Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2.[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]=[C:30]=[O:31].C(N(CC)CC)C.Cl>CN(C)C=O>[Cl:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29][C:30]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[CH2:7]2)=[O:31]
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: O=C=Nc1ccccc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccccc4Cl)ccc3C2=O)C(=O)N1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.50 g, 1.40 mmol) and 2-chlorophenylisocyanate (0.16 mL, 1.40 mmol) in N,N-dimethylformamide (10 mL), was added triethylamine (0.38 mL, 2.7 mmol) at room temperature under nitrogen. After 2 h, 1 N aq. HCl (40 mL) was added and the solids were isolated by filtration and washed with water (20 mL). The crude product was triturated in EtOAc (50 mL) for 0.5 h. The product was isolated by filtration and dried in vacuo to give 1-(2-chloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (0.56 g, 97% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 6.35 min (98.37%); mp: 235-237° C.; 1H NMR (DMSO-d6) δ 1.77-2.14 (m, 1H, CHH), 2.23-2.47 (m, 1H, CHH), 2.60 (d, J=17.2 Hz, 1H, CHH), 2.77-3.04 (m, 1H, CHH), 4.32 (d, J=17.4 Hz, 1H, CHH), 4.39-4.61 (m, 3H, CHH, CH2), 5.11 (dd, J=4.9, 13.2 Hz, 1H, CH), 6.88-7.04 (m, 1H, Ar), 7.15-7.32 (m, 1H, Ar), 7.34-7.50 (m, 2H, Ar), 7.54 (s, 1H, NH), 7.58 (t, J=5.8 Hz, 1H, NH), 7.71 (d, J=7.7 Hz, 1H, Ar), 8.17 (d, J=6.0 Hz, 2H, Ar), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.50, 31.21, 42.83, 47.14, 51.59, 120.86, 121.28, 122.01, 122.61, 123.03, 127.00, 127.45, 129.08, 130.44, 136.57, 142.48, 144.30, 154.83, 167.92, 171.00, 172.85; LCMS: MH=427/429; Anal Calcd for C21H19N4O4Cl: C, 59.09; H, 4.49; N, 13.13; Cl, 8.31. Found: C, 58.86; H, 4.26; N, 12.88; Cl, 8.32.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1(C)C=CC=CC=1>[CH2:1]([N:3]([CH2:7][CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: ClCC=Cc1ccccc1
Reactant: CCNCC
Solvent: Cc1ccccc1
Product: CCN(CC)CC=Cc1ccccc1
Yield: 63.5 %

Procedure:
175.4 g of diethylamine and 152.5 g of chloromethylstyrene (mixture of m- and p- compounds) were dissolved in 300 ml of toluene, and the resulting solution was heated to 60°-70° C. for 13 hours. Diethylamine hydrochloride was separated during the progress of the reaction. After the hydrochloride was filtered out, the filtrate was washed with water. The toluene phase was dried with anhydrous sodium sulfate and thereafter concentrated. After adding 1 g of di-tert-butylcatechol, reduced pressure distillation was carried out to obtain 120.2 g of diethylaminomethylstyrene. (b.p.: 60° C./2 mm Hg, colorless liquid)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[C:16]([O:25][CH3:26])[CH:17]=[C:18]3[C:23]=2[N:22]=[C:21](C)[CH:20]=[CH:19]3)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N[C:28]1C=C(OC)C=C2C=1N=CC(C)=C2.NC1C=C(OC)C=C2C=1N=C(C)C=C2>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[C:16]([O:25][CH3:26])[CH:17]=[C:18]3[C:23]=2[N:22]=[CH:21][C:20]([CH3:28])=[CH:19]3)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(N)c2ncc(C)cc2c1
Reactant: COc1cc(N2CCN(Cc3ccccc3)CC2)c2nc(C)ccc2c1
Agent: COc1cc(N)c2nc(C)ccc2c1
Product: COc1cc(N2CCN(Cc3ccccc3)CC2)c2ncc(C)cc2c1
Yield: 22 %

