Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH3:35][O:34][C:32](=[O:33])[NH:30][S:27]([C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][N:10]3[CH:15]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:13]=[CH:12][C:11]=23)=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Reaction time: 24 h
Yield: 26.4 %

Procedure:
A Mixture of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.1 g 0.23 mmol), methyl chloroformate (Aldrich) (0.028 g 0.3 mmol) and potassium carbonate (0.07 g 0.05 mmol) were stirred and heated at reflux under nitrogen in acetone (10 ml) for 18 hr. Additional methyl chloroformate (0.028 g) and potassium carbonate (0.07 g) were added and heating continued for a further 24 hr. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate (3×50 ml). The combined extracts were washed with brine (30 ml), dried (MgSO4) and the solvent removed. The residues were purified by SPE chromatography, elution with cyclohexane:ethyl acetate (3:1) gave the title compound as a white solid (0.03 g 26%). MH− 492
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[N+:30]([O-])=O)[O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([OH:26])[CH:18]=3)=[CH:11][CH:12]=2)[CH:7]=1.[K+].[Br-]>>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][C:10]2[CH:11]=[CH:12][C:13]3[C:8](=[CH:7][C:6]([O:5][C:4]4[CH:27]=[CH:28][C:29]([NH2:30])=[C:2]([OH:1])[CH:3]=4)=[CH:15][CH:14]=3)[CH:9]=2)=[CH:18][C:19]=1[OH:26]
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3ccc(Oc4ccc([N+](=O)[O-])c(O)c4)cc3c2)cc1O
Agent: [Br-]
Agent: [K+]
Product: Nc1ccc(Oc2ccc3ccc(Oc4ccc(N)c(O)c4)cc3c2)cc1O
Yield: 78.6 %

Procedure:
2,7-Bis(4-amino-3-hydroxyphenoxy)naphthalene was synthesized in a manner analogous to Example 2 from 2,7-bis(3-hydroxy-4-nitrophenoxy)naphthalene. Yield: 78.6%; mp 201˜210° C.; IR (KBr) 3295, 3362, 1495 cm−1; MS (EI) m/z 374 (M+, 100); Elemental Anal. Calcd. for C22H18N2O4: C, 70.59; H, 4.81; N, 7.49. Found: C, 70.42; H, 4.88; N, 7.42.
Reaction SMILES: [N:1]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:2]=[O:3].C(N(CC)CC)C.[OH:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:45])([F:44])[F:43])[NH:31][C:32]3=[O:35])=[CH:27][CH:26]=2)[CH2:20]1.[Cl-].[NH4+]>ClCCl>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][NH:1][C:2]([O:17][CH2:18][C@@H:19]1[O:23][C:22](=[O:24])[N:21]([C:25]2[CH:34]=[C:33]3[C:28]([CH:29]=[C:30]([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=4[C:42]([F:43])([F:45])[F:44])[NH:31][C:32]3=[O:35])=[CH:27][CH:26]=2)[CH2:20]1)=[O:3])[CH3:9]
Reactant: CCOC(=O)CN=C=O
Reactant: O=C1O[C@@H](CO)CN1c1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)OC[C@H]1CN(c2ccc3cc(-c4ccccc4C(F)(F)F)[nH]c(=O)c3c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90 %

Procedure:
Ethyl isocyanatoacetate (6.6 μL, 0.059 mmol) and triethylamine (10.3 μL, 0.074 mmol) were added to a solution of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14 (20 mg, 0.050 mmol) in dichloromethane, and the mixture was stirred at room temperature for four hours. Aqueous saturated ammonium chloride was added to the mixture, followed by extraction with dichloromethane. The extract was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by aminosilica gel column chromatography (methylene chloride:methanol=50:1) to obtain 24 mg (92%) of ethyl{(R)-2-oxo-3-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]oxazolidin-5-ylmethoxycarbonylamino}acetate as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[C:34]([OH:36])[CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:32]1[CH:33]=[C:34]([OH:36])[CH:35]=[C:30]([F:29])[CH:31]=1
Reactant: OB(O)c1cc(O)cc(F)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3cc(O)cc(F)c3)n(-c3ccccc3)c(=O)c12
Yield: 24 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (3-fluoro-5-hydroxyphenyl)boronic acid (24 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 17 mg (35% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5](C)=[CH:4][N:3]=1.Cl.[C:10]([Cl:14])(Cl)([Cl:12])[Cl:11]>CCOCC>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:10]([Cl:14])([Cl:12])[Cl:11])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1
Reactant: ClC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOCC
Product: Clc1ncc(C(Cl)(Cl)Cl)cn1

