Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:28][CH2:29][CH3:30])[CH:14]3[CH2:19][CH2:18][N:17]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:16][CH2:15]3)[CH2:10]2)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.ClCCl>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([N:13]([CH2:28][CH2:29][CH3:30])[CH:14]3[CH2:15][CH2:16][N:17]([C:20]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[O:21])[CH2:18][CH2:19]3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(OC)cc2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: ClB(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: CCCN(C1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc(O)cc2C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 44.3 %

Procedure:
To a −78° C. solution of {4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (300 mg, 0.72 mmol) and tetrabutylammonium iodide (292 mg, 0.79 mmol) in dichloromethane (20 mL) under an inert atmosphere was added boron trichloride (1M, 2.5 mL, 2.5 mmol) dropwise. The reaction was warmed to room temperature and stirred for 2.5 h. The reaction was quenched by slow addition of water and the organic layer separated and dried (MgSO4). This was concentrated onto silica (1.5 g) and placed on top of a flash column. Chromatography eluting with 30% acetone in hexanes afforded {4-[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-piperidin-1-yl}-morpholin-4-yl-methanone (128 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17](I)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)#[CH:22].C(NCC)C>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:22]#[C:21][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1ccccn1
Reactant: C#Cc1cccc(Nc2ncnc3ccc(I)cc23)c1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: C#Cc1cccc(Nc2ncnc3ccc(C#Cc4ccccn4)cc23)c1

Procedure:
The title compound was synthesized according to the method of Example 2 using (3-Ethynyl-phenyl)-(6-iodo-quinazolin-4-yl)-amine (125 mg, 0.506 mmol), 2-ethynyl-pyridine (66 mg, 0.505 mmol) and diethyl amine (72 mg, 0.99 mmol) in 2 mL, of DMF.
Reaction SMILES: [CH2:1]([N:3]([CH2:19][CH3:20])[CH2:4][CH2:5][CH2:6][S:7]([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=[NH:9])=[O:8])[CH3:2].C=O.[CH:23](O)=O.[OH-].[Na+]>O>[CH3:23][N:9]=[S:7]([CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:19][CH3:20])([C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=CO
Reactant: CCN(CC)CCCS(=N)(=O)c1ccc([N+](=O)[O-])cc1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCN(CC)CCCS(=O)(=NC)c1ccc([N+](=O)[O-])cc1

Procedure:
A mixture of S-(3-diethylaminopropyl)-S-(4-nitrophenyl)sulfoximine (0.03 mole), 17 ml of 37% formaldehyde, and 22.6 ml of 98% formic acid is heated at reflux temperature for 48 hr. Water is added to the reaction mixture which is then made slightly basic by addition of 50% sodium hydroxide solution. The mixture is extracted with chloroform and the extract is dried and concentrated to obtain the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]([O:24]CC)=O)[CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.CO.[NH3:29]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[N:21]=[C:20]([C:22]([NH2:29])=[O:24])[CH:19]=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N
Reactant: CCOC(=O)c1cccc(-c2ccc(OCc3cccc(F)c3)cc2)n1
Solvent: CO
Product: NC(=O)c1cccc(-c2ccc(OCc3cccc(F)c3)cc2)n1

Procedure:
A solution of ethyl 6-(4-{[(3-fluorophenyl)methyl]oxy}phenyl)-2-pyridinecarboxylate (D3, 110 mg, 0.30 mmol) in MeOH/NH3 (7M, 5 ml) was stirred at 60° C. in a sealed tube for 6 h. The solvent was then evaporated under reduced pressure to afford the title compound (95 mg); MS: (ES/+) m/z: 323 [MH+], C19H15FNO3 requires 322; 1H-NMR (300 MHz, DMSO) δ (ppm): 8.25 (bs, 2H), 8.20 (d, 1H), 8.05 (d, 1H), 7.95 (t, 1H), 7.85 (d, 1H), 7.65 (bs, 1H), 7.40 (t, 1H), 7.30 (d, 2H), 7.15 (t, 1H), 7.10 (d, 2H), 5.20 (s, 2H).
Reaction SMILES: [CH3:1][C:2]([CH2:9][CH2:10][CH2:11][CH3:12])=[CH:3][CH2:4][CH2:5][C:6](=[O:8])[CH3:7].[CH:13]([Mg]Br)=[CH2:14]>>[CH3:7][C:6]([OH:8])([CH2:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:13]=[CH2:14]
Reactant: C=C[Mg]Br
Reactant: CCCCC(C)=CCCC(C)=O
Product: C=CC(C)(O)CCC=C(C)CCCC

