Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][C:34]([N:36]=[C:37]=[O:38])=[O:35]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:37]([NH:36][C:34](=[O:35])[CH2:33][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])=[O:38])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: O=C=NC(=O)Cc1ccccc1F
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5F)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 308 (320 mg, 0.90 mmol) and (2-fluoro-phenyl)-acetyl isocyanate (600 mg, 3.35 mmoL) [A. J. Hill et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and gradient eluted with EtOAc, to MeOH/EtOAc (20:80), to afford the title compound 309b in 42% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.10 (s, 1H), 10.58 (s, 1H), 8.42(d, 1H, J=5.5 Hz), 7.94(d, 1H, J=1.1 Hz), 7.82-7.77 (m, 2H), 7.65 (s, 1H), 7.45-7.30 (m, 4H), 7.19-7.16 (m, 2H), 6.54(dd, 1H, J1=0.7 Hz, J2=5.4 Hz), 4.04(q, 2H), 3.83 (s, 2H), 1.38(t, 3H). MS (m/z): 534.1 (M+H) (found).
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])[OH:4].[CH2:12]=[C:13]1[O:17][C:15](=[O:16])[CH2:14]1>CN(C)C1C=CN=CC=1>[O:17]=[C:13]([CH3:12])[CH2:14][C:15]([O:4][C:3]([CH3:5])([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])[CH:2]=[CH2:1])=[O:16]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: C=C1CC(=O)O1
Agent: CN(C)c1ccncc1
Product: C=CC(C)(CCC=C(C)C)OC(=O)CC(C)=O
Temperature: 55 °C
Yield: 92 %

Procedure:
A mixture of linalool (100 g, 0.648 mol) and 4-dimethylaminopyridine (0.40 g, 3.20 mmol) in a 500 mL three-necked round-bottomed flask fitted with a condenser, argon inlet, addition funnel, magnetic stirrer and internal thermometer is heated to 55° C. Diketene (54.50 g, 0.648 mol) is added dropwise in the course of 30 min. The mixture has a slight exotherm and turns from yellow to red during this time. After stirring an additional hour at 50° C., the mixture is cooled to room temperature. At this point, NMR analysis indicates the reaction is complete. The material from this lot is carried onto the next step. Purification of an earlier sample from this route by flash chromatography (elution with dichloromethane) yields the desired product in 92% yield and nearly colorless.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:16][C:17](=O)[CH3:18])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:16]=[C:17]([CH3:18])[N:1]([C:2]2[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[CH:3]=2)[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:28])[CH3:12]
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Reactant: Nc1cccc(C(=O)O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(C(=O)O)c2)c1-c1ccccc1

Procedure:
3-Aminobenzoic acid (10 mmol, 1.4 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (10 mmol, 2.5 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was resuspended in chloroform-ether, then the insoluble material was filtered from the reaction product. The soluble material was purified over silica gel which yielded the named product (m.p. 161.0° C.-162.7° C.).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23]>CN(C=O)C>[CH3:25][O:24][C:22](=[O:23])[CH:21]([N:14]1[C:15]2[C:11](=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:17][CH:16]=2)[CH:12]=[CH:13]1)[CH3:26]
Reactant: COC(=O)C(C)Br
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
