Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=C[C:26](C#N)=[C:25](N)[CH:24]=1)=[O:4].[N:32]1[CH:37]=[N:36][CH:35]=[N:34][CH:33]=1.CC(O)=O>CCO>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][N:9]([C:11](=[O:20])[CH2:12][O:13][C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:8][C:7](=[O:21])[N:6]1[CH2:22][C:23]1[CH:28]=[C:33]2[C:26]([C:37]([NH2:32])=[N:36][CH:35]=[N:34]2)=[CH:25][CH:24]=1)=[O:4]
Reactant: c1ncncn1
Reactant: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc(C#N)c(N)c1
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)C1CN(C(=O)COc2ccc(Cl)s2)CC(=O)N1Cc1ccc2c(N)ncnc2c1
Yield: 40.8 %

Procedure:
A solution containing (±)-1-(3-amino-4-cyano-benzyl)-4-[(5-chloro-thiophen-2-yloxy)-acetyl]-6-oxo-piperazine-2-carboxylic acid methyl ester (110 mg, 0.25 mmol), 1,3,5-triazine (207 mg, 2.55 mmol), and glacial HOAc (157 mg, 2.55 mmol) in absolute EtOH (5 mL) is maintained at reflux for 16 hours. The reaction mixture is concentrated to dryness and then purified by reverse-phase HPLC [Buffer A: water w/0.1% TFA; Buffer B: CH3CN w/0.1% TFA; Gradient: 0% B to 60% B over 30 min] to provide 50 mg (32%) of the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ3.34-3.89 (m, 2H), 3.60 (s, 3H), 4.14-4.54 (m, 3H), 4.64 (br d, J=14.4 Hz, 1H), 4.78-5.11 (m, 3H), 6.19 (d, J=4.1 Hz, 1H), 6.73 (d, J=4.1 Hz, 1H), 7.64 (s, 1H), 7.65 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.79 (s, 1H), 9.71 (br s, 2H) ppm; MS (ion spray): m/z 490 (M+H).
Reaction SMILES: [C:1]([C:9]1[C:10](=[O:20])[N:11]([CH3:19])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=1[CH2:15]Br)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][C@@H:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:36])[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].C(N(CC)CC)C>O1CCOCC1>[CH3:17][N:13]1[C:14]2=[CH:15][N:21]([C@@H:22]([CH2:33][CH2:34][C:35]([O:37][CH2:38][C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)=[O:36])[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[C:9]2[C:10](=[O:20])[N:11]([CH3:19])[C:12]1=[O:18]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Reactant: Cn1c(CBr)c(C(=O)c2ccccc2)c(=O)n(C)c1=O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](CCC(=O)OCc3ccccc3)C(=O)OCc3ccccc3)cc2n(C)c1=O
Temperature: 25 °C

Procedure:
5-benzoyl-6-(bromomethyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (Intermediate C) (2.04 g, 6.05 mmol), (S)-dibenzyl 2-aminopentanedioate (commercially available) (4.53 g, 9.08 mmol) and triethylamine (3.37 mL, 24.20 mmol) were suspended in dioxane (30 mL) and the mixture was heated at reflux for 2 hours. The mixture was cooled to room temperature and evaporated under vacuum. The residue was partitioned between DCM and 0.1M HCl(aq) and the phases separated. The organic phase was passed through a hydrophobic frit. Purification by chromatography on silica, eluting with 20-60% EtOAc/hexane, afforded the title compound.
Reaction SMILES: CS([C:4]1[N:9]=[C:8]([C:10]2[N:14]3[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:21])[CH3:20])[C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)=O.[CH3:23][S:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)(=[O:26])=[O:25]>CN1C(=O)CCC1.O>[CH3:23][S:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH:31]([NH:34][C:4]2[N:9]=[C:8]([C:10]3[N:14]4[CH:15]=[CH:16][CH:17]=[C:18]([C:19]([OH:22])([CH3:20])[CH3:21])[C:13]4=[N:12][CH:11]=3)[CH:7]=[CH:6][N:5]=2)[CH2:30][CH2:29]1)(=[O:25])=[O:26]
Reactant: CS(=O)c1nccc(-c2cnc3c(C(C)(C)O)cccn23)n1
Reactant: CS(=O)(=O)CC1CCC(N)CC1
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)(O)c1cccn2c(-c3ccnc(NC4CCC(CS(C)(=O)=O)CC4)n3)cnc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 52.8 %