Procedure:
By the procedure described in Example 13, from 6-methyl-5-decen-2-one and vinyl-magnesium bromide there is obtained 3,7-dimethyl-1,6-undecadien-3-ol; nD26 = 1.4618, boiling point 116° C./9 mm Hg. This alcohol is reacted with phosphorus tribromide by the procedure of Example 13 to give 1-bromo-3,7-dimethyl-2,6-undecadiene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[CH3:21][C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:31]2[CH2:32][CH2:33][N:28]([C:24]3[CH:25]=[CH:26][CH:27]=[C:22]([CH3:21])[CH:23]=3)[CH2:29][CH2:30]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([CH3:20])=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: Cc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(C)c(C)cc2nc1OC
Product: COc1nc2cc(C)c(C)cc2nc1NC(=O)N1CCN(c2cccc(C)c2)CC1
Yield: 49 %

Procedure:
Ethyl N-(2-methoxy-6,7-dimethylquinoxalin-3-yl)carbamate and 1-(3-methylphenyl)piperazine were reacted by the same way with the example 183 to obtain the titled compound (yield, 49%). 1H NMR (300 MHz, CDCl3) δ 2.33 (s, 6H), 2.40 (s, 3H), 3.21-3.31 (m, 4H), 3.74-4.11 (m, 3H), 4.13 (s, 4H), 6.71-6.78 (m, 3H), 7.16-7.20 (m, 1H), 7.36 (br s, 1H), 7.52 (s, 1H), 7.60 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]([NH:19][C:20](=[O:22])[CH3:21])([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18])[C:6](OCC)=[O:7])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CCO>[CH2:1]([O:3][C:4]([C:5]1([NH:19][C:20](=[O:22])[CH3:21])[CH2:11][C:12]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:18][C:6]1=[O:7])=[O:23])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccccc1N)(NC(C)=O)C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1(NC(C)=O)Cc2ccccc2NC1=O
Temperature: 25 °C

Procedure:
A solution of 1.0 eq. of 80 and 0.3 eq of p-toluenesulfonic acid hydrate in EtOH was refluxed for 2 hrs. The mixture was then stirred at rt for a time sufficient for reaction completion. After rotary evaporation, 100 mL of saturated aqueous NaHCO3 was added and the mixture was extracted with EtOAc. The combined organic extracts were dried over MgSO4 and vacuum filtered. The filtrate was rotary evaporated and dried under vacuum to yield 81.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]=[O:12].[H-].[Na+].[CH3:15]I>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:15])[CH:8]=[C:7]2[CH:11]=[O:12]
Reactant: CI
Reactant: O=Cc1c[nH]c2c(F)cccc12
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(C=O)c2cccc(F)c21
Reaction time: 1 h

Procedure:
7-Fluoroindole-3-carboxaldehyde (2.5 g) in dry THF (20 ml) was added to a cold (0°) suspension of sodium hydride (73.2% dispersion in oil; 652 mg) in dry THF (20 ml) under nitrogen and the mixture was stirred for 1h. Methyl iodide (2.5 ml) was added, and the resulting mixture was stirred for 2h at 0°. The mixture was then poured into saturated brine solution (300 ml) and extracted with ether (2×300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (2.66 g), m.p. 92°-94°.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=2.C([O-])([O-])=O.[Cs+].[Cs+].[F:27][C:28]([F:47])([F:46])[C:29]1[CH:30]=[C:31]([C:39]2[O:43][N:42]=[C:41]([CH2:44]Cl)[N:40]=2)[CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1.CC#N>CCOC(C)=O>[F:47][C:28]([F:27])([F:46])[C:29]1[CH:30]=[C:31]([C:39]2[O:43][N:42]=[C:41]([CH2:44][N:5]3[C:6]4[C:11](=[C:10]([C:13]([F:16])([F:15])[F:14])[C:9]([C:17]#[N:18])=[CH:8][CH:7]=4)[CH:12]=[C:4]3[CH2:3][C:2]([F:1])([F:19])[F:20])[N:40]=2)[CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1
Reactant: N#Cc1ccc2[nH]c(CC(F)(F)F)cc2c1C(F)(F)F
Reactant: FC(F)(F)c1cc(-c2nc(CCl)no2)cc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1ccc2c(cc(CC(F)(F)F)n2Cc2noc(-c3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c1C(F)(F)F
Temperature: 50 °C
Reaction time: 24 h
Yield: 18.3 %

