Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].ClP(Cl)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[OH:31][C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2[Cl:42])[N:35]([CH3:43])[C:34](=[O:44])[C:33]=1[C:45](O)=[O:46]>C(Cl)Cl>[CH3:2][CH2:1][N:3]([C:45]([C:33]1[C:34](=[O:44])[N:35]([CH3:43])[C:36]2[CH:37]=[CH:38][CH:39]=[C:40]([Cl:42])[C:41]=2[C:32]=1[OH:31])=[O:46])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cn1c(=O)c(C(=O)O)c(O)c2c(Cl)cccc21
Reactant: CCNc1ccccc1
Agent: ClP(Cl)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCN(C(=O)c1c(O)c2c(Cl)cccc2n(C)c1=O)c1ccccc1
Temperature: 27.5 °C
Reaction time: 0.17 h
Yield: 83.2 %

Procedure:
N-Ethyl aniline (5.2 gm) was taken in methylene chloride (100 ml) and stirred for 10 minutes at 25-30° C. under nitrogen atmosphere. The resulting mass was followed by the addition of dichlorotriphenyl phosphorane (26.6 gm) at 25-30° C. and the reaction mixture was stirred for 15 minutes. 1,2-Dihydro-4-hydroxy-5-chloro-1-methyl-2-oxo-quinoline-3-carboxylic acid (10 gm) was added to the resulting mass at 25-30° C. followed by heating to reflux (40-45° C.) and then stirred for 3 hours at reflux. Methylene chloride was distilled out from the reaction mass under vacuum at below 45° C. The resulting residue was cooled to 25-30° C., followed by the addition of ethyl acetate (50 ml) and water (50 ml) at 25-30° C. and the resulting mixture was stirred for 30 minutes at 25-30° C. The separated solid was filtered, washed with water and then dried to yield 11.7 gm of laquinimod as a white colored solid (HPLC purity: 99.47%).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=O)[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].Cl.[NH2:30][OH:31]>N1C=CC=CC=1>[CH3:1][C:2](=[CH:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16](=[CH:17][C:18](=[N:30][OH:31])[CH2:19][CH2:20]2)[CH2:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3]
Reactant: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CC(C)=CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CCC4=CC(=NO)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Yield: 50 %

Procedure:
100 mg of 4,24-cholestadien-3-one (0.26 mmol) is solubilized in 5 ml of pyridine in a 10 ml flask, then 100 mg of hydroxylamine hydrochloride is added. Stirring is maintained for 24 hours at ambient temperature, and the solvent is evaporated off under reduced pressure. Water then ethyl acetate are added in order to carry out an extraction. Then the organic phase is washed with an acidified aqueous solution (HCl 1%). The ethyl acetate is evaporated off under reduced pressure. A white powder is obtained with a yield greater than 50%.
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([O:6][C:7]([C:9]1[N:29]=[CH:28][C:12]2[NH:13][C:14]3[C:19]([C:11]=2[C:10]=1[CH2:30][O:31][CH3:32])=[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]=[CH:16][CH:15]=3)=[O:8])[CH3:5].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]Br)=[CH:37][CH:36]=1>O1CCCC1>[CH3:5][CH:4]([O:6][C:7]([C:9]1[N:29]=[CH:28][C:12]2[N:13]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][C:38]3[CH:37]=[CH:36][C:35]([O:34][CH3:33])=[CH:40][CH:39]=3)[C:14]3[C:19]([C:11]=2[C:10]=1[CH2:30][O:31][CH3:32])=[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:17]=[CH:16][CH:15]=3)=[O:8])[CH3:3]
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3cccc(OCc4ccccc4)c3c12
Reactant: COc1ccc(CCCCCCBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1c(C(=O)OC(C)C)ncc2c1c1c(OCc3ccccc3)cccc1n2CCCCCCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 55.5 %