Procedure:
A mixture of 2-[3-(2-methylsulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyridin-8-yl]-propan-2-ol (75 mg), 4-methanesulfonylmethyl-cyclohexylamine (162 mg), and TEA (0.165 mL) in NMP (2 mL) was stirred at 100° C. overnight. The reaction mixture was then cooled to RT, and diluted with water. The resulting precipitate was filtered and dried, then purified by ISCO using 100% DCM to 10% MeOH/DCM. The fractions were collected, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide 2-{3-[2-(4-methanesulfonylmethyl-cyclohexylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyridin-8-yl}-propan-2-ol (Compound 1, 55.5 mg). Mp=223-224° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[NH:5][CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)[CH3:2].O[C:24]([C:27](O)(C)C)([CH3:26])[CH3:25].CC(C)=CB([O-])[O-].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCCC1>O>[CH2:1]([O:3][C:4](=[O:22])[NH:5][CH:6]1[CH2:9][C:8]2([CH2:14][CH2:13][N:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:25]=[C:24]([CH3:27])[CH3:26])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)[CH2:7]1)[CH3:2]
Reactant: CCOC(=O)NC1CC2(CCN(c3ccc(Br)cn3)CC2)C1
Reactant: CC(C)(O)C(C)(C)O
Agent: CC(C)=CB([O-])[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)NC1CC2(CCN(c3ccc(C=C(C)C)cn3)CC2)C1
Yield: 83.5 %

Procedure:
The process is performed according to the method described in Example 2 (step 2.7.). Starting with 0.50 g (1.36 mmol) of ethyl[7-(5-bromopyridin-2-yl)-7-azaspiro[3.5]non-2-yl]carbamate, prepared in the preceding step, 0.33 mL (1.63 mmol) of pinacol 2-methyl-1-propenylboronate (commercial) and 1.33 g (4.07 mmol) of caesium carbonate, suspended in 9 mL of a 9/1 mixture of tetrahydrofuran and water, and 0.11 g (0.14 mmol) of PdCl2dppf.CH2Cl2, and after purifying on a column of silica gel, eluting with a 100/0/0 to 99/1/0.1 mixture of dichloromethane, methanol and 28% aqueous ammonia, 0.39 g of expected product is obtained in the form of a wax.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([F:14])[C:10]=2[O:12][CH3:13])[C:5](=[O:16])[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3]1.[N+:22]([O-])([O-:24])=[O:23].[K+]>OS(O)(=O)=O>[CH3:1][N:2]1[C:11]2[C:6](=[C:7]([N+:22]([O-:24])=[O:23])[C:8]([F:15])=[C:9]([F:14])[C:10]=2[O:12][CH3:13])[C:5](=[O:16])[C:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:3]1
Reactant: O=[N+]([O-])[O-]
Reactant: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CCOC(=O)c1cn(C)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
A solution of ethyl 1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylate (800 mg, 2.69 mmol) in concentrated H2SO4 (7 mL) was treated portionwise at 0° C. with solid KNO3 (380 mg, 3.76 mmol). After stirring at 0° C. for 1 h, the reaction mixture was poured into ice-water and the resulting precipitate was removed by filtration. The resulting solid washed with EtOH, dried to yield ethyl 1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (765 mg, 83%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([C:17]#[N:18])[C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[C:6]([Cl:19])=[CH:5][C:3]=1[NH2:4].[F:20][C:21]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:22]=1[C:23]([N:25]=[C:26]=[O:27])=[O:24]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:8]=[C:7]([CH:9]([C:17]#[N:18])[C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)[C:6]([Cl:19])=[CH:5][C:3]=1[NH:4][C:26]([NH:25][C:23](=[O:24])[C:22]1[C:28]([F:32])=[CH:29][CH:30]=[CH:31][C:21]=1[F:20])=[O:27]
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: N#CC(c1ccc(F)cc1)c1cc(Cl)c(N)cc1Cl
Solvent: Cc1ccccc1
Product: N#CC(c1ccc(F)cc1)c1cc(Cl)c(NC(=O)NC(=O)c2c(F)cccc2F)cc1Cl
Temperature: 25 °C

