Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([NH:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH2:16]([N:19]1[CH2:24][CH2:23][S:22](=[O:26])(=[O:25])[CH2:21][CH2:20]1)[C:17]#[CH:18].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:10]1[C:3]2[N:4]=[C:5]([C:8]#[N:9])[N:6]=[CH:7][C:2]=2[CH:18]=[C:17]1[CH2:16][N:19]1[CH2:20][CH2:21][S:22](=[O:25])(=[O:26])[CH2:23][CH2:24]1
Reactant: C#CCN1CCS(=O)(=O)CC1
Reactant: CC(C)(C)CNc1nc(C#N)ncc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2CCS(=O)(=O)CC2)cc2cnc(C#N)nc21
Temperature: 80 °C
Reaction time: 31 h
Yield: 1.4 %

Procedure:
To a solution of 0.54 g (2 mmoles) of 5-bromo-4-(2,2-dimethyl-propylamino)-pyrimidine-2-carbonitrile and 0.75 g (4.3 mmoles) of 4-propargylthiomorpholine-1,1-dioxide in 5 ml of DMF are added 0.841 ml (6 mmoles) of triethylamine, 0.38 g (2 mmoles) of copper(I) iodide and 0.14 g (0.2 mmoles) of Pd(PPh3)2Cl2under nitrogen atmosphere. The mixture is stirred for 31 hours at 80° C. The mixture is filtered through celite, diluted with AcOEt, washed with H2O and brine, dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by HPLC(H2O—0.1% TFA/CH3CN—0.1% TFA). Fractions are collected, basified with 5% aqueous NaHCO3, extracted with AcOEt, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The resulting residue is then purified by HPLC (n-Hexane/AcOEt) to give 0.01 g of desired 7-(2,2-dimethyl-propyl)-6-(1,1-dioxo-1λ6-thiomorpholin-4-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 1.4% yield.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:10])[CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][OH:25].C([O-])(O)=O.[Na+]>C1C=CC=CC=1.CCO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]2[O:25][CH2:24][CH2:23][O:7]2)=[C:4]([F:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Solvent: O
Product: Fc1cc(Br)ccc1C1OCCO1
Temperature: 0 °C
Yield: 99 %

Procedure:
A mixture of 4-bromo-2-fluorobenzaldehyde (5.00 g, 24.6 mmol), p-toluenesulfonic acid monohydrate (190 mg, 1.00 mmol) and ethylene glycol (10 mL) were refluxed in benzene (50 mL) and EtOH (10 mL) under a Dean-Stark trap for 3 h. The reaction mixture was cooled and poured into a mixture of 5% aqueous NaHCO3 (100 mL) and ice (100 mL). The mixture was extracted with ether (3×150 mL), and the combined ethereal extracts were washed with brine (200 mL) and dried (MgSO4). Concentration under reduced pressure afforded 6.02 g (99%) of 88 that was used without further purification. 1H NMR (400 MHz, CDCl3): δ 4.01-4.14 (m, 4H), 6.02 (s, 1H), 7.24-7.31 (m, 2H), 7.41 (t, J=7.9 Hz, 1H).
Reaction SMILES: [C:1]1([CH:7]([CH2:11][C:12]([OH:14])=[O:13])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS(O)(=O)=O.[C:20]1(C)C=CC=C[CH:21]=1.[CH3:27][CH2:28]O>>[C:1]1([CH:7]([CH2:11][C:12]([O:14][CH2:27][CH3:28])=[O:13])[C:8]([O:10][CH2:20][CH3:21])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CC(C(=O)O)c1ccccc1
Reactant: CCO
Reactant: Cc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CC(C(=O)OCC)c1ccccc1
Temperature: 25 °C
Yield: 46 %

