Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[CH:26]=[N+:27]([O-:50])[CH:28]=[C:29]([Cl:49])[C:30]=1[CH2:31][C@@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:43])[F:42])=[C:36]([O:44][CH2:45][CH:46]2[CH2:48][CH2:47]2)[CH:35]=1)O.C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH2:9][C:10]([O:12][C@H:32]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH:41]([F:42])[F:43])=[C:36]([O:44][CH2:45][CH:46]2[CH2:47][CH2:48]2)[CH:35]=1)[CH2:31][C:30]1[C:29]([Cl:49])=[CH:28][N+:27]([O-:50])=[CH:26][C:25]=1[Cl:24])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(CN(CC(=O)O)C(=O)OC(C)(C)C)cc1OC
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(CN(CC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)C(=O)OC(C)(C)C)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.4 %

Procedure:
A mixture of 2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino)acetic acid (0.209 g, 0.642 mmol), (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.150 g, 0.357 mmol), EDC (0.205 g, 1.071 mmol), and DMAP (0.087 g, 0.714 mmol) in DCM (5 ml) was stirred at RT overnight. The reaction mixture was diluted with DCM (20 ml) and washed with HCl 1M and with NaHCO3 5%. The organic layer was dried over Na2SO4, and the solvent was removed under vacuum. The crude was purified by chromatography on silica gel column (DCM:EtOAc=70:30) affording (S)-4-(2-(2-(tert-butoxycarbonyl(3,4-dimethoxybenzyl)amino) acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.258 g, 0.355 mmol, 99% yield, MS/ESI+ 727.3 [MH]+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:5]=[CH:4][C:3]=1[C:19]1[NH:23]C2C=CC(F)=C(C)C=2N=1.[CH3:30][O-:31].[Na+]>CO>[CH3:30][O:31][C:2]1[C:3]([C:19]#[N:23])=[CH:4][N:5]=[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH:7]=1
Reactant: C[O-]
Reactant: Cc1c(F)ccc2[nH]c(-c3cnc(OCCCC4CCN(C)CC4)cc3Cl)nc12
Agent: [Na+]
Solvent: CO
Product: COc1cc(OCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 4-chloro-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (Example 115) in methanol (0.2 M) was treated with sodium methoxide (4 equiv) at reflux temperature for 4 h. The mixture was cooled to rt, diluted with satd. aq. NaHCO3, and extracted with chloroform. The organic extract was dried (Na2SO4), filtered, and concentrated to yield 4-methoxy-6-[3-(1-methyl-piperidin-4-yl)-propoxy]-nicotinonitrile (100%). This intermediate was converted to the title compound according to Example 115. MS (electrospray): mass calculated for C23H30ClN4O2, 394.24; m/z found, 395.4 [M+H]+.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Na+].Br[C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)(C)C>[NH2:26][C:25]1[CH:27]=[CH:28][C:22]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6]([NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])(=[O:8])=[O:7])=[CH:23][CH:24]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-[(tert-butyl amino)sulfonyl]phenyl boronic acid (6.00 g, 23.35 mmol) in 120 ml toluene was added water (16 ml), isopropanol (60 ml), and NaOH (40 ml, 5M aqueous solution). To this were added 4-bromoaniline and Pd(Ph3P)4. This heterogeneous mixture is then refluxed for 6 hr, then stirred at room temperature over night before refluxing for another 1.5 hr. The reaction mixture is then extracted with water and ethyl acetate. The aqueous layer is extracted twice with ethyl acetate. The organic layers are then dried over MgSO4, filtered and concentrated in vacuo. The crude residue is purified by silica gel flash chromatography. The desired product can be eluded with 30% ethyl acetate in hexanes and concentrated to an orange solid (5.06 g, 16.65, 71%). ES-MS(M+H)+=305.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl[CH2:21][Si:22]([CH3:25])([CH3:24])[Cl:23].[Cl:26][SiH:27]([Cl:29])[Cl:28]>>[Cl:26][Si:27]([Cl:29])([Cl:28])[CH2:21][Si:22]([Cl:23])([CH3:25])[CH3:24].[Cl:26][SiH:27]([Cl:28])[CH2:21][Si:22]([Cl:23])([CH3:25])[CH3:24]
Reactant: Cl[SiH](Cl)Cl
Reactant: C[Si](C)(Cl)CCl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[Si](C)(Cl)C[SiH](Cl)Cl
Product: C[Si](C)(Cl)C[Si](Cl)(Cl)Cl
Yield: 58 %
Yield: 8 %

