Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[C:12]([CH3:17])=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[O:18]1CCOCC1>>[CH3:17][C:12]1[C:11]([C:9]2[CH:8]=[CH:7][NH:6][C:5](=[O:18])[N:10]=2)=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: C1COCCO1
Reactant: Cc1ncccc1-c1ccnc(S(C)(=O)=O)n1
Product: Cc1ncccc1-c1cc[nH]c(=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Methanesulfonyl-4-(2-methyl-pyridin-3-yl)-pyrimidine (446 mg, 1.79 mmol) was dissolved in dioxane (13 ml) and then 2N NaOHaq (8.9 ml, 17.9 mmol) was added. After stirring at room temperature for 1 hour, the solution was acidified with 37% HClaq. The mixture was evaporated and the residue was re-dissolved in DCM-MeOH—NH4OH (95-5-0.5) and evaporated. The crude was purified by flash chromatography with DCM-MeOH (9-1) to give 343 mg of the title compound. (quantitative yield).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[CH2:5][O:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][N:15]([CH3:29])[S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][CH2:9]1.[NH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1>CN(C)C(=O)C>[CH3:29][N:15]([CH2:14][C@H:11]1[CH2:12][CH2:13][C@H:8]([CH2:7][O:6][CH2:5]/[CH:4]=[CH:3]/[CH2:2][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH2:9][CH2:10]1)[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17]
Reactant: C1CCNC1
Reactant: CN(C[C@H]1CC[C@H](COC/C=C/CBr)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Solvent: CC(=O)N(C)C
Product: CN(C[C@H]1CC[C@H](COC/C=C/CN2CCCC2)CC1)S(=O)(=O)c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the method described in example 12.1, trans-N-[4-(4-bromo-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-N-methyl-4-trifluoromethyl-benzenesulfonamide was reacted with pyrrolidine in N,N-dimethylacetamide at room temperature to yield trans-N-methyl-N-[4-(4-pyrrolidin-1-yl-(E)-but-2-enyloxymethyl)-cyclohexylmethyl]-4-trifluoromethyl-benzenesulfonamide as light yellow solid, MS: 489 (MH+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[O:31])=[CH:26][CH:25]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:11][CH:10]=1)(C)(C)C.[ClH:40]>O1CCOCC1>[ClH:40].[ClH:40].[NH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([N:32]5[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]5)=[O:31])=[CH:28][CH:29]=4)=[CH:23][C:18]3=[N:17][CH:16]=2)=[CH:13][CH:14]=1
Reactant: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CNC(=O)OC(C)(C)C)cc5)cnc4c3)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CN1CCN(C(=O)c2ccc(-c3ccn4c(-c5ccc(CN)cc5)cnc4c3)cc2)CC1
Yield: 100 %

Procedure:
Combine (4-{7-[4-(4-methyl-piperazine-1-carbonyl)-phenyl]-imidazo[1,2-a]pyridin-3-yl}-benzyl)-carbamic acid tert-butyl ester (0.87 g, 1.65 mmol), 4N HCl in 1,4-dioxane (15 mL, 60 mmol) in 1,4-dioxane (35 mL) and stir overnight (16 hours). Concentrate slurry to a residue. Dissolve residue in methanol (50 mL) and concentrate to afford the title compound (0.90 g, 100%). MS(ES), m/z 426 (M+1 for free base).
Reaction SMILES: [BH4-].[Na+].[CH2:3]([C:7]1[N:8]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Cl>C(O)C>[CH2:3]([C:7]1[N:8]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)[C:23]([OH:25])=[O:24])=[CH:20][CH:21]=2)[C:9]([CH2:13][OH:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc(C(C(=O)O)C2CCCC2)cc1
Reaction time: 1 h

Procedure:
0.1 g (2.9 mmol) of sodium borohydride is added to 1.5 g (2.9 mmol) of the compound from Example V in 25 ml of ethanol. After 1 h at room temperature, the reaction mixture is acidified (pH 4) with 2N HCl and extracted three times with CH2Cl2. The organic phase is dried over Na2SO4 and concentrated, and the product is crystallised from ethyl acetate/petroleum ether. A 1:1 mixture of the diastereomers is obtained.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[C@@H:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:8][C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:4]1=[O:27].[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[ClH:1].[C:28]([O:2][C@H:3]1[C@@H:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)[CH2:8][C:7]2[CH:18]=[CH:19][CH:20]=[CH:21][C:6]=2[N:5]([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[C:4]1=[O:27])(=[O:30])[CH3:29]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc([C@H]2Cc3ccccc3N(CCN(C)C)C(=O)[C@H]2O)cc1
Agent: Cl
Product: COc1ccc([C@H]2Cc3ccccc3N(CCN(C)C)C(=O)[C@H]2OC(C)=O)cc1
Temperature: 100 °C