Procedure:
A mixture of the indole (0.040 g, 0.14 mmol) from step A, Cs2CO3 (0.054 g, 0.16 mmol), 5-[3,5-bis(trifluoromethyl)phenyl]-3-(chloromethyl)-1,2,4-oxadiazole (0.091 g, 0.27 mmol) and CH3CN (4 mL) was stirred at 50° C. for 24 h. The mixture was diluted with EtOAc (25 mL) and washed with water (15 mL) and brine (15 mL). Drying (MgSO4), filtration, and concentration was followed by purification (SiO2, 0-30% EtOAc in hexanes) to afford the title compound (0.015 g, 19%) as an off-white solid: 1H NMR (400 MHz, CDCl3) δ 8.48 (s, 2H), 8.10 (s, 1H), 7.80 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 6.96 (s, 1H), 5.58 (s, 2H), 3.94 (q, 2H); MS m/z 585 (M−H).
Reaction SMILES: C([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([OH:24])[CH3:23])[C:13](=[O:25])[N:12]([CH3:26])[C:11]=2[N:10]=[CH:9]1)C1C=CC=CC=1.CO.[H][H]>[Pd].C(O)(=O)C>[OH:24][C@H:22]([CH3:23])[CH2:21][CH2:20][CH2:19][CH2:18][N:14]1[C:15](=[O:17])[C:16]2[NH:8][CH:9]=[N:10][C:11]=2[N:12]([CH3:26])[C:13]1=[O:25]
Reactant: [H][H]
Reactant: C[C@@H](O)CCCCn1c(=O)c2c(ncn2Cc2ccccc2)n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H](O)CCCCn1c(=O)c2[nH]cnc2n(C)c1=O
Reaction time: 14 h
Yield: 66.5 %

Procedure:
A mixture of (R)-7-benzyl-1-(5-hydroxyhexyl)-3-methylxanthine (33.7 g, 84.7 mmol), methanol (60 ml), acetic acid (60 ml), and 10% palladium on carbon (6 g) was treated with hydrogen gas (40 psi) on a Parr shaker. After 14 hours, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with 10% methanol/ethyl acetate to provide (R)-1-(5-hydroxyhexyl)-3-methylxanthine (15 g).
Reaction SMILES: [Na].[Cl-].[NH2:3][C:4]([NH2:6])=[NH2+:5].[CH2:7]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH2:24][C:25](OCC)=[O:26])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(O)C>[CH2:7]([N:14]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]1[CH2:24][C:25]([NH:5][C:4]([NH2:6])=[NH:3])=[O:26])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC1c2ccccc2C(=O)N1Cc1ccccc1
Reactant: NC(N)=[NH2+]
Agent: [Cl-]
Agent: [Na]
Solvent: CCO
Product: N=C(N)NC(=O)CC1c2ccccc2C(=O)N1Cc1ccccc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
0.22 g of sodium is added to 20 cm3 of absolute ethanol under an inert atmosphere. After the sodium has totally disappeared, 0.94 g of guanidinium chloride is added. The reaction mixture is stirred under an inert atmosphere at a temperature in the region of 20° C. for 1 hour, followed by addition of a solution of 2 g of ethyl (2-benzyl-3-oxo-2,3dihydro-1H-isoindol-1-yl)acetate in 5 cm3 of absolute ethanol. The reaction mixture is stirred at a temperature in the region of 20° C. for 18 hours and is then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in a mixture of 10 cm3 of water and 30 cm3 of diethyl ether and is then stirred at a temperature in the region of 0° C. for 15 minutes. The precipitate obtained is filtered off, washed with twice 10 cm3 of ice-cold water and then dried in a desiccator under reduced pressure (2 kPa) at a temperature in the region of 20° C. 1.2 g of N-[(2-benzyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)acetyl]guanidine are thus obtained in the form of a white powder melting at 222-225° C. Infrared spectrum (KBr) 3488; 3410; 3344; 1662; 1621; 1521; 1382 and 704 cm−1.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=2[O:18][CH3:19])=[O:9])=[CH:6][N:5]=[C:4](S(CC)=O)[N:3]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]1>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[C:11]([O:18][CH3:19])=[CH:12][CH:13]=[CH:14][C:15]=2[O:16][CH3:17])=[CH:6][N:5]=[C:4]([NH:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:33])[CH3:32])[CH2:27][CH2:26]2)[N:3]=1
Reactant: CCS(=O)c1ncc(C(=O)c2c(OC)cccc2OC)c(N)n1
Reactant: CC(=O)N1CCC(N)CC1
Product: COc1cccc(OC)c1C(=O)c1cnc(NC2CCN(C(C)=O)CC2)nc1N

