrahydrofuran (40 ml) was added triethylamine (0.96 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 12 hours and cooled. Insoluble materials were filtered off, and under reduced pressure, the solvent was evaporated. The residue was stirred at 250° C. for 3.5 hours, cooled and purified with silica gel column chromatography (EtOAc/hexane) to give oil of 7-(5-chloro-2-thienyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (0.79 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.C([O-])([O-])=O.[Na+].[Na+].CO.C(Cl)Cl.O1CCO[CH2:40][CH2:39]1>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>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([CH:39]=[CH2:40])[CH:3]=1)=[O:15]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)nc3c2cnn3C(C)C)c(=O)[nH]1
Reactant: C1COCCO1
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: ClCCl
Solvent: O
Solvent: CO
Product: C=Cc1cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c2cnn(C(C)C)c2n1
Temperature: 100 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
A solution of 6-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (1 g, 2.39 mmol), boronic ester (0.442 g, 2.87 mmol) and Pd(PPh3)4 (0.276 g, 0.238 mmol) in 1,4-dioxane (10 mL) was purged with argon for 10 min. Then, solution of Na2CO3 (0.91 g, 8.58 mmol) in water (4.3 mL) was added to it and again argon was purged through it for 10 min. The reaction mixture was stirred at 100° C. for 1 h. After completion of the reaction, water was added to it and extraction was carried out using 20% MeOH/DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography to give the desired compound (0.8 g, 91.6%).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:18]1[CH2:23][CH2:22][N:21]([S:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[CH2:20][CH2:19]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1>[O:18]1[CH2:19][CH2:20][N:21]([S:24]([C:27]2[CH:28]=[CH:29][C:30]([NH:31][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)=[CH:32][CH:33]=2)(=[O:26])=[O:25])[CH2:22][CH2:23]1
Reactant: Nc1ccc(S(=O)(=O)N2CCOCC2)cc1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc(S(=O)(=O)N4CCOCC4)cc3)n2)c1
Reaction time: 16 h
Yield: 31.2 %