Procedure:
(cis)-3-Hydroxy-1-[2-(dimethylamino)ethyl]-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one, monohydrochloride (1.27 g, 2.83 mmol) was slurried in 28 ml of acetic anhydride and heated at 100° C. under argon for 3 hours. The resulting solution was then concentrated and the residue dissolved in ethyl acetate. After crystallization commenced, hydrogen chloride saturated ether was added and the mixture was filtered to afford 1.25 g of the desired material as an off-white powder, melting point 215°-216° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=2)=[O:11])=[O:9])=[CH:4][CH:3]=1.[C:19]1([C:25]#[CH:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(NCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[C:19]1([C:25]#[C:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:10]#[C:8][C:5]4[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=4)=[CH:14][CH:13]=3)=[O:11])=[O:9])=[CH:4][CH:3]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: C#Cc1ccccc1
Reactant: O=C(C(=O)c1ccc(Br)cc1)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: O=C(C(=O)c1ccc(C#Cc2ccccc2)cc1)c1ccc(C#Cc2ccccc2)cc1

Procedure:
A solution of 4,4′-dibromobenzil (15.8 g, 0.0431 mol), phenylacetylene (5.06 g, 0.0495 mol), (PPh3)2PdCl2 (0.151 g, 0.0002 mol) and CuI (0.820 g, 0.0043 mol) in diethylamine (150 mL) is heated at reflux overnight. The reaction mixture is concentrated to dryness, then taken up in CH2Cl2 (150 mL), washed with 1 M HCl, 10 percent Na2CO3/H2O, brine and dried (Na2SO4), then concentrated. Crystallization from 2-propanol gives 7.92 g (45 percent) as a light tan solid, mp 168° C. to 170° C. 1H NMR (CDCl3) δ 7.97 (d, J=8.2 Hz, 4H), 7.64 (d, J=8.2 Hz, 4H), 7.55 (m, 4H), 7.37 (m, 6H); 13C NMR (CDCl3) δ 193.03, 132.46, 132.03, 131.82, 130.21, 129.84, 129.06, 128.47, 122.37, 94.28, 88.55.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[C:13]([NH:14][C:15]3[C:16]4[C:23]([CH3:24])=[C:22]([C:25](OC)=[O:26])[S:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:12][CH:11]=[C:10]([C:29]([F:32])([F:31])[F:30])[N:9]=2)[CH2:3][CH2:2]1.[OH-].[Na+].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:68][N:69]([CH3:74])[CH2:70][CH2:71][CH2:72][NH2:73]>CCO.C1COCC1.C(Cl)Cl.OS([O-])(=O)=O.[K+]>[O:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[C:13]([NH:14][C:15]3[C:16]4[C:23]([CH3:24])=[C:22]([C:25]([NH:73][CH2:72][CH2:71][CH2:70][N:69]([CH3:74])[CH3:68])=[O:26])[S:21][C:17]=4[N:18]=[CH:19][N:20]=3)=[CH:12][CH:11]=[C:10]([C:29]([F:31])([F:32])[F:30])[N:9]=2)[CH2:5][CH2:6]1
Reactant: CN(C)CCCN
Reactant: COC(=O)c1sc2ncnc(Nc3ccc(C(F)(F)F)nc3OC3CCOCC3)c2c1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(C(F)(F)F)nc3OC3CCOCC3)c12
Temperature: 25 °C
Reaction time: 24 h
Yield: 6.4 %