Procedure:
In the same apparatus and procedure as Example 1 above, 1.0 g (3.8 mmol) of triphenylphosphine, 6.21 g (38.0 mmol) of (chloromethyl)dimethylchlorosilane, and 27.5 g (190.0 mmol) of trichlorosilane were reacted at 150° C. for 12 hrs. The resulting mixture was distilled to give 5.8 g of 1,1,1,3-tetrachloro-3-methyl-1,3-disilabutane (bp; 169-170° C., yield; 58%) and 1.2 g of 1,1,3-trichloro-3-methyl-1,3-disilabutane (bp; 153-155° C., yield; 8%).
Reaction SMILES: Cl.[NH2:2]O.[F:4][C:5]1[CH:10]=[C:9]([CH:11]([CH3:17])[C:12]([NH:14][C:15]#[N:16])=[O:13])[CH:8]=[CH:7][C:6]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[OH-].[Na+]>N1C=CC=CC=1.C(O)C>[NH2:16][C:15]1[N:14]=[C:12]([CH:11]([C:9]2[CH:8]=[CH:7][C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:5]([F:4])[CH:10]=2)[CH3:17])[O:13][N:2]=1
Reactant: NO
Reactant: CC(C(=O)NC#N)c1ccc(-c2ccccc2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: c1ccncc1
Product: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(N)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
A mixture of 2-(2-fluoro-4-biphenylyl)propionic acid (5.00 g, 20.5 mmol) and thionyl chloride (10 ml) in benzene (50 ml) was stirred under reflux for 4 hr and the solution was evaporated under reduced pressure to afford the acid chloride. After the acid chloride was dissolved in acetone (15 ml), the solution was added to cyanamide (1.44 g, 30.8 mmol) in 2N-NaOH (16 ml) by portions at 0°-5° C. The mixture was controlled above pH 10 by 2N-NaOH during addition. After the addition, the mixture was stirred at room temperature for 15 hr, then diluted with water, acidified with 1N-HCl to pH 6 and extracted with ether. The water phase was acidified with 1N-HCl to pH 3 and then extracted with chloroform. The chloroform extracts were washed with saturated NaCl aq., dried with magnesium sulfate, then evaporated under reduced pressure to a residue, which was chlomatographed to afford N-(2-(2-fluoro-4-biphenylyl)propionyl)cyanamide. To hydroxylamine hydrochloride (2.20 g, 30.4 mmol) in pyridine (5 ml) was added N-(2-(2-fluoro-4-biphenylyl) propionyl)cyanamide in ethanol (15 ml) by portion under cooling for 15 minute and the mixture was stirred at room temperature for 1 hr, then standed at room temperature overnight. To the reaction mixture was added 2N-NaOH (40 ml) to afford the precipitates. The precipitates were collected, washed with water, dried and recrystallized with ethyl acetate to afford 3-amino-5-(1-(2-fluoro-4-biphenylyl)ethyl)-1,2,4-oxadiazole (3.00 g, 52% yield): mp 174.5°-175.0° C.
Reaction SMILES: [OH:1][NH2:2].C(O[C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:34])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH2:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1cc(OCc2ccccc2)ccn1)NO
Reaction time: 72 h
Yield: 41 %

Procedure:
HONH2 (50% aqueous, 1 mL) was added to III (47 mg, 0.11 mmol) in DMF (0.2 mL) and MeOH (0.5 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5) to furnish IV as a colourless oil (19 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.[OH2:16]>CC1CCCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]([N:10]2[CH2:15][CH2:14][O:16][CH2:12][CH2:11]2)[N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O
Reactant: C1COCCN1
Solvent: CC1CCCCC1
Product: Clc1ccc(C(N2CCOCC2)N2CCOCC2)cc1

Procedure:
70 g of p-chlorobenzaldehyde and 105 g of morpholine were heated to boiling in 260 g of methylcyclohexane in a water separator. Over the course of 45 minutes, 8.4 ml of water were removed azeotropically. The mixture was left to cool with slow stirring. At 58° C., the solution was seeded, and very fine crystals slowly precipitated out. The mixture was cooled in an ice bath to +5° C. After a post-stirring time of 1 hour, the solid which had precipitated out was filtered off with suction. The white product was washed with 2×50 ml of methylcyclohexane and dried overnight in a drying cabinet at 20° C. and 100 mbar. 129.2 g of product were obtained in the form of white crystals (87% of theory).
Reaction SMILES: C([CH:3]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[NH:10][CH:9]=1)[C:4]([OH:6])=[O:5])C.[H-].[Na+].[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C1COCC1.CN(C=O)C>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28])[CH:9]=[C:8]2[CH2:7][CH2:3][C:4]([OH:6])=[O:5]
Reactant: CCC(Cc1c[nH]c2ccc(OC)cc12)C(=O)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32926.4 %

