Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[N:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:20])[O:18][CH3:19])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:23]I>CN(C)C=O>[CH3:23][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:6]2[CH:7]=[CH:8][C:9]3[N:4]([CH:3]=[N:2][N:1]=3)[N:5]=2)[CH:11]=1)[C:17](=[O:20])[O:18][CH3:19]
Reactant: CI
Reactant: COC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 2.25 g of [3-(1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl carbamic acid, methyl ester, 0.42 g of sodium hydride (50% in oil) and 200 ml of dimethylformamide was stirred under argon, for 1 hour and then 0.55 ml of methyl iodide was added. This mixture was stirred overnight, then treated as described in Example 1, giving 1.3 g of the desired product as tan crystals, mp 195°-199° C.
Reaction SMILES: Cl.C([C@@H]1C(OC)=[N:9][C@@H:8]([CH2:13][C@@H:14]([CH:26]([CH3:28])[CH3:27])[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:7]([O:29]C)=N1)(C)C.[C:31]([O-])(O)=[O:32].[Na+]>C(#N)C>[CH3:31][O:32][C:7](=[O:29])[C@@H:8]([NH2:9])[CH2:13][C@@H:14]([CH:26]([CH3:27])[CH3:28])[CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]([CH3:24])([CH3:23])[CH3:25])=[CH:20][CH:21]=1
Reactant: COC1=N[C@H](C(C)C)C(OC)=N[C@H]1C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)[C@@H](N)C[C@H](Cc1ccc(C(C)(C)C)cc1)C(C)C
Temperature: 25 °C

Procedure:
With stirring at room temperature, 36 ml of 1N hydrochloric acid are added to a solution of 3.55 g of 2(R)-isopropyl-5(S)-[2(S)-isopropyl-3-(p-tert-butylphenyl)-propyl]-2,5-dihydro-3,6-dimethoxy-pyrazine in 36 ml of acetonitrile and the mixture is then stirred for a further 3 hours. The reaction solution is then poured onto a mixture of 45 ml of saturated NaHCO3 solution and ice and the suspension is extracted with dichloromethane. The extracts are concentrated by evaporation and purified by FC (700 g of silica gel, eluant: dichloromethane/methanol/NH3 =200:10:1), yielding the title compound: Rf (dichloromethane/methanol/conc. ammonia=200:10:1)=0.70.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([C:11]3[O:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[C:6]2[C:5]2[CH:16]=[CH:17][N:18]([CH2:19][CH2:20][OH:21])[C:4]=2[N:3]=1.N1C=CC=CC=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C1COCC1>[CH3:28][S:29]([O:21][CH2:20][CH2:19][N:18]1[C:4]2[N:3]=[C:2]([NH2:1])[N:7]3[N:8]=[C:9]([C:11]4[O:12][CH:13]=[CH:14][CH:15]=4)[N:10]=[C:6]3[C:5]=2[CH:16]=[CH:17]1)(=[O:31])=[O:30]
Reactant: Nc1nc2c(ccn2CCO)c2nc(-c3ccco3)nn12
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the title C compound, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethanol (15 g, 5.28 mmol) in 45 mL of dry THF is added 75 mL of TEA, 75 mL of pyridine and methanesulfonyl chloride (0.6 mL, 7.75 mmol) at 0° C. The mixture is stirred at RT under N2 for 12 h. The solvent is evaporated in vacuo and the residue is purified by flash chromatography using EtOAc as eluent to give 2-{5-amino-2-(furan-2-yl) -7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate as a white solid: LC/MS (M+1=363.4). 1H NMR (DMSO-d6, 400 MHz) δ 3.07 (s, 3H), 4.47 (t, 2H, J=5.2 Hz), 4.59 (t 2H, J=5.2 Hz), 6.65 (d, 1H, J=3.6 Hz), 6.72 (dd, 1H, J=3.2 Hz and 1.6 Hz), 7.18 (d, 1H, J=3.6 Hz), 7.20 (d, 1H, J=3.2 Hz), 7.60 (s, 2H), 7.92 (d, 1H, J=1.2 Hz).