Procedure:
The title compound was prepared by the same method used for 1-benzyl4-(6-methoxy-2-methylquinolin-8-yl)piperazine, except substituting 8-amino-6-methoxy-3-methylquinoline (2.82 g, 15.0 mmol) for the 8-amino-6-methoxy-2-methylquinoline. Flash chromatography on 6×20 cm SiO2 (25-30% EtOAc/hexane), with rechromatography of the mixed fractions, provided 1.13 g (22%) of the title compound as a yellow gum. Crystallization from hexane afforded 0.88 g of analytically pure compound as yellow crystals: mp 112-113° C.
Reaction SMILES: [CH3:1][S:2]([C:4]1[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=1)=[O:3].[CH3:12][NH:13][CH2:14][CH:15]=[O:16]>C1C=CC=CC=1>[CH3:12][N:13]([CH2:14][CH:15]=[O:16])[C:10]([NH:9][C:7]1[S:8][C:4]([S:2]([CH3:1])=[O:3])=[N:5][N:6]=1)=[O:11]
Reactant: CNCC=O
Reactant: CS(=O)c1nnc(N=C=O)s1
Solvent: c1ccccc1
Product: CN(CC=O)C(=O)Nc1nnc(S(C)=O)s1

Procedure:
A mixture of 5-methylsulfinyl-1,3,4-thiadiazol-2-yl isocyanate dimer (0.05 mole), the dimethyl acetal of 2-methylaminoacetaldehyde (0.1 mole) and benzene (60 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 15 minutes. After this time the mixture is stripped of benzene under reduced pressure to yield a solid product as the residue. The residue is then recrystallized to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-methylsulfinyl-1,3,4-thiadiazol-2-yl)ureido]-acetaldehyde.
Reaction SMILES: C[N:2](C)[C:3](=[N:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]2[CH:18]=[C:17]([NH:19][CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[N:16]=[C:15]([O:30][CH3:31])[N:14]=2)[CH:8]=1)[CH3:4].O.[NH2:35]N>C(O)(=O)C>[CH3:31][O:30][C:15]1[N:16]=[C:17]([NH:19][CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)[CH:18]=[C:13]([C:9]2[CH:10]=[CH:11][CH:12]=[C:7]([C:6]3[NH:35][N:2]=[C:3]([CH3:4])[N:5]=3)[CH:8]=2)[N:14]=1
Reactant: COc1ccc(CCNc2cc(-c3cccc(C(=O)N=C(C)N(C)C)c3)nc(OC)n2)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(CCNc2cc(-c3cccc(-c4nc(C)n[nH]4)c3)nc(OC)n2)cc1
Reaction time: 0.5 h
Yield: 69.1 %

Procedure:
A solution of N-(1-dimethylamino-ethylidene)-3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzamide [0.132 mmol, Intermediate (46)] and hydrazine hydrate (15 μL, 0.48 mmol) in acetic acid (1 mL) is heated to 90° C. After stirring for 30 minutes removed from heat, quenched with saturated sodium bicarbonate solution (20 mL) and extracted twice with EtOAc (20 mL). The organic extracts are dried over magnesium sulfate, filtered and concentrated by rotary evaporator. The resulting oil is subjected to flash column chromatography on silica gel eluting with 40% EtOAc in heptane gradient to afford {2-methoxy-6-[3-(5-methyl-2H-[1,2,4]triazol-3-yl)-phenyl]-pyrimidin-4-yl}-[2-(4-methoxy-phenyl)-ethyl]-amine [38 mg, 69%, Example 37]. LCMS: RT=2.59 minutes MS: 417 (M+H). IC50=3.7 nM
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:35])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=2)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]1=[O:34])[CH:2]=C.I([O-])(=O)(=O)=[O:37].[Na+]>C1COCC1.O.[Os](=O)(=O)(=O)=O>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][N:18]=3)[N:6]([C@@H:24]([CH2:32][CH3:33])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[C:5](=[O:34])[C@:4]([CH2:1][CH:2]=[O:37])([CH3:35])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cn2)N([C@@H](CC)CN2CCOCC2)C1=O
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC[C@@H](CN1CCOCC1)N1C(=O)[C@@](C)(CC=O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 0.05 h