Procedure:
In THF(640 ml)-DMF(130 ml) was dissolved ethyl 3-(5-methoxy-1H-indol-3-yl)propionic acid (99.3 g, 0.4 mol). To the solution was added in limited amounts, under ice-cooling, a suspension of 60% sodium hydride in oil (18.4 g, 0.46 mol) in THF(50 ml)-DMF(10 ml). The mixture was stirred at room temperature for one hour, and the mixture was again cooled with ice. To the mixture was gradually added p-toluenesulfonyl chloride (83.9 g, 0.44 mmol), followed by stirring for a further 3 hours at room temperature. The reaction mixture was poured into an ice-saturated NH4Cl solution (180 ml). The upper layer was subjected to extraction with ethyl acetate (100 ml+500 ml). The extract solution was washed with a saturated aqueous saline solution (300 ml×2), followed by drying over Na2SO4. The residue was purified by means of silica gel chromatography (eluent: hexane-ethyl acetate (2:1)) and then were added hydrochloric acid (100 ml) and acetic acid (400 ml), and was refluxed for 1 hour. The reaction mixture was concentrated and the resulting crystals were washed with water, dried under reduced pressure and washed with methanol-isopropyl ether (1:3) to obtain the title compound (54.1 g: m.p. 172°-174° C.)
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[ClH:18].[CH:16]1[C:17]2[N:5]([CH2:4][CH2:3][CH2:2][N:28]3[CH2:27][CH2:26][C:25]([C:22]4[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=4)([OH:31])[CH2:30][CH2:29]3)[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]=2[CH:13]=[CH:14][CH:15]=1
Reactant: ICCCn1c2ccccc2c2ccccc21
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cl
Product: OC1(c2ccc(Cl)cc2)CCN(CCCn2c3ccccc3c3ccccc32)CC1
Temperature: 55 °C
Reaction time: 48 h
Yield: 448.5 %

Procedure:
Compound 3 (2.58 g, 0.0056 mol) was dissolved in dry DMF (80 mL), 4-(4-chlorophenyl)piperidin-4-ol (1.0 g, 0.0047 mol) and K2CO3 (0.57 g, 0.0056 mol) were added. The resulting mixture was stirred at 50-60° C for 12 h and at room temperature for 48 h. The reaction mixture was concentrated to dryness in vacuo and CH2Cl2 (100 mL) was added. The organic phase was washed with 5% NaHCO3 (aq) (100 mL), brine (50 mL), dried (MgSO4), filtered and the solvent evaporated in vacuo, to give 4.8 g of an oil. The residual oil was purified on a silica gel column (Eluent: ethyl acetate/n-heptane (1:1)). The product was acidified with 2M HCl(g) in diethylether, giving the title compound 1.6 g (75%). M.p. 194.5-195.5° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18][CH2:17]1)([CH3:15])[CH3:14].O[C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=1)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH:13]([N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:18][CH2:17]1)([CH3:15])[CH3:14]
Reactant: CC(C)N1CCC(O)CC1
Reactant: CCOC(=O)c1cccc(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(OC2CCN(C(C)C)CC2)c1
Temperature: 0 °C
Reaction time: 42 h
Yield: 52.6 %

Procedure:
Diethyl azodicarboxylate (2.26 g) was added dropwise to a stirred mixture of N-isopropyl-4-hydroxypiperidine (Helv. Chim. Acta, 1966, 46, 693; 1.57 g), ethyl 3-hydroxybenzoate (1.66 g), triphenylphosphine (3.4 g) and THF (40 ml) which had been cooled to 0° C. The mixture was stirred at ambient temperature for 42 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and 2N aqueous hydrochloric acid. The aqueous phase was washed with ethyl acetate, basified to pH10 by the addition of solid potassium carbonate and extracted with diethyl ether. The organic extract was dried over magnesium sulphate and evaporated to give ethyl 3-(N-isopropypiperidin-4-yloxy)benzoate as an oil (1.53 g); NMR Spectrum: (CDCl3) 1.06 (d, 6H), 1.38 (t, 3H), 1.8 (m, 2H), 2.07 (m, 2H), 2.41 (m, 2H), 2.72 (m, 1H), 2.78 (m, 2H), 4.38 (m, 2H), 7.08 (m, 1H), 7.32 (t, 1H), 7.57 (d, 1H), 7.62 (d, 1H). The oil so obtained was dissolved in diethyl ether (20 ml) and a 1M solution of hydrogen chloride in diethyl ether (12 ml) was added. The resultant precipitate was isolated to give ethyl 3-(N-isopropypiperidin-4-yloxy)benzoate hydrochloride salt (1.55 g).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([CH2:14][NH2:15])O.[OH2:16]>>[OH:6][CH2:1][CH2:2][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:4]([NH:15][C:14](=[O:16])[C:12]=12)=[O:5]
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCO
Reactant: O
Product: O=C1NC(=O)c2c(CCO)cccc21

