Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[C:5](Cl)=[O:6])[CH3:2].[C:9]([C:12]1[CH:29]=[CH:28][C:15]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[C:14]([CH2:30][CH2:31][CH3:32])[C:13]=1[O:33][CH3:34])(=[O:11])[CH3:10].N(CCO)(CCO)CCO>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:8])[C:5]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[C:21]([O:20][CH2:19][CH2:18][CH2:17][O:16][C:15]2[CH:28]=[CH:29][C:12]([C:9](=[O:11])[CH3:10])=[C:13]([O:33][CH3:34])[C:14]=2[CH2:30][CH2:31][CH3:32])[CH:22]=1)=[O:6])[CH3:2]
Reactant: CCCc1c(OCCCOc2cccc(N)c2)ccc(C(C)=O)c1OC
Reactant: CCOC(=O)C(=O)Cl
Solvent: OCCN(CCO)CCO
Solvent: ClCCl
Product: CCCc1c(OCCCOc2cccc(NC(=O)C(=O)OCC)c2)ccc(C(C)=O)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In the course of 10 minutes a solution of 3.45 ml of chloro-oxalic acid ethyl ester in 10 ml of methylene chloride is added dropwise to a solution of 9.2 g of 3-[3-(4-acetyl-3-methoxy-2-n-propylphenoxy)-propoxy]-aniline and 4.3 ml of triethanolamine in 90 ml of methylene chloride. After stirring for 5 hours at room temperature the mixture is poured onto water and extracted with methylene chloride. Concentration of the extracts by evaporation and recrystallisation of the residue from ether yields N-{3-[3-(4-acetyl-3-methoxy-2-n-propylphenoxy)-propoxy]-phenyl}-oxamic acid ethyl ester having a melting point of 91°-92°.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[OH-].[K+].[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1)([CH3:20])[CH3:19]>CN1CCCC1=O.O>[CH:18]([C:21]1[N:22]=[CH:23][C:24]([CH2:27][CH2:28][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)=[CH:25][CH:26]=1)([CH3:20])[CH3:19]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: C=Cc1ccc(C(C)C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(C)C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.4 %

Procedure:
To a solution of 2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g. 0.5 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.140 g, 2.5 mmol) and allowed to stir for 10 min at RT. 2-Isopropyl-5-vinyl-pyridine (0.185 g, 1.25 mol) was added and stirred for further 4 h at 100 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.025 g, 14% yield). 5-[2-(6-Isopropyl-pyridin-3-yl)-ethyl]-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.00007 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0095 g, 0.00007 mol) in THF (0.5 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.024 g, 77% yield).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:12])=[C:8]([CH:11]=1)[CH:9]=O)(=[O:3])[CH3:2].Br[CH2:14][C:15]1[S:16][CH:17]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[N:19]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:20]([C:18]1[N:19]=[C:15]([C:14]2[O:12][C:7]3[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[CH:11][C:8]=3[CH:9]=2)[S:16][CH:17]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(=O)c1ccc(O)c(C=O)c1
Reactant: CC(C)(C)c1csc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of 5-acetyl-2-hydroxybenzaldehyde (1.68 g), 2-bromomethyl-4-tert-butylthiazole, potassium carbonate (1.24 g) and potassium iodide (0.59 g) in N,N-dimethylformamide (10 ml) was stirred at room temperature for 5 hours. The resulting mixture was poured into ice-water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. A mixture of the resulting syrup and acetic anhydride in xylene was stirred under reflux for 1 day. After being cooled to room temperature, the reaction mixture was concentrated under reduced -pressure. The resulting syrup was subjected to column chromatography on silica gel and eluted with a mixture of toluene and ethyl acetate. The fractions containing the objective compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-(5-acetylbenzofuran-2-yl)thiazole (1.83 g).
Reaction SMILES: [I: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=O.[OH-:13].[Na+].[N:15]([O-])=O.[Na+].S(=O)(=O)(O)O.[Sn](Cl)(Cl)(Cl)Cl>O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:15]=[C:5]2[C:6]([OH:11])=[O:13]
Reactant: O=N[O-]
Reactant: O=C1Nc2ccc(I)cc2C1=O
Reactant: [OH-]
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1n[nH]c2ccc(I)cc12
Temperature: 0 °C