Procedure:
10 mg of an 80% suspension of sodium hydride in oil is mixed with 10 ml of tetrahydrofuran and to 0° C. 404.5 mg of 5-benzyloxy-4-methoxymethyl-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is added to the suspension, it is stirred for 10 minutes at 0° C., mixed with 406 mg of 6-(4-methoxyphenyl)-hexyl bromide, and the reaction mixture is stirred for 16 hours at room temperature. After the reaction mixture is worked up as described, 330 mg of 5-benzyloxy-4-methoxymethyl-9-[6-(4-methoxyphenyl)-hexyl]-9H-pyrido[3,4-b]indole-3-carboxylic acid-(1-methylethyl)-ester is obtained.
Reaction SMILES: ClC1C=CC=CC=1C(Cl)=O.N[C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[CH2:17][CH2:16][CH2:15]2.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>O>[CH2:17]1[C:18]2[C:14](=[CH:13][CH:12]=[CH:20][CH:19]=2)[CH2:15][CH2:16]1
Reactant: Nc1ccc2c(c1)CCC2
Agent: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: c1ccc2c(c1)CCC2

Procedure:
2-Chlorobenzoyl chloride (11.8 g) was added dropwise to a stirred mixture of 5-aminoindan (9.0 g), potassium carbonate (9.3 g), ethyl acetate (90 ml) and water (90 ml) under ice-cooling. The mixture was further stirred under ice-cooling for one hour, at the end of which time the organic layer was separated, washed with water, dried (MgSO4) and distilled to remove the solvent. The procedure gave crystals of 5-2-chlorobenzoylamino)indan. The crystals were collected by filtration and recrystallized from isopropyl ether to give colorless needles, m.p. 144°-145° C.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[N:18]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:19]([CH:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[N:20][CH:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1>CCO>[C:30]([O:29][C:27]([N:23]1[CH2:24][CH2:25][CH2:26][CH:22]1[C:19]1[N:18]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[C:17]([CH:14]2[CH2:13][CH2:12][NH:11][CH2:16][CH2:15]2)=[CH:21][N:20]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(C2CCN(C(=O)OCc3ccccc3)CC2)n1COCC[Si](C)(C)C
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC1c1ncc(C2CCNCC2)n1COCC[Si](C)(C)C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
4-[2-(1-tert-Butoxycarbonyl-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-piperidine-1-carboxylic acid benzyl ester (2.8 g, 6.1 mmol) in EtOH (60 mL) was treated with 20% PdOH/C (600 mg) and placed under an atmosphere of H2. The reaction was stirred for 18 hours and filtered through a CELITE plug to afford crude 2-[5-piperidin-4-yl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (2.0 g), which was used without further purification: MS (ESI) m/z 451 [M+H]+.
Reaction SMILES: CCN(C(C)C)C(C)C.[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH2:17])[CH2:12][CH2:11]1.[C:18](OC(=O)C)(=[O:20])[CH3:19]>C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH2:12][CH2:11]1
Reactant: NCC1CCOCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCC1CCOCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
PS-DIEA (Argonaut Technologies, 1.35 g, 4.5 mmol) is added to a mixture of C-(tetrahydropyran-4-yl)methylamine (345 mg, 3.0 mmol) in CH2Cl2 (20 ml) at ambient temperature. Acetic anhydride (367 mg, 3.6 mmol) is added to the mixture. After stirring at ambient temperature for 18 hours, methylisocyanate polystyrene (Novabiochem, 1.84 g, 3.0 mmol) and N-(2-aminoethyl)aminomethyl polystyrene (Novabiochem, 1.07 g, 3.0 mmol) are added. After stirring at room temperature for 4 h, the resins are removed by filtration, and the resins are washed with dichloromethane. The filtrate and washing are combined, and the solvent is removed by evaporation in vacuo to give N-(tetrahydropyran-4-ylmethyl)acetamide.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][O:4][N:3]=1.[Br:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25](Cl)(=[O:27])=[O:26])=[CH:22][CH:23]=3)[C:18]([CH3:29])=[CH:17][C:16]2=[O:30])=[C:10]([O:31][CH3:32])[CH:9]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.O1CCOCC1>C1COCC1>[Br:7][C:8]1[C:13]([Cl:14])=[CH:12][C:11]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([S:25]([NH:1][C:2]4[CH:6]=[CH:5][O:4][N:3]=4)(=[O:26])=[O:27])=[CH:22][CH:23]=3)[C:18]([CH3:29])=[CH:17][C:16]2=[O:30])=[C:10]([O:31][CH3:32])[CH:9]=1
Reactant: COc1cc(Br)c(Cl)cc1-n1c(=O)cc(C)c2cc(S(=O)(=O)Cl)ccc21
Reactant: Nc1ccon1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COc1cc(Br)c(Cl)cc1-n1c(=O)cc(C)c2cc(S(=O)(=O)Nc3ccon3)ccc21
Yield: 24.9 %