To a solution of 5-benzyloxyindole (13.5 g, 60.46 mmol) in DMF (300 mL) was added sodium hydride (60% dispersion in mineral oil, 3.63 g, 90.7 mmol). The resulting suspension was stirred at rt for 1 h after which methyl 2-bromopropionate (11.1 g, 66.51 mmol) was added. The resulting suspension was stirred at rt for 6 h. The reaction mixture was quenched with sat. aqueous ammonium chloride solution (25 mL), and diluted with 200 mL of EtOAc. The organic layer was washed with water three times. The aqueous layer was extracted again with EtOAc. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated via rotary evaporation. The resulting brown oil was purified on silica gel (EtOAc/hexanes 1:1) to give the title compound as a brownish oil (15.3 g, 82%). LC/MS m/z 310 (M+H)+, RT 4.04 min. 1H NMR (400 MHz, Acetone-d6) δ 7.57 (d, 2H), 7.23-7.41 (m, 5H), 7.19 (d, 1H), 6.84 (d, 1H), 6.40 (d, 1H), 5.37 (q, 1H), 5.17 (s, 2H), 3.66 (s, 3H), 1.79 (d, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[C:7]([F:15])[C:8]([F:14])=[CH:9][CH:10]=2)[C:5]=1[F:16])[CH3:2].C([Li])CCC.CCCCCC.[CH2:28]([C@H:32]1[CH2:37][CH2:36][C@H:35]([C@H:38]2[CH2:43][CH2:42][C@H:41]([CH2:44][CH:45]=[O:46])[CH2:40][CH2:39]2)[CH2:34][CH2:33]1)[CH2:29][CH2:30][CH3:31].Cl>O1CCCC1>[CH2:1]([O:3][C:4]1[C:5]([F:16])=[C:6]2[C:11]([CH:10]=[C:9]([CH:45]([OH:46])[CH2:44][C@H:41]3[CH2:40][CH2:39][C@H:38]([C@H:35]4[CH2:36][CH2:37][C@H:32]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:33][CH2:34]4)[CH2:43][CH2:42]3)[C:8]([F:14])=[C:7]2[F:15])=[CH:12][CH:13]=1)[CH3:2]
Reactant: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC=O)CC2)CC1
Reactant: CCOc1ccc2ccc(F)c(F)c2c1F
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](CC(O)c3cc4ccc(OCC)c(F)c4c(F)c3F)CC2)CC1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A tetrahydrofuran (50 ml) solution of 2-ethoxy-1,7,8-trifluoronaphthalene (9.4 g) was cooled to −60° C. Then, a 1.58 M butyllithium/hexane solution (47 ml) was added dropwise to this solution, followed by stirring for 2 hours. A tetrahydrofuran (50 ml) solution of trans-4-(trans-4-butylcyclohexyl)cyclohexylacetoaldehyde (13.2 g) was added dropwise at −50° C. . After stirring for 2 hours, the reaction temperature was increased to 0° C. 10% hydrochloric acid was added to the reaction solution. The reaction solution was extracted with ethyl acetate, washed with brine, and concentrated. The residue was recrystallized from ethyl acetate, and 7-ethoxy-3-[2-[trans-4-(trans-4-butylcyclohexyl)cyclohexyl]-1-hydroxyethyl]-1,2,8-trifluoronaphthalene was obtained.
Reaction SMILES: N(OC(C)(C)C)=O.[Br:8][C:9]1[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=1N.[ClH:21]>C(#N)C.[Cu](Cl)Cl>[Br:8][C:9]1[CH:15]=[C:14]([O:16][C:17]([F:20])([F:19])[F:18])[CH:13]=[CH:12][C:10]=1[Cl:21]
Reactant: Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Agent: Cl[Cu]Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: FC(F)(F)Oc1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To anhydrous copper(II)chloride (6.3 g, 47 mmol) in acetonitrile (100 mL) was added tert-butyl nitrite (6.85 mL, 58 mmol), followed dropwise by a solution of 2-bromo-4-(trifluoromethoxy)aniline (10 g, 39 mmol) in acetonitrile (15 mL). The solution was stirred at ambient temperature for 1 hour then poured into hydrochloric acid (250 mL, 2M). The suspension formed was extracted with diethyl ether (2×250 mL) and the extracts were dried (MgSO4). Concentration yielded the title compound as an oil (7.82 g, 28 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[F:8].CO.[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(F)c(Br)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2ccc(F)c(Br)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37.1 %