Procedure:
5-Iodoisatin (5 g, 18.3 mmol) is heated in the presence of sodium hydroxide (0.77 g, 19.2 mmol in 12 ml of H2O) until it is dissolved, and the reaction mixture is then cooled to 0° C. A solution of sodium nitrite precooled to 0° C. (1.26 g, 18.3 mmol in 5.5 ml of H2O) is added. The paste obtained is added portionwise, with vigorous stirring, to a solution of sulphuric acid (3.40 g, 34.8 mmol in 37 ml of H2O) precooled to 0° C. such that the temperature does not exceed 4° C. The stirring is maintained for 15 min and then a tin chloride solution (SnCl2.2H2O, 9.91 g, 43.9 mmol in 15 ml of concentrated HCl) is added slowly such that the temperature does not exceed 4° C. The mixture is left to react for several hours. The reaction mixture is filtered. The solid is washed with boiling water and then taken up with ethanol under hot conditions. The insoluble impurities are eliminated by filtration. 2 g of product are obtained.
Reaction SMILES: C1(OC)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23]CC1C=CC(Cl)=CC=1>O>[CH3:13][O:14][N:15]=[C:16]([C:32]1[O:33][CH2:34][CH2:35][N:36]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[OH:23]
Reactant: CON=C(C1=NCCO1)c1ccccc1OCc1ccc(Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: COc1ccccc1
Product: CON=C(C1=NCCO1)c1ccccc1O
Yield: 56 %

Procedure:
Anisole (152 ml) and aluminium chloride (16.3 g, 122 mmol) were added to 2-(4-chlorobenzyloxy)phenyl 2-oxazolin-2-yl ketone O-methyloxime (19.08 g, 55.3 mmol), and the mixture was stirred under ice-cooling for 1.5 hours. After completion of the reaction, water (100 ml) was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-hydroxyphenyl 2-oxazolin-2-yl ketone O-methyloxime (6.82 g, 56.0%) as an oil.
Reaction SMILES: I[Si](C)(C)C.[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:21])[N:13](C(OC)=O)[CH2:14]2)=[CH:9][CH:8]=1.CO>C(Cl)Cl>[Br:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH3:21])[NH:13][CH2:14]2)=[CH:9][CH:8]=1
Reactant: COC(=O)N1Cc2cc(Br)ccc2CC1C
Agent: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CO
Product: CC1Cc2ccc(Br)cc2CN1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
Iodotrimethylsilane (0.982 mL, 0.00690 mol, Aldrich, Cat. No. 195529) was added to a solution of methyl 7-bromo-3-methyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (490 mg, 0.0017 mol) in methylene chloride (10 mL) and the reaction was stirred at 50° C. for 2 h. The reaction was cooled to r.t. and anhydrous methanol (2 mL) was added. The reaction mixture was stirred for additional 5 min, and the volatiles were removed under reduced pressure. The residue was treated with diethyl ether and filtered. The solid was washed with ether, dried under vacuum to provide the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=226.2.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17]([Cl:19])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CS(C)=O>[ClH:19].[ClH:19].[N:1]1([C:10]2[N:18]=[C:17]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: Cl
Product: c1ccc2c(c1)ncn2-c1nc(N2CCOCC2)nc2[nH]cnc12
Temperature: 120 °C

Procedure:
230 mg of product obtained in stage 1 above are mixed with 3 ml of DMSO and 370 mg (5 equivalents) of morpholine, and the mixture is then heated at 120° C. for approximately 16 hours. The mixture is allowed to return to ambient temperature. The DMSO is concentrated to dryness. A paste is formed in CH2Cl2 (methylene chloride). Drying is carried out under vacuum. The dry product is taken up in 5 ml of HCl (8M) and 10 ml of ethanol and concentrated to dryness, and 209 mg of expected product are obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]1)([O-:3])=[O:2].C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([C:31](Cl)=[O:32])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([C:31]([O:13][CH:10]2[CH2:11][CH2:12][N:7]([CH2:6][C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:8][CH2:9]2)=[O:32])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1ccccc1CN1CCC(O)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)OC2CCN(Cc3ccccc3[N+](=O)[O-])CC2)cc1
Yield: 92.6 %