Procedure:
Into a 100 milliliter round bottom flask equipped with a thermometer, magnetic stirrer and condenser was added 30 milliliters of toluene, 1.2 grams (0.004 moles) of 2,5-dichloro-4-(alpha-cyano-4-fluorobenzyl)aniline prepared in Part B and 1.0 grams (0.005 moles) of 2,6-difluorobenzoyl isocyanate under a nitrogen atmosphere at ambient temperature. The reaction mixture was then heated in an oil bath for a period of 2 hours. After cooling to ambient temperature, the reaction mixture was filtered and dried overnight in a vacuum oven at 50° C. This afforded 1.3 grams of a white solid having a melting point of 216° C.-218° C. Elemental analysis of the white solid indicated the following:
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:21]([O:23][C:24]([N:26]=[C:27]=[S:28])=[O:25])[CH3:22]>CN(C=O)C.C(OCC)(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH:15][CH2:16][C:27]([NH:26][C:24]([O:23][CH2:21][CH3:22])=[O:25])=[S:28])[CH:12]=[CH:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Reactant: CCOC(=O)N=C=S
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)NC(=S)CNc1ccc(C(=O)OC)c(S(=O)(=O)NC(C)(C)C)c1
Yield: 75 %

Procedure:
1.20 g (4.0 mmol) of N-tert-butyl-2-methoxycarbonyl-5-methylaminobenzenesulfonamide is dissolved in 5 ml of anhydrous DMF, and 0.60 g (4.3 mmol) of 95% strength ethoxycarbonyl isothiocyanate is added. After 3 h at room temperature the mixture is taken up in ethyl acetate and washed with 1N hydrochloric acid and water. The organic phase is dried over magnesium sulfate and the solvent is removed by distillation. The residue is taken up in a little ethyl acetate and precipitated with heptane at -25° C. The precipitate is filtered off with suction and dried to give 1.29 g (75% of theory) of colorless N-tert-butyl-5-[N-(ethoxycarbonylaminothiocarbonyl)methylamino]-2-methoxycarbonylbenzenesulfonamide. m.p.: 110° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]2[CH:21]=[CH:20][CH:19]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:32]1[C:33]2[C:38]([C:39]([Br:46])=[C:40]3[C:45]=1[CH:44]=[CH:43][CH:42]=[CH:41]3)=[CH:37][CH:36]=[CH:35][CH:34]=2.C([O-])([O-])=O.[Na+].[Na+].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.O1CCCC1>[Br:46][C:39]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([C:20]2[CH:21]=[C:16]([C:8]3[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH:17]=[CH:18][CH:19]=2)=[C:45]2[C:40]=1[CH:41]=[CH:42][CH:43]=[CH:44]2
Reactant: CC1(C)OB(c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)OC1(C)C
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
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: C1CCOC1
Solvent: O
Product: Brc1c2ccccc2c(-c2cccc(-c3nc4ccccc4n3-c3ccccc3)c2)c2ccccc12
Temperature: 85 °C
Yield: 75.1 %

