Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[O:6]1[CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]1>C(#N)C>[CH2:8]([C:7]12[O:6][CH:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7][N:1]1[CH2:2][CH:3]([CH3:4])[O:5]2)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCC1CO1
Reactant: CC(O)CN
Solvent: CC#N
Product: CCCCCCC1CN2CC(C)OC2(CCCC)O1
Temperature: 180 °C
Yield: 20 %

Procedure:
Under atmospheric nitrogen, 30.79 g of 1-amino-2-propanol was added drop-wise to a solution of 52.59 g of 1,2-epoxyoctane (in a ratio of 1:1 mol) in acetonitrile (100 g). The mixture was stirred and eventually solidified followed by the removal of acetonitrile in vacuum. Under atmospheric nitrogen, 30.00 g of valeric acid and the product of the first step, 83.33 g of 2-(2-hydroxypropylamino)octan-1-ol (in a ratio of 1:1.5 mol) were added to a flask with a Dean Stark trap and a condenser. The reaction mixture was heated to 180° C. and stirred. Water was collected in the trap. The reaction flask was connected to a distillation apparatus. At 180° C. and under a vacuum of 1.33 Pa, approximately 30 g were distilled over to a flask containing molecular sieves to absorb the final equivalent of water. The product was distilled from the reaction mixture and further purified by extraction with petroleum ether followed by distillation. The product, 7a-butyl-2-hexyl-6-methyl-tetrahydro-2H-oxazolo[2,3-b]oxazole, was isolated with 20% yield.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:20])[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[CH2:7][CH2:6]1.[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](O)=[O:29])(=[O:24])=[O:23]>>[Cl:19][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[Cl:18])[O:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][C@H:3]([OH:20])[CH2:2][NH:1][C:28](=[O:29])[C:27]2[CH:31]=[CH:32][CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=2)[CH2:6][CH2:7]1
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: CS(=O)(=O)c1cccc(C(=O)O)c1
Product: CS(=O)(=O)c1cccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c1

Procedure:
Prepared as described in Example 1 from (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.1 g) and 3-(methylsulfonyl)benzoic acid (0.063 g). Title compound obtained as white solid (0.017 g).
Reaction SMILES: C1OC1.[NH2:4][C@@H:5]1[C:20](=[O:21])[N:7]2[C:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:9]([CH3:12])[CH2:10][S:11][C@H:6]12.[O:22]([CH2:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:12][C:9]1[CH2:10][S:11][C@@H:6]2[C@H:5]([NH:4][C:30](=[O:31])[CH2:29][O:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:20](=[O:21])[N:7]2[C:8]=1[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14]
Reactant: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: O=C(Cl)COc1ccccc1
Solvent: C1CO1
Solvent: ClCCl
Product: CC1=C(C(=O)OC(C)(C)C)N2C(=O)[C@@H](NC(=O)COc3ccccc3)[C@H]2SC1

Procedure:
A solution of ethylene oxide (12 ml) in dry methylene chloride (30 ml) was added to a solution of t-butyl 7β-amino-3-methylceph-3-em-4-carboxylate (52 g, 0.193 mole) in dry methylene chloride (200 ml) cooled in an ice-water bath. A solution of redistilled phenoxyacetyl chloride (33.2 g, 0.194 mole) in dry methylene chloride (25 ml) was added over 2 minutes with stirring. The mixture was stirred for 2 hours, washed with 3% sodium hydrogen carbonate solution (2 × 70 ml), and water, N-hydrochloric acid and brine (70 ml of each), dried and evaporated to a foam. This foam was redissolved in methylene chloride (200 ml) and part (3 ml) of the solution was reevaporated to a white foam (1.13 g), [α]D + 107°, λmax 268.5 nm (ε 7,850) 274.5 nm (ε 7,000), inflexion