Procedure:
A solution of 3-aminoisoxazole (0.867 ml, 11.74 mmol) and 1-(4-bromo-5-chloro-2-methoxyphenyl)-4-methyl-2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride (1.120 g, 2.347 mmol) in 10 mL THF, was cooled to 0° C. LHMDS 1N in THF (11.74 ml, 11.74 mmol) was added, and the cooling bath was removed. After stirring for an additional hour, the reaction mixture was treated with hcl 4N in dioxane (5.87 ml, 23.47 mmol) and was concentrated. Purification of the crude residue by reverse phase column chromatography [Redisep Gold C18, 10-100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] gave 1-(4-bromo-5-chloro-2-methoxyphenyl)-N-(isoxazol-3-yl)-4-methyl-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.307 g, 0.585 mmol, 24.92% yield). In/z (ESI) 525.9 (M+H)+.
Reaction SMILES: C(O[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])C.[CH3:13][C:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][NH:23][CH2:24][C:25]#[N:26])([CH3:16])[CH3:15]>C(O)C>[CH3:16][C:14]([O:17][C:18](=[O:27])[NH:19][CH2:20][CH2:21][CH2:22][N:23]([CH2:24][C:25]#[N:26])[C:4]1[C:5](=[O:12])[C:6](=[O:11])[C:7]=1[O:8][CH2:9][CH3:10])([CH3:13])[CH3:15]
Reactant: CCOc1c(OCC)c(=O)c1=O
Reactant: CC(C)(C)OC(=O)NCCCNCC#N
Solvent: CCO
Product: CCOc1c(N(CC#N)CCCNC(=O)OC(C)(C)C)c(=O)c1=O
Yield: 90.2 %

Procedure:
A solution of 3,4-diethoxy-3-cyclobutene-1,2-dione (2.6 mL, 18 mmol) in absolute ethanol (90 mL) was treated with [3-(cyanomethylamino)propyl]carbamic acid 1,1-dimethylethyl ester (3.90 g, 18 mmol) in ethanol (30 mL) over 90 min. After 40 hours the reaction mixture was evaporated, dissolved in dichloromethane, preadsorbed onto silica gel, and purified by flash chromatography (7 cm diameter, gradient elution with 0-5% methanol in dichloromethane) to yield [3-[(cyanomethyl)-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)amino]-propyl]carbamic acid 1,1-dimethylethyl ester as a yellow oil (5.48 g, 90%); IR (neat, cm-1): 3360, 1800; MS (+FAB): 282 (76), 238 (98), 158 (100); 1H NMR (CDCl3, 400 MHz): δ 4.81 (q, J=7 Hz, 2H), 4.75 (br s, NH), 4.45, 3.66 (s, 2H), 3.84, 3.60 (br m, 2H), 3.26-3.15 (m, 2H), 1.91 (p, J=6.5 Hz, 2H), 1.50 (t, J=7 Hz, 3H), 1.45 (s, 9H).
Reaction SMILES: [CH2:1]([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:12][C:13](Cl)=[C:8]2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1>COOCCOOC>[CH2:1]([N:5]1[C:9]2=[N:10][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])=[N:12][C:13]([NH:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[C:8]2[C:7]([CH3:22])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C)c2c(Cl)nc(-c3ccccc3F)nc21
Reactant: Nc1ccncc1
Agent: COOCCOOC
Product: CCCCn1nc(C)c2c(Nc3ccncc3)nc(-c3ccccc3F)nc21
Yield: 113.1 %