Procedure:
0.5 g (0.00212 mol) of 1-(2-nitro-benzyl)-piperidin-4-ol and 0.595 ml (0.00424 mol) of triethylamine were dissolved in 15 ml of toluene, treated with 0.561 ml (0.00424 mol) of p-toluoyl chloride and boiled at reflux for 18 hrs. The reaction mixture was concentrated and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.696 g (93%) of 1-(2-nitro-benzyl)-piperidin-4-yl 4-methyl-benzoate was obtained as yellow crystals; m.p. 86°-87°.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].[CH2:33]([O:40][P:41]([O:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)([O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[C:45]=1[C:52]([CH3:58])([CH3:57])[CH2:53][C:54](O)=[O:55])=[O:42])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl.C(N=C=NCCCN(C)C)C.O>CN(C)C1C=CN=CC=1.ClCCl>[CH2:60]([O:59][P:41]([O:40][CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)([O:43][C:44]1[CH:49]=[C:48]([CH3:50])[CH:47]=[C:46]([CH3:51])[C:45]=1[C:52]([CH3:58])([CH3:57])[CH2:53][C:54]([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)=[O:55])=[O:42])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Cc1cc(C)c(C(C)(C)CC(=O)O)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(C(C)(C)CC(=O)OC2CCCN(C(=O)c3ccc(NC(=O)c4ccccc4C)cc3C)c3ccc(Cl)cc32)c(OP(=O)(OCc2ccccc2)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.8 %

Procedure:
Tolvaptan (0.63 g), 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyric acid (0.70 g), and 4-dimethylaminopyridine (DMAP) (24 mg, 0.22 mmol) were suspended in dichloromethane (10 ml). N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (WSC) (383 mg) was added thereto, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by silica gel flash chromatography (n-hexane:ethyl acetate=70:30→35:65). The purified product was concentrated under reduced pressure to obtain 0.92 g of 7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 3-[2-(bis-benzyloxy-phosphoryloxy)-4,6-dimethyl-phenyl]-3-methyl-butyrate as white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:25])([F:24])[F:23])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[CH3:30][NH:31][CH3:32]>>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][C:21]=3[C:22]([F:23])([F:25])[F:24])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([N:31]([CH3:32])[CH3:30])=[O:5]
Reactant: CNC
Reactant: O=C(O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F
Solvent: O=S(Cl)Cl
Product: CN(C)C(=O)c1cc(-c2csc(-c3cnccc3C(F)(F)F)n2)ccc1F

Procedure:
By the reaction in the same manner as in Example 60 using 2-fluoro-5-{2-[4-(trifluoromethyl)pyridin-3-yl]-1,3-thiazol-4-yl}benzoic acid (201 mg), thionyl chloride (0.06 ml) and aqueous dimethylamine solution (50%, 5 ml), the title compound (90 mg) was obtained as a colorless amorphous compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH2:7])=O.C(O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:7])[CH:8]=[CH:9][C:10]=1[CH3:11]
Reactant: Cc1ccc(C(N)=O)cc1Br
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(CN)cc1Br
Temperature: 50 °C
Reaction time: 120 h

Procedure:
To 3-bromo-4-methylbenzamide (2.14 g, 10 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (2 mL, 20 mmol) at 0° C. The mixture was then heated to 50° C. for 16 h. Additional borane dimethyl sulfide complex (1 mL, 10 mmol) was added and heating continued at 60° C. for an additional 5 days. The reaction was cooled to room temperature and ethanol was cautiously added. When bubbling ceased, 1N HCl was added until pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous was washed 3× with EtOAc. The aqueous was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were dried over anhydrous Na2SO4, filtered, and concentrated to afford the title compound. LC-MS m/z 199.8 (M+H)+, 1.01 min (ret time).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1F)[O:9][CH2:8][CH2:7][CH:6]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])#[N:2].[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH2:28])=[O:27])=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1.C(OCC)(=O)C>[C:26]([C:25]1[CH:29]=[CH:30][C:22]([O:21][C:12]2[CH:11]=[C:10]3[C:5]([CH:6]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7][CH2:8][O:9]3)=[CH:4][C:3]=2[C:1]#[N:2])=[CH:23][CH:24]=1)(=[O:27])[NH2:28]
Reactant: NC(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)C1CCOc2cc(F)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)C1CCOc2cc(Oc3ccc(C(N)=O)cc3)c(C#N)cc21
Temperature: 120 °C
Yield: 82.8 %