Procedure:
The same procedure as described in Example 326 was used, starting with (4-amino-2-ethanesulfinyl-pyrimidin-5-yl)-(2,6-dimethoxyphenyl)-methanone (Example 333) and 1-(4-amino-piperidin-1-yl)-ethanone to give 1-[4-[4-amino-5-(2,6-dimethoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-ethanone as a white solid. MS (M+H)+, 400.
Reaction SMILES: [OH:1][C:2]1[N:3]=[C:4]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=[C:5]2[N:6]=1>CO.[H][H].[Pt]=O>[OH:1][C:2]1[NH:3][C:4]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:5]=2[N:6]=1
Reactant: [H][H]
Reactant: Oc1nc2cccccc-2n1
Agent: O=[Pt]
Solvent: CO
Product: Oc1nc2c([nH]1)CCCCC2
Yield: 87.6 %

Procedure:
A solution of 2-Hydroxy-cycloheptimidazole (16.0 g) in methanol was stirred vigorously with platinum oxide (0.2 g) in the hydrogen stream. An off-white suspended solution obtained after 16 hrs, was refluxed and filtered. The insoluble material was extracted again with hot methanol (200 ml) and filtered. The combined filtrate was concentrated in reduced pressure. Obtained yellow powder was washed with ethanol (50 ml) and filtered. 14.6 g of the desired compound was obtained. m.p. 272 ° C./dec.
Reaction SMILES: [CH3:1][Mg]Cl.[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:12]1[CH2:17][CH2:16][CH2:15][C:14](=[O:18])[CH2:13]1.Cl>O1CCCC1>[OH:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:6]=1[CH:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:1])([OH:18])[CH2:13]1
Reactant: C[Mg]Cl
Reactant: O=C1CCCC(c2ccc(O)cc2O)C1
Agent: Cl
Solvent: C1CCOC1
Product: CC1(O)CCCC(c2ccc(O)cc2O)C1
Reaction time: 16 h
Yield: 28 %

Procedure:
Methyl magnesium chloride (0.132 ml of a 22% w/w solution in tetrahydrofuran) was added to a solution of (±)-3-(2,4-dihydroxyphenyl)cyclohexanone (20 mg) in tetrahydrofuran (3 ml) at 0° C. under argon. After 16 hr, dilute hydrochloric acid (1 ml) was added dropwise and the reaction mixture was partitioned between ethyl acetate (50 ml) and brine (50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml), and the combined organic extracts were dried over magnesium sulfate and evaporated in vacuo. The crude residue was purified by preparative HPLC to furnish the title compound as a white solid (6 mg, 28%). δH (d4-MeOH) 1.20 (3H, s), 1.22-1.39 (2H, overlapping m), 1.46 (1H, t), 1.54-1.87 (5H, overlapping m), 3.22 (1H, m), 6.19-6.25 (2H, overlapping m), 6.86 91H, d); m/z (ES−) 281 (M+60−H)−.
Reaction SMILES: Cl[CH:2]([CH3:4])[CH3:3].[CH3:5][NH:6][C:7](=[O:25])/[C:8](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:9]/[O:10][CH3:11]>>[CH3:5][NH:6][C:7](=[O:25])/[C:8](/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][C:19]1[CH:20]=[CH:21][C:22]([CH:2]([CH3:4])[CH3:3])=[CH:23][CH:24]=1)=[N:9]/[O:10][CH3:11]
Reactant: CC(C)Cl
Reactant: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccccc1
Product: CNC(=O)/C(=N/OC)c1ccccc1Oc1ccc(C(C)C)cc1