Procedure:
888 g (6 mols) of phthalic anhydride are added in portions to 412.5 g of 98% strength ethanolamine (6.6 mols), and the mixture is heated in the course of 2 hours from 110° to 190° C., until 114 g of water have been distilled off. Excess ethanolamine is then removed under reduced pressure down to 145° C./0.1 mbar. The yield is quantitative: 1,145 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13].C(N(CC)CC)C.O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([S:8][CH2:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(S)c1
Reactant: COC(=O)CCBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)CCSc1cccc(C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.7 %

Procedure:
The reaction was repeated by cooling a solution of 15.7 grams (0.126 mole) of 3-methylbenzenethiol and 23.3 grams (0.139 mole) of methyl 3-bromopropanoate in about 140 mL of DMF in an ice water bath prior to the addition of 14.1 grams (0.139 mole) of triethylamine. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for an 18 hour period. The reaction mixture was then poured into 200 mL of water, and the mixture was extracted with three 200 mL portions of ethyl acetate. The combined extracts were washed with water, and then with three 50 mL portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate, and the mixture was filtered. The filtrate was concentrated under reduced pressure to a residue, yielding 23.5 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[CH3:7][S:8](Cl)(=[O:10])=[O:9].O>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:2]([CH:3]([O:6][S:8]([CH3:7])(=[O:10])=[O:9])[CH2:4][CH3:5])[CH3:1]
Reactant: CCC(O)CC
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCC(CC)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a colorless solution of 88.15 g 3-pentanol (1.0 mol) in 150 ml pyridine were added under stirring at 0° C. 126.0 g methanesulfonyl chloride (1.1 mol) over 1 h. After warming up (15 min.) and stirring at room temperature for 1 h, 50 ml deionized water were added all at once and stirring at room temperature was continued for 1 h. The reaction mixture was diluted with 500 ml ethyl acetate and washed with 800 ml 1N HCl and 250 ml 10% brine. Both aqueous layers were extracted sequentially with 250 ml ethyl acetate. After drying the combined organic layers over ca. 20 g Na2SO4, the solvent was removed on the rotary evaporator (50° C./≧1 mbar) affording 154.4 g (92.9%) yellow, oily title product, which could be used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([NH:28]C(OCC5C=CC=CC=5)=O)[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH2:21][C@H:22]4[CH2:27][CH2:26][C@H:25]([NH2:28])[CH2:24][CH2:23]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(N[C@H]1CC[C@H](CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1)OCc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: N[C@H]1CC[C@H](CNc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-(trans-4-(benzyloxycarbonylamino)cyclohexylmethylamino]pyrimido-[5,4-d]pyrimidine by catalytic hydrogenation. Melting point: 166°-169° C.; Rf : 0.53 (silica gel; methylene chloride/methanol/concentrated ammonia=10:1:0.05); Mass spectrum: M+ =401/403 (Cl)
Reaction SMILES: C(OC(CN[C@H](C)[C@@H](C1C=CC(OC2C=CC=CC=2)=CC=1)CCC1C=CC=CC=1)=O)(C)(C)C.[CH2:34]([O:41][C:42]([CH2:44][NH:45][C@H:46]([CH3:69])[C@@H:47]([C:56]1[CH:61]=[CH:60][C:59]([O:62][C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)=[CH:58][CH:57]=1)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.O1[C@@H](C(OC(C)(C)C)=O)[C@H](C([O-])=O)OC1(C(OCC)=O)C(OCC)=O.[O:95]1[C@H:99]([C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[C@@H:98]([C:107]([O-])=[O:108])[O:97][C:96]1([C:119]([O:121][CH2:122][CH2:123][Si:124]([CH3:127])([CH3:126])[CH3:125])=[O:120])[C:110]([O:112][CH2:113][CH2:114][Si:115]([CH3:118])([CH3:117])[CH3:116])=[O:111]>>[CH2:34]([O:41][C:42]([CH2:44][N:45]([C@H:46]([CH3:69])[C@@H:47]([C:56]1[CH:57]=[CH:58][C:59]([O:62][C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)=[CH:60][CH:61]=1)[CH2:48][CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:107]([C@@H:98]1[C@@H:99]([C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[O:95][C:96]([C:119]([O:121][CH2:122][CH2:123][Si:124]([CH3:125])([CH3:126])[CH3:127])=[O:120])([C:110]([O:112][CH2:113][CH2:114][Si:115]([CH3:116])([CH3:118])[CH3:117])=[O:111])[O:97]1)=[O:108])=[O:43])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)[C@H]1OC(C(=O)OCC[Si](C)(C)C)(C(=O)OCC[Si](C)(C)C)O[C@@H]1C(=O)[O-]
Reactant: C[C@@H](NCC(=O)OCc1ccccc1)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Agent: CCOC(=O)C1(C(=O)OCC)O[C@@H](C(=O)[O-])[C@H](C(=O)OC(C)(C)C)O1
Agent: C[C@@H](NCC(=O)OC(C)(C)C)[C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1
Product: C[C@H]([C@H](CCc1ccccc1)c1ccc(Oc2ccccc2)cc1)N(CC(=O)OCc1ccccc1)C(=O)[C@H]1OC(C(=O)OCC[Si](C)(C)C)(C(=O)OCC[Si](C)(C)C)O[C@@H]1C(=O)OC(C)(C)C