Procedure:
Compound 5 (see WO 2007046658 A1, US 20070205412 A1 and WO 2007086695 A1, which are incorporated by reference herein for their relevant teachings) was prepared as follows: a mixture of Compound 2 (5.270 g, 13.30 mmol), 9,10-dibromoanthracene (13.41 g, 39.90 mmol), tetrakis(triphenylphosphine)palladium(0) (0.922 g, 0.798 mmol), Na2CO3 (9.539 g, 90.00 mmol), H2O (90 mL) and tetrahydrofuran (THF) (150 mL) was degassed with argon for 1.5 h. while stirring. The reaction mixture was then maintained under argon at 85° C. while stirring for 46 h. Upon completion, the reaction was cooled to RT and poured over dichloromethane (about 500 mL). The soluble organics were then washed with H2O and brine, dried over MgSO4, filter and concentrated in vacuo. The crude product was purified via flash chromatography (SiO2, 100% dichloromethane) to provide Compound 5 (5.25 g, 75%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[CH:10][C:4]=2[O:3]1.Cl[CH:19](Cl)[O:20]C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:17])[CH2:6][C:5]2[CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:9]=[C:10]([CH:19]=[O:20])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(-c3ccccc3)ccc2O1
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)Cc2cc(-c3ccccc3)cc(C=O)c2O1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran (544) (2.24 g, 10.0 mmol) in dichloromethane (15 mL) was added slowly titanium tetrachloride (2 mL, 18 mmol). After stirring of 5 minutes, dichloro(methoxy)methane (1 mL, 1 μmol) was added slowly. The resulting mixture was stirred at 0° C. for 3 hours, quenched slowly with ice water. The product was extracted with dichloromethane. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide 2,2-dimethyl-5-phenyl-2,3-dihydrobenzofuran-7-carbaldehyde (545).
Reaction SMILES: [OH-:1].[K+].C([O:11][CH:12]1[CH2:17][C:16]([CH3:19])([CH3:18])[N:15]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1)(=O)C1C=CC=CC=1>C(O)C>[OH:1][CH:12]1[CH2:17][C:16]([CH3:18])([CH3:19])[N:15]([O:20][CH:21]([O:20][N:15]2[C:14]([CH3:29])([CH3:30])[CH2:13][CH:12]([OH:11])[CH2:17][C:16]2([CH3:18])[CH3:19])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]([CH3:30])([CH3:29])[CH2:13]1
Reactant: CCCCCCCCON1C(C)(C)CC(OC(=O)c2ccccc2)CC1(C)C
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCCC(ON1C(C)(C)CC(O)CC1(C)C)ON1C(C)(C)CC(O)CC1(C)C

Procedure:
The title compound is prepared by basic hydrolysis (potassium hydroxide in ethanol) of the compound prepared in Example 22A.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][SH:7].C(N(C(C)C)CC)(C)C.Cl[C:23]1[CH:24]=[C:25]([CH3:33])[C:26]([N+:30]([O-:32])=[O:31])=[CH:27][C:28]=1[CH3:29]>CN1CCCC1=O>[N+:30]([C:26]1[CH:27]=[C:28]([CH3:29])[C:23]([S:7][CH2:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:11])([F:12])[F:1])[CH:4]=2)=[CH:24][C:25]=1[CH3:33])([O-:32])=[O:31]
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1Cl
Reactant: FC(F)(F)c1cccc(CS)c1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])c(C)cc1SCc1cccc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
A mixture of 3-trifluoromethylbenzyl mercaptan (3.42 g), diisopropylethylamine (2.3 g) and 3-chloro-6-nitro-p-xylene (3.0 g) in dry N-methylpyrrolidinone (20 ml) was heated at 130° C. for 6 hours. On cooling, the mixture was poured into ice-water and the resulting mixture was filtered to give a solid which was washed with ice-water and then air dried. The solid was purified by silica gel chromatography eluting with light petroleum (60-80° C.)/ethyl acetate (9:1) to give the title product as a solid, m.p. 85-7° C.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][C@H:13]2[O:18][C@@:17]3([C:26]4[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]5[CH:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][CH:29]=5)[CH:25]=4)[CH2:20][O:19]3)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]2[OH:39])(=O)=O)=CC=1.[C:40]([O-])(=[O:42])[CH3:41].[Na+].O>CN(C=O)C>[C:40]([O:11][CH2:12][C@H:13]1[O:18][C@@:17]2([C:26]3[C:21](=[CH:22][C:23]([Cl:36])=[C:24]([CH2:27][C:28]4[CH:35]=[CH:34][C:31]([CH2:32][CH3:33])=[CH:30][CH:29]=4)[CH:25]=3)[CH2:20][O:19]2)[C@H:16]([OH:37])[C@@H:15]([OH:38])[C@@H:14]1[OH:39])(=[O:42])[CH3:41]
Reactant: CC(=O)[O-]
Reactant: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COS(=O)(=O)c3ccc(C)cc3)[C@@H](O)[C@H](O)[C@H]2O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Cc2cc3c(cc2Cl)CO[C@]32O[C@H](COC(C)=O)[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 80 °C
Yield: 38.1 %

