Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])([CH3:4])(C)C.Cl[C:16](OCC=C)=O>ClCCl.C(N(C(C)C)CC)(C)C>[CH2:1]([O:5][C:6]([CH:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])=[O:7])[CH:4]=[CH2:16]
Reactant: C=CCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)C(N)CCCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCOC(=O)C(N)CCCCN
Temperature: 0 °C

Procedure:
Mono-t-butyloxycarbonyl (BOC) 1,5-pentanediamine was synthesized by using 1,5-diaminopentane (12.5 g, 122 mmol) in place of 1,3-diaminopropane in the synthesis of mono-allyloxycarbonyl-1,3-diaminopropane described in Example 1 above, yielding 10 g (49 mmol) of mono-tert-butyloxycarbonyl-1,5-diaminopentane (1). The mono-tert-butyloxycarbonyl-1,5-diaminopentane (1) (5.8 g, 28.7 mmol) was dissolved in 75 mL of dichloromethane with 7.5 mL of diisopropylethylamine and cooled to 0° C. A solution of allyl chloroformate (3.3 mL) in dichloromethane (25 mL) was added over five minutes. The reaction was allowed to warm to room temperature for one hour and then solvent was removed by rotary evaporation. The residue was dissolved in 100 mL of ethyl acetate and washed with three 100 mL portions of 10% citric acid, once with 100 mL saturated aqueous sodium bicarbonate and once with 100 mL of saturated aqueous sodium chloride. The organic phase was dried over magnesium sulfate and solvent was removed by rotary evaporation. The resulting oil (2) was treated with 25 mL of trifluoroacetic acid for 30 minutes. The trifluoroacetic acid was removed by rotary evaporation and the resulting reside was twice dissolved in dichloromethane and then evaporated to remove residual solvent. The residue was dissolved in 50 mL of 3N hydrochloric acid and washed with two 50 mL portions of dichloromethane. The aqueous phase was cooled in an ice bath and the pH was adjusted to approximately 13 with 50% aqueous sodium hydroxide. The basic aqueous phase was extracted with three 100 mL portions of dichloromethane, the combined organics were washed with 100 mL of saturated aqueous sodium chloride and then dried over potassium carbonate. The mixture was filtered, the solvent removed first by rotary evaporation and then by high vacuum to yield 3.95 g of mono-allyloxycarbonyl-1,5-diaminopentane (3) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:18][CH2:19][CH2:20][Cl:21])=[C:7]([O:16][CH3:17])[CH:8]=2)[N:3]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)C>C1(C)C=CC=CC=1>[Cl:21][CH2:20][CH2:19][O:18][C:6]1[CH:5]=[C:4]2[C:9]([CH:10]=[C:11]([C:12]([O:14][CH3:15])=[O:13])[C:2](/[N:1]=[CH:24]/[N:25]([CH3:27])[CH3:26])=[N:3]2)=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COC(=O)c1cc2cc(OC)c(OCCCl)cc2nc1/N=C/N(C)C
Temperature: 25 °C
Yield: 64.7 %

Procedure:
A mixture of methyl 2-amino-7-[2-chloroethoxy]-6-methoxy-3-quinolinecarboxylate (5.00 g, 16.09 mmol) and 5.10 g of dimethylformamide dimethylacetal in 75 mL of toluene containing 50 mg of p-toluenesulfonic acid is heated at reflux for 10 minutes then cooled to room temperature. Diethyl ether is added and the solids are collected by filtration to provide 3.81 g of methyl 7-(2-chloroethoxy)-2-{[(IE)-(dimethylamino)methylidene]amino}-6-methoxy-3-quinolinecarboxylate as a pale yellow solid, mp 108-110° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][CH:12]=1)(=[O:10])=[O:9].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]2[O:41][CH2:42][O:43][C:38]2=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([CH3:26])=[N:4][O:5][C:6]=1[N:7]([CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[S:8]([C:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[S:13][C:12]=1[CH:35]([OH:36])[C:34]1[CH:37]=[C:38]2[O:43][CH2:42][O:41][C:39]2=[CH:40][C:33]=1[CH3:32])(=[O:9])=[O:10]
Reactant: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Reactant: Cc1cc2c(cc1C=O)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1onc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 36.7 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-3-methyl-5-isoxazolyl)-N-(methoxyethoxy-methyl)thieno [2,3-b]pyridine-3-sulfonamide (0.31 g, 0.75 mmoles)[Example 4(A)], THF (4 ml), t-BuLi (1.7 M, 0.53 ml, 0.90 mmoles) and 2-methyl-4,5-(methylenedioxy)benzaldehyde (0.15 g, 0.90 mmoles). Flash chromatography (40% EtOAc/hexanes) provided 0.16 g (38%) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][CH2:12][CH:13]=O)=[CH:8][CH:9]=2)[CH2:4][O:3]1.[CH3:15][NH:16][CH2:17][CH:18]([OH:21])[CH2:19][OH:20]>>[OH:21][CH:18]([CH2:19][OH:20])[CH2:17][N:16]([CH3:15])[CH2:13][CH2:12][CH2:11][C:7]1[N:6]=[C:5]2[CH2:4][O:3][C:2](=[O:1])[C:10]2=[CH:9][CH:8]=1
Reactant: CNCC(O)CO
Reactant: O=CCCc1ccc2c(n1)COC2=O
Product: CN(CCCc1ccc2c(n1)COC2=O)CC(O)CO
Yield: 52.8 %