Procedure:
Using Method L, 2-(3-acetamidophenyl)-6-chloropyrazine (4a) (60 mg, 0.24 mmol), 4-(morpholinosulfonyl) aniline (84.8 mg, 0.35 mmol), Pd(0)2 dba3 (9 mg, 0.01 mmol), BINAP (50 mg, 0.04 mmol), sodium tert-butoxide (33 mg, 0.34 mmol) and toluene (5 mL) were reacted at 85° C. and kept for 16 hours. The same workup as for Method L followed by column chromatography afforded 34 mg of title compound. Yield: 31.2%. 1H NMR (250 MHz, DMSO-d6) δ 2.11 (s, 3 H), 2.86-2.89 (m, 4 H), 3.62-3.65 (m, 4 H), 7.45 (t, 1 H, 7.8 Hz), 7.54 (d, 1 H, 8.1 Hz), 7.73-7.80 (m, 3 H), 8.14 (d, 2 H, 8.9 Hz), 8.28 (s, 1 H), 8.57 (bs, 1 H), 8.61 (s, 1 H), 10.13 (s, 1 H), 10.18 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.19, 45.90, 65.28, 117.09, 117.50, 120.06, 121.09, 125.43, 129.22, 129.33, 131.54, 134.02, 136.56, 140.07, 145.24, 147.83, 150.66, 168.57; m/z 454.2 [(M+H)+, calcd for C22H23N5O4S 453.2].
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@@H:11]3[CH2:13][N:14](C(OC(C)(C)C)=O)[CH2:15][C@@H:10]3[CH2:9]2)[CH:5]=[N:6][CH:7]=1.[ClH:23].O1CCOCC1>C(OCC)(=O)C.CO>[ClH:23].[ClH:23].[OH:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][C@@H:10]3[C@@H:11]([CH2:13][NH:14][CH2:15]3)[CH2:12]2)[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(O)c3)C[C@@H]2C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Oc1cncc(N2C[C@H]3CNC[C@H]3C2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
The product from Example 6B (150 mg, 0.49 mmol) in ethyl acetate:methanol (1:2, 15 mL) was treated with HCl/1,4-dioxane (4M, 1 mL, 4 mmol). The mixture was stirred at ambient temperature overnight and then cooled in ice to complete precipitation. The mixture was filtered to provide the title compound as a white solid (136 mg, 99% yield). 1H NMR (CD3OD, 300 MHz) δ 3.30 (m, 4H), 3.51 (dd, J=10, 3 Hz, 2H), 3.60 (m, 4H), 7.06 (t, J=3 Hz, 1H), 7.62 (d, J=3 Hz, 1H), 7.69 (d, J=3 Hz, 1H); MS (DCI/NH3) m/z 206 (M+H)+; Anal. calculated for C11H15N3O.2HCl.0.5H2O: C, 46.01; H, 6.32; N, 14.63. Found: C, 46.29; H, 6.49; N, 14.33.
Reaction SMILES: C([O:5][C:6](=[O:34])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:33])[C@@H:13]([CH2:22][S:23]CC1C=CC(OC)=CC=1)[NH:14]C(OC(C)(C)C)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)S(O)(=O)=O>ClCCl>[C:6]([OH:34])(=[O:5])[CH3:7].[NH2:14][C@@H:13]([C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C@H:7]1[C:6]([OH:34])=[O:5])=[O:33])[CH2:22][SH:23]
Reactant: COc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OC(C)(C)C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: COc1ccccc1
Product: CC(=O)O
Product: N[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-tert-butyloxycarbonyl-S-p-methoxybenzyl-D-cysteinyl-L-proline tert-butyl ester (1.8 g) and anisole (4.4 ml) in dichloromethane (8 ml) chilled in an ice bath, trifluoromethane sulfonic acid (6.0 g) is added. The ice bath is removed and the mixture is stirred at room temperature for 30 minutes. The dichloromethane is removed in vacuo and the residue is triturated with hexane (2 × 200 ml). The residue is dissolved in water and extracted twice with ether. The aqueous phase is applied to a column of 200 ml of cation exchange resin [Dowex 50] in the hydrogen cycle. The column is washed with water until no more acidic material is eluted. The D-cysteinyl-L-proline acetate is eluted with a pyridine-acetic acid buffer pH 6.5, yield 0.66 g. Rf =0.38 (silica gel, chloroform:methanol:acetic acid:water).
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]2=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)([N:16]=[C:17]=[O:18])=[O:15]>C(OCC)(=O)C>[C:1]1([CH:7]2[C:8]3[O:13][C:17](=[O:18])[NH:16][C:14](=[O:15])[C:9]=3[CH2:10][CH2:11][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C:7]23[CH2:12][CH2:11][CH2:10][CH:9]=[C:8]2[O:13][C:17](=[O:18])[NH:16][C:14]3=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1CCCCC1c1ccccc1
Reactant: O=C=NC(=O)Cl
Solvent: CCOC(C)=O
Product: O=C1NC(=O)C2(c3ccccc3)CCCC=C2O1
Product: O=c1[nH]c(=O)c2c(o1)C(c1ccccc1)CCC2
Temperature: 130 °C
Reaction time: 2 h
Yield: 35.3 %
Yield: 19.62 %