Procedure:
To a suspension of methyl 4-(2-(tetrahydro-2H-pyran-4-yloxy)-6-(trifluoromethyl)-pyridin-3-ylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylate (0.139 g, 0.29 mmol) in EtOH/THF (5 mL; 3:2) was added aqueous sodium hydroxide (2 M, 0.625 mL, 1.25 mmol) and the reaction mixture stirred at ambient temperature for 24 hours. The mixture was diluted with DCM and 10% aqueous KHSO4 and the mixture separated. The organic phase was washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was diluted with DMF (2.0 mL) and cooled in ice-water. Hünig's base (44 L, 0.25 mmol) and HATU (0.105 g, 0.28 mmol) were added and the mixture was stirred at this temperature for 20 minutes when 3-(dimethylamino)-propylamine (0.136 mL, 1.24 mmol) was added. The coolant was removed and the reaction stirred at ambient temperature for 18 hours. The mixture was diluted with EtOAc, washed with water and with brine (×2). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography (100% iso-hexane→100% DCM→250:10:1 DCM/MeOH/NH4OH) followed by trituration of the major component with diethyl ether to afford the title compound as off-white solid (0.01 g, 8%).
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:48])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH:33]5[CH2:37][O:36]C(C)(C)[O:34]5)[N:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:48])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[C:30]5[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=5)[N:24]([CH2:32][CH:33]([OH:34])[CH2:37][OH:36])[N:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(CC4COC(C)(C)O4)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3nn(CC(O)CO)c4cc(Cl)ccc34)nc12)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
To a solution of 2-[6-chloro-1-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-indazol-3-yl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide (crude from Step 2) in CH2Cl2 (3 mL) was added TFA (1 mL). The reaction mixture was stirred at room temperature for 48 h then concentrated. The residue was redissolved in 10:90:0.5 MeOH/CH2Cl2/NH4OH (3 mL) and stirred at room temperature for 3 h. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with 0% to 10% MeOH/CH2Cl2 to afford 22 mg (20%, 2 steps) of 2-[6-Chloro-1-(2,3-dihydroxy-propyl)-1H-indazol-3-yl]-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a white solid. MS: (M+Na)+=545; mp=165-180° C.; 1H NMR (DMSO-d6, 300 MHz): δ (ppm) 9.14 (s, 1H), 8.69 (d, J=8.7 Hz, 1H), 8.47 (d, J=7.6 Hz, 2H), 7.91 (s, 1H), 7.23 (d, J=6.8 Hz, 1H), 5.15 (d, J=5.3 Hz, 1H), 5.03 (dd, J=5.3, 3.0 Hz, 1H), 4.84 (t, J=5.5 Hz, 1H), 4.35-4.80 (m, 5H), 4.18-4.26 (m, 1H), 3.93-4.15 (m, 2H), 3.79-3.90 (m, 1H), 3.34-3.49 (m, 2H), 1.33-1.45 (m, 3H).
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=1)=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:26][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:27])[C:10]3([CH:9]([C:28]4[CH:33]=[C:32]([F:34])[CH:31]=[C:30]([Cl:35])[CH:29]=4)[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:25]2=[CH:24][CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cc(F)cc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.2 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.5 g, 2.9 mmol) in dichloromethane (18 mL) was added trifluoroacetic acid (7 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a white solid (1.6 g, 96%).
Reaction SMILES: [K+].[CH:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH-:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3].[O-:15][Mn](=O)(=O)=O.[K+].Cl>O>[OH:15][C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CC(C)c1ccc(S([NH-])(=O)=O)nc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(C)(O)c1ccc(S(N)(=O)=O)nc1
Temperature: 25 °C

Procedure:
To a solution of 5-isopropyl-pyridine-2-sulfonamide potassium salt (synthesis described in EP 799 209) in water (10 ml) were added 1.2 g of KMnO4 at RT and the mixture was then refluxed for 30 minutes. The mixture was cooled to RT, acidified with diluted HCl and the product was extracted into AcOEt. The organic layer was washed with water, dried over Na2SO4 and concentrated in vacuo to give (5-(1-hydroxy-1-methyl-ethyl))-pyridine-2-sulfonic acid amide as yellow oil. El mass spectrum, m/e 216 (M calculated for: C8H12N2O3S 216).
Reaction SMILES: [CH3:1][CH:2]([CH3:5])[CH2:3][SH:4].Cl[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:17])[CH:15]=2)[N:10]=[CH:9][C:8]=1[C:18]#[N:19].[H-].[K+]>O1CCCC1>[I:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:18]#[N:19])=[C:7]2[S:4][CH2:3][CH:2]([CH3:5])[CH3:1]
Reactant: CC(C)CS
Reactant: N#Cc1cnc2ccc(I)cc2c1Cl
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)CSc1c(C#N)cnc2ccc(I)cc12