at 264 nm (ε 7,500), νmax (CHBr3) 3417 (NH), 1786 (azetidin-2-one), 1718 (CO2R) and 1697 and 1530 cm-1 (CONH), τ 0.99 (1H,d, J 8.5 Hz; NH), 2.5 to 3.2 (5H,m; C6H5OCH2), 4.34 (1H,dd, J 8.5, 5 Hz; C7 -H), 4.91 1H,d, J 5 Hz; C6 -H), 5.38 (2H,s; C6H5OCH2), 6.38, 6.66 (2H, AB-q, J 18 Hz; C2 -H2), 8.01 (3H,s; C3 -CH3), 8.52 (9H,s; CO2C(CH3)3) (Found: C, 58.3, 58.4; H, 5.95, 6.0; N, 6.7, 7.0; S, 7.7 C20H24N2O5S (404.5) requires C, 59.4; H, 6.0; N, 6.9; S, 7.7%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:19]=2)[C:14]([CH3:29])=[CH:13][C:12]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[O:34]1CCOCC1>CCOCC>[C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:19]=2)[C:14]([CH2:29][OH:34])=[CH:13][C:12]1([CH3:31])[CH3:30])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: C1COCCO1
Reactant: CC1=CC(C)(C)N(CCCC(=O)OC(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCCN1c2cc(O[Si](C)(C)C(C)(C)C)ccc2C(CO)=CC1(C)C
Reaction time: 1 h

Procedure:
SeO2 (1.50 g, 13.5 mmol) was added in portions to a hot (60° C.) solution of compound 4 (3.24 g, 6.74 mmol) in dioxane (50 mL). Then the reaction mixture was at this temperature for 1 h. After cooling, it was diluted with ether, and the organic layer was washed with sat. aq. NaHCO3 and dried over MgSO4. Solvents were evaporated, and the residue was purified by column chromatography (with hexane/ether/dichloromethane [10/3/1] as an eluent). After evaporation of solvents, the compound 5 (1.3 g) was dissolved in THF/MeOH (20/1), and NaBH4 (100 mg, 2.6 mmol) was added in portions at room temp. After 5 min, the reaction was complete (TLC). The excess of NaBH4 was destroyed by adding acetone (0.5 mL); all volatile materials were evaporated in vacuo, and the alcohol 6a was isolated by column chromatography (with hexane/ether/dichloromethane/MeOH mixture (10/3/4/0.3) as an eluent; Rf=0.42); yield 0.745 g (22%) of light yellow oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[NH:12][C:11]1=[O:28].Cl.[CH2:30]([N:37]([CH2:39][CH2:40][CH2:41]Cl)[CH3:38])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([CH3:27])=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]=2[CH3:21])[N:12]([CH2:41][CH2:40][CH2:39][N:37]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH3:38])[C:11]1=[O:28]
Reactant: CCOC(=O)c1c(C)cc2[nH]c(=O)n(-c3ccccc3Cl)c(=O)c2c1C
Reactant: CN(CCCCl)Cc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc2c(c1C)c(=O)n(-c1ccccc1Cl)c(=O)n2CCCN(C)Cc1ccccc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A portion (96 mg) of 50% sodium hydride suspension in mineral oil was added to a solution of 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-2,4(1H, 3H)-quinazolinedione (372 mg) in dimethylformamide (20 ml). After stirring the mixture at 100° C. for one hour, 3-(N-benzyl-N-methylamino)propyl chloride hydrochloride (320 mg) was added. The mixture was heated to 140°-145° C. and maintained at this temperature for 6 hours with stirring. The mixture was concentrated under reduced pressure, and the mixture was then partitioned between CHCl3 and 10% aqueous K2CO3 solution. The CHCl3 phase was separated, dried over MgSO4 and concentrated. The residue was chromatographed over a column of silica gel, and the fractions eluted with CHCl3 -methanol (v/v, 9:1) were concentrated and recrystallized from diethyl ether/n-hexane to give 3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-1-[3-(N-benzyl-N-methylamino)propyl]-2,4(1H, 3H)-quinazolinedione (355 mg, 66.5%) melting at 145°-146° C. After treating the crystals with ethanol containing hydrogen chloride and recrystallizing from ethanol/diethyl ether, the hydrochloride melting at 207°-209° C. was obtained.