Procedure:
To a solution of 42 mg (0.08 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(5-chloropyridin-2-yl)-3-methyl-1-((S)-1-morpholinobutan-2-yl)piperidin-2-one (Example 121, Step N) in THF (6 mL) and water (2 mL) added a catalytic amount of osmium tetroxide. After 3 min, 87 mg (0.41 mmol) of sodium periodate was added. The resulting white slurry was stirred at room temperature for 4.25 h, and then filtered through a fritted funnel. The filtrate was partially concentrated under reduced pressure, and then was diluted with a mixture of water and saturated aqueous sodium chloride and extracted with ethyl acetate (2×). The combined organic layers were washed with saturated aqueous sodium thiosulfate and then saturated aqueous sodium chloride. The organic layer was dried over Na2SO4, filtered and the filtrate was concentrated. Purification of the residue by reversed phase prep. HPLC (Sunfire™ Prep C18 OBD 10 μm column (Waters, Milford, Mass.), gradient elution of 35% MeCN in water to 75% MeCN in water over a 35 min period, where both solvents contain 0.1% TFA provided the title compound as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([CH3:20])[C:17]([Br:21])=[C:16]([CH3:22])[CH:15]=2)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[Br:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([O:13][CH2:12][CH:10]2[CH2:11][NH:8][CH2:9]2)=[CH:15][C:16]=1[CH3:22]
Reactant: Cc1cc(OCC2CN(C(=O)OC(C)(C)C)C2)cc(C)c1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(OCC2CNC2)cc(C)c1Br
Temperature: 0 °C
Yield: 76.1 %

Procedure:
3-(4-Bromo-3,5-dimethyl-phenoxymethyl)-azetidine-1-carboxylic acid tert-butyl ester (3.9 g, 6.32 mmol) is dissolved in 30 mL of dichloromethane and stirred at 0° C. Trifluoroacetic acid (1.45 g, 12.64 mmol) is added and the reaction mixture is stirred at 0° C. for 6 h. 15 mL of saturated aqueous NaHCO3 is added, the organic phase is separated, dried over sodium sulfate and concentrated under vacuum to give the title compound (Yield: 1.30 g).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](Cl)=[O:24])=[CH:18][CH:17]=1>>[C:1]([C:5]1[C:6]([NH:14][C:23](=[O:24])[CH2:22][C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CC(C)(C)c1c(NC(=O)Cc2ccc(F)cc2)nn2cccnc12

Procedure:
The product from Example 105B and 4-fluorophenylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.38 (s, 9H), 3.63 (s, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 7.13-7.18 (m, 2H), 7.31-7.41 (m, 2H), 8.48 (dd, J=4.1, 1.7 Hz, 1H), 8.91 (dd, J=7.1, 1.7 Hz, 1H), 9.94 (s, 1H); MS (DCI) m/z 327 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:14](=[O:15])[C@@H:13]2[CH2:16][C@H:9]1[CH2:10][CH2:11][C@@H:12]2[NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[BH4-].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@@H:9]1[CH2:10][CH2:11][C@H:12]([NH:17][C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[C@H:13]([CH2:14][OH:15])[CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)[C@@H]2C[C@H]1CC[C@@H]2NC(=O)OCc1ccccc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A solution of (1R,2S,5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester (10.21 g, 27.3 mmol) in tetrahydrofuran (200 mL) was treated with water (40 mL) and then with sodium borohydride (5.16 g, 136 mmol). The mixture was stirred at room temperature for 2 h, then was treated with saturated aqueous sodium bicarbonate and stirred until the bubbling subsided. The mixture was extracted three times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The residue was recrystallized from ethyl acetate-hexane to provide (1R,3R,4S)-(4-benzyloxycarbonylamino-3-hydroxymethylcyclohexyl)carbamic acid tert-butyl ester as a white solid (6.8 g); additional product (2.1 g) was obtained by flash column chromatography of the residue from concentration of the mother liquors, eluting with 40%, then 50% ethyl acetate-hexane. MS found: (M+H)+=379.28.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([SH:15])[CH2:12][CH2:13][SH:14].B(F)(F)F.CCOCC>C(Cl)Cl>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:1]1[S:15][CH2:11][CH2:12][CH2:13][S:14]1
Reactant: COc1ccccc1C=O
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccccc1C1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 104.3 %