Procedure:
Similar procedure as described in example 28a was used, starting from 2-methyl-propane-1-thiol, 4-chloro-6-iodo-quinoline-3-carbonitrile (example 14c) and potassium hydride in a solvent system of tetrahydrofuran to give 6-iodo-4-isobutylsulfanyl-quinoline-3-carbonitrile. LC-MS m/e 369(MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][CH2:11][C:10]2=O)[CH:6]=[CH:7][CH:8]=1.[CH3:18][O:19][C:20](=[O:41])[CH:21]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOCC>[CH3:18][O:19][C:20](=[O:41])[CH:21]=[C:10]1[CH2:11][CH2:12][C:13]([CH3:16])([CH3:15])[CH2:14][CH:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C2CC(C)(C)CCC2=O)c1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COC(=O)C=C1CCC(C)(C)CC1c1cccc(OC)c1
Yield: 33 %

Procedure:
Dissolve 2-(3-methoxy-phenyl)-4,4-dimethyl-cyclohexanone (13.1 g, 56.4 mmol) in toluene (135 ml), add (triphenyl-λ5-phosphanylidene)-acetic acid methyl ester (28.3 g, 84.6 mmol. Heat reaction mixture at reflux stirring over night. Dilute with ether, filter and concentrate. Chromatograph on a biotage eluting with 10% ethyl acetate in hexanes to give the title compound (5.3 g 33%): 1H NMR (CDCl3) δ 7.27-7.23(m, 1H), 6.88-6.77 (m, 3H),5.01 (s, 1H), 3.77 (s, 3H), 3.56 (s, 3H), 3.53-3.48 (m, 1H), 2.19-2.10 (m, 1H), 1.78-1.58 (m, 3H), 1.46-1.38 (m, 1H), 1.25-1.20 (m, 1H), 1.11 (s, 3H), 0.96 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[CH:16]1[O:20][CH2:19][CH2:18][CH2:17]1>CC(C)=O>[O:20]1[CH2:19][CH2:18][CH2:17][CH:16]1[CH2:15][S:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: Sc1ccc(Br)cc1
Reactant: BrCC1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccc(SCC2CCCO2)cc1
Temperature: 45 °C
Yield: 113.5 %