Procedure:
In Dean-Stark apparatus, a mixture of 37 g (190.5 mmol) of 2-phenylbutanedioic acid, 6 mL of conc. H2SO4, 80 mL of toluene and 80 mL of EtOH is refluxed for 72 hours. After cooling to room temperature, the reaction mixture is concentrated under reduced pressure and then treated with 300 mL of water, and extracted with Et2O (2×400 mL). The organic phases are combined, dried over Na2SO4, filtered and then concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, eluting with a cyclohexane/EtOAc gradient of 0 to 10% EtOAc. 22 g of diethyl 2-phenylbutanedioate are obtained in the form of an oil.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([N:24]3[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]3)=[CH:19][C:18]=2[Cl:32])[CH:13]=[CH:12][C:11]=1[OH:33].C(N(CC)CC)C.[CH3:42][C@H:43]1[CH2:48][C@@H:47]([CH3:49])[CH2:46][NH:45][CH2:44]1>C(COC)OC>[Cl:32][C:18]1[CH:19]=[C:20]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]2)[CH:21]=[C:22]([Cl:23])[C:17]=1[O:16][C:14]1[CH:13]=[CH:12][C:11]([OH:33])=[C:10]([C:9]([N:45]2[CH2:46][C@H:47]([CH3:49])[CH2:48][C@H:43]([CH3:42])[CH2:44]2)=[O:8])[CH:15]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)ccc1O
Reactant: C[C@@H]1CNC[C@H](C)C1
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: C[C@@H]1C[C@H](C)CN(C(=O)c2cc(Oc3c(Cl)cc(-n4ncc(=O)[nH]c4=O)cc3Cl)ccc2O)C1
Reaction time: 2 h

Procedure:
To solution of 5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-(1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (320 mg) and triethylamine (265 μL) in dimethoxyethane (1.3 mL) was added 3,5-cis-dimethylpiperidine (189 mg). After 2 h, the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes) to afford the title compound of this Example as a colorless solid, 130 mg. MS Calc.:505.3 Found:505.2
Reaction SMILES: [H-].[Na+].C(S)C.[Br:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[O:17]C)[C:13]([CH3:20])([CH3:19])[CH2:12][CH:11]=[C:10]2[CH3:21].Cl>CN(C=O)C.O>[Br:6][C:7]1[C:16]([OH:17])=[CH:15][C:14]2[C:13]([CH3:20])([CH3:19])[CH2:12][CH:11]=[C:10]([CH3:21])[C:9]=2[CH:8]=1
Reactant: COc1cc2c(cc1Br)C(C)=CCC2(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCS
Solvent: O
Product: CC1=CCC(C)(C)c2cc(O)c(Br)cc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.5 %

Procedure:
To a suspension of sodium hydride 60% w/w (0.12 g, 3.0 mmol) in 10 mL of DMF under the argon atmosphere was added slowly ethanethiol 98% (0.2 mL, 3.0 mmol), and the resulting solution was stirred for 15 min. A solution 6-bromo-7-methoxy-1,1,4-trimethyl-1,2-dihydronaphthalene (Compound 93, 0.24 g, 0.84 mmol) in 2 mL of DMF was added, and the reaction mixture was refluxed for 4 h, then cooled to room temperature, acidified with 2 N HCl, diluted with water and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to afford 0.23 g (100%) of the title compound as a clear oil.
Reaction SMILES: C[O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1.C1C(=O)N([Br:23])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.O>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:15])=[CH:5][C:6]=1[C:11]([F:14])([F:13])[F:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C)c(C(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)c1ccc(CBr)c(C(F)(F)F)c1
Yield: 140.4 %

Procedure:
4-Methyl-3-(trifluoromethyl)benzoic acid methyl ester (3.73 g, 18.3 mmol) in CCl4 (40 mL) with NBS (3.9 g, 22 mmol) and benzoylperoxide with 25% of water (0.55 g, 1.7 mmol) were stirred and heated to reflux for 6 h. Solvent was evaporated, a water solution of K2CO3 was added and product is extracted with EtOAc to obtain a pale yellow solid (7.64 g, 25.7 mmol). Yield=140% (crude).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1.[CH2:18]([SH:20])[CH3:19].C[O-].[Na+]>CO>[ClH:1].[ClH:1].[CH2:18]([S:20][C:2]1[C:3]([O:8][CH2:9][CH:10]([OH:17])[CH2:11][NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[N:4][CH:5]=[CH:6][N:7]=1)[CH3:19]
Reactant: CC(C)(C)NCC(O)COc1nccnc1Cl
Reactant: CCS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCSc1nccnc1OCC(O)CNC(C)(C)C
Product: Cl