Procedure:
2-Chloro-5-methylpyrimidine (5.0 g) was finely powdered and dissolved in dry carbon tetrachloride (250 ml). The solution was treated with dry hydrogen chloride gas to precipitate the hydrochloride salt. The reaction mixture was heated to reflux and illuminated with an internal ultra-violet lamp whilst chlorine was bubbled through the stirred suspension. After 41/2 hours the solution was cooled and filtered and the filtrate concentrated under reduced pressure to give a semi-crystalline residue. The residue was dissolved in ether and filtered and the filtrate concentrated to a colourless oil which on standing gave crystals of 2-chloro-5-trichloromethylpyrimidine (8.9 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]3[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][CH2:18][N:17]([CH3:24])[C:16](=[O:25])[C:12]3=2)[C:7]1=[O:28].C(N(C(C)C)CC)(C)C>CCO.[OH-].[OH-].[Pd+2]>[F:32][C:31]1[CH:2]=[CH:3][C:4]([CH2:5][N:6]2[CH2:15][CH2:14][C:13]3[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]4[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][CH2:18][N:17]([CH3:24])[C:16](=[O:25])[C:12]4=3)[C:7]2=[O:28])=[CH:29][CH:30]=1
Reactant: CN1CCC[C@H](CO)n2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)c(Cl)c2)CC3)C1=O
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC[C@H](CO)n2c(c3c(c(O)c2=O)C(=O)N(Cc2ccc(F)cc2)CC3)C1=O
Reaction time: 20 h

Procedure:
A mixture of (6R)-11-(3-chloro-4-fluorobenzyl)-9-hydroxy-6-(hydroxymethyl)-2-methyl-3,4,5,6,12,13-hexahydro-2H-[1,4]diazocino[2,1-a]-2,6-naphthyridine-1,8,10(11H)-trione (109 mg, 0.24 mmol), 20% Pd(OH)2 on carbon (40 mg) and diisopropylethylamine (0.1 mL) in EtOH (2.4 mL) was stirred under hydrogen atmosphere for 20 hours. The reaction mixture was filtered through a Celite pad and the filtrate concentrated under vacuum to afford the title compound.
Reaction SMILES: [C:1]([N:4]1[CH:9]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[S:19]CC2C=CC(OC)=CC=2)[C:8]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:7]([CH3:34])[NH:6][C:5]1=[O:35])(=[O:3])[CH3:2].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[C:1]([N:4]1[CH:9]2[CH:8]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[C:7]([CH3:34])([S:19][C:11]3[CH:12]=[CH:13][C:14]([N+:16]([O-:18])=[O:17])=[CH:15][C:10]=32)[NH:6][C:5]1=[O:35])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1=C(C)NC(=O)N(C(C)=O)C1c1cc([N+](=O)[O-])ccc1SCc1ccc(OC)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCOC(=O)C1C2c3cc([N+](=O)[O-])ccc3SC1(C)NC(=O)N2C(C)=O

Procedure:
The compound 2b is treated with anhydrous trifluoroacetic acid:anisole (1:1) at 25° C. for 1 hour to yield a mixture of the diastereomers of the desired product. The individual diastereomers may be separated by chromatography.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[C:3]=1[S:13](Cl)(=O)=O>O1CCCC1.[Zn].[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([CH3:12])[C:3]=1[S:13][S:13][C:3]1[C:2]([CH3:1])=[CH:7][C:6]([C:8]([CH3:10])([CH3:9])[CH3:11])=[CH:5][C:4]=1[CH3:12]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1S(=O)(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: Cc1cc(C(C)(C)C)cc(C)c1SSc1c(C)cc(C(C)(C)C)cc1C
Temperature: 60 °C
Yield: 64.1 %

