Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=1[Cl:12])=[O:4].[S:22]([O-:26])([OH:25])(=[O:24])=[O:23].[K+].CC(C)=O>O>[CH3:1][O:2][C:3]([C@@H:5]([N:13]1[CH2:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH2:15][CH2:14]1)[C:6]1[C:11]([Cl:12])=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[OH:25][S:22]([OH:26])(=[O:24])=[O:23]
Reactant: O=S(=O)([O-])O
Agent: COC(=O)[C@H](c1ccccc1Cl)N1CCc2sccc2C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: O=S(=O)(O)O
Reaction time: 0.25 h

Procedure:
To a stirred suspension of clopidogrel base (3.83 g, 0.0119 mole) in water (3 mL) was added potassium hydrogen sulfate (1.62 g, 0.0119 mole) at 25-30° C. The reaction mixture was stirred for 15 minutes and acetone (25 mL) was added, further stirred for 30 minutes and filtered. The filtrate was distilled at 50-55° C. under reduce pressure (5-10 mm). Benzene (10 mL) was added to the reaction mixture and distilled at 90-95° C., di-isopropyl ether (20 mL) was added and stirred at 25-30° C. for 1 hour and filtered. The semi sold material was dissolved in dichloromethane (25 mL) and distilled under reduced pressure (5-10 mm) to give clopidogrel hydrogen sulfate (2.1 g). The amorphous form was similarly characterized by XRD, DSC, IR, chemical purity (HPLC)>99% and chiral purity (chiral HPLC) 99.5% (e.e.), % water 3.0, m.p. 94-98° C. (softens).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:50]([OH:52])=[O:51])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH2:5]1.C(OCC)(=[O:55])C.CO>CCCCCC.C(OCC)(=O)C>[CH3:1][CH2:2][C@@H:3]([C:50]([OH:52])=[O:51])[C@@H:4]1[O:9][C@@H:8]([C@H:10]([C@H:12]([OH:48])[C@@H:13]([C:15]([C@@H:17]([C@H:20]2[O:25][C@@:24]3([O:30][C@:29]4([O:34][C@@:33]([C@@H:36]5[O:41][C@@H:40]([CH3:42])[C@@:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[C@H:28]([OH:55])[CH:27]=[CH:26]3)[C@H:23]([CH3:46])[CH2:22][C@@H:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[C@@H:7]([CH3:49])[CH2:6][CH2:5]1.[CH3:1][CH2:2][CH:3]([C:50]([OH:52])=[O:51])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH2:5]1
Reactant: CCOC(C)=O
Agent: CCC(C(=O)O)C1CCC(C)C(C(C)C(O)C(C)C(=O)C(CC)C2OC3(C=CCC4(CCC(C)(C5CCC(O)(CC)C(C)O5)O4)O3)C(C)CC2C)O1
Solvent: CCCCCC
Solvent: CO
Product: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@H](C)[C@@H]1O[C@@H]([C@@H](CC)C(=O)O)CC[C@@H]1C)[C@H]1O[C@]2(C=C[C@@H](O)[C@]3(CC[C@@](C)([C@H]4CC[C@](O)(CC)[C@H](C)O4)O3)O2)[C@H](C)C[C@@H]1C

Procedure:
The mother liquor separated from crystals in the process in (D) is concentrated to dryness to give 9.7 kg of the complex containing SY-1 through -8. The complex is dissolved in 100 liters of a 2:1 mixture of hexane-ethyl acetate, applied to the column of 20 kg of almina in the same manner as described in Example 2 (E) and developed with 30 liters of a 100:2 mixture of ethyl acetate-methanol to elute SY-1, SY-3 and SY-7. The effluent is treated in the same manner as described in Example 2 (E) to give 400 g of salinomycin-SY-1 mixture and 130 g of crude powder containing SY-3 and SY-7.
Reaction SMILES: [CH:1]([N:4]1[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=2)[CH2:21][CH2:20]1.[O-2].[Al+3].[O-2].[O-2].[Al+3]>C(Cl)(Cl)Cl>[CH:1]([N:4]1[C:9]2[N:10]=[C:11]([NH:29][C:28]3[CH:27]=[CH:26][C:25]([N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:31][CH:30]=3)[N:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2]
Reactant: CC(C)n1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: [Al+3]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: CC(C)n1c(=O)ccc2cnc(Nc3ccc(N4CCN(C)CC4)cc3)nc21
Temperature: 175 °C
Yield: 49.7 %