Procedure:
A solution of 2-phenylcyclohexanone (1.500 g, 8.61 mmol) and carbonisocyanatidic chloride (0.966 mL, 12 mmol) was stirred at 58° C. in a high-pressure vessel (75 mL) for 1 h. The temperature was raised to 130° C. and the reaction mixture was stirred for 2 h. After cooling to room temperature, the reaction mixture solidified. The solid residue was dissolved in ethyl acetate and washed with saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate and filtered. The solvent was removed in vacuum and the oily residue was purified by column chromatography on silica gel to provide 8-phenyl-5,6,7,8-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (415.0 mg, 1.689 mmol, 19.62% yield) as white solid and 4a-phenyl-4a,5,6,7-tetrahydro-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (746.4 mg, 3.04 mmol, 35.3% yield) as white solid.
Reaction SMILES: [C@H:1]1(C=CC=[CH:5][C@@H:3]1[OH:4])[OH:2].[CH2-:9][C:10]([CH3:12])=[O:11].ClC1C(C(OO)=[O:21])=CC=CC=1>C1(C)C=CC=CC=1>[CH:12]1[CH:10]([OH:11])[CH:9]([OH:21])[CH:1]([OH:2])[CH:3]([OH:4])[CH:5]=1
Reactant: O=C(OO)c1ccccc1Cl
Reactant: O[C@@H]1C=CC=C[C@@H]1O
Reactant: [CH2-]C(C)=O
Solvent: Cc1ccccc1
Product: OC1C=CC(O)C(O)C1O

Procedure:
Compound 7 was readily obtained in large quantity and enantiomerically pure form by the biotransformation of iodobenzene using the genetically engineered micro-organism E. coli JM109 (pDTG601) which over expresses toluene dioxygenase (TDO), the enzyme responsible for this dihydroxylation reaction. In the first step of the reaction sequence, cis-1,2-dihydrocatechol 7 was converted into the corresponding acetonide, 8, under standard conditions. The acetonide was immediately reacted with ml-chloroperbenzoic acid (m-CPBA) so as to produce, in a completely regio- and diastereo-selective manner, the epoxide 10. This compound represented a potent electrophile which reacted with a range of nucleophiles at the allylic carbon of the epoxide ring so as to give conduritol and conduramine derivatives. In particular, reaction of compound 10 with 1,6-hexadiamine in dichloromethane at 18° C. for 4 days gave the dimeric species 11 in quantitative yield. The readily obtained bis-acetamido-derivative, 12, of the latter compound was subject to a Pd[0]-mediated carbomethoxylation reaction thereby producing the diester 13 wherein each six-membered ring incorporates an exocyclic carbon in an appropriate oxidation state as required for elaboration to pseudo-sugars.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][C:4]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([OH:27])=[CH:24][C:25]=1[OH:26])=[O:19].CC(C1C(O)=CC(O)=CC=1O)=O>>[OH:26][C:25]1[CH:24]=[C:23]([OH:27])[CH:22]=[C:21]2[C:20]=1[C:18](=[O:19])[CH:17]=[C:7]([C:6]1[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1)[O:8]2
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CCCCCc1cc(C(=O)Cl)ccc1OC
Agent: CC(=O)c1c(O)cc(O)cc1O
Product: CCCCCc1cc(-c2cc(=O)c3c(O)cc(O)cc3o2)ccc1OC

Procedure:
Using the procedure described in Preparation B, replacing 3-cyclopentyloxy-4-methoxybenzoyl chloride by 4-methoxy-3-pentylbenzoyl chloride, and 2,4-dihydroxyacetophenone by 2,4,6-trihydroxyacetophenone, the expected compound is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8](=[O:14])[N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH:5]=[CH:4][N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][OH:19].[H-].[Na+]>>[CH2:10]([N:9]([CH2:12][CH3:13])[C:8]([C:6]1[CH:5]=[CH:4][N:3]=[C:2]([O:19][CH2:18][CH2:17][CH2:16][NH2:15])[CH:7]=1)=[O:14])[CH3:11]
Reactant: CCN(CC)C(=O)c1ccnc(Cl)c1
Reactant: NCCCO
Agent: [H-]
Agent: [Na+]
Product: CCN(CC)C(=O)c1ccnc(OCCCN)c1