Procedure:
tert-butyl 6-cyano-7-fluorochroman-4-carboxylate (290 mg, 1.05 mmol), 4-hydroxybenzamide (172 mg, 1.25 mmol) and potassium carbonate (347 mg, 2.51 mmol) were diluted with dry NMP (4 mL). The reaction was bubbled with argon for 10 minutes and then heated at 120° C. for 12 hours under a slight argon bubble. The reaction was cooled and loaded directly onto a biotage 40 M cartridge, eluting with 20% ethyl acetate/hexanes to 100% ethyl acetate to yield 1 g of the crude product which was found to contain NMP. The residue was taken up in ethyl acetate and washed twice with water and then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to provide the desired product (343 mg, 83.2% yield) as a white foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([O:28][Si](C)(C)C(C)(C)C(C)C)[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1.[F-].[NH4+].[ClH:43]>CO.C(OCC)(=O)C.C(OCC)C>[ClH:43].[NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]2[NH:21][C:20](=[S:22])[CH2:19][CH2:18][CH2:17][CH2:16][O:15][C:14](=[O:23])[C:13]3[C:24]([CH3:40])=[C:25]([O:38][CH3:39])[CH:26]=[C:27]([OH:28])[C:12]=3[CH2:11][S:10][CH2:9]2)[O:5][N:4]=1
Reactant: COc1cc(O[Si](C)(C)C(C)(C)C(C)C)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](c1nc(CN)no1)CSC2
Agent: Cl
Agent: [F-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCOCC
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](c1nc(CN)no1)CSC2

Procedure:
(R)-4-(3-Aminomethyl-1,2,4-oxadiazol-5-yl) -16-[dimethyl-(1,1,2-trimethyl-propyl)-silanyloxy]-14-methoxy-13-methyl-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one was treated with ammonium fluoride in methanol in an analogous manner to the procedure described in Example 1. The resulting product was dissolved in ethyl acetate. Upon the addition of a 3N solution of hydrochloric acid in diethyl ether, a precipitate formed which was isolated to yield (R)-4-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-16-hydroxy-14-methoxy-13-methyl-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecin-12-one hydrochloride as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[N:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:32])[F:31])[C:9]2=[O:36])=[CH:4][C:3]=1[CH3:37].[CH:38]([N:42]=[C:43]=[O:44])([CH2:40][CH3:41])[CH3:39].O>ClCCCl>[CH3:14][C:11]1([CH3:15])[C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:43]([NH:42][CH:38]([CH3:39])[CH2:40][CH3:41])=[O:44])=[C:3]([CH3:37])[CH:4]=2)[C:9](=[O:36])[N:10]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][S:25][CH2:26][CH2:27][CH2:28][C:29]([F:35])([F:34])[C:30]([F:33])([F:31])[F:32]
Reactant: CCC(C)N=C=O
Reactant: Cc1cc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)ccc1N
Solvent: ClCCCl
Solvent: O
Product: CCC(C)NC(=O)Nc1ccc(N2C(=O)N(CCCCCCCCCSCCCC(F)(F)C(F)(F)F)C(C)(C)C2=O)cc1C
Yield: 36 %

Procedure:
The compound of Example 25 (395 mg, 0.72 mmole) is dissolved in anhydrous 1,2-dichloroethane (10 ml) under an argon atmosphere, before the dropwise addition of sec-butylisocyanate (0.35 ml, 3 mmoles) at 23° C. The mixture is then heated under reflux for 24 hours. The reaction medium is then poured onto cold water and extracted using CH2Cl2. After decantation, the organic phase is washed with water and salt water. The organic solution is then dried over MgSO4, filtered, concentrated to dryness under vacuum and the evaporation residue is purified on a silica column (eluent: heptane/AcOEt: 1/0 to 4/6). The expected compound is obtained in the form of a colourless oil with a yield of 36%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:12]=[CH:11][CH:10]=[C:9]([C@H:13]([OH:24])[C@@H:14]3[N:19]4[CH2:20][C@H:21]([CH:22]=[CH2:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[C:7]=2[CH:8]=1.[CH2:25]([O:27][C:28](=[O:33])[CH2:29][N:30]=[C:31]=[O:32])[CH3:26].CO>ClCCl>[CH2:25]([O:27][C:28](=[O:33])[CH2:29][NH:30][C:31]([O:24][C@@H:13]([C:9]1[C:7]2[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[N:12]=[CH:11][CH:10]=1)[C@@H:14]1[N:19]2[CH2:18][CH2:17][C@H:16]([C@@H:21]([CH:22]=[CH2:23])[CH2:20]2)[CH2:15]1)=[O:32])[CH3:26]
Reactant: C=C[C@H]1CN2CCC1C[C@@H]2[C@@H](O)c1ccnc2ccc(OC)cc12
Reactant: CCOC(=O)CN=C=O
Solvent: CO
Solvent: ClCCl
Product: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](OC(=O)NCC(=O)OCC)c1ccnc2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.9 %