Reaction SMILES: [CH3:1][I:2].[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1>C(#N)C>[I-:2].[Cl:3][C:4]1[CH:34]=[CH:33][C:7]([CH2:8][N+:9]2([CH3:1])[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][NH:19][C:20](=[O:31])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:29])([F:30])[F:28])[CH:22]=3)[CH2:11][CH2:10]2)=[CH:6][CH:5]=1
Reactant: CI
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Solvent: CC#N
Product: C[N+]1(Cc2ccc(Cl)cc2)CCC(CNC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)CC1
Product: [I-]
Temperature: 70 °C
Reaction time: 4 h

Procedure:
Methyl iodide (28 mg, 0.20 mmol) was added to an acetonitrile (2.0 mL) solution of 1-(4-chlorobenzyl)-4-[[N-[3-(trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidine. The resulting reaction mixture was stirred at 70° C. for 4 hours. The solvent was removed under reduced pressure to provide 1-(4-chlorobenzyl)-1-methyl-4-[[N-[3-(trifluoromethyl)benzoyl]glycyl]aminomethyl]piperidinium iodide as yellow oil. (31.7 mg, 71%). The purity was determined by RPLC/MS (99%). ESI/MS m/e 482.1 (M++H, C24H28ClF3N3O2).
Reaction SMILES: [OH:1][C:2]1[CH:27]=[C:26]([C:28]2[S:29][C:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C@H:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2.C([O-])([O-])=O.[Cs+].[Cs+].I[CH2:44][CH2:45][CH3:46]>CN(C=O)C.O>[CH2:44]([O:1][C:2]1[CH:27]=[C:26]([C:28]2[S:29][C:30]3[CH2:36][CH2:35][CH2:34][CH2:33][C:31]=3[N:32]=2)[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[C@H:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2)[CH2:45][CH3:46]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc5c(s4)CCCC5)cc3O)ccc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1cc(-c2nc3c(s2)CCCC3)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.2 %

Procedure:
Ethyl ((1S)-5-{3-[2-hydroxy-4-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)-phenoxy]-propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (Example 165, 90 mg, 0.177 mmol) was dissolved in DMF (3 mL) after which Cs2CO3 (69.3 mg, 0.213 mmol) and water (3 drops) were added. Iodopropane (0.02 mL, 0.213 mmol) was added to the flask, and the reaction mixture was stirred at room temperature for 18 h. The mixture was then filtered and the filtrate purified by preparative HPLC giving the desired ester as a white solid (88.7 mg, 91%). 1H NMR (400 MHz, CD2Cl2): δ 7.47 (s, 1H), 7.37 (dd, 1H), 7.05 (d, 1H), 6.93 (d, 1H), 6.79 (s, 1H), 6.71 (dd, 1H), 4.23 (t, 2H), 4.19-4.13 (m, 4H), 4.03 (t, 2H), 3.50 (m, 1H), 2.94-2.78 (m, 6H), 2.70 (dd, 1H), 2.44-2.25 (m, 4H), 1.92-1.70 (m, 7H), 1.28 (t, 3H), 1.07 (t, 3H).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1)[NH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=CC=1.ClCCl.Cl[C:42]([O:44][CH3:45])=[O:43]>O>[CH2:12]([O:19][C:20](=[O:31])[C@H:21]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([OH:30])=[CH:28][CH:29]=1)[NH:22][C:42]([O:44][CH3:45])=[O:43])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)Cl
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To an ice-cooled mixture of L-tyrosine benzyl ester p-toluenesulfonate (41.0 g), pyridine (16.4 ml), and dichloromethane (92 ml) was added methyl chloroformate (7.8 ml). The mixture was stirred in an ice-bath for 1 hour, diluted with water, and extracted once with dichloromethane. The extract was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the crude product by column chromatography on silica gel (gradient elution; 10:1 to 5:1 chloroform-ethyl acetate) gave N-methoxycarbonyl-L-tyrosine benzyl ester (22.0 g).