Procedure:
13.0 g of 3-chloro-2-(3-tert.-butylamino-2-hydroxy-1-propyloxy)-pyrazine, 4.65 g of ethylmercaptan and 4.05 g of sodium methylate in 250 ml of methanol are refluxed for 30 hours. After processing according to Example 8, there is obtained 14.0 g of crude base, and from this, with ethereal hydrochloric acid, there is obtained 3-ethylthio-2-(3'-tert.-butylamino-2'-hydroxy-1-propyloxy)-pyrazine-hydrochloride, which is recrystallised from methanol/ether; m.p 147°-148°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:20][CH3:21])=[CH:9][C:10]=2[O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[N:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:27]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[NH:25][N:24]=1.C(OCC)C>CC(N(C)C)=O.Cl.O1CCOCC1>[CH3:21][O:20][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:22][C:23]3[NH:24][N:25]=[C:26]([CH2:28][C:29]([OH:31])=[O:30])[CH:27]=3)=[N:3][CH:4]=[N:5]2)=[C:10]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)[CH:9]=1
Reactant: Nc1cc(CC(=O)O)[nH]n1
Reactant: COc1cc(OC2CCN(C)CC2)c2c(Cl)ncnc2c1
Agent: Cl
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Solvent: C1COCCO1
Product: COc1cc(OC2CCN(C)CC2)c2c(Nc3cc(CC(=O)O)n[nH]3)ncnc2c1
Yield: 91.3 %