Procedure:
To 8-isopropyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (212 mg, 0.85 mmol) was added 4-(4-methylpiperazin-1-yl)-aniline (323 mg, 1.69 mmol). The reaction mixture was heated at 175° C. for 10 minutes then cooled to room temperature and partitioned between saturated sodium bicarbonate and chloroform. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10% methanol in ethyl acetate. The fractions containing product were concentrated, and hexane and ethyl acetate were added to give a solid that was dissolved in chloroform and passed through an aluminum oxide column. The fractions containing product were concentrated, and upon addition of hexane and ethyl acetate, a solid formed providing 160 mg (50%) of 8-isopropyl-2-[4-(4-methylpiperazin-1-yl)-phenylamino]-8H-pyrido[2,3-d]pyrimidin-7-one, mp 221-222° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(O)C>[C:32]([C:31]1[CH:30]=[N:29][CH:28]=[CH:27][C:26]=1[C:10]1([CH:15]=[CH:14][CH:13]=[CH:12][CH:11]1[NH:16][CH2:17][CH:18]1[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]1)[C:9]([NH:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:24])([OH:34])=[O:33]
Reactant: O=C(O)c1cnccc1Cl
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cnccc1C1(C(=O)Nc2ccc(Cl)cn2)C=CC=CC1NCC1CCNCC1

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (100 mg, 0.29 mmol), 4-chloronicotinic acid (91 mg, 0.58 mmol), triethylamine (59 mg, 0.58 mmol), and ethanol (5 mL) yielded, after RPHPLC purification, 45 mg (33%) of the title compound as a trifluoroacetate salt.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23]([O:25]C)=O)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[NH4+:29]>C1COCC1.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:21]3[CH:20]=[CH:19][CH:18]=[C:17]([OH:22])[C:16]=3[C:15]3[C:10]2=[CH:11][CH:12]=[CH:13][C:14]=3[C:23](=[O:25])[NH2:29])[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1cccc(C)c1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cccc(Cn2c3cccc(O)c3c3c(C(N)=O)cccc32)c1
Yield: 40 %

Procedure:
A solution of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (300 mg, 0.87 mM) in 10 mL THF and 30 mL concentrated aqueous ammonium hydroxide was sonicated for 5 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 114 mg (40%) of the 9-[(3-methylphenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as an off-white solid. 1H NMR (DMSO-d6) δ 10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.8 (dd, 1H, J=1 and 8 Hz), 7.4 (m, 2H), 7.3 (t, 1H, J=8 Hz), 7.15-7.0 (m, 3H), 6.85 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 5.95 (d, 1H, J=8 Hz), 5.65 (s, 2H), and 2.25 (s, 3H). IR (KBr, cm−1) 3434, 3203, 1629, 1599, 1579, 1552, 1443, 1330, 1262, 1214, and 776. MS (ES) m/e 329, 331.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:23][CH2:22]2)=[O:20])=[CH:12]3)=[N:6][CH:7]=1.[Cl:34][C:35]1[CH:36]=[C:37]2[C:42](=[O:43])[O:41][C:39](=[O:40])[C:38]2=[CH:44][C:45]=1[Cl:46]>ClCCCl>[CH2:27]([N:24]1[CH2:25][CH2:26][N:21]([C:19]([C:13]2[N:14]([CH3:18])[C:15]3[C:11]([CH:12]=2)=[CH:10][C:9]([O:8][C:5]2[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:40])[C:38]4[C:37](=[CH:36][C:35]([Cl:34])=[C:45]([Cl:46])[CH:44]=4)[C:42]([OH:43])=[O:41])=[CH:3][CH:4]=2)=[CH:17][CH:16]=3)=[O:20])[CH2:22][CH2:23]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cn1c(C(=O)N2CCN(Cc3ccccc3)CC2)cc2cc(Oc3ccc(N)cn3)ccc21
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: ClCCCl
Product: Cn1c(C(=O)N2CCN(Cc3ccccc3)CC2)cc2cc(Oc3ccc(NC(=O)c4cc(Cl)c(Cl)cc4C(=O)O)cn3)ccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.8 %