Reaction SMILES: [CH2:1]([C:10]1[CH:11]=[CH:12][C:13]2[CH2:14][C:15]3[C:28]([C:29](=O)[C:30]=2[CH:31]=1)=[CH:27][C:26]1[CH2:25][C:24]2[C:19](=[CH:20][C:21]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[CH:22][CH:23]=2)[C:18](=O)[C:17]=1[CH:16]=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>COCCOCCOC>[CH2:33]([C:21]1[CH:22]=[CH:23][C:24]2[C:19](=[CH:18][C:17]3[C:26]([CH:25]=2)=[CH:27][C:28]2[C:15](=[CH:14][C:13]4[C:30]([CH:29]=2)=[CH:31][C:10]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=4)[CH:16]=3)[CH:20]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCc1ccc2c(c1)C(=O)c1cc3c(cc1C2)C(=O)c1cc(CCCCCCCCC)ccc1C3
Solvent: COCCOCCOC
Product: CCCCCCCCCc1ccc2cc3cc4cc5cc(CCCCCCCCC)ccc5cc4cc3cc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 20 grams of 7,14-dihydro-3,10-dinonylpentacene-5,12-dione and 400 mL of 2-methoxyethyl ether was stirred and flushed with nitrogen for 15 minutes. To this was added 11.4 grams of sodium borohydride and stirring was continued at 60° C. for 18 hours. The resulting mixture was cooled to room temperature, 3.0 grams of sodium borohydride was added, and stirring was continued for 16 hours at room temperature. To the resulting mixture was added 170 mL of acetic acid, and the mixture was heated at 60° C. for one hour. To this mixture was added 120 mL of concentrated hydrochloric acid and heating was continued at 60° C. for one hour. The resulting mixture was cooled to room temperature and the resulting solid was collected by filtration and dried to give 2,9-dinonylpentacene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([OH:29])=O)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH:30]1[CH2:34][CH2:33][N:32]=[C:31]1[C:35]1[CH:47]=[CH:46][C:38]([CH2:39][CH:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]2[CH:25]([CH2:26][C:27]([N:43]3[CH2:44][CH2:45][CH:40]([CH2:39][C:38]4[CH:37]=[CH:36][C:35]([C:31]5[NH:32][CH2:33][CH2:34][N:30]=5)=[CH:47][CH:46]=4)[CH2:41][CH2:42]3)=[O:29])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: c1cc(C2=NCCN2)ccc1CC1CCNCC1
Reactant: O=C(O)CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Product: O=C(CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1)N1CCC(Cc2ccc(C3=NCCN3)cc2)CC1

Procedure:
The title compound was prepared from [5-(3,4-dichloro-benzenesulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid (Example 2c) and 4-[4-(4,5-dihydro-1H-imidazol-2-yl)-benzyl]-piperidine (Reference Example 6) according to the method described in Example 1e. MS (EI) 674.3 (MH+).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)=[C:2]=[S:3].ClCCl.[NH3:27]>CO>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:7]3[CH:8]=[CH:9][C:4]([NH:1][C:2]([NH2:27])=[S:3])=[CH:5][CH:6]=3)[CH2:11][CH2:12]2)=[CH:17][CH:18]=1
Reactant: COc1ccc(N2CCN(c3ccc(N=C=S)cc3)CC2)cc1
Reactant: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(N2CCN(c3ccc(NC(N)=S)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 98.1 %

Procedure:
To a stirred solution of 20 parts of 1-(4-isothiocyanatophenyl)-4-(4-methoxyphenyl)piperazine in 325 parts of dichloromethane were added 40 parts of methanol, saturated with ammonia. The reaction mixture was stirred for 5 days at room temperature. The precipitated product was filtered off, washed with dichloromethane and dried, yielding 20.5 parts (98.1%) of N-[4-[4-(4-methoxyphenyl)-1-piperazinyl]phenyl]thiourea; mp. 265.2° C. (int. 1).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=[O:7])=[CH:4][CH:3]=1.[NH:25]1[CH2:34][CH2:33][CH2:32][C@H:26]1[C:27]([O:29]CC)=[O:28].[OH-].[K+]>C(O)C>[F:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([C:15]([CH3:22])([CH3:21])[CH2:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9][CH2:10][CH2:11][C:12]([N:25]2[CH2:34][CH2:33][CH2:32][C@H:26]2[C:27]([OH:29])=[O:28])=[O:13])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(C)(C)CC(C)(C)N(CCCC(=O)O)C(=O)c1ccc(F)cc1
Reactant: CCOC(=O)[C@@H]1CCCN1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)CC(C)(C)N(CCCC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-fluorobenzoyl)-4-[(1,1,3,3-tetramethylbutyl)amino]butyric acid and ethyl L-prolinate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-(p-fluorobenzoyl)-4-(1,1,3,3-tetramethylbutylamino)butyryl]-L-proline.
Reaction SMILES: [C:1]1([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](O)=[O:27])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:62]1([S:65]([NH2:68])(=[O:67])=[O:66])[CH2:64][CH2:63]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[C:1]1([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:38][N:10]3[C:11](=[O:37])[C@@H:12]([NH:29][C:30](=[O:31])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:19][C@@H:20]4[CH2:25][C@@:21]4([C:26](=[O:27])[NH:68][S:65]([CH:62]4[CH2:64][CH2:63]4)(=[O:67])=[O:66])[NH:22][C:23](=[O:24])[C@@H:9]3[CH2:8]2)=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)C1CC1
Reactant: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)O)C[C@H]3/C=C\CCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@H]2C(=O)N[C@]3(C(=O)NS(=O)(=O)C4CC4)C[C@H]3C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-6-(tert-butoxycarbonylamino)-2-(butylthio)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylic acid (15 mg, 0.022 mmol) and CDI (7.05 mg, 0.043 mmol) in tetrahydrofuran (1 mL) was heated to gentle reflux for 3 h. Cooled down to rt, cyclopropanesulfonamide (5.27 mg, 0.043 mmol) and DBU (9.83 μL, 0.065 mmol) were added and the reaction continued at r.t. overnight. Removed the solvent in vacuo. The residue was purified by prep-HPLC to afford the desired product tert-butyl (2R,6S,13aS,14aR,16aS,Z)-2-(biphenyl-4-yl)-2-(butylthio)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-1,2,3,5,6,7,8,9,10,11,13a,14,14a,15,16,16a-hexadecahydrocyclopropa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecin-6-ylcarbamate (11 mg, 0.014 mmol, 63.8% yield) as a white solid. 1H NMR (500 MHz, MeOD) δ ppm 0.84 (t, J=7.32 Hz, 3 H) 1.00-1.06 (m, 1 H) 1.09-1.17 (m, 2 H) 1.27-1.38 (m,5 H) 1.38-1.47 (m, 5 H) 1.46-1.63 (m, 14 H) 1.70 (dd, J=8.09, 5.34 Hz, 1 H) 1.86-2.00 (m, 2 H)2.24-2.33 (m, 1 H) 2.39-2.48 (m, 2 H) 2.50-2.58 (m, 1 H) 2.63 (s, 1 H) 2.88-2.97 (m, 2 H) 3.98-4.07 (m,2 H) 4.46 (d, J=9.46 Hz, 1 H) 5.08 (t, J=9.31 Hz, 1 H) 5.28 (d, J=10.38 Hz, 1 H) 5.65-5.75 (m, 1 H) 7.36 (t, J=7.48 Hz, 1 H) 7.46 (t, J=7.63 Hz, 2 H) 7.59 (d, J=8.55 Hz, 4 H) 7.79 (t, J=9.00 Hz, 2 H). LC-MS (retention time: 3.48 min, method C), MS m/z 793(M+H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]4[O:34][CH2:35][O:36][C:30]=4[CH:29]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:42]>C(O)C>[ClH:42].