Procedure:
In a process similar to that described in Preparation 8, 3-(5-Oxo-5,7-dihydro-furo[3,4-b]pyridin-2-yl)-propionaldehyde (139 mg, 0.73 mmol) and 3-methylamino-1,2-propanediol (77 mg, 0.73 mmol) are reacted to provide the title compound as an oil (108 mg, 52%).
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:20][C:19]3[CH2:18][NH:17][CH2:16][C:15]=3[CH2:14]2)=[N:10][CH:9]=1)=[O:7].FC(F)(F)C([O-])=O.C(N(CC)CC)C.[F:36][C:37]([F:48])([F:47])[C:38]1[CH:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](Cl)=[O:41]>CN(C=O)C>[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[S:12][C:11]([N:13]2[CH2:14][C:15]3[CH2:16][N:17]([C:40](=[O:41])[C:39]4[CH:43]=[CH:44][CH:45]=[CH:46][C:38]=4[C:37]([F:36])([F:47])[F:48])[CH2:18][C:19]=3[CH2:20]2)=[N:10][CH:9]=1)=[O:7]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: CC(C)CCNC(=O)c1cnc(N2CC3=C(CNC3)C2)s1
Agent: O=C([O-])C(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1cnc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(3-Methylbutyl)-2-(3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl)thiazole-5-carboxamide, trifluoroacetate (220 mg, 0.52 mmol) and triethylamine (0.22 ml, 1.57 mmol) were dissolved in 10 ml of DMF and admixed in an ice bath with 2-trifluoromethylbenzoyl chloride (218 mg, 1.04 mmol). The mixture was stirred further for 1 h and allowed to warm to room temperature, and concentrated, water and ethyl acetate were added and the organic phase was removed, concentrated and purified by preparative HPLC (PR18, acetonitrile/water 0.1% TFA). Yield: 25 mg (10%), M+H+: 479.06.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([O:10]C)=[CH:6][C:4]=1[NH2:5].C[O:13][C:14]1[CH:22]=[CH:21][C:17](C(Cl)=O)=[CH:16][CH:15]=1>>[OH:13][C:14]1[CH:22]=[CH:21][C:17]([C:1]2[O:2][C:3]3[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:4]=3[N:5]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1ccc(OC)c(N)c1
Product: Oc1ccc(-c2nc3cc(O)ccc3o2)cc1

Procedure:
The title compound was prepared in substantially the same manner as described in Example 1, from 2,5-dimethoxyaniline, and 4-methoxybenzoyl chloride and was obtained as a light yellow solid, m.p. 264–267° C.; MS m/e 228 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:13])[CH:5]=1)([O-])=O.[H][H]>[Ni].C(OCC)(=O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:20](=[O:21])[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[C:12]2=[O:13])[CH:5]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1N1C(=O)c2cccnc2C1=O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1N1C(=O)c2cccnc2C1=O