Procedure:
To a solution of [5-(5-aminopyridin-2-yloxy)-1-methyl-1H-indol-2-yl](4-benzylpiperazin-1-yl)methanone (1.00 g, 2.26 mmol) in 1,2-dichloroethane (22 mL) was added 4,5-dichlorophthalic anhydride (0.57 g, 2.62 mmol), and the mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration and dried to give 1.5 g of the title compound as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH:18]([CH3:20])[CH3:19])=[C:15]([C:21](O)=[O:22])[C:14]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[N:30]1([CH2:35][CH2:36][CH2:37][NH2:38])[CH2:34][CH2:33][CH2:32][CH2:31]1>>[N:30]1([CH2:35][CH2:36][CH2:37][NH:38][C:21]([C:15]2[C:14]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:13]([CH:12]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:17][C:16]=2[CH:18]([CH3:20])[CH3:19])=[O:22])[CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NCCCN1CCCC1
Reactant: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)O
Product: CC(C)c1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(-c2ccccc2)c1C(=O)NCCCN1CCCC1
Yield: 89 %

Procedure:
5-(5-bromo-2-oxo-1,2-dihydroindol-3-ylidenemethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid (127 mg, 0.28 mmol) was condensed with 3-pyrrolidin-1-yl-propylamine (43 mg, 0.336 mmol) to give 140 mg (66%) of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([CH:8]1[O:12][CH2:11][CH2:10][O:9]1)([CH3:7])[CH3:6].[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O.O>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:5]([CH3:7])([CH3:6])[CH2:4][CH2:3][CH2:2][N:13]=[N+:14]=[N-:15]
Reactant: CC(C)(CCCCl)C1OCCO1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(CCCN=[N+]=[N-])C1OCCO1
Temperature: 25 °C
Yield: 91.1 %

Procedure:
A solution of 0.74 g (3.8 mmol) of 2-(4-chloro-1,1-dimethylbutyl)-1,3-dioxolane and 0.50 g (7.7 mmol) of sodium azide in 5 mL of DMSO was heated to 100° C. with stirring. After 18 hours the solution was cooled to RT, diluted with water, and the mixture extracted with ether (3×). The combined ether extracts were washed with water (3×), dried over MgSO4, and concentrated in vacuo to afford 0.69 g (90%) of the desired compound as a light yellow liquid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[S:31][C:27]2[S:28][CH:29]=[CH:30][C:26]=2[CH:25]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[S:31][C:27]3[S:28][CH:29]=[CH:30][C:26]=3[CH:25]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1cc2ccsc2s1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1cc2ccsc2s1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(thieno[2,3-b]thiophen-2-yl)acetate (from Example D4 above), the title compound was prepared as a solid. The product was purified by tituration from Et2O/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>C(OCC)(=O)C.CCCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:18](=[O:19])[N:17]([CH3:16])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(Oc2ccc(Cl)cn2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)Oc1ccc(Oc2ccc(Cl)cn2)cc1)c1ccccc1

Procedure:
The title product was prepared from 4-(5-chloro-pyridin-2-yloxy)-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to column chromatography (ethyl acetate/heptane (1:5) (85%, white solid). HPLC-MS: m/z=355.1 (M+1); Rt: 4.56 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([NH2:9])[NH:7][N:8]=2)[CH2:3][CH2:2]1.[Cl:10][C:11]1[N:16]=[C:15](Cl)[N:14]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:12]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:10][C:11]1[N:12]=[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:14]=[C:15]([NH:9][C:6]2[NH:7][N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[CH:5]=2)[N:16]=1
Reactant: Clc1nc(Cl)nc(-c2ccccc2)n1
Reactant: Nc1cc(C2CC2)n[nH]1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Clc1nc(Nc2cc(C3CC3)n[nH]2)nc(-c2ccccc2)n1
Reaction time: 18 h
Yield: 53.2 %