Procedure:
To methyl 4-[(2-{1-[5-(3-bromo-4-fluorophenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.051 mmol, 24.9 mg), methanol (2.5 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.255 mL) was added at room temperature. After 10 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.255 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was dried to give the desired product as a yellow solid (9.0 mg, yield 37%)
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[Br:13][C:14]1[CH:22]=[C:18]([C:19]([OH:21])=O)[C:17]([OH:23])=[CH:16][CH:15]=1.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:29][NH2:30].Cl>CN(C)C1C=CN=CC=1.O1CCCC1>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH2:29][NH:30][C:19](=[O:21])[C:18]2[CH:22]=[C:14]([Br:13])[CH:15]=[CH:16][C:17]=2[OH:23])[CH:31]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:33]=1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
Under argon atmosphere, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (it is abbreviated as WSC•HCl hereafter; 192 mg, 1 mmol) was added to a mixture of 5-bromosalicylic acid (217 mg, 1 mmol), 3,5-bis(trifluoromethyl)benzylamine (243 mg, 1 mmol), 4-dimethylaminopyridine (12 mg, 0.1 mmol) and tetrahydrofuran (10 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=4:1) to give the title compound (244.8 mg, 55.4%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([SH:10])=[N:7][C:6]=2[CH:11]=1.[H-].[Na+].I[CH3:15]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH3:15])=[N:7][C:6]=2[CH:11]=1
Reactant: Fc1ccc2sc(S)nc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1nc2cc(F)ccc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.3 %

Procedure:
To a solution of 5-fluoro-2-mercaptobenzothiazole (0.15 g, 0.810 mmol) in THF (8.10 mL) cooled to 0° C. was added sodium hydride (0.036 g, 0.891 mmol). After stirring 10 min, iodomethane (0.076 mL, 1.215 mmol) was added and the reaction mixture was slowly warmed to room temperature over 2 h. The reaction was diluted with ethyl acetate and quenched with saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. 5-fluoro-2-(methylthio)benzo[d]thiazole (0.178 g, 110% yield) was isolated as a white solid. Material was used without any further purification.
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([CH3:15])[N:6]=1)(=O)=O.[NH3:16]>C(Cl)(Cl)Cl.C(Cl)Cl>[NH2:16][C:5]1[N:10]=[C:9]([O:11][CH:12]([F:14])[F:13])[CH:8]=[C:7]([CH3:15])[N:6]=1
Reactant: N
Reactant: Cc1cc(OC(F)F)nc(S(C)(=O)=O)n1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: Cc1cc(OC(F)F)nc(N)n1
Reaction time: 3 h
Yield: 85 %

Procedure:
4.0 g (0.017 mol) of 2-methylsulfonyl-4-difluoromethoxy-6-methylpyrimidine are suspended in 60 ml of chloroform. This suspension is saturated with gaseous ammonia, and then stirred for 3 hours at a temperature of between 20° and 25° C. The reaction mixture is subsequently diluted with 50 ml of methylene chloride; the organic phase is separated, washed with water and concentrated by evaporation. There are obtained, as crystalline residue, 2.5 g (85% of theory) of 2-amino-4-difluoromethoxy-6-methylpyrimidine, m.p. 137°-139° C.