Procedure:
A two liter, three-neck flask, was obtained. A condenser with a drying tube, a thermometer, and a dropping funnel were each attached to the flask. Zinc dust (<10 micron, 43.6 g, 0.667 mol) and anhydrous tetrahydrofuran (400 ml) were added to the flask. The mixture was stirred and cooled on an ice-water bath and 58.6 ml (0.534 mmol) of titanium tetrachloride added drop wise (˜45 minutes). During the entire addition of titanium tetrachloride, the temperature of the mixture was maintained below 25° C. Once the addition was complete, a solution of 2,6-dimethyl-4-tert-buylbenzenesulfonyl chloride (69.48 g, 0.267 mol) in 200 ml of anhydrous tetrahydrofuran was added drop wise (˜60 minutes). During the entire addition of the material, the temperature of the mixture was maintained below 20° C. At the conclusion of the 2,6-dimethyl-4-tert-buylbenzenesulfonyl chloride addition, the ice-water bath was removed, the mixture was allowed to stir an additional 30 minutes. The mixture was then heated on an oil bath at 60° C. for four hours. The mixture was then cooled to room temperature and 800 ml of 1N hydrochloric acid and 300 ml of ice water added. The resultant pale yellow precipitates were collected by filtration and washed with water (300 ml×3). The precipitate was then dried under vacuum and the precipitates recrystallized from hexanes, giving 33.1 g bis(2,6-dimethyl-4-tert-butylphenyl) disulfide (see Formula III, Table 3). The yield of the reaction was 70% and the material had the following spectral data: 1H NMR (CDCl3) δ 7.04 (s, 4H), 2.23 (s, 12H), 1.30 (s, 18H).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]4[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]4)[C:18](=[O:36])[CH2:17]3)(=[O:15])=[O:14])=[CH:9][CH:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:37]>C(OCC)(=O)C.CO>[ClH:37].[ClH:37].[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([S:13]([N:16]3[CH2:21][CH2:20][N:19]([CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[C:18](=[O:36])[CH2:17]3)(=[O:14])=[O:15])=[CH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3ccc(Cn4ccnc4)cc3)CC2=O)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1CN(S(=O)(=O)c2ccc(Cn3ccnc3)cc2)CCN1CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 4-[4-(1H-imidazol-1-ylmethyl)benzenesulfonyl]-1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-2-piperazinone (420 mg) was added 4N hydrochloric acid in ethyl acetate (15 ml) and methanol (4 ml), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated to give amorphous of the title compound (442 mg).
Reaction SMILES: C1(C([NH:14][CH:15]([PH:23](=[O:25])[OH:24])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)C2C=CC=CC=2)C=CC=CC=1.[BrH:26]>>[BrH:26].[NH2:14][CH:15]([PH:23](=[O:24])[OH:25])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=[PH](O)C(Cc1ccccc1)NC(c1ccccc1)c1ccccc1
Agent: Br
Product: NC(Cc1ccccc1)[PH](=O)O
Yield: 87.9 %

Procedure:
A mixture of 14.6 g (41.6 mmol) of [1-[(diphenylmethyl)amino]-2-phenylethyl]phosphinic acid and 94 ml of aqueous 48% hydrobromic acid is refluxed for 2 hours. Two phases appear. The mixture is brought to dryness by evaporation under vacuum and under warm conditions and is then taken up in 94 ml of water. The aqueous phase is washed three times with diethyl ether. The aqueous phase, again evaporated, gives (1-amino-2-phenylethyl)phosphinic acid hydrobromide, which is taken up in 58 ml of absolute ethanol. 20.4 ml of propylene oxide are added dropwise, with stirring, at 0° C. The formation of an abundant white precipitate is observed, which is filtered off and washed with diethyl ether. 6.77 g of product are recovered (yield=87.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH3:10])[NH2:5].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][CH:15]=[CH:14][N:13]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=4)[N:19]=3)=[CH:16][CH:15]=[CH:14][N:13]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3F)n2)cc1
Reactant: COc1ccc(N)cc1F
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc(OC)c(F)c3)n2)cc1

Procedure:
The title compound was prepared in an analogous manner to that described in Example 164 using 3-fluoro-4-methoxyaniline (Aldrich) and 4-(2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine and isolated as a brown solid (100%). 1H NMR (400 MHz, d6-DMSO) δ 11.82 (br. s., 1H); 8.77 (d, J=7.0 Hz, 1H); 8.34 (br. s., 1H); 7.75 (d, J=14.1 Hz, 1H); 7.18-7.31 (m, 4H); 7.11-7.17 (m, 1H); 7.05 (t, J=9.8 Hz, 1H); 6.89 (t, J=7.4 Hz, 5H); 4.81 (d, J=8.6 Hz, 3H); 3.80 (br. s., 3H); 3.72 (d, J=10.4 Hz, 7H); 2.56 (br. s., 3H). m/z (ESI, +ve ion) 567.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[C:25](=[O:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[O:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[CH:25]([OH:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCCOC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCCOC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Reaction time: 1 h