Procedure:
A solution of 20.4 g (150 mmol) of o-anisaldehyde and 24 mL (239 mmol) of propane-1,3-dithiol in 300 mL of methylene chloride was cooled to 0° C. Boron trifluoride etherate (4.0 mL, 33 mmol) was added dropwise to the cooled solution and the reaction mixture was stirred at 0° C. for 0.5 h, then at ambient temperature for 18 h. The methylene chloride solution was washed with 2×100 mL of 10% aqueous sodium hydroxide solution, 100 mL of water and 100 mL of brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give 35.4 g (95% yield) of 2-(2'-methoxyphenyl)-1,3-dithiane, m.p. 127°-128° C.; 1H NMR (CDCl3) δ 1.8-2.0 (m, 1H), 2.1-2.25 (m, 1H), 2.87 (t, 1H), 2.92 (t, 1H), 3.05-3.2 (m, 2H), 3.85 (s, 3H), 5.69 (s, 1H), 6.87 (d, 1H), 6.97 (t, 1H), 7.25 (dt, 1 H), 7.59 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([NH:7][C:8]2[S:12][C:11]3[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=3[C:9]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]([N+:24]([O-])=O)[CH:4]=1.[H][H]>[C].[Pd].C(OCC)(=O)C>[NH2:24][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:23]=[CH:22][C:6]=1[NH:7][C:8]1[S:12][C:11]2[CH:13]=[CH:14][CH:15]=[CH:16][C:10]=2[C:9]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)c1c(Nc2ccc(OC)cc2[N+](=O)[O-])sc2ccccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Nc2ccc(OC)cc2N)sc2ccccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 19 and using ethyl 2-(4-methoxy-2-nitroanilino)benzo[b]thiophene-3-carboxylate, ethyl acetate, 10% palladium-carbon and hydrogen (60 atm kg/cm2), ethyl 2-(2-amino-4-methoxyanilino)benzo[b]thiophene-3-carboxylate is obtained.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]([C:13]1[C:14]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15](B(O)O)[CH:16]=[C:17]([CH3:19])[CH:18]=1)=[O:12]>COCCOC>[CH:24]([O:23][C:14]1[C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:16][C:17]([CH3:19])=[CH:18][C:13]=1[CH:11]=[O:12])([CH3:26])[CH3:25]
Reactant: Cc1cc(C=O)c(OC(C)C)c(B(O)O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: COCCOC
Product: Cc1cc(C=O)c(OC(C)C)c(-c2ccc([N+](=O)[O-])cn2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.7 %

Procedure:
2-Chloro-5-nitropyridine (0.28 g, 1.76 mmol), 3-formyl-2-isopropoxy-5-methylphenylboronic acid (0.78 g, 3.52 mmol) and bis(di-tert-butyl(4-dimethylaminophenylphosphine)dichloropalladium(II) (0.012 g, 0.02 mmol) were added to 1,2-dimethoxyethan (9 ml), degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 30 minutes, 1M aqueous sodium carbonate (9 ml) was poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 23 hours, the mixture was cooled to room temperature and crystallized with addition of water. The crystallized crystals were filtered to give the title compound (0.49 g, 92.5%).
Reaction SMILES: C(O[C:4](=[O:21])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][CH3:19])[N:16]=[C:15]([CH3:20])[CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:21])=[C:14]2[C:15]([CH3:20])=[N:16][N:17]([CH2:18][CH3:19])[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1cc(C)nn1CC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1cnc2c(c(C)nn2CC)c1O