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.CO.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([N:32]([CH3:36])[C:33](Cl)=[O:34])[CH3:31]>C(O)CO>[I-:1].[CH2:30]([N:32]([CH3:36])[C:33]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:34])[CH3:31]
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Reactant: CCN(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OCCO
Solvent: CO
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Mix 7.9 g (0.02 mol) of (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 100 ml of methanol, 4.1 g (0.03 mol) of potassium carbonate, 3.6 g (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, heat it to 60° C. and react it for 12 hours. After it is cooled to room temperature, filter it and reduce the pressure to recover the solvent and receive 9.0 g of red-brown liquid to be directly used in the next reaction.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[C:31]([Cl:35])[C:32]=1[O:33][CH3:34].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:28]=[C:29]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)[CH:30]=[C:31]([Cl:35])[C:32]=1[O:33][CH3:34]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Reactant: COc1c(Cl)cc(B(O)O)cc1Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: COc1c(Cl)cc(-c2ccc3ncc(C(C)=O)c(N[C@H]4CC[C@H](CN(C)C)CC4)c3n2)cc1Cl

Procedure:
Following general procedure II, 1-(6-chloro-4-{trans-4-[(dimethylamino)methyl]-cyclohexylamino}-1,5-naphthyridin-3-yl)ethanone (77 g, 0.21 mmol) was reacted with (3,5-dichloro-4-methoxyphenyl)boronic acid (70 g, 0.32 mmol) followed by formation of the dihydrochloride salt to afford the desired product (80 g, 66%) as a brown solid: 1H NMR (300 MHz, CD3OD) δ 9.18 (s, 1H), 8.52 (d, J=9.0 Hz, 1H), 8.39 (d, J=9.0 Hz, 1H), 8.20 (s, 2H), 5.74-5.59 (m, 1H), 3.99 (s, 3H), 3.09 (d, J=6.6 Hz, 2H), 2.94 (s, 6H), 2.76 (s, 3H), 2.48-2.40 (m, 2H), 2.10-2.00 (m, 3H), 1.79-1.61 (m, 2H), 1.50-1.31 (m, 2H); ESI MS m/z 501 [M+H]+; HPLC>99% (AUC), tR=10.49 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:29][CH2:30][C:31](Cl)=[O:32].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([C:31](=[O:32])[CH2:30][Cl:29])[C@H:12]1[CH2:17][CH2:16][C@H:15]([C:18]([O:20][CH3:21])=[O:19])[CH2:14][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H]1CC[C@H](NCCNC(=O)OC(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H]1CC[C@H](N(CCNC(=O)OC(C)(C)C)C(=O)CCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-({2-[(t-butoxycarbonyl)amino]ethyl}amino)cyclohexanecarboxylate (785 mg) obtained in Reference Example 71 (1) is dissolved in chloroform (8 ml), and thereto are added triethylamine (1.82 ml) and chloroacetyl chloride (249 μl) under ice-cooling. The mixture is then stirred at room temperature for 2 hours. The reaction solution is cooled with ice again, and chloroacetyl chloride (62 μl) is supplied thereto. The mixture is stirred at room temperature for 1 hour. To the reaction solution, saturated aqueous sodium hydrogen carbonate solution is poured and the mixture is extracted with chloroform. The organic layer is washed with water and saturated brine successively, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, followed by 1/1) to give methyl trans-4-[{2-[(t-butoxycarbonyl)amino]ethyl}-(chloroacetyl)amino]cyclohexanecarboxylate (568 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[O:8][CH:9]=1)=[O:4].CO.[OH-].[Na+].Cl>O>[CH3:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][C:7]2[O:8][CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1coc(Cc2ccc(OC)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(Cc2nc(C(=O)O)co2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
A mixture of 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid methyl ester (40 mg, 0.16 mmol), methanol (2 mL) and 1N NaOH (1 mL) was heated at 60° C. for 2 hours and allowed to stand at 25° C. for 30 minutes. After dilution with water, the mixture was adjusted to pH 2 with 2N HCl and extracted with ether. The organic layers were combined, dried with MgSO4 and evaporated to dryness to yield 25 mg (66%) of 2-(4-Methoxy-benzyl)-oxazole-4-carboxylic acid as a white solid. ESI-MS m/z calc. 233.2, found 234.2 (M+1)+. Retention time of 2.27 minutes.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][O:43][C:44]1[CH:51]=[CH:50][CH:49]=[CH:48][C:45]=1[C:46]#[N:47]>>[C:46]([C:45]1[CH:48]=[CH:49][CH:50]=[CH:51][C:44]=1[O:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1)#[N:47]