Procedure:
1-Butyl-4-chloro-6-(2-fluoro-phenyl)-3-methyl-1H-pyrazolo[3,4-d]pyrimidine (100 mg, 0.31 mmole) and 4-aminopyridine (58 mg, 0.626 mmole) were combined in ethyleneglycol dimethoxy ether and heated to reflux for 4 hours. The reaction mixture was cooled and the product was isolated by filtration, washed with minimum cold solvent and dried to give 132 mg of product. 50 mg of this material was subjected to HPLC purification on reversed phase C18 column, eluting with gradient of water/acetonitrile/0.1% trifluoroacetic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:13])[NH2:12])=[O:4].[NH:17]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@@H:18]([C:28](ON1C(=O)CCC1=O)=[O:29])[CH2:19][CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>CN(C=O)C>[NH:17]([C:38]([O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:39])[C@@H:18]([C:28]([NH:1][CH2:2][C:3]([NH:5][C@H:6]([C:14]([OH:16])=[O:15])[CH2:7][CH2:8][CH2:9][NH:10][C:11](=[NH:12])[NH2:13])=[O:4])=[O:29])[CH2:19][CH2:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: N=C(N)NCCC[C@H](NC(=O)CN)C(=O)O
Reactant: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)N[C@@H](CCCNC(=N)N)C(=O)O
Yield: 111.9 %

Procedure:
After 4.4 g (10 mM) of H-Gly-Arg-CHA.2HCl was dissolved in 20 ml of 0.75N NEM/DMF, 4.3 g (10 mM) of Z-D-Glu(OtBu)-OSu was added to the solution while cooling to 0° to 5° C. with stirring. The resulting mixture was reacted at room temperature for 15 hours. After completion of the reaction, the solvent was distilled under reduced pressure. The residue was dissolved in MeOH and the solution was reprecipitated in 1 liter of AcOEt. The precipitated crystals were taken by filtration and dried to give 6.1 g (84.5%) of Z-D-Glu(OtBu)-Gly-Arg-CHA.HCl.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[C:17](=[CH:18][C:19]4[O:20][CH2:21][O:22][C:23]=4[CH:24]=3)[C:16](=[O:26])[CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5].[N-:28]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O>O>[CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[CH:24]=[C:23]4[O:22][CH2:21][O:20][C:19]4=[CH:18][C:17]=3[C:16](=[O:26])[NH:28][CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCN1C(=O)C2(CNC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
A mixture of 1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione (0.10 g, 0.28 mmol), sodium azide (0.09 g, 1.40 mmol) and trifluoroacetic acid (2.00 mL) was stirred at 50° C. overnight. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.08 g, 74%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), 7.30 (td, 1H), 7.20 (dd, 1H), 6.98 (td, 1H), 6.93 (d, 1H), 6.32 (br, 1H), 6.21 (s, 1H), 5.97-5.92 (m, 2H), 4.02 (dd, 1H), 3.87-3.70 (m, 2H), 3.47 (dd, 1H), 1.80-1.66 (m, 2H), 1.42-4.30 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 175.8, 165.2, 151.6, 147.9, 141.7, 134.3, 130.9, 129.0, 124.5, 123.2, 122.9, 109.0, 108.5, 105.4, 101.9, 51.9, 48.2, 40.4, 29.1, 27.1, 22.3, 14.0; MS (ES+) m/z 379.3 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)=[O:4]>[Pd].C(OCC)(=O)C>[NH2:13][C:12]1[C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: COC(=O)COc1ncccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)COc1ncccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.4 %