Procedure:
A solution of 5-cyclopropyl-2H-pyrazol-3-ylamine (172 mg, 1.4 mmol) in 5 ml of THF was added dropwise to a solution of 2,4-dichloro-6-phenyl-[1,3,5]triazine (452 mg, 2 mmol) (ref: WO 0125220, p.190) and diisopropylethylamine (0.35 ml, 2 mmol) in 15 ml of THF at room temperature then stirred for 18 hours. The reaction was filtered and the filtrate evaporated in vacuo and the residue purified by flash chromatography (SiO2) eluting with 8:2 dichloromethane: ethyl acetate to afford 233 mg of the desired product. HPLC: Rt 6.803 mins. MS: m/z 313.0 (M+H)
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].Br[C@@:10]1([O:33][C@H:32]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]1[O:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)O>C(#N)C>[C:14]([O:13][C@H:12]1[C@H:22]([O:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:32]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:33][C@H:10]1[N:5]1[CH:6]=[CH:7][N:8]=[C:4]1[N+:1]([O-:3])=[O:2])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=[N+]([O-])c1ncc[nH]1
Reactant: O=C(OC[C@H]1O[C@@](O)(Br)[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: O=C(OC[C@H]1O[C@@H](n2ccnc2[N+](=O)[O-])[C@@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The coupling procedure of Sakaguchi (17) (12) was modified to give a higher yield and selective formation of the β-anomer. 2-Nitroimidazole (118 mg; 1.05 mmol) was added to a stirred solution of 1-bromo-2,3,5-tri-O-benzoyl-α-D-arabinofuranose (500 mg; 0.95 mmol) and mercuric cyanide (600 mg; 2.04 mmol) in dry acetonitrile (50 mL). The mixture was stirred for 6 hours at room temperature, after which the solvent was removed under vacuum. The residue was dissolved in dichloromethane (200 mL) and filtered. The filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution, 30% aqueous potassium iodide, and water, then dried over anhydrous magnesium sulfate. The solvent was evaporated under vacuum and the residue applied to a silica gel column and eluted with ethyl acetate:toluene=90:10 (v/v). The coupled product was recovered in 69% chemical yield (367 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([CH:12]3[C:21](=[O:22])[CH2:20][CH2:19][C:14]4([O:18][CH2:17][CH2:16][O:15]4)[CH2:13]3)=[O:11])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[O-:23][CH2:24][CH3:25].[Na+]>C(O)C>[CH2:24]([O:23][C:21](=[O:22])[CH2:20][CH2:19][C:14]1([CH2:13][CH2:12][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[O:11])[O:18][CH2:17][CH2:16][O:15]1)[CH3:25]
Reactant: O=C1CCC2(CC1C(=O)c1ccc3ncsc3c1)OCCO2
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCC1(CCC(=O)c2ccc3ncsc3c2)OCCO1
Reaction time: 12 h

Procedure:
Under a nitrogen atmosphere, 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (271 mg, 0.85 mmol) was dissolved in ethanol (1 mL). 2.43 M sodium ethoxide solution (0.01 mL, 0.03 mmol) was added. After 12 hrs, reaction was concentrated in vacuo. The residue was diluted with 10 mL EtOAc/5 mL 10% citric acid. The layers were separated. The aqueous layer was further extracted with EtOAc (3×3 mL). The combined organic layers were washed with water (5 mL) and brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column (40% EtOAc/hexanes) to yield 3-[2-(3-Benzothiazol-6-yl-3-oxo-propyl)-[1,3]dioxolan-2-yl]-propionic acid ethyl ester (100 mg, 38%, light yellow oil).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[CH:31]1([C:34](Cl)=[O:35])[CH2:33][CH2:32]1>>[CH:31]1([C:34]([NH:1][C@H:2]2[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]3[C:15]4[N:16]=[CH:17][N:18]=[C:19]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[O:26][CH2:27][CH:28]5[CH2:29][CH2:30]5)[C:14]=4[NH:13][CH:12]=3)=[O:10])[CH2:4][CH2:3]2)=[O:35])[CH2:33][CH2:32]1
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccccc4OCC4CC4)ncnc23)CC1
Reactant: O=C(Cl)C1CC1
Product: O=C(N[C@H]1CC[C@H](NC(=O)C2CC2)CC1)c1c[nH]c2c(-c3ccccc3OCC3CC3)ncnc12

Procedure:
Starting from trans-4-(2-Cyclopropylmethoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A161) and cyclopropanecarbonyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([CH:23]=O)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[F:25][C:26]([F:40])([F:39])[C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1>>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)[CH:15]([CH2:23][N:36]3[CH2:35][CH2:34][CH:33]([C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:39])[F:40])=[CH:32][CH:31]=4)[CH2:38][CH2:37]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reactant: O=CC1CN(C(=O)c2cccc3ccccc23)CC1c1ccsc1
Product: O=C(c1cccc2ccccc12)N1CC(CN2CCC(c3ccc(C(F)(F)F)cc3)CC2)C(c2ccsc2)C1