Procedure:
To a solution of ((1S,3′R,4′S,5′S,6′R)-5-chloro-6-(4-ethylbenzyl)-3′,4′,5′-trihydroxy-3′,4′,5′,6′-tetrahydro-3H-spiro[isobenzofuran-1,2′-pyran]-6′-yl)methyl 4-methylbenzenesulfonate (20 mg, 0.034 mmol) in 1 mL of DMF, was added sodium acetate (36 mg, 0.44 mmol). The solution was warmed to 80° C. and kept at the same temperature overnight. 5 mL of water was added and the solution was extracted with ethyl acetate. The combined organic layers were washed with brine prior to drying over sodium sulfate. Concentration under reduced pressure provided the crude product, which was purified by preparative TLC to give 6 mg of title compound. 1H NMR (CD3OD, 400 MHz) δ 7.37 (s, 1H), 7.19 (s, 1H), 7.11 (s, 4H), 5.12 (d, J=13.0 Hz, 1H), 5.08 (d, J=13.0 Hz, 1H), 4.32 (dd, J=11.6, 2.0 Hz, 1H), 4.17-4.09 (m, 3H), 3.99-3.94 (m, 1H), 3.77-3.68 (m, 2H), 3.43 (dd, J=9.8, 8.6 Hz, 1H), 2.60 (q, J=7.6 Hz, 2H), 1.99 (s, 3H), 1.20 (t, J=7.6 Hz, 3H); MS ESI (m/z) 485 (M+Na)+, calc. 462.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])=[CH2:3].CO.[H][H]>CO.O1CCCC1.C(C1C=C(C(C)(C)C)C2OP([C-]3C=CC=C3)OC3C(C(C)(C)C)=CC(C(C)(C)C)=CC=3C=2C=1)(C)(C)C.[C-]1(P2OC3C(C(C)(C)C)=CC(C(C)(C)C)=CC=3C3C=C(C(C)(C)C)C=C(C(C)(C)C)C=3O2)C=CC=C1.[Fe+2]>[CH3:3][CH:2]([CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:1]([O:10][CH3:11])=[O:9]
Reactant: [H][H]
Reactant: C=C(CC(=O)OC)C(=O)OC
Agent: [Fe+2]
Agent: CC(C)(C)c1cc(C(C)(C)C)c2op(-[c-]3cccc3)oc3c(C(C)(C)C)cc(C(C)(C)C)cc3c2c1
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CC(C)C(=O)OC
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A mixture of 33 mg (0.031 mmol) of the ferrocenyl bis(phosphonite) prepared in Example 1 and 12 mg (0.031 mmol) of bis(bicyclo[2.2.1]hepta-2,5-diene)rhodium(I) perchlorate in 2 mL of methanol/tetrahydrofuran (1:1) solution is stirred for two hours. Then, to the resultant solution of rhodium complex is added a solution of 490 mg (3.1 mmol) of dimethyl itaconate and 13 mL of methanol in a pressure reactor. The reactor is then pressurized to 1018 psi with hydrogen and the reaction is stirred at ambient temperature for 88 hours. 1H nmr analysis of the reaction mixtures shows a 100% conversion of dimethyl itaconate starting material to product. Workup of the reaction mixture gives 492 mg (99% yield) of desired dimethyl 2-methylsuccinate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][C:21](I)=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([C:16]([C:18]1[CH:23]=[CH:22][C:21]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])=[CH:20][CH:19]=1)=[CH2:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: C#C[Si](C)(C)C
Reactant: C=C(c1ccc(I)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C=C(c1ccc(C#C[Si](C)(C)C)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
A mixture of 2-(2,4-difluorophenyl)-3-(4-iodophenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (7.0 g, 15.5 mmol-see Preparation 20), trimethylsilylacetylene (2.6 ml, 18.5 mmol), cuprous iodide (0.015 g, 0.15 mmol), bis(triphenylphosphine) palladium (II) dichloride (0.21 g, 0.3 mmol) and triethylamine (80 ml) was stirred at room temperature under a nitrogen atmosphere for 24 hours. Volatile materials were removed under reduced pressure and the residue was partitioned between dichloromethane (200 ml) and a solution of ethylenediaminetetraacetic acid (2 g) in water (100 ml). The organic phase was dried (MgSO4) and evaporated under reduced pressure. The crude product was chromatographed on silica by elution with dichloromethanelmethanol (95:5). Fractions containing the desired product were combined and evaporated under reduced pressure to give 2-(2,4-difluorophenyl)-3-(4-[trimethylsilylethynyl]phenyl)-1-(1,2,4-triazol-1-yl)-3-buten-2-ol (6.4 g, 98%) as a yellow foam which was characterised by 1H-N.M.R. spectroscopy, (300 MHz, CDCl3): δ=0.22 (s,9H), 4.57 (d,1H), 4.89 (d,1H), 5.16 (s,1H), 5.26 (d,2H), 6.60-6.80 (m,2H), 7.21 (d,2H), 7.38 (d,2H), 7.42 (m,1H), 7.80 (s,2H) ppm.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)[CH2:27][CH2:26]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: NC1CCN(C2CCCCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=S(=O)(NC1CCN(C2CCCCC2)CC1)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Temperature: 0 °C