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]3[O:34][CH2:35][O:36][C:30]=3[CH:29]=2)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=1)([CH2:9][OH:10])[CH2:13][OH:12]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc4c(c3)OCO4)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc3c(c2)OCO3)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Compound 21-3 (860 mg) was dissolved in ethanol (15 ml), concentrated hydrochloric acid (1.5 ml) was added, and the mixture was stirred at 80° C. for 2 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (570 mg) as a white powder.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[N:8]([CH2:9][CH2:10][C@@H:11]([OH:19])[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15]([OH:17])=O)[C:7]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)=[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]=1[C:33](NC1C=CC=CC=1)=[O:34])[CH3:3].[OH-:42].[Na+].Cl>C1COCC1.O>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:7]2[N:8]([CH2:9][CH2:10][C@@H:11]3[CH2:12][C@@H:13]([OH:18])[CH2:14][C:15](=[O:17])[O:19]3)[C:4]([CH:2]([CH3:3])[CH3:1])=[C:5]([C:33]([OH:34])=[O:42])[C:6]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:22]=1
Reactant: [OH-]
Reactant: CC(C)c1c(C(=O)Nc2ccccc2)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H](O)C[C@@H](O)CC(=O)O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1c(C(=O)O)c(-c2ccccc2)c(-c2ccc(F)cc2)n1CC[C@@H]1C[C@@H](O)CC(=O)O1

Procedure:
A solution of atorvastatin (prepared as described in U.S. Pat. Nos. 5,397,792 and 5,446,054) (1 mmol) and NaOH (10 mmol) in THF (30 mL) and water (10 mL) is maintained at 50° C. The progress of the reaction is monitored by tlc. When the reaction is complete, the solution is acidified with dilute HCl and extracted with CH2Cl2. The extract is then dried and evaporated. The residue is dissolved in toluene (50 mL) and the solution is heated at reflux until tlc monitoring shows that formation of the lactone moiety is complete. The solvent is removed under reduced pressure and compound 18 is purified by chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1([O:13][CH3:14])[CH2:8][CH2:7][C:6]([CH2:11][OH:12])([CH2:9][OH:10])[CH2:5][CH2:4]1.[S:15](Cl)([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)(=[O:17])=[O:16]>N1C=CC=CC=1.CCOC(C)=O>[CH3:22][C:21]1[CH:23]=[CH:24][C:18]([S:15]([O:12][CH2:11][C:6]2([CH2:9][O:10][S:15]([C:18]3[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH2:5][CH2:4][C:3]([O:2][CH3:1])([O:13][CH3:14])[CH2:8][CH2:7]2)(=[O:17])=[O:16])=[CH:19][CH:20]=1
Reactant: COC1(OC)CCC(CO)(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC1(OC)CCC(COS(=O)(=O)c2ccc(C)cc2)(COS(=O)(=O)c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
To a solution of (4,4-dimethoxycyclohexane-1,1-diyl)dimethanol (3.6 g, 17.62 mmol) in pyridine (20 mL) was added tosyl chloride (7.39 mL, 38.8 mmol). The reaction mixture was stirred at rt for 18 h and then diluted with EtOAc (50 mL). The organic mixture and washed with 10% aq. citric acid, dried (Na2SO4) and concentrated in vacuo to afford the title compound (5.4 g, 60% yield) as a white solid. 1H NMR (500 MHz, CDCl3) δ 7.73 (d, J=8.3 Hz, 4H), 7.35 (d, J=8.2 Hz, 4H), 3.84 (s, 4H), 3.09 (s, 6H), 2.45 (s, 6H), 1.54-1.45 (m, 4H), 1.42-1.34 (m, 4H).