Procedure:
The mixture of 2.83 g of N-(4-nitro-o-tolyl)-pyridine-2,3-dicarboximide, 200 ml of ethyl acetate and 1.6 g of prewashed Raney nickel is hydrogenated at 3.1 atm. and room temperature until the hydrogen uptake ceases. It is filtered, evaporated, the residue taken up in chloroform, the solution treated with charcoal, filtered, evaporated and the residue recrystallized from methanol, to yield the N-(4-amino-o-tolyl)-pyridine-2,3-dicarboximide of the formula ##STR6## melting at 180°-182°.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=3[C:12]=2[CH2:13][O:14][CH3:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(F)cc3c2COC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCc1c(C(Nc2ccc(C(=O)NCCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.1 %

Procedure:
To a mixture of ethyl 3-({[4-({cyclohexyl[5-fluoro-3-(methoxymethyl)-1-benzofuran-2-yl]methyl}amino)phenyl]carbonyl}amino)propanoate (207 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 5 hr and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (186 mg, 95%) as a white solid.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[Cl:10][C:11]1[C:16](Cl)=[N:15][CH:14]=[CH:13][N:12]=1>C1COCC1>[Cl:10][C:11]1[C:16]([O:9][CH:6]2[CH2:7][CH2:8][O:3][CH2:4][CH2:5]2)=[N:15][CH:14]=[CH:13][N:12]=1
Reactant: Clc1nccnc1Cl
Reactant: OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Clc1nccnc1OC1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.2 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.22 g, 5.39 mmol) was added to a solution of tetrahydro-4H-pyran-4-ol (0.47 mL, 4.90 mmol) in THF (10 mL) and the mixture was stirred for 30 mins, during which time a suspension formed. This mixture was added dropwise to a solution of 2,3-dichloropyrazine (0.73 g, 4.90 mmol) in THF (10 mL) at −78° C. under argon. The cooling bath was removed and the mixture was stirred for 3 h with warming to RT. Ethyl acetate and saturated aqueous ammonium chloride were added, the layers were separated, and the organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give an oil that was purified by silica gel chromatography to give 2-chloro-3-(tetrahydro-2H-pyran-4-yloxy)pyrazine (0.75 g, 3.49 mmol, 71% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:12][C:11]=2[F:21])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([CH3:31])[N:24]=1>>[C:27]([C:26]1[CH:29]=[CH:30][C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[C:11]([F:21])=[CH:12][C:13]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:14][C:15]=3[F:16])=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])=[N:24][C:25]=1[CH3:31])#[N:28]
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: Cc1nc(Cl)ccc1C#N
Product: Cc1nc(Nc2sc(-c3c(F)cc(C(C)(C)O)cc3F)cc2C(N)=O)ccc1C#N

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (150 mg, 0.48 mmol) and 6-chloro-2-methylnicotinonitrile (73 mg, 0.48 mmol) as starting materials.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8](I)=[CH:7][N:6]=2)[CH2:3][CH2:2]1.Cl[C:13]1[CH:18]=CC(C#C)=CN=1.ClC1C=CC(I)=CN=1.C1(N)CC1.[CH:33]1([CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([I:44])=[CH:40][N:39]=2)[CH2:35]C1>>[CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:13]#[CH:18])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[CH:36]1([NH:37][C:38]2[CH:43]=[CH:42][C:41]([I:44])=[CH:40][N:39]=2)[CH2:33][CH2:35]1
Reactant: C#Cc1ccc(Cl)nc1
Reactant: Ic1ccc(NCC2CC2)nc1
Agent: Clc1ccc(I)cn1
Agent: Ic1ccc(NC2CC2)nc1
Agent: NC1CC1
Product: C#Cc1ccc(NC2CC2)nc1

Procedure:
Cyclopropyl-(5-ethynyl-pyridin-2-yl)-amine was prepared from cyclopropyl-(5-iodo-pyridin-2-yl)-amine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1). Cyclopropyl-(5-iodo-pyridin-2-yl)-amine was prepared from 2-chloro-5-iodo-pyridine and cyclopropyl amine in the same manner as cyclopropylmethyl-(5-iodo-pyridin-2-yl)-amine (Example 2).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:9][CH:8]=2)[N:6]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[C:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][CH2:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[CH:11][CH:12]=2)[N:6]=1)(=[O:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(-c2csc(N)n2)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(-c2ccc(CCNC(=O)OC(C)(C)C)cc2)cs1
Reaction time: 8 h
Yield: 85.3 %