Procedure:
4-chloro-7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazoline (307 mg, 0.85 mmol) was condensed with (3-amino-1H-pyrazol-5-yl)acetic acid (132 mg, 0.93 mmol) in dimethylacetamide (3 ml) and hydrochloric acid in dioxane (4.0 N solution, 467 μl) at 90° C. for 1 hour. The solvent was evaporated, and the residual oil was triturated with ethanol:diethyl ether to yield [5-({7-methoxy-5-[(1-methylpiperidin-4-yl)oxy]quinazolin-4-yl}amino)-1H-pyrazol-3-yl]acetic acid as a beige solid (320 mg, 78% yield):
Reaction SMILES: C[C:2]1[CH2:7][CH2:6][CH2:5][C:4](C)(C)[C:3]=1/[CH:10]=C/C(/C)=C/C=C/C(/C)=C/CO.[CH3:22][C:23]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:24]=1[CH2:25]Cl.CC[O:34][CH2:35][CH3:36]>>[CH3:22][C:23]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:24]=1[CH2:25][O:34][CH2:35][C:36]1[CH:4]=[C:3]([CH3:10])[CH:2]=[CH:7][C:6]=1[CH3:5]
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Reactant: CCOCC
Reactant: Cc1ccc(C)c(CCl)c1
Product: Cc1ccc(C)c(COCc2cc(C)ccc2C)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Retinyl 2,5-Dimethylbenzyl Ether (3c) was prepared from retinol and 2,5-dimethylbenzyl chloride as outlined by the general procedure. The reaction mixture was stirred at room temperature during 2 hr and at 80° C. during 3 hr. After the crude product had been obtained from the ether extract, successive chromatographic operations were performed on silica gel 60 as follows: flash chromatography with 2:1 chloroform-pentane; flash chromatography with 95:5 cyclohexane-ethyl acetate; gravity chromatography with 97:3 cyclohexane-ethyl acetate. The product obtained by combining the purified specimens from each chromatographic procedure was a syrup: yield, 30%; HPLC (at 340 nm or 254 nm), 100%; MS m/z 404 (M), 285 (C2OF29O), 269 (C20H29), 255 (C19H27), 119 (2,5-dimethylbenzyl); UV λmax326 nm (ε 50 800), 251 (6100); 1H NMR (CDCl3) δ 7.14 (bs, 1H, H6′), 7.04 (bd, 1H, H3′, J3′,4′=7.7 Hz), 7.00 (dd, 1H, H4′, J4′,6′=1.6 Hz), 6.60 (dd, 1H, H11, J10,11=11.1 Hz, J11,12=15.1 Hz), 6.31 (d, 1H, H12), 6.15 (d, 1H, H8, J7,8=16.2 Hz), 6.11 (d, 1H, H7), 6.09 (d, 1H, H10), 5.70 (t, 1H, H14), 4.48 (s, 2H, H21), 4.20 (d, 2H, H15, J14,15=6.8 Hz), 2.31 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.01 (t, 2H, H14), 1.95 (d, 3H, H19, J10,19=0.6 Hz), 1.85 (bs, 3H, H20), 1.71 (s, 3H, H18), 1.65-1.57 (m, 2H, H3), 1.48-1.44 (m, 2H, H2), 1.02 (s, 6H, H16, H17). Anal. Calcd. for C29H40O: C, 86.08; H, 9.96. Found: C, 85.75; H, 10.32.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][S:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[O:10])=[CH:5][C:4]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:34][CH2:33][CH:32]([C:35]([F:38])([F:37])[F:36])[CH2:31][CH2:30]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1.ClC1C=C(C=CC=1)C(OO)=[O:46].C(Cl)(Cl)Cl.P(Br)(Br)Br>[Cl-].[Na+].O.O.C(Cl)Cl>[F:40][C:2]([F:1])([F:39])[C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][S:9]([C:11]([CH3:12])([CH3:14])[CH3:13])(=[O:46])=[O:10])=[CH:5][C:4]=1[NH:17][C:18]1[N:22]([CH3:23])[C:21]2[CH:24]=[C:25]([N:29]3[CH2:30][CH2:31][CH:32]([C:35]([F:37])([F:36])[F:38])[CH2:33][CH2:34]3)[C:26]([Cl:28])=[CH:27][C:20]=2[N:19]=1
Reactant: Cn1c(Nc2cc(CNS(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: BrP(Br)Br
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cn1c(Nc2cc(CNS(=O)(=O)C(C)(C)C)ccc2C(F)(F)F)nc2cc(Cl)c(N3CCC(C(F)(F)F)CC3)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of N-(4-trifluoromethyl-3-(5-chloro-1-methyl-6-(4-trifluoromethyl-piperidin-1-yl)-1H-benzo[d]imidazol-2-ylamino)benzyl)-2-methylpropane-2-sulfinamide (140 mg, 0.23 mmol), m-chloroperoxybenzoic acid (198 mg, 1.15 mmol) and CHCl3 (7 mL) was stirred at rt for 15 min. The mixture was poured into brine and extracted with DCM. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was mixed with PBr3 (144 mg, 0.50 mmol) and DCM (5 ml) and the mixture was stirred at rt overnight. The mixture was poured into H2O and extracted with DCM. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated. Purification by column chromatography gave the title compound.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]2=[C:11]([C:14]([OH:16])=O)[N:12]=[CH:13][N:3]12.C(N(CC)CC)C.[CH2:24]([O:31][NH2:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1.CN(C=O)C>[CH2:24]([O:31][NH:32][C:14]([C:11]1[N:12]=[CH:13][N:3]2[C:2](=[O:1])[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]=12)=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NOCc1ccccc1
Reactant: C#CCn1nnc2c(C(=O)O)ncn2c1=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C#CCn1nnc2c(C(=O)NOCc3ccccc3)ncn2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
4-oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxylic acid (0.46 mmol, 100 mg, 1 eq.), O-Benzotriazole-N,N,N′,N′-tetramethyl-uronium-hexafluoro-phosphate (HBTU) (0.55 mmol, 208 mg, 1.2 eq.) and triethylamine (0.55 mmol, 77 μL, 1.2 eq.) were dissolved in THF (30 mL) and DMF (1 mL). The mixture was stirred at room temperature for 1 hour before adding O-benzylhydroxylamine (0.55 mmol, 68 mg, 1.2 eq.) in one portion. After 24 hours of room temperature stirring, the volume of the solution was reduced to 5 mL and poured into ice/water. The formed solid was filtered and washed with water, ethyl acetate and ether, and dried under vacuum. Yield: 72%. δH (DMSO-d6) 11.93 (1H, bs), 8.89 (1H, s), 7.48 (2H, m), 7.40 (3H, m), 5.15 (2H, d, J: 1.84), 4.97 (2H, s), 3.53 (1H, bs).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][N:9]([CH2:21][CH2:22][CH3:23])[CH:10]2[CH2:19][CH2:18][C:17]3[C:16]([OH:20])=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:11]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[C:25]1[C:33](O)=[O:34]>>[OH:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH2:18][CH2:19][CH:10]([N:9]([CH2:21][CH2:22][CH3:23])[CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][N:4]([C:33]([C:25]3[NH:24][C:32]4[C:27]([CH:26]=3)=[CH:28][CH:29]=[CH:30][CH:31]=4)=[O:34])[CH2:3][CH2:2]1)[CH2:11]2
Reactant: CCCN(CCN1CCNCC1)C1CCc2c(O)cccc2C1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Product: CCCN(CCN1CCN(C(=O)c2cc3ccccc3[nH]2)CC1)C1CCc2c(O)cccc2C1
Yield: 49.6 %