Procedure:
A mixture of 55.9 g of 2-(methoxycarbonyl)methoxy-3-nitropyridine, 8.64 g of 10% palladium/carbon and 600 ml of ethyl acetate was stirred for 2 hours at room temperature under hydrogen atmosphere. The reaction system was purged with nitrogen, then, the reaction solution was filtrated through Celite, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 46.76 g of 3-amino-2-(methoxycarbonyl)methoxypyridine. Intermediate Production Example 8
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[C:49]([NH:52][CH2:53][S:54][CH2:55][C@H:56]([NH2:67])[C:57]1[NH:61][C:60]2[CH:62]=[CH:63][C:64]([Cl:66])=[CH:65][C:59]=2[N:58]=1)(=[O:51])[CH3:50].ClCl>O1CCCC1.ClCCl.C(O)C>[C:49]([NH:52][CH2:53][S:54][CH2:55][C@H:56]([NH:67][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])=[C:2]([CH3:1])[CH:3]=1)[C:57]1[NH:61][C:60]2[CH:62]=[CH:63][C:64]([Cl:66])=[CH:65][C:59]=2[N:58]=1)(=[O:51])[CH3:50]
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: CC(=O)NCSC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCSC[C@H](NC(=O)c1ccc(C(=O)N2CCCC2)c(C)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 89 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1R)-2-(acetylaminomethylsulfanyl)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 89%; Rf value: 0.40 (silica gel: dichloromethane/ethanol=9:1; C25H28ClN5O3S (514.05); mass spectrum: (M+H)+=514/516 (chlorine isotope).
Reaction SMILES: Cl[CH:2]1[CH2:6][CH2:5][CH:4]=[CH:3]1.[OH:7][N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].C(N(CC)CC)C>C(#N)C>[CH:2]1([O:7][N:8]2[C:9](=[O:18])[C:10]3=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]3[C:12]2=[O:13])[CH2:6][CH2:5][CH:4]=[CH:3]1
Reactant: ClC1C=CCC1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OC1C=CCC1
Temperature: 0 °C
Yield: 69.1 %

Procedure:
A mixture of 3-chlorocyclopentene (36.9 g), N-hydroxyphthalimide (58.2 g) and triethylamine (53.9 g) in acetonitrile (370 ml) was refluxed for 2 hours. The reaction mixture was poured into ice-water. The precipitated crystals were collected by filtration, washed with water and dried over phosphorus pentoxide to give N-(2-cyclopenten-1-yl)oxyphthalimide (56.5 g).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:13]([F:14])=[CH:12][C:11]([N:15]=[C:16]=[S:17])=[CH:10][C:9]=2[F:18])[CH:7]=1>>[Cl:2][C:3]1[N:4]=[CH:5][N:6]([C:8]2[C:9]([F:18])=[CH:10][C:11]([NH:15][C:16]([NH2:1])=[S:17])=[CH:12][C:13]=2[F:14])[CH:7]=1
Reactant: Fc1cc(N=C=S)cc(F)c1-n1cnc(Cl)c1
Reactant: N
Product: NC(=S)Nc1cc(F)c(-n2cnc(Cl)c2)c(F)c1
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Step J (4): Methanolic ammonia (2.0 M, 5 mL, 10 mmol) was added to a flask charged with 4-chloro-1-(2,6-difluoro-4-isothiocyanatophenyl)-1H-imidazole (195 mg, 0.718 mmol). After 3 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(4-(4-chloro-1H-imidazol-1-yl)-3,5-difluorophenyl)thiourea (207 mg, 100% yield) as a white solid. LC-MS (M+H)+ 289.2
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([Br:20])[C:18]=1[OH:19])[CH:14]=O>CN(C=O)C>[Br:10][C:11]1[CH:12]=[C:13]([C:14]2[S:9][C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[N:1]=2)[CH:16]=[C:17]([Br:20])[C:18]=1[OH:19]
Reactant: O=Cc1cc(Br)c(O)c(Br)c1
Reactant: Nc1cc(Cl)ccc1S
Solvent: CN(C)C=O
Product: Oc1c(Br)cc(-c2nc3cc(Cl)ccc3s2)cc1Br
Temperature: 100 °C
Yield: 13 %