Procedure:
The above identified compound was obtained by carrying out the same reaction as in Example 19(1) except that instead of N-(tert-butoxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine used as the starting material in Example 19(1), N-(benzyloxycarbonylmethyl)-{(1R,2R)-1-methyl-2-(4-phenoxyphenyl)-4-phenylbutyl}amine obtained in Example 52, was used, and instead of 5-tert-butyl 2,2-diethyl (4R,5R)-1,3-dioxolane-2,2,4,5-tetracarboxylate, 5-tert-butyl 2,2-bis{2-(trimethylsilyl)ethyl} (4S,5S)-1,3-dioxolane-2,2,4,5-tetracarboxylate obtained in Example 73, was used.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.P([O-])([O-])([O-])=[O:15].[K+].[K+].[K+]>CS(C)=O>[CH2:3]1[C:4]2[C:9](=[CH:8][C:7]([C:6]([CH:5]=2)=[O:15])=[O:10])[NH:1][CH:2]1[C:11]([OH:13])=[O:12]
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Reactant: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C1C=C2CC(C(=O)O)NC2=CC1=O

Procedure:
The concentration of enzyme, substrate and inhibitor was denoted as [E], [S] and [J], respectively. 80 microliters of 0.067 M potassium phosphate buffer (pH 6.8), 40 microliters of L-tyrosine in 0.067 M potassium phosphate buffer (pH 6.8), 40 microliters of inhibitor in 5% DMSO solution, and 40 microliters of mushroom tyrosinase solution were added to a 96-well microplate, to make the final concentration of each reagent to be: 0.2 mg/ml [S], and 96 units/ml [E], with varying [I]. 5% DMSO solution instead of an inhibitor solution was added to a blank solution and adjusted to the total volume of 200 microliters as control. The assay mixture was incubated at 37° C. The amount of dopachrome produced in the reaction mixture was measured at 475 nm in a microplate reader at different time periods. The percentage of inhibition of tyrosinase activity was calculated as follows: Inhibition(%)=[(A−B)−C−D)]/(A−B)×100
Reaction SMILES: Cl[C:2]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[OH:18][CH2:19][CH:20]1[CH2:22][CH2:21]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:2]([O:18][CH2:19][CH:20]3[CH2:22][CH2:21]3)=[N:3][CH:4]=[C:5]([CH:9]=2)[C:6]([OH:8])=[O:7])=[CH:12][CH:13]=1
Reactant: O=C(O)c1cnc(Cl)c(-c2ccc(F)cc2)c1
Reactant: OCC1CC1
Product: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(F)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 5c, using 6-chloro-5-(4-fluoro-phenyl)-nicotinic acid and (hydroxymethyl)cyclopropane as starting materials, MS (ISP) 286.0 (M−H).