Procedure:
7.8 Grams of 4-(7-Chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred ice-cooled mixture of 3.63 grams of 4-amino-1-cyclohexyl-piperidine and 21.2 grams of sodium carbonate in 60 milliliters of water and 50 milliliters of chloroform. After stirring overnight at room temperature the chloroform layer was separated, washed with water, dried and evaporated to give a brown solid. This was triturated with hexane, the resultant solid dissolved in chloroform and diiso-propyl ether added to precipitate a solid which was triturated with hexane to give 1.9 grams of the title compound as the hemihydrate. Melting point 192°-193°C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.CN(C)CCN(C)C.[Li+].CCC[CH2-].[CH3:22][S:23]SC>>[F:8][C:5]1[CH:4]=[CH:3][C:2]([S:23][CH3:22])=[CH:7][N:6]=1
Reactant: Fc1ccc(Br)cn1
Reactant: CSSC
Agent: CN(C)CCN(C)C
Agent: [CH2-]CCC
Agent: [Li+]
Product: CSc1ccc(F)nc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A mixture of 5-bromo-2-fluoropyridine (2.05 g, 11.7 mmol) and N1,N1,N2,N2-tetramethylethane-1,2-diamine (2.27 mL, 15.1 mmol) was purged with nitrogen for 45 minutes. Toluene (116 mL) was added and the reaction mixture was cooled to −78° C. N-butyllithium (2.5 M in hexanes, 5.59 mL, 14.0 mmol) was added dropwise over 6 minutes. The reaction mixture was stirred at −78° C. for 1 hour. Dimethyl disulfide (1.26 mL, 14.0 mmol) was added. The reaction mixture was stirred at −78° C. for 1 hour. The reaction mixture was warmed to 0° C., then immediately quenched with saturated aqueous ammonium chloride. The layers were separated, and the organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (10% ethyl acetate/heptane) to provide the title compound (1.00 g, 60%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH:24](OC)[O:25]C)=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl.C(=O)(O)[O-].[Na+]>CC(C)=O.O>[CH3:1][C:2]1[NH:3][C:4]([CH:24]=[O:25])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]#[N:19])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C(OC)OC)=C(C(=O)OC)C1c1ccccc1C#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)C1=C(C)NC(C=O)=C(C(=O)OC)C1c1ccccc1C#N
Yield: 98.2 %

Procedure:
To a solution of dimethyl 2-methyl-4-(2-cyanophenyl)-6-dimethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (6.0 g) in acetone (60 mg) was added 6 N hydrochloric acid (6 ml), and the resultant mixture was stirred for 3 hours at room temperature. The reaction mixture was diluted with water (30 ml), and adjusted to pH 7.5 with an aqueous sodium bicarbonate solution, and acetone was distilled off under reduced pressure. The resultant crystalline mass was crushed as finely as possible with a glass rod, washed with an additional water (100 ml), collected by filtration, further washed thoroughly with water, and air-dried to give crystalline powder of dimethyl 2-methyl-4-(2-cyanophenyl)-6-formyl-1,4-dihydropyridine-3,5-dicarboxylate (5.19 g).