Procedure:
To a solution of 200 mg (0.61 mmol) of quinidine in 5 ml of dry dichloromethane was added 74 ml (0.65 mmol) of ethylisocyanatoacetate. The mixture was allowed to stir magnetically at room temperature for 18 h and concentrated under reduced pressure. The residue was purified on preparative thin layer chromatography (silica, 2 mm) using a mixture of 1:9 ethyl acetate:methanol as the eluent and yielded 130 mg (0.28 mmol, 46%) of (8). MS, IR and NMR data confirmed identity of the compound.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[CH2:8](Cl)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[OH-:21].[Na+]>C(Cl)(Cl)Cl>[N:2]([CH2:3][CH2:4][CH2:5][O:6][C:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:21])([CH3:7])[CH3:1]
Reactant: CN(C)CCCO
Reactant: [OH-]
Reactant: CCCCCCCCCCCCCl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCC(=O)OCCCN(C)C

Procedure:
In accordance with the procedure of Example 10, 72.2 g of 3-dimethylamino-1-propanol and 153.1 g of lauryl chloride are reacted in altogether 250 ml of CHCl3. The reaction mixture is neutralised with 147 ml of 20% NaOH. Yield: 157.2 g (82.1%) of product with a boiling point of 110° C./0.1 torr.
Reaction SMILES: [CH2:1]([C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10](Cl)=[O:11])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C(N([CH2:18][CH3:19])CC)C.[OH2:20].Cl>C(O)C>[CH2:18]([O:20][C:10]([C@H:7]1[CH2:8][CH2:9][C@H:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6]1)=[O:11])[CH3:19]
Reactant: O
Reactant: CCC[C@H]1CC[C@H](C(=O)Cl)CC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCO
Product: CCC[C@H]1CC[C@H](C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
10 g (53.6 mmol) of trans-4-n-propylcyclohexanecarbonyl chloride was dissolved in 30 ml of ethanol, and a small amount of triethylamine was added thereto, followed by 10 hours of stirring at room temperature. The reaction mixture was injected into 100 ml of iced water, acidified with 6N-hydrochloric acid aqueous solution and extracted with isopropyl ether. The organic layer was repeatedly washed with water until the washing liquid became neutral and then dried with magnesium sulfate. After distilling off the solvent, the product was purified by silica gel column chromatography to obtain 9.9 g of trans-4-n-propylcyclohexanecarboxylic acid-ethyl-ester.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2F)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH2:31][O:32][CH:33]3[CH2:38]CC[CH2:35][O:34]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18].Cl[C:41]1C=C(NC2C=CC(F)=CC=2)C=CC=1C(C1C=C(C#C)C=CC=1C)=O.N(CC1COC(C)(C)O1)=[N+]=[N-]>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([C:25]2[N:26]=[N:27][N:28]([CH2:30][CH:31]3[CH2:35][O:34][C:33]([CH3:38])([CH3:41])[O:32]3)[CH:29]=2)[CH:22]=[CH:21][C:20]=1[CH3:39])=[O:18]
Reactant: Cc1ccc(-c2cn(CCOC3CCCCO3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: C#Cc1ccc(C)c(C(=O)c2ccc(Nc3ccc(F)cc3)cc2Cl)c1
Agent: CC1(C)OCC(CN=[N+]=[N-])O1
Product: Cc1ccc(-c2cn(CC3COC(C)(C)O3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 101, using compound 432 (2.75 mmol) and compound 410 (2.75 mmol). The crude product was purified by continuous gradient flash chromatography using EtOAc/petroleum ether (40-60) 20:80 to 65:35 as the eluent to afford the title compound as foam.