Procedure:
14.8 g. of [[(1-Ethyl-3-methyl-5-pyrazolyl)amino]methylene]malonic acid diethyl ester (0.05 mol.) are dissolved in 50 g. of diphenyl ether. The reaction mixture is heated to 235°-250° (bath temperature) and allowed to react at this temperature for 1 to 2 hours, while the resulting ethanol is continuously distilled off. The last part of the alcohol is removed by means of a water aspirator. The diphenyl ether is separated by distillation with a fractionating column in vacuo. The 1-ethyl-4-hydroxy-3-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester is obtained at b.p. 0.1-0.5 125°-129°, yield 10.7 g. (86%), m.p. 91°-93°. The compound is recrystallized from ligroin (90°-100°), m.p. 93°-94°.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([F:27])[C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[NH:11][C:12](=[O:16])[C@@H:13]([CH3:15])[O:14][C:9]=2[CH:8]=1.O.[CH3:29]I>CN(C)C=O>[Cl:3][C:4]1[CH:22]=[C:21]([C:23]([F:24])([F:25])[F:26])[CH:20]=[C:19]([F:27])[C:5]=1[O:6][C:7]1[CH:18]=[CH:17][C:10]2[N:11]([CH3:29])[C:12](=[O:16])[C@@H:13]([CH3:15])[O:14][C:9]=2[CH:8]=1
Reactant: C[C@H]1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=O
Reaction time: 0.17 h

Procedure:
Then, 60% sodium hydride (0.03 g) was suspended in dimethylformamide (5 ml), and a solution of the abovedescribed 7-(2-chloro-6-fluoro-4-trifluoromethylphenoxy)-2(R)-methyl-2H-1,4-benzoxazine-3 (4H)-one (0.3 g) in dimethylformamide (5 ml) was dropwise added thereto while cooling with water. The mixture was stirred for 10 min, methyl iodide (0.1 g) was added thereto, and the mixture was stirred for an additional 10 min. Water (10 ml) was added thereto to terminate the reaction, and the reaction mixture was extracted with ethyl acetate (20 ml×2), washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel column chromatography (developing solvent: n-hexane/ethyl acetate=3/1) to prepare the title compound (0.3 g) as a colorless crystal. The compound thus prepared was subjected to HPLC analysis for chiral separation and found to be in agreement with the first eluted fraction in the case of racemate (Example 26) modification and have an optical purity of 80%.
Reaction SMILES: N1C=CC=CC=1NC(N)=S.CI.COC1C=CC=CC=1CN.[C:23]([O-:26])(=[O:25])[CH3:24].[CH3:27][O:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1[CH2:31][NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[NH:34]>CO>[C:23]([OH:26])(=[O:25])[CH3:24].[CH3:27][O:28][C:29]1[CH:45]=[CH:44][CH:43]=[CH:42][C:30]=1[CH2:31][NH:32][C:33]([NH:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1)=[NH:34]
Reactant: CC(=O)[O-]
Agent: COc1ccccc1CN
Agent: COc1ccccc1CNC(=N)Nc1ccccn1
Agent: NC(=S)Nc1ccccn1
Solvent: CI
Solvent: CO
Product: CC(=O)O
Temperature: 70 °C