Procedure:
Compound 40e was prepared following Procedure G using 39b (43 mg, 0.14 mmol) and indole-2-carboxylic acid (30 mg, 0.19 mmol) to give 40e (32 mg, 62%) after column chromatography. 1H NMR (400 MHz, CD3OD) δ 1.02-1.06 (t, 3H, J=7.2 Hz), 1.77-1.79 (m, 3H), 2.27 (m, 1H), 2.63-2.66 (bs, 4H), 3.03-3.16 (m, 5H), 3.30-3.41 (m, 3H), 3.89 (bs, 4H), 6.59-6.61 (d, 1H, J=7.6 Hz), 6.63-6.65 (d, 1H, J=8 Hz), 6.84 (s, 1H), 6.94-6.98 (t, 1H, J=7.2 Hz), 7.04-7.08 (t, 1H, J=7.2 Hz), 7.19-7.23 (t, 1H, J=7.2 Hz), 7.41-7.61 (d, 1H, J=8 Hz), 7.59-7.61 (d, 1H, J=8 Hz). The free base of 40e was then converted into its HCl salt. m.p. 166-165° C. Anal. [C28H36N4O2.3HCl] C, H, N.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])(=[O:16])=[O:15])[CH2:11][N:10]2[C:24]([C:26]2([C:30]3[C:35]([F:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=3)[CH2:29][NH:28][CH2:27]2)=[O:25])=[O:8])[CH2:5][CH2:4]1)#[N:2].[C:38]([O-])(=O)C.[Na+].C(O)(=O)C.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])(=[O:15])=[O:16])[CH2:11][N:10]2[C:24]([C:26]2([C:30]3[C:35]([F:36])=[CH:34][C:33]([Br:37])=[CH:32][N:31]=3)[CH2:29][N:28]([CH3:38])[CH2:27]2)=[O:25])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccccc3Cl)CN2C(=O)C2(c3ncc(Br)cc3F)CNC2)CC1
Reactant: CC(=O)[O-]
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CC(C(=O)N2C[C@H](S(=O)(=O)c3ccccc3Cl)C[C@H]2C(=O)NC2(C#N)CC2)(c2ncc(Br)cc2F)C1
Reaction time: 0.75 h
Yield: 40.3 %

Procedure:
To a mixture of example 13 (0.05 g, 81.8 μmol, Eq: 1.00), sodium acetate (14.8 mg, 180 μmol, Eq: 2.2) and acetic acid (10.8 mg, 10.3 μl, 180 μmol, Eq: 2.2) in dichloromethane (0.5 ml) was added at 25° C. aqueous formaldehyde solution (36%; 19.1 mg, 17.5 μl, 229 μmol, Eq: 2.8). The mixture was stirred for 45 min, then sodium triacetoxyborohydride (55.5 mg, 262 μmol, Eq: 3.2) was added in one portion at 0-5° C. The cooling bath was removed after 10 min and stirring was continued at 25° C. for further 18 h. The reaction mixture was quenched with aqueous 0.5 M NaOH-solution (2 ml), stirred for 2 min, then the layers were separated. The aqueous layer was extracted with three portions of AcOEt (each 5 ml). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by preparative HPLC to yield the title compound as a colorless amorphous solid (0.0206 g; 40%). m/z=626.1 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1)#[N:2].C(OC1C=C(C=C(OCC2C=CC=CC=2)C=1)CN)C1C=CC=CC=1>>[OH:8][CH2:7][C:6]1[CH:9]=[CH:10][C:3]([CH2:1][NH2:2])=[CH:4][CH:5]=1
Reactant: N#Cc1ccc(C=O)cc1
Agent: NCc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Product: NCc1ccc(CO)cc1
Yield: 46 %