Procedure:
In the same manner as in Example 14, the objective compound was prepared from 2-chloropropane and (E)-N-methyl-2-(2-phenoxyphenyl)-2-methoxyiminoacetamide.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30](O)=[O:31].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[CH:33][C:27]=1[CH:28]=[CH:29][C:30]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:31]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(O)C=Cc1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1F
Yield: 98.7 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (5.0 g), triethylamine (2.9 mL), 2-fluorocinnamic acid (3.4 g), WSC.HCl (3.9 g), and methylene chloride (130 mL), to give the captioned compound (7.1 g, 99%) as an oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][OH:15])[CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].FC(F)(F)C1C=CC(C2(C[O:30][S:31]([CH3:34])(=O)=[O:32])CCCC2)=CC=1>>[CH3:34][S:31]([O:15][CH2:14][C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1)(=[O:32])=[O:30]
Reactant: OCC1(c2ccc(Cl)c(Cl)c2)CCCC1
Reactant: CS(=O)(=O)OCC1(c2ccc(C(F)(F)F)cc2)CCCC1
Product: CS(=O)(=O)OCC1(c2ccc(Cl)c(Cl)c2)CCCC1

Procedure:
(1-(3,4-Dichlorophenyl)cyclopentyl)methyl methanesulfonate (484) was synthesized from (1-(3,4-dichlorophenyl)cyclopentyl)methanol (483) following the procedure described for methanesulfonic acid 1-(4-trifluoromethyl-phenyl)-cyclopentylmethyl ester (240).
Reaction SMILES: C([O:8][C@@H:9]1[C@@H:14]([CH2:15][O:16]CC2C=CC=CC=2)[N:13]2[CH:24]=[C:25]([C:27]#[C:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:12]2[C@H:11]([O:35]CC2C=CC=CC=2)[C@H:10]1[O:43]CC1C=CC=CC=1)C1C=CC=CC=1>C1COCC1.CCO.[OH-].[OH-].[Pd+2]>[OH:16][CH2:15][C@H:14]1[N:13]2[CH:24]=[C:25]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[N:26]=[C:12]2[C@H:11]([OH:35])[C@@H:10]([OH:43])[C@@H:9]1[OH:8]
Reactant: CCCCCCC#Cc1cn2c(n1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H]2COCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCCCCCCCc1cn2c(n1)[C@H](O)[C@@H](O)[C@H](O)[C@H]2CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (5R,6R,7S,8S)-6,7,8-Tris(benzyloxy)-5-[(benzyloxy)methyl]-2-(1-octynyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (120 mg, 0.179 mmol) in THF/EtOH (2:1) (3 ml) is rapidly stirred with Pd(OH)2/C (0.1 g) under an atmosphere of hydrogen for 14 h. After filtration of the catalyst, the organic solution is concentrated on a rotovap and the residue is dissolved in CH2Cl2 (10 ml). The solution is cooled in an acetone-dry ice bath and a solution of BCl3 (1.0 M) in CH2Cl2 is slowly added. The reaction mixture is warmed room temperature and stirred for 3 hours. The reaction mixture is cooled in an ice-water bath, water added and for 0.5 hour. Most of the solvent is removed using a rotovap and the crude product is purified by chromatography (CHCl3/MeOH/H2O 64:25:4). Lyophilization from water gives the title compound as white foam. 1H NMR (400 MHz, CD3OD): δ7.22 (s, 1H), 4.56 (d, 1H, J=8 Hz), 4.20-4.16 (m, 1H), 3.98-3.93 (m, 2H), 3.83 (t, 1H, J=8.4 Hz), 3.70 (dd, 1H, J=8.8 Hz and 10 Hz), 2.60 (t, 2H, J=7.2 Hz), 1.67-1.63 (m, 2H), 1.35-1.30 (m, 10H), 0.90 (t, 3H, J=6.8 Hz). MS (ES+): 313 [M+1].
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=23)[S:5]1(=[O:17])=[O:16].C(N(CC)CC)C.[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:26]1>CN(C)C=O>[S:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[C:27]([N:34]2[CH2:35][CH2:36][N:37]([CH2:2][CH2:3][N:4]3[C:8]4[CH:9]=[CH:10][CH:11]=[C:12]5[CH:13]=[CH:14][CH:15]=[C:6]([C:7]=45)[S:5]3(=[O:17])=[O:16])[CH2:38][CH2:39]2)=[N:26]1
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCl
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S1(=O)c2cccc3cccc(c23)N1CCN1CCN(c2nsc3ccccc23)CC1
Temperature: 20 °C
Yield: 33.9 %