Procedure:
0.800 g (5.117 mmol) N-pyridin-2-yl-thiourea was dissolved in 10 mL methanol, 0.45 mL (7.164 mmol) methyl iodide in 5 mL methanol was added dropwise, and the mixture was heated for 1 hr at 70° C. (oil bath temperature) and subsequently stirred at room temperature. The solvent was removed under vacuum and the intermediate product, methyl N-(pyridin-2-yl)imidothiocarbamate hydroiodide, was redissolved in 15 mL ethanol. 1.36 mL (10.235 mmol) 2-methoxybenzylamine was added dropwise, and the mixture was heated for 2.75 hr at 85° C. (oil bath temperature) and subsequently stirred at room temperature. The solvent was then evaporated under vacuum. The crude product was redissolved with dichloromethane and extracted with water (2×30 mL). After drying over magnesium sulfate and removal of the solvent, purification was carried out via preparative HPLC (Merck Chromolith RP-18 100×25 mm, eluent: water/acetonitrile/0.1 M acetic acid). For complete ion exchange with the ion exchanger (Fluka, acetate on 1.5 mmol CH3COO/g/resign polymer substrate), the purified N-(2-methoxybenzyl)-N′-pyridin-2-yl-guanidine was converted to the acetate salt in a yield of 0.357 g (1.128 mmol).
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].[CH2:9](Br)[CH:10]=[CH2:11].[Cl-].[NH4+]>C1COCC1.O>[CH3:7][CH:6]([CH3:8])[CH2:5][CH2:4][CH2:3][CH2:11][CH:10]=[CH2:9]
Reactant: C=CCBr
Reactant: CC(C)CCCBr
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCCCCC(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
Under a protective gas, 20 g. (0.82 gram atom) of magnesium filings in 150 ml. of tetrahydrofuran is charged into a 1-liter three-necked flask. Within about 60 minutes, 120 g. (0.73 mole) of 1-bromo-4-methylpentane in 270 ml. of tetrahydrofuran is added dropwise to the reaction mixture so that a reaction temperature of 60° C. evolves. The agitation is continued for another 11/2 hours at 50° C. The thus-formed Grignard compound is separated from the unreacted magnesium by means of a glass pipette and transferred into a dropping funnel placed on top of a 2-liter three-necked flask. This flask is to be used for dissolving 84.0 g. (0.7 mole) of allyl bromide in 620 ml. of tetrahydrofuran and for combining this solution with 2.5 millimoles of Li2CuCl4 (as a 0.1-molar solution in THF). Within 60 minutes, the Grignard solution is to be dropped under stirring to this mixture, which latter has been cooled to -10° to -5° C. The reaction mixture is maintained at 0° C. for another 11/2 hours before Grignard compound is gently decomposed with saturated ammonium chloride solution (or about 50 ml. of water). The organic phase is separated, the residue is extracted repeatedly with ether, and the combined, olefin-containing phases are dried over sodium sulfate. After the solvents have been evaporated, 7-methyl-1-octene can be obtained in the pure form by fractionation over a Vigreux attachment or a column:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.Br[CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[O:1][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCCBr
Reactant: O=C(Cc1cccc(O)c1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCOc1cccc(CC(=O)OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
A mixture of benzyl 2-(3-hydroxyphenyl)acetate (1.39 g, 5.74 mmol), ethyl 4-bromobutanoate (1.23 g, 6.3 mmol), anhydrous K2CO3 (1.98 g, 14.4 mmol) and anhydrous DMF (10 mL) was stirred at room temperature overnight. Water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate in petroleum ether, 25% to 50% v/v) to yield ethyl 4-(3-(2-(benzyloxy)-2-oxoethyl)phenoxy)butanoate (2.05 g, 100%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.17 (t, J=7.2 Hz, 3H), 1.96 (m, 2H), 2.45 (t, J=7.2 Hz, 2H), δ 3.70 (s, 2H), 3.94 (t, J=6.4 Hz, 2H), 4.07 (q, J=7.2 Hz, 2H), 5.11 (s, 2H), 6.83 (m, 3H), 7.20 (t, 1H), 7.20 (m, 5H).