Procedure:
To a cooled solution of 5.55 g of 3,4-dihydro-9-[[2-[bis(4-fluorophenyl)methoxy]ethyl]amino]acridin-1(2H)-one in 100 ml of tetrahydrofuran was added 6.5 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour at ice bath temperature.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:4][CH2:3]1.[C-:26]#[N:27].[K+]>CN(C)C=O>[C:26]([C:2]1([OH:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][C:15]3=[O:24])=[CH:10][C:9]=2[F:25])[CH2:6][CH2:7]1)#[N:27]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(O)(C#N)CC3)c(F)c2)C(=O)O1
Yield: 42 %

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(4-oxopiperidin-1-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (12.0 mmol) and potassium cyanide (18.0 mmol) in dimethylformamide (25 ml) at a temperature 25° C. for four hours and by purifying the compound by silica gel column chromatography in 42% yield.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH2:12]([C:14]1[O:18][C:17]([CH:19]=O)=[CH:16][CH:15]=1)[CH3:13]>C(O)(=O)C.CCO>[CH2:12]([C:14]1[O:18][C:17]([CH:19]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:16][CH:15]=1)[CH3:13]
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: CCc1ccc(C=O)o1
Solvent: CC(=O)O
Solvent: CCO
Product: CCc1ccc(C=NNC(=O)c2ccc(O)cc2)o1
Temperature: 25 °C
Yield: 85.2 %

Procedure:
To a solution of 4-hydroxy-benzoic acid hydrazide (0.3 g, 0.002 mol) and 5-ethyl-2-furaldehyde (0.25 g, 0.002 mol) in abs. EtOH (10 mL), was added 1 drop of acetic acid. The reaction mixture was refluxed for 5 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by pet ether to give red solid 0.44 g, in 85% yield, mp: 60.5° C. 1H NMR (DMSO-d6) δ 11.53 (s, 1H), 10.16 (s, 1H), 8.24 (s, 1H), 7.79 (d, 2H), 6.87 (d, 2H), 6.81 (s, 1H), 2.71 (q, 2H), 1.24 (t, 3H). 13C NMR (DMSO-d6) δ164.5, 162.1, 161.2, 149.8, 138.5, 131.5, 125.7, 116.9, 116.7, 108.9, 22.8, 13.8. Anal. Calcd for C14H14N2O3: C, 65.11; H, 5.46; N, 10.85. Found: C, 65.00; H, 5.36; N, 10.55.
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[N:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)(=O)C.Br>CCCCCC>[CH2:1]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[N:13]=2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCCCCC
Product: CCCCCc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Temperature: 0 °C
Yield: 86.8 %

Procedure:
0.70 g (2.29 mM) of 2-(4-pentylphenyl)-6-methoxyquinoline, 4.6 ml of acetic acid and 4.3 ml of 47%-hydrobromic acid were placed in a 30 ml-round bottomed flask, followed by refluxing for 33 hours under stirring. After the reaction, the reaction mixture was poured into ice water to precipitate a crystal. The crystal was recovered by filtration and dispersed in water. To the mixture, an appropriate amount of ethyl acetate was added, followed by stirring at room temperature. Under stirring, 1.5 g of sodium hydrogencarbonate was gradually added to the resultant mixture. The organic (ethyl acetate) layer was washed with water and dried with anhydrous sodium sulfate, followed by evaporation under reduced pressure to obtain a residue. To the residue, an appropriate amount of hexane was added, followed by filtration to obtain 0.58 g of 2-(4-pentylphenyl)-6-hydroxyquinoline (as a precipitated crystal) (Yield: 86.8%).
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][C@:5]([NH2:17])([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[F:16])[CH3:6].[CH3:19][NH:20][C:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=S>>[C:26]([O:25][C:24](=[O:30])[NH:23][C:21]1[N:20]([CH3:19])[C:3](=[O:18])[CH2:4][C@:5]([C:7]2[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=2[F:16])([CH3:6])[N:17]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: CNC(=S)NC(=O)OC(C)(C)C
Reactant: COC(=O)C[C@](C)(N)c1cc([N+](=O)[O-])ccc1F
Product: CN1C(=O)C[C@@](C)(c2cc([N+](=O)[O-])ccc2F)N=C1NC(=O)OC(C)(C)C