Procedure:
tert-Butyl {2-[4-(2-amino-1,3-thiazol-4-yl)phenyl]ethyl}carbamate (290 mg) was dissolved in dichloromethane (5 mL), then acetic anhydride (0.103 mL), 4-dimethylaminopyridine (10 mg) and pyridine (0.147 mL) were added. The mixture was stirred overnight. The mixture was extracted with chloroform, washed with water and saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The solid was washed with ethyl ether, and dried in vacuo to give tert-butyl (2-{4-[2-(acetylamino)-1,3-thiazol-4-yl]phenyl}ethyl)carbamate as a white solid (280 mg, 85.3%).
Reaction SMILES: C(O[O-])(=O)C1C(=CC=CC=1)C([O-])=[O:5].[Mg+2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1>CO.ClCCl>[F:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:23])=[O:5])=[C:18]([N+:24]([O-:26])=[O:25])[CH:17]=1
Reactant: O=C([O-])c1ccccc1C(=O)O[O-]
Reactant: CSc1ccc(F)cc1[N+](=O)[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 20 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
4-Fluoro-1-methylsulfinyl-2-nitrobenzene can be obtained in the following way: 4.7 g of magnesium monoperoxyphthalate are added portionwise to a solution, under argon, of 1.9 g of 4-fluoro-1-methylsulfanyl-2-nitrobenzene in 6 ml of methanol and 30 ml of dichloromethane. The reaction mixture is then stirred at a temperature in the region of 20° C. for 3 hours, and is then filtered through sintered glass and the solid is washed with dichloromethane. The filtrate is washed with an aqueous sodium hydrogencarbonate solution then with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a column of 125 g of silice (particle size 40-63 μm), eluting with pure dichloromethane. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.3 g of 4-fluoro-1-methylsulfinyl-2-nitrobenzene are thus obtained in the form of a yellow foam (Rf=0.23, silica gel thin layer chromatography, eluent: dichloromethane/ethyl acetate 90/10)).
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].Cl[C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1.CN(C=O)C.[H-].[Na+]>O>[CH2:1]([S:3][C:5]1[C:6]([C:11]#[N:12])=[N:7][CH:8]=[CH:9][CH:10]=1)[CH3:2]
Reactant: N#Cc1ncccc1Cl
Reactant: CCS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cccnc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.9 mL of ethanethiol was added to a mixture of 1.39 g of 3-chloropyridine-2-carbonitrile and 10 mL of DMF, 0.52 g of 60% sodium hydride (oil-based) was added to the reaction mixture under ice cooling, and then the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure, and the resulting residue was applied to a silica gel column chromatography to obtain 1.52 g of 3-ethylsulfanylpyridine-2-carbonitrile.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[CH:3]=1.C(OC)(OC)OC.[CH2:18]([O:20][C:21](=[O:27])[CH:22]=[C:23]1[CH2:26][CH2:25][CH2:24]1)C>CO.S(=O)(=O)(O)O>[OH:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([S:1][C:23]2([CH2:22][C:21]([O:20][CH3:18])=[O:27])[CH2:26][CH2:25][CH2:24]2)=[CH:3][C:4]=1[CH3:10]
Reactant: CCOC(=O)C=C1CCC1
Reactant: Cc1cc(S)cc(C)c1O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: COC(OC)OC
Product: COC(=O)CC1(Sc2cc(C)c(O)c(C)c2)CCC1
Yield: 68.2 %

Procedure:
To a solution of 4-mercapto-2,6-dimethylphenol (2.5 g) in anhydrous methanol (40 mL) containing trimethyl orthoformate (3 mL), was added cyclobutylidene-acetic acid ethyl ester (7.6 g) and then 5 drops of concentrated sulfuric acid. The solution was deoxygenated by bubbling with nitrogen, and was allowed to reflux for 4 days. The mixture was concentrated, washed with saturated NaHCO3 and extracted with ethyl acetate. After concentrated in vacuo, the residue was purified by flash chromatography eluted with 10-20% ethyl acetate in hexane to give 3.1 g of methyl {1-[(4-hydroxy-3,5-dimethylphenyl)thio]cyclobutyl}acetate as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O.O1CCOCC1>[C:35]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1)(=[O:37])[CH3:36]
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)n1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 15 h