Procedure:
In a DMF (3 mL) solvent, a solution including 2-amino-4-chlorobenzenethiol (100 mg, 0.63 mmol) and 3,5-dibromo-4-hydroxybenzaldehyde (127 mg, 0.63 mmol) was heated at a temperature of 100° C. for 8.5 hours. After DMF was evaporated therefrom, the residual was purified by silica gel column chromatography using hexane and ethyl acetate (5:1) as a developer to obtain a solid Compound 96 (34.3 mg, 18.1%).
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].[C:15]([O-:18])(O)=[O:16].[Na+]>O.O1CCOCC1>[NH:1]([C:15]([O:18][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][CH2:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
H-Glu(OtBu)-OH (Rf(BuOH/AcOH/H2O 4:1:1 v/v/v): 0.52, [α]D=+9.3° C.=1.05 H2O, mp: 181° C. (dec.); lit24: [α]D=+9.8° C.=2 H2O, mp: 182° C.) (2.0 g, 9.85 mmol), NaHCO3 (1.86 g, 22.2 mmol, 2.25 eq.) were dissolved in H2O (40 mL) and Boc2O25 (2.36 g, 10.8 mmol, 1.10 eq.) dissolved in dioxane (20 mL) was added. The reaction mixture became turbid and gas evolution started. After 3 hrs of stirring at room temperature, the reaction mixture was partially evaporated in vacuo. The aqueous solution was acidified with 10% citric acid and the precipitating oil was taken up into EtOAc (three extractions 20 mL). The EtOAc layer was subsequently washed with H2O (five times 30 mL), saturated NaCl (three times 30 mL) and dried on Na2SO4. The residue obtained after evaporation in vacuo was an oil which crystallized slowly. Yield: 2.91 g (98%), Rf(BuOH/AcOH/H2O 4:1:1 v/v/v): 0.87, Rf(CH2Cl2/MeOH 9:1 v/v): 0.17, [α]D=−10.3° C.=0.93 MeOH, mp: 98-99° C. (lit26: [α]D=−10.9° C.=1 MeOH, mp:101-102° C.), 1H NMR (CDCl3): δ=1.44 (s, 18H, Boc/OtBu (2×9H)); 1.99/2.18 (dm, 2H, β-CH2); 2.38 (m, 2H, γ-CH2); 4.34 (m, 1H, α-CH); 5.23 (d, 1H, NH).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[C:20](=[O:21])[N:19]([CH3:22])[C:10]3[N:11]=[C:12](S(C)(=O)=O)[N:13]=[CH:14][C:9]=3[CH:8]=2)=[CH:4][CH:3]=1.[CH2:25]([NH2:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.CO>CN1CCCC1=O>[CH2:25]([NH:32][C:12]1[N:13]=[CH:14][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:23]=[CH:24][C:2]([F:1])=[CH:3][CH:4]=3)[C:20](=[O:21])[N:19]([CH3:22])[C:10]=2[N:11]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCc1ccccc1
Reactant: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(S(C)(=O)=O)nc21
Solvent: CN1CCCC1=O
Solvent: CO
Product: Cn1c(=O)c(Oc2ccc(F)cc2)cc2cnc(NCc3ccccc3)nc21
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 6-(4-fluorophenoxy)-8-methyl-2-(methylsulfonyl)pyrido[2,3-d]pyrimidin-7(8H)-one (see Example 8 made by replacing methyl 2-fluorophenoxyacetate with methyl 4-fluorophenoxyacetate-Steps A and B, 0.35 g, 1.0 mmol) and benzylamine (0.33 mL, 3 mmol) in 0.5 mL of 1-methyl-2-pyrrolidinone was stirred at 110° C. for 12 hours and then cooled to room temperature. Methanol (2 mL) was added and the suspension was stirred for 30 minutes. Filtration and washing of the precipitate thoroughly with methanol followed by drying provided the free amine. This was dissolved in ethyl acetate (1-2 mL) and hydrochloric acid in ether (1M, 1.5 eq) was added. Isolation of the solid via filtration and drying provided 0.317 g of the hydrochloride salt (Mass spec. M+1=377, MP=203.2-204° C.).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[CH:15]([CH3:16])[C:14](=[O:17])[C:13]([CH3:19])([CH3:18])[C:12]2=[O:20])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:21][Mg]Br.C1COCC1>>[Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([N:11]2[C:12](=[O:20])[C:13]([CH3:19])([CH3:18])[C@:14]([OH:17])([CH3:21])[C@H:15]2[CH3:16])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: C[Mg]Br
Reactant: Cc1c(N2C(=O)C(C)(C)C(=O)C2C)ccc(C#N)c1Cl
Solvent: C1CCOC1
Product: Cc1c(N2C(=O)C(C)(C)[C@@](C)(O)[C@H]2C)ccc(C#N)c1Cl

Procedure:
Using 2-chloro-3-methyl-4-(3,3,5-trimethyl-2,4-dioxopyrrolidin-1-yl)benzonitrile (40 mg) and methylmagnesium bromide-THF solution (1.38 mL, 1.0 mol/L), and in the same manner as in Example 2, the title compound was obtained as a colorless solid (yield: 24 mg, 57%).