Procedure:
Starting from (S)-3-amino-3-(2-fluoro-5-nitro-phenyl)-butyric acid methyl ester (14.8 mmole) and tert-butyl [(methylamino)carbonothioyl]carbamate, the product [(S)-4-(2-fluoro-5-nitro-phenyl)-1,4-dimethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (3.13 g) was obtained as pale yellow foam. MS (ESI): m/z=381.2 [ M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([O:46]CC)=[O:45])[CH2:40][CH2:39]2)=[O:37])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]/[C:19](/[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[OH-].[Na+].Cl>O1CCOCC1>[C:1]([NH:4][C:5]1[S:6][C:7]([C:36]([N:38]2[CH2:43][CH2:42][CH:41]([C:44]([OH:46])=[O:45])[CH2:40][CH2:39]2)=[O:37])=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18]/[C:19](/[NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[N:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C1CCN(C(=O)c2sc(NC(C)=O)nc2CCc2ccc(N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(=O)Nc1nc(CCc2ccc(N/C(=N/C(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc2)c(C(=O)N2CCC(C(=O)O)CC2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.4 %

Procedure:
Ethyl 1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)carbonyl]-4-piperidinecarboxylate (277.9 mg), 1N—NaOH (1.01 ml) and 1,4-dioxane (3 ml) were combined at 0° C., and the reaction mixture was stirred at r.t. for 3 hours. The mixture was neutrallized with 1N—HCl, and the organic solvent was evaporated in vacuo. The residual aqueous solution was extracted with AcOEt. The organic layer was washed with water and brine, dried over anhydrous MgSO4, and concentrated in vacuo to give 1-[(2-(acetylamino)-4-{2-[4-({(Z)-[(tert-butoxycarbonyl)amino][(tert-butoxycarbonyl)imino]methyl}amino)phenyl]ethyl}-1,3-thiazol-5-yl)carbonyl]-4-piperidinecarboxylic acid (262.4 mg) as a pale yellow amorphous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[S:10][CH:11]=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8].[CH3:27]OC(C1SC(C)=CC=1NC1C2C=CNC=2N=CN=1)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([CH3:27])=[CH:12][C:13]=1[NH:14][C:15]1[C:16]2[CH:23]=[CH:22][NH:21][C:17]=2[N:18]=[CH:19][N:20]=1)=[O:8]
Reactant: O=C(NCc1cccc(Cl)c1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: COC(=O)c1sc(C)cc1Nc1ncnc2[nH]ccc12
Product: Cc1cc(Nc2ncnc3[nH]ccc23)c(C(=O)NCc2cccc(Cl)c2)s1
Yield: 50 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid 3-chloro-benzylamide using 5-methyl-3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester instead of 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid methyl ester and obtained in 50% yield (HPLC: 98%, RT: 3.85 min). 1H NMR (DMSO-d6) 11.98 (br s, 1H), 11.39 (s, 1H), 8.68 (t, J=6.0 Hz, 1H), 8.39 (s, 1H), 8.28 (d, J=1.1 Hz, 1H), 7.40-7.28 (m, 5H), 6.41 (dd, J=3.3, 1.8 Hz, 1H), 4.48 (d, J=5.9 Hz, 2H), 2.55 (s, 3H); MS (m/z) 398 [M+H]+ (35Cl).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][CH3:22])=[N:18][C:17]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>CC#N>[CH3:23][C:17]1[N:18]=[C:19]([NH:21][CH3:22])[S:20][C:16]=1[C:14]1[CH:13]=[CH:12][N:11]=[C:10]([NH:9][C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][S:25]([CH3:24])(=[O:27])=[O:26])[N:15]=1
Reactant: CS(=O)(=O)Cl
Reactant: CNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNS(C)(=O)=O)c3)n2)s1

Procedure:
By treatment of (3-aminomethyl-phenyl)-[4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl]-amine with methane-sulfonyl chloride. Yellow solid. Anal. RP-HPLC: tR=12.8 min (0-60% MeCN, purity>95%). 1H-NMR (CD3OD) δ: 2.53 (s, 3H, CH3), 2.88 (s, 3H, CH3), 2.98 (s, 3H, CH3), 4.28 (s, 2H, CH2), 6.94 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.02 (d, 1H, J=7.5 Hz, Ph-H), 7.29 (t, 1H, J=8.0 Hz, Ph-H), 7.52 (d, 1H, J=8.0 Hz, Ph-H), 7.90 (s, 1H, Ph-H), 7.98 (s, 1H, NH), 8.28 (d, 1H, J=5.5 Hz, pyrimidinyl-H).