Procedure:
The experiment is carried out as in Example 44, starting with 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g) in dimethylformamide (150 cc), acetyl chloride (1.95 cc) in dioxane (50 cc) and sodium hydride (1.3 g as a 50% dispersion in vaseline oil). The mixture is stirred for 15 hours at 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), firstly with dichloromethane as eluant and then with ethyl acetate as eluant, then recrystallization from boiling acetonitrile (45 cc), 2-{3-[4-(1-acetyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (1.3 g) is obtained, m.p. 163° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([C:10](=[O:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].Cl[CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:10]([C:4]1[C:3]([O:13][CH3:14])=[C:2]([N:1]2[CH2:16][CH2:17][CH2:18][C:19]2=[O:20])[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=1)(=[O:12])[CH3:11]
Reactant: O=C(Cl)CCCCl
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1N
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1N1CCCC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 14.2 %

Procedure:
To a mixture of 1-(3-amino-5-chloro-2-methoxy-4-methylphenyl)ethanone (100 mg, 0.5 mmol) and 4-dimethylaminopyridine (69 mg, 0.56 mmol) in tetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.058 mL, 0.52 mmol). The reaction was stirred at room temperature for 1 hour. To the reaction mixture was added 1.0 M potassium tert-butoxide in tetrahydrofuran (1.03 mL, 1.03 mmol). The resulting mixture was stirred at room temperature for 2 hours, quenched with aq. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated. The residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the product (20 mg, 20%). LCMS calculated for C14H17ClNO3 (M+H)+: m/z=282.1. found: 282.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:22][N:23]([CH3:36])[C:24](=[O:35])[CH:25]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:26](O)=[O:27].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[CH:18][CH:19]=2)[C:26](=[O:27])[CH:25]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:24]([N:23]([CH3:36])[CH3:22])=[O:35])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C(=O)C(C(=O)O)c1ccccc1
Reactant: COc1ccc(NCCc2ccc(OC)c(OC)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(CCc2ccc(OC)c(OC)c2)C(=O)C(C(=O)N(C)C)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.7 %

Procedure:
A mixture of 28.7 mg (0.1 mmol) [2-(3,4-Dimethoxy-phenyl)-ethyl]-(4-methoxy-phenyl)-amine (intermediate 2), 20.7 mg (0.1 mmol) N,N-Dimethyl-2-phenyl-malonamic acid (WO2000009481), 38.5 mg (0.12 mmol) TBTU and 38.7 mg (0.3 mmol) DIPEA in 3 mL DMF was stirred at room temperature for 16 h. The mixture was concentrated diluted with methanol and formic acid and purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and formic acid, the product containing fractions were evaporated to yield 23.2 mg (61%) of the title compound. MS(m/e): 477.2 (MH+).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:34])[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16][C:17]([C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=O)=[CH:11][CH:10]=1)[CH:4]([CH3:6])[CH3:5].Cl.[NH2:36][OH:37].C(=O)([O-])O.[Na+]>>[OH:1][CH2:2][C@@H:3]([NH:7][C:8](=[O:34])[C:9]1[CH:10]=[CH:11][C:12]([CH:15]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH2:16]/[C:17](=[N:36]\[OH:37])/[C:19]2[CH:24]=[CH:23][C:22](=[O:25])[N:21]([CH3:26])[CH:20]=2)=[CH:13][CH:14]=1)[CH:4]([CH3:5])[CH3:6]
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](CO)C(C)C)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(C(=O)N[C@H](CO)C(C)C)cc1

Procedure:
In analogy to example 151, step 3, N—((S)-1-hydroxy-3-methylbutan-2-yl)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolylpropyl)benzamide was reacted with hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate to give the title compound as an off-white solid containing <10% of the corresponding Z isomer, MS (ESI+): m/z=476.2 [M+H]+.
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[Cl:16][CH2:17]I.C(N(CC)CC)C>CN(C=O)C>[Cl:16][CH2:17][O:14][C:13](=[O:15])[CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: ClCI
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)OCc1ccccc1)OCCl

Procedure:
A solution of N-carbobenzoxy-glycine (4.2 g), chloroiodomethane (6.0 ml), and triethylamine (3.5 ml) in DMF (10 ml) was stirred for 2 hours at room temperature. The mixture was worked up and purified in the same way as described in Example 6A to yield the desired compound as a slightly yellowish oil.