Procedure:
2-Chloro-4-diethylcarbamoylpyridine is reacted with 3-aminopropanol and sodium hydride to give 3-(4-diethylcarbamoyl-2-pyridyloxy)propylamine, which is reduced with lithium aluminium hydride in tetrahydrofuran to give 3-(4-diethylaminomethyl-2-pyridyloxy)propylamine;
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH3:47])=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:48])[N:20]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH2:46][CH3:47])=[CH:43][CH:44]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccc(OCC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 73.3 %

Procedure:
A mixture of hydroxylammonium chloride (1.82 g), sodium hydrogen carbonate (2.64 g) and dimethyl sulfoxide (13 mL) was stirred at 40° C. for 30 min, 4′-{[4-butyl-1-(4-ethoxyphenyl)-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl]methyl}biphenyl-2-carbonitrile (1.25 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (13 mL), N,N′-carbonyldiimidazole (0.54 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.51 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (1.03 g, 73%).
Reaction SMILES: [F:1][C:2]1([F:17])[C:10]2[C:5](=[CH:6][C:7]([OH:14])=[C:8]([N+:11]([O-])=O)[CH:9]=2)[C:4]([F:16])([F:15])[O:3]1.C(O)(=O)C>[Fe].O>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5]([C:4]([F:16])([F:15])[O:3][C:2]2([F:1])[F:17])=[CH:6][C:7]=1[OH:14]
Reactant: O=[N+]([O-])c1cc2c(cc1O)C(F)(F)OC2(F)F
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1cc2c(cc1O)C(F)(F)OC2(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A mixture of 6.8 g of 1,1,3,3-tetrafluoro-5-hydroxy-6-nitro-1,3-dihydroisobenzofuran and 20 ml of acetic acid was added dropwise to a mixture, which was heated to 80° C., of 7.8 g of electrolytic iron, 20 ml of acetic acid and 20 ml of water, and then the reaction mixture was stirred for one hour. The mixture was cooled to room temperature, and then water was added, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated sodium chloride solution, and dried over magnesium sulfate. Activated carbon was added, followed by filtration through Celite™. The filtrates were concentrated under reduced pressure to give 4.43 g of 6-amino-1,1,3,3-tetrafluoro-5-hydroxy-1,3-dihydroisobenzofuran.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([C:30]#[N:31])[CH:27]=[CH:26][C:3]=1[NH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.[CH:32](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:30]([C:28]1[CH:27]=[CH:26][C:3]2[N:4]([CH:5]3[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:7][CH2:6]3)[CH:32]=[N:1][C:2]=2[CH:29]=1)#[N:31]
Reactant: COC(OC)OC
Reactant: N#Cc1ccc(NC2CCN(CCC(c3ccccc3)c3ccccc3)CC2)c(N)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: N#Cc1ccc2c(c1)ncn2C1CCN(CCC(c2ccccc2)c2ccccc2)CC1

Procedure:
A solution of 2-amino-4-cyano-1-N-[1-(3,3-diphenylpropyl)-piperidin-4-yl]aniline (prepared as described below) (60 mg, 0.15 mmol), trimethyl orthoformate (0.7 ml) and para-toluenesulphonic acid monohydrate (2 mg, 0.11 mmol) was stirred at 100° C. After 2.5 h the mixture was cooled and water (10 ml) was added. The solution was partitioned with EtOAc (2×40 ml) then the organics were combined, dried (MgSO4) and concentrated to give the title compound as an oil (58 mg, 0.15 mmol); MS: 421.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[NH2:11].[C:13]([Cu])#[N:14].Cl.CCOC(C)=O>CN1C(=O)CCC1.O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([C:13]#[N:14])[CH:7]=[CH:6][C:5]=1[NH2:11]
Reactant: N#C[Cu]
Reactant: COC(=O)c1cc(Br)ccc1N
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)c1cc(C#N)ccc1N
Temperature: 25 °C
Yield: 85 %