Procedure:
The experiment is carried out as in Example 1, starting with 2-(2-chloroethyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (8.9 g), triethylamine (4.5 cc) and 4-(1,2-benzisothiazole-3-yl)piperazine (6.6 g) in dimethylformamide (95 cc). The mixture is heated for 8 hours at boiling point, then cooled to a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar) with ethyl acetate as eluant, and recrystallization from boiling acetonitrile (90 cc), 2-{2-[4-(1,2-benziso-thiazol-3-yl)-1-piperazinyl]ethyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (4.6 g) is obtained, m.p. 162°.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:34])[CH2:30][NH:31][CH2:32][CH3:33])=[C:23]([CH2:35][CH3:36])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11]C1=O)([CH3:4])([CH3:3])[CH3:2].C(#N)C>O>[C:1]([C:5]1[CH:6]=[C:7]([CH:38]=[CH:39][CH:40]=1)[CH2:8][NH:9][C@H:17]1[CH2:16][S:15](=[O:18])(=[O:19])[CH2:14][C@@H:13]([CH2:20][C:21]2[CH:26]=[C:25]([F:27])[C:24]([NH:28][C:29](=[O:34])[CH2:30][NH:31][CH2:32][CH3:33])=[C:23]([CH2:35][CH3:36])[CH:22]=2)[C@@H:12]1[OH:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCNCC(=O)Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1CC
Solvent: O
Solvent: CC#N
Product: CCNCC(=O)Nc1c(F)cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc1CC

Procedure:
The title compound was prepared in analogous manner as described for example 1o from N-{4-[(3aR,7S,7aS)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-ethyl-6-fluoro-phenyl}-2-ethylamino-acetamide to yield after preparative HPLC (Sunfire C18 OBD 5 μm, 100×30, 5-50% ACN in water+0.1% TFA gradient, 25 min) the title compound as a light yellow amorphous solid: UPLC RtD=1.084 min; ESIMS [M+H]+=548; 1H NMR (600 MHz, DMSO-d6+TFA): δ 9.96 (s, 1H), 9.70 (s, 1H), 9.0 (s, 1H), 8.90 (s, 1H), 7.63 (s, 1H), 7.44 (m, 1H), 7.37 (m, 1H), 6.98 (d, 1H), 6.95 (s, 1H), 4.26 (m, 2H), 4.02 (m, 2H), 3.84 (d, 1H), 3.66 (dd, 1H), 3.61 (dd, 1H), 3.1-3.3 (m (3H), 3.0 (m, 2H), 2.78 (d, 1H), 2.50 (m, 3H), 2.11 (m, 1H), 1.26 (s, 9H), 1.19 (t, 3H), 1.10 (t, 3H).
Reaction SMILES: [OH:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH:5]([NH2:10])[CH2:4][C:3]1([CH3:12])[CH3:11].[CH2:13]([N:17]=[C:18]=[O:19])[CH2:14][CH2:15][CH3:16]>C1(C)C=CC=CC=1>[CH2:13]([NH:17][C:18]([NH:10][CH:5]1[CH2:6][C:7]([CH3:8])([CH3:9])[N:2]([OH:1])[C:3]([CH3:12])([CH3:11])[CH2:4]1)=[O:19])[CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)CC(N)CC(C)(C)N1O
Reactant: CCCCN=C=O
Solvent: Cc1ccccc1
Product: CCCCNC(=O)NC1CC(C)(C)N(O)C(C)(C)C1
Reaction time: 16 h

Procedure:
To a stirred solution of 1.0 g of 1-oxyl-4-amino-2,2,6,6-tetramethylpiperidine in 75 mL of dry toluene is added dropwise 0.65 mL of butyl isocyanate. The reaction mixture is stirred for 16 hours. The solution is then concentrated to yield the title compound as a red oil.