Procedure:
This compound was prepared by reduction of 4-cyanobenzaldehyde according to the procedure described in preparation of 3,5-dibenzyloxybenzylamine. Yield was 46%: MP 102-123° C.; 1H NMR (Acetone-d6, 500 MHz) 7.27 (m, complex 4H), 4.58 (s, 2H), 3.72 (s, 2H), 3.69 (s, 1H) 2.77 (br, 1H), 2.45 (br, 1H).
Reaction SMILES: CO.C([Cl:6])(=O)C.[C:7]([O:11][C:12](=[O:30])[C@@H:13]([NH:22]C(OC(C)(C)C)=O)[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)([CH3:10])([CH3:9])[CH3:8]>C(OCC)(=O)C>[ClH:6].[C:7]([O:11][C:12](=[O:30])[C@@H:13]([NH2:22])[CH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(F)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of ethyl acetate (10 mL) and methanol (0.60 mL, 14.7 mmol) was cooled to 0° C. under an argon atmosphere. Acetyl chloride (1.05 mL, 14.7 mmol) was added dropwise, and the solution warmed to rt and stirred for 30 min. 2-(S)-tert-butoxycarbonylamino-3-(4-fluorophenyl)propionic acid tert-butyl ester (Preparation 113, 1 g, 2.95 mmol) was added, and the reaction mixture stirred at rt for 4 h. The reaction mixture was filtered, washed several times with diethyl ether and dried under vacuum to give the title compound. δH (DMSO): 1.30 (9H, s), 3.01 (1H, dd), 3.20 (1H, dd), 4.08 (1H, m), 7.15 (2H, m), 7.32 (2H, m), 8.64 (3H, br s).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([S:10][CH2:11][CH2:12][N:13]3[C:17](=[O:18])[CH2:16][S:15][C:14]3=[O:19])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:20](=O)[CH2:21][CH2:22][CH3:23].N1CCCCC1>C(O)C>[CH:20](=[C:16]1[S:15][C:14](=[O:19])[N:13]([CH2:12][CH2:11][S:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:17]1=[O:18])[CH2:21][CH2:22][CH3:23]
Reactant: O=C1CSC(=O)N1CCSc1cccc2nccn12
Reactant: CCCC=O
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCSc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.49 g (3.9 mmol) of 3-[2-(imidazo-[1,2-a]pyridin-5-ylthio)ethyl]thiazolidine-2,4-dione and 0.36 ml (4.0 mmol) of n-butyraldehyde in 30 ml of ethanol, 0.04 ml (0.4 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=2/1→1/4), followed by recrystallization (solvent, chloroform-diethyl ether-n-hexane) to yield 0.872 g (56.1%, white crystal) of the desired product.
Reaction SMILES: C([O:4][CH:5]1[S:22][C@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(O)(=O)C.Cl>CN(C)C=O.CNN>[C:8]([O:7][C@@H:6]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:21]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[S:22][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)OC[C@H]1SC(OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CNN
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)OC[C@H]1SC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 88.2 %

Procedure:
To a solution of 1,2,3,4,6-penta-O-acetyl-5-thio-D-glucopyranose (34.0 g, 0.0837 mol) in N,N-dimethylformamide (200 mL), a mixture of methylhydrazine (6.70 mL, 0.125 mmol), acetic acid (7.2 mL, 0.125 mol) and N,N-dimethylformamide (25 mL) was added under ice cooling. After stirring the raction mixture at room temperature for 2.5 hours, 0.5M HCl (300 mL) was added under ice cooling, and the resulting mixture was then extracted twice with ethyl acetate (250 mL). The combined organic phases were washed sequentially with water (200 mL), saturated aqueous NaHCO3 (100 mL), water (100 mL) and saturated aqueous sodium chloride (100 mL), followed by addition of MgSO4 and activated charcoal (1 g). After filtration to remove the insoluble materials, the filtrate was concentrated under reduced pressure. The resulting residue was crystallized from isopropyl ether (70 mL) to give 2,3,4,6-tetra-O-acetyl-5-thio-glucopyranose (26.9 g, 88%) as a colorless crystal.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[Br:18][CH2:19][CH2:20][CH2:21][CH2:22]Br>CCCCC>[Br:18][CH2:19][CH2:20][CH2:21][CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: BrCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCC
Product: O=C(c1ccccc1)c1ccc(OCCCCBr)cc1
Temperature: 25 °C
Reaction time: 20.5 h

Procedure:
Combine 4-hydroxybenzophenone (14.11 g, 71.2 mmol) and aqueous 1M sodium hydroxide solution (70 mL). Add 1,4-dibromobutane (43.4 g, 200 mmol). Heat the reaction mixture to reflux. After 20.5 hours, cool to ambient temperature. Add pentane (100 mL) and again heat to reflux. After 0.5 hours, cool to ambient temperature to give a solid. Collect the solid by filtration. recrystallize the solid from ethanol to give the title compound: mp; 42°-43° C.