Procedure:
The title compound was prepared from 1-(1-naphthoyl)-3-(SR)-formyl-4-(RS)-(3-thienyl)pyrrolidine (Example 82 and 4-(4-trifluoromethylphenyl)piperidine according to procedures described in Example 1, Step F. 1H NMR (CDCl3) δ7.34 (d, 2H, J=8 Hz), 7.58 (d, 2H, J=8 Hz); Mass Spectrum (CI) m/e=549 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9](=[O:28])[C@:10]3([C@@H:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][CH2:13][C:12](=[O:23])[N:11]3[CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:5]2=[CH:4][CH:3]=1.[Li+].[CH3:38][CH:39]([N-]C(C)C)[CH3:40].C(Br)C=C>C1COCC1>[CH2:40]([C@@H:13]1[C:12](=[O:23])[N:11]([CH2:24][CH:25]2[CH2:26][CH2:27]2)[C@:10]2([C:5]3[C:6](=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:8]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:9]2=[O:28])[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH2:14]1)[CH:39]=[CH2:38]
Reactant: CC(C)[N-]C(C)C
Reactant: C[Si](C)(C)CCOCN1C(=O)[C@@]2(c3ccc(Cl)cc31)[C@@H](c1cccc(Cl)c1)CCC(=O)N2CC1CC1
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@H]1C[C@H](c2cccc(Cl)c2)[C@]2(C(=O)N(COCC[Si](C)(C)C)c3cc(Cl)ccc32)N(CC2CC2)C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of (rac) (2′S,3′R)-6-chloro-3′-(3-chlorophenyl)-1′-(cyclopropylmethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)spiro[indoline-3,2′-piperidine]-2,6′-dione (Example 62, Step I) (97 mg, 0.178 mmol) in THF (1 mL) at −78° C. under Ar was added freshly prepared LDA (1.0 M in THF) (178 μL, 0.178 mmol). The reaction color turned yellowish orange. The reaction was stirred at −78° C. for 30 min then distilled allyl bromide (15.39 μL, 0.178 mmol) was added. The reaction was stirred at −78° C. for 10 min then warmed to 0° C. The reaction was quenched with sat. NH4Cl and warmed to room temperature. The mixture was diluted with EtOAc and the layers were separated. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (eluent: 0 to 25% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.C[O:8][C:9](=O)[CH:10]([C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1)[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1.C[O-].[Mg+2].C[O-].CO>>[CH3:33][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH:10]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:9]([NH:1][C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[O:8])=[CH:29][CH:28]=1)(=[O:32])=[O:31]
Reactant: COC(=O)C(CC1CCCC1OC1CCCCO1)c1ccc(S(C)(=O)=O)cc1
Reactant: Nc1nccs1
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2OC2CCCCO2)C(=O)Nc2nccs2)cc1
Temperature: 25 °C
Yield: 37.7 %

Procedure:
2-Aminothiazole (314.3 mg, 3.14 mmol) and 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-propionic acid methyl ester (859.2 g, 2.09 mmol) were treated with a solution of magnesium methoxide in methanol (7.4 wt. %, 12 mL, 8.37 mmol). The resulting reaction mixture was heated under reflux for 24 h. The reaction mixture was allowed to cool to 25° C. and then filtered through a pad of celite. The pad of celite was washed well with ethyl acetate until the washings indicated the absence of product by thin layer chromatography. The filtrate was then washed with a 10% aqueous hydrochloric acid solution (3×100 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 1/1 hexanes/ethyl acetate) afforded 2-(4-methanesulfonyl-phenyl)-3-[2-(tetrahydropyran-2-yloxy)-cyclopentyl]-N-thiazol-2-yl-propionamide (377.4 mg, 38%) as a yellow oil: EI-HRMS m/e calcd for C23H30N2O5S2 (M+) 478.1596, found 478.1604.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:22][CH2:23][OH:24]>O>[OH:24][CH2:23][CH2:22][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCO)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
12.2 g (0.1 mol) of 4-hydroxybenzaldehyde, 16.6 g (0.12 mol) of potassium carbonate and 100 ml of N,N-dimethylformamide were put in a three-neck 300 ml-flask equipped with a thermometer and a stirrer and heated up to 60° C. To this mixture was dropwise added 25.0 g (0.2 mol) of 2-bromoethanol. The internal temperature rose up to 80° C. due to the reaction heat. Afterwards, the reaction system was heated and stirred at 100° C. for 2 hours. The reaction mixture was cooled to room temperature, poured into water and extracted with ethyl acetate. The resulting extract was dried with anhydrous sodium sulfate, and ethyl acetate was removed therefrom by distillation. The residue was subjected to silica gel column chromatography (using an eluent of ethyl acetate/n-hexane of 1/1) to obtain the intended 4-(2-hydroxyethoxy)benzaldehyde as an oily product. The yield of the product was 5.8 g (34.9%).