Procedure:
4-Bromothiophenol (1.9 g, 10 mmol) and potassium carbonate (1.5 g, 11 mmol) were stirred in acetone (40 ml). Tetrahydrofurfurylbromide (2 g, 12 mmol) was added dropwise, and the mixture was then heated at 45° C. for 2 hours. The mixture was allowed to cool, the insolubles removed by filtration and the filter pad washed with acetone. The volatiles were removed from the filtrate by evaporation to give crude 1-(2-tetrahyrofurylmethylthio)-4-bromobenzene (3.1 g) an oil (m/z 273). This crude product was dissolved in methanol (60 ml) and water (10 ml). Oxone (8 g) added in portions and the mixture stirred for 2.5 hours. Water (20 ml) was added and the methanol was removed by evaporation. Further water (20 ml) was added to the aqueous residue, which was then extracted with DCM (2×50 ml). The extracts were combined, washed with brine (15 ml), dried and the solvent evaporated. The residue was purified by chromatography on silica eluting with DCM/isohexane/EtOAc (10:8:2) to give the title compound (1.7 g, 56%) as a solid. NMR (CDCl3): 1.56 (m, 1H), 1.88 (m, 2H), 2.13 (m, 1H), 3.20 (dd, 1H), 3.39 (dd, 1H), 3.72 (m, 2H), 4.26 (m, 1H), 7.68 (d, 2H), 7.79 (d, 2H); m/z 305.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[C:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH2:30])(=[O:22])[NH2:21]>>[C:20]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])(=[O:22])[NH2:21]
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Reactant: NC(=O)Cc1ccccc1N
Product: CCc1cc(-c2cncc(C(=O)Nc3ccccc3CC(N)=O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and (2-carbamoylmethyl-phenyl)-amine to afford the title compound. MS: m/e=391 (M+H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Br)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[C:38]([C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1)#[N:39]>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:43]3[CH:44]=[CH:45][C:40]([C:38]#[N:39])=[CH:41][CH:42]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(Br)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(-c4ccc(C#N)cc4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-Tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-bromo-2-thienylmethyl)-4-chlorobenzene obtained in Example 128-(4) and 4-cyanophenylboronic acid were treated in a manner similar to Example 168-(1) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene as colorless powder. APCI-Mass m/Z 657/659 (M+NH4). (2) The above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-4-chloro-3-(5-(4-cyanophenyl)-2-thienylmethyl)benzene (128 mg) was suspended in ethanol (2 ml) and added thereto was a concentrated hydrochloric acid aqueous solution (1 ml). The mixture was heated reflux for 8.5 hours. The reaction solution was cooled and diluted with ethyl acetate and water. The organic layer was washed with water and successively washed with brine. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=9:1) to give the desired 1-(β-D-glucopyranosyl)-4-chloro-3-(5-(4-ethoxycarbonylphenyl)-2-thienylmethyl)benzene (39 mg) as pale yellow foam. APCI-Mass m/Z 536/538 (M+NH4).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([OH:17])[C:3]=1[CH:4]=[O:5].[C:18](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[Br:1][C:2]1[CH:9]=[C:8]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:7]=[C:6]([O:17][CH3:18])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(O)cc(OC2CCCCO2)cc1Br
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1cc(OC2CCCCO2)cc(Br)c1C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
To a solution of 2-bromo-6-hydroxy-4-(tetrahydro-2H-pyran-2-yloxy)benzaldehyde (4.52 g, 15.0 mmol) in THF (50 mL) was added potassium carbonate (2.07 g, 15.0 mmol), followed by iodomethane (4.23 g, 30.0 mmol). The reaction mixture was stirred at room temperature overnight and quenched by saturated NaHCO3 aqueous solution (20 mL). The resulting mixture was extracted with EtOAc (25 mL×2) and the combined extracts were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (EtOAc/PE=1/8) on silica gel to give the title compound as a white solid. (4.53 g, Yield: 95.8%). 1H NMR (400 MHz, DMSO-d) δ0.19 (s, 1H), 6.98-6.98 (d, J=2.0 Hz, 1H), 6.81-6.82 (d, J=2.0 Hz, 1H), 6.73-6.74 (m, 1H), 3.88 (s, 3H), 3.60-3.75 (m, 2H), 1.75-1.89 (m, 3H), 1.53-1.67 (m, 3H). MS (ESI) m/z=315 [M+H]+.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].S(=O)(=O)(O)O.[CH2:13]([CH:15]1CCC(=O)CC1)[CH3:14]>C(OC(=O)C)(=O)C>[CH3:14][C:13]1([CH3:15])[O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[O:4]1
Reactant: O=C(O)CC(=O)O
Reactant: CCC1CCC(=O)CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Product: CC1(C)OC(=O)CC(=O)O1
Temperature: 25 °C
Yield: 124.9 %

Procedure:
Malonic acid (5.2 g, 0.05 mol) and concentrated sulfuric acid (0.5 ml) were added to acetic anhydride (10 ml), and therein the source compound was dissolved thoroughly while stirring at room temperature. Thereto, 4-ethylcyclohexanone (6.31 g, 0.05 mol) was slowly added dropwise while cooling in an ice bath. The stirring of the admixture was continued in an ice bath, and colorless crystals separated out as the reaction progressed. These crystals were filtered off, washed with distilled water, and dried. Thus, 9.0 g of a meldrum's acid derivative was obtained as colorless crystals (in a 85.1% yield). The thus obtained meldrum's acid derivative (4.25 g, 0.02 mol) and N,N′-1,3-pentadiene-1-yl-5-ylidenedianiline hydrochloride (5.70 g, 0.02 mol) were dissolved in methanol (50 ml), and thereto triethylamine (3.04 g, 0.03 mol) was added. The stirring of the resulting admixture was continued at room temperature to result in deposition of violet crystals. Then, these crystals were filtered off, and washed with methanol. Thus, 5.61 g of violet crystals corresponding to Compound (3-I) was obtained (in a 76.3% yield). These violet crystals (4.40 g, 12.0 mmol) and the Compound (1-I) obtained in the foregoing Synthesis (1.71 g, 6.0 mmol) were dissolved in dimethylformamide (20 ml), and thereto triethylamine (1.82 g, 18 mmol) was added dropwise. The resulting admixture was stirred for 4 hours at 50° C. Thereafter, the reaction solution obtained was admixed with distilled water, and extracted with ethyl acetate. The organic layer thus extracted was purified by column chromatography (dichloromethane/methanol=6/1) on silica gel to give 2.0 g of violet powder corresponding to Compound (3-II) (in a 39.5% yield).