Procedure:
A mixture of 2-amino-5-bromo-benzoic acid methyl ester (5.00 g, 21.7 mmol) and CuCN (2.34 g, 26.1 mmol, 2.0 M) in 25 ml of NMP was stirred at reflux for 5 h, then cooled to rt. The mixture was poured into a solution of hydrated FeCl3 (15 g of FeCl3.6H2O) and conc. HCl (2.2 ml) in 15 ml of H2O. The resulting mixture was stirred at 60° C. for 1 h, cooled to rt. Treated with 200 ml of EtOAc, the mixture was washed with H2O (40 ml), 1N NaOH (3×30 ml), brine (30 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave a slightly dark solid. Recrystalization of the solid in hexanes/DCM/EtOAc yielded 3.25 g (85%) of product as a yellow solid: 1H-NMR (CDCl3; 400 MHz) δ 8.20 (d, 1H, J=1.9 Hz), 7.45 (dd, 1H, J=8.9, 1.9 Hz), 6.67 (d, 1H, J=8.9 Hz), 6.29 (br s, 2H), 3.90 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C9H8N2O2, 177.1 (M+H), found 177.2.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5](OCC)=[O:6]>CO>[O:3]=[C:4]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[C:5]([NH:2][CH3:1])=[O:6]
Reactant: CCOC(=O)C(=O)c1ccccc1COC1CCCCO1
Reactant: CN
Solvent: CO
Product: CNC(=O)C(=O)c1ccccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
40% monomethylamine--methanol (2.65 g, 34.1 mmol) solution was added to a solution of ethyl 2-oxo-2-[2-(tetra-hydropyran-2-yloxymethyl)phenyl]acetate (2.00 g, 6.8 mmol) in methanol (20 ml), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated, and the residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound 2-oxo-N-methyl-2-[2-(tetrahydropyran-2-yloxymethyl)phenyl]-acetamide (1.30 g, 69%) as an oil.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH:33]([OH:35])[CH:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:38]=2)[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:34][C:33](=[O:35])[CH:32]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[N:38]=2)[CH2:31]1)=[O:29])([CH3:25])([CH3:26])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CC2CN(C(=O)OC(C)(C)C)CC2O)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cccc(CC2CN(C(=O)OC(C)(C)C)CC2=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
To a suspension of Dess-Martin periodinane (0.0014 mol) in 10 mL CH2Cl2 was added a solution of 3-(6-tert-butoxycarbonylamino-pyridin-2-ylmethyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester III-2 (0.001 mol) in 5 mL CH2Cl2 and the reaction mixture was stirred at room temperature for 18 h. 1 M Na2S2O3 (10 mL) was added to the reaction, and after stirring for 10 min, the reaction mixture was extracted with CH2Cl2(10 mL×3). The combined organic layers were washed with 5% aqueous NaHCO3 (20 mL×3) and brine (20 mL×2). The organic layer was dried over anhydrous Na2SO4. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes:EtOAc, 8:2) to give pure product (96%).
Reaction SMILES: Cl[CH2:2][C:3]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=1[F:20])([OH:12])[C:4]([F:11])([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N12CCCN=C1CCCCC2.O.Cl>C(Cl)Cl>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:3]1([O:12][CH2:2]1)[C:4]([F:11])([F:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(F)(F)C(O)(CCl)c1ccc(F)cc1F
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(F)(F)C1(c2ccc(F)cc2F)CO1
Yield: 80 %

Procedure:
In 150 ml of methylene chloride was dissolved 15.7 g of ethyl 4-chloro-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxybutyrate. To the solution was dropwise added 8.4 g of 1,8-diazabicyclo[5.4.0]undec-7-ene at 5°-10° C. The mixture was subjected to reaction at the same temperature for 2 hours. The resulting reaction mixture was introduced into 150 ml of water and adjusted to pH 1.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: n-hexane/toluene=2/1) to obtain 11.1 g of oily ethyl 3-(2,4-difluorophenyl)-3,4-epoxy-2,2-difluorobutyrate.