Reactant: N#Cc1ccccc1OCCCBr
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCOc4ccccc4C#N)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.057 g of 2-(3-bromopropoxy)benzonitrile are used to prepare the title compound. Rf=0.18 (2:1 EtOAc-heptane); Rt=5.58.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][OH:13])[CH2:5][CH2:6][S:7]([OH:10])(=[O:9])=[O:8].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19](Cl)=[O:20]>N1C=CC=CC=1.C(O)C>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[C:19]([O:1][CH2:2][CH2:3][N:4]([CH2:11][CH2:12][O:13][C:19](=[O:20])[C:18]1[CH:17]=[C:16]([O:15][CH3:14])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=1)[CH2:5][CH2:6][S:7]([OH:10])(=[O:8])=[O:9])=[O:20]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: O=S(=O)(O)CCN(CCO)CCO
Solvent: CCO
Solvent: c1ccncc1
Product: COc1cc(C(=O)OCCN(CCOC(=O)c2cc(OC)c(OC)c(OC)c2)CCS(=O)(=O)O)cc(OC)c1OC
Temperature: 80 °C
Reaction time: 1 h

Procedure:
8.5 G of the product obtained in Example 2 (a) was suspended in 25 ml of anhydrous pyridine, and 18.4 g of 3,4,5-trimethoxybenzoyl chloride added slowly under agitation. After being left for one hour at ambient temperature the mixture was heated to 80° C. for a further hour. It was then cooled to ambient temperature, diluted with 50 ml of ethanol and left to stand in a refrigerator. A colourless crystalline compound precipitated which milted at 174°-178° C. After recrystallisation from methanol, the melting point was 180°-183° C. The yield was 11.5 g of pure product.
Reaction SMILES: [O:1]=[C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][C:4]#[N:5].N1C=CC=CC=1.[Br:18]Br>C(Cl)(Cl)Cl>[Br:18][CH:3]([C:2](=[O:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5]
Reactant: BrBr
Reactant: N#CCC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: N#CC(Br)C(=O)c1ccccc1
Temperature: 45 °C

Procedure:
3-Oxo-3-phenylpropionitril (1.5 g, 10 mmol) was dissolved in dry chloroform (10 mL) at 0° C., and pyridine (0.81 mL, 10 mmol) was added. Bromine (4.7 mL, 10 mmol) dissolved in chloroform (4.7 mL) was added dropwise over an hour, then the reaction mixture was heated at 45° C. over night. The reaction mixture was diluted with chloroform and washed with water. The organic phases were dried over sodium sulfate and evaporated to give the crude product, which was used in the next reaction without any further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(NC(C)C)(C)C.C1C(=O)N([Br:27])C(=O)C1.Cl>C(Cl)Cl>[Br:27][C:7]1[C:2]([OH:1])=[C:3]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COC(=O)Cc1cccc(Br)c1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of methyl (2-hydroxyphenyl)acetate (14.0 g, 84.3 mmol) in 100 mL of DCM was added diisopropyl-amine (1.70 g, 16.8 mmol) and NBS (15 g, 84.2 mmol) at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction was poured into 1N HCl, extracted with DCM, and concentrated to give crude methyl (3-bromo-2-hydroxyphenyl)acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:12][C:13]=2[Cl:14])=[CH:4][CH:3]=1.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:12][C:13]=2[Cl:14])=[CH:6][C:7]=1[N+:21]([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)cc2)c1=O
Agent: O=S(=O)(O)O
Product: Cn1c(C(F)(F)F)cc(Cl)c(-c2ccc(Cl)c([N+](=O)[O-])c2)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
0.2 g (0.62 mmol) of 3-(4-chlorophenyl)-4-chloro-1-methyl-6-trifluoromethyl-2(1H)-pyridone was dissolved in 2 ml of concentrated sulfuric acid, and 0.04 g (0.64 mmol) of fuming nitric acid was added thereto under cooling with ice, followed by stirring for 1 hour. After completion of the reaction, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium hydrogencarbonate aqueous solution and dried over anhydrous magnesium sulfate. The organic layer was distilled off under reduced pressure, and the obtained crude crystals were washed with isopropyl ether to obtain 0.21 g (yield: 91%) of the desired product. 1H-NMR (300 MHz, CDCl3) δ value: 3.74(3H,s), 6.66(1H,s), 7.40(1H,dd), 7.61(1H,d), 7.59(1H,s), 7.82(1H,d)ppm.