Reaction SMILES: [N:1]1[NH:2][N:3]=[C:4]([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)=[N:12][CH:13]=2)[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][O:39][C:40]([C@H:42]1[CH2:47][C@@H:46](O)[CH2:45][CH2:44][N:43]1[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[O:41]>C1COCC1>[N:14]1([C:11]2[N:12]=[CH:13][C:8]([O:7][CH2:6][C:4]3[CH:5]=[N:1][N:2]([C@@H:46]4[CH2:45][CH2:44][N:43]([C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])[C@@H:42]([C:40]([O:39][CH3:38])=[O:41])[CH2:47]4)[N:3]=3)=[CH:9][CH:10]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: COC(=O)[C@H]1C[C@@H](O)CCN1C(=O)OC(C)(C)C
Reactant: c1cc(-n2cnnn2)ncc1OCc1cn[nH]n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1C[C@H](n2ncc(COc3ccc(-n4cnnn4)nc3)n2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
To a solution of 5-((2H-1,2,3-triazol-4-yl)methoxy)-2-(1H-tetrazol-1-yl)pyridine (600 mg, 2.45 mmol), triphenylphosphine (1.5 eq.), and (2R,4S)-N-Boc-4-hydroxypiperidine-2-carboxylic acid methyl ester (1.5 eq.) dissolved in THF (20 mL) at 0° C. was added a solution of di-tertbutylazodicarboxylate (1.5 eq.) in THF (5 mL) drop wise. The reaction was allowed to warm to room temperature overnight and the solvents removed in vacuo The crude material was purified by flash column chromatography on silica gel to afford the desired product. 1H NMR (CDCl3): δ 9.44 (1H, s), 8.27 (1H, d), 8.03 (1H, d), 7.71 (1H, s), 7.58 (1H, dd), 5.27 (2H, s), 4.99-5.19 (1H, m), 4.57 (1H, m), 4.11-4.31 (1H, m), 3.79 (3H, s), 3.04-3.24 (1H, m), 2.75 (1H, m), 2.18-2.32 (2H, m), 2.05 (1H, m), 1.50 (9H, s). ES+-MS found: 486.1.
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[C:7]1([C:13]2[O:22][C:21]3[CH2:20][CH2:19][CH2:18][NH:17][CH2:16][C:15]=3[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:7]1([C:13]2[O:22][C:21]3[CH2:20][CH2:19][CH2:18][N:17]([C:4]([CH:1]4[CH2:3][CH2:2]4)=[O:5])[CH2:16][C:15]=3[CH:14]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C(Cl)C1CC1
Reactant: c1ccc(-c2cc3c(o2)CCCNC3)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(C1CC1)N1CCCc2oc(-c3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1.8 g. of cyclopropylcarbonyl chloride in 50 ml. of dry chloroform is added dropwise to a cooled mixture of 3.1 g. of 2-phenyl-4,6,7,8-tetrahydrofuro[3,2-c]azepine and 1.7 g. of triethylamine in 50 ml. of dry chloroform. After addition, the reaction mixture is stirred at ambient temperature for 20 hours, washed with water and dried. The chloroform is removed and the residue is triturated with n-hexane to produce a solid product. The product is recrystallized from n-hexane to give 2-phenyl-5-cyclopropylcarbonyl-4,6,7,8-tetrahydrofuro[3,2-c]azepine, m.p. 108°-110°C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C.Br[CH2:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:12]1
Reactant: Clc1cccc2c(C3CCNCC3)c[nH]c12
Reactant: CC(C)(C)OC(=O)CCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(O)CCN1CCC(c2c[nH]c3c(Cl)cccc23)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A 25 mL round bottom flask was charged with polymer bound 7-chloro-3-(piperidin-4-yl)-1H-indole (1.0 g, 0.98 mmol), triethylamine (80.2 mL), tert-butyl 3-bromopropionate and dry acetonitrile (5 mL). The mixture was stirred at 80° C. for 3 h. After cooling to room temperature, the resin was filtered off and washed with dry acetonitrile (3×10 mL) and dry dichloromethane (3×10 mL). The resin was treated for 20 minutes with 8 mL of a 1:1 mixture of dichloromethane and trifluoroacetic acid containing anisole (2%, w/w) and methionine (0.2%, w/w) (Caution: Generation of carbon dioxide). The resin was filtered off and washed with dry dichloromethane (10 mL), a 1:1 mixture of dichloromethane:triethylamine (3×10 mL) and dry dichloromethane (3×10 mL). The resin was dried in vacuo (20° C., 20 h) to yield the title resin (1.0 g).
Reaction SMILES: [F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14](Cl)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:18][O:19][C:20]1[N:25]=[CH:24][C:23]([C:26]2[C:31]([CH3:32])=[CH:30][N:29]=[C:28]([NH2:33])[N:27]=2)=[CH:22][CH:21]=1>N1C=CC=CC=1>[F:1][C:2]1([F:17])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:33][C:28]4[N:27]=[C:26]([C:23]5[CH:24]=[N:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=5)[C:31]([CH3:32])=[CH:30][N:29]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Reactant: COc1ccc(-c2nc(N)ncc2C)cn1
Solvent: c1ccncc1
Product: COc1ccc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ncc2C)cn1
Temperature: 90 °C

Procedure:
To 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (369 mg, 1.42 mmol) and 4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-amine (153 mg, 0.71 mmol), pyridine (4 mL) was added. The reaction was heated at 90° C. for three and a half hours. The pyridine was evaporated under reduced pressure. The resulting mixture was dissolved in ethyl acetate and filtered. The filtrate was washed with saturated aqueous NaHCO3 (×3). The organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel to yield 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(4-(6-methoxypyridin-3-yl)-5-methylpyrimidin-2-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 440.13, found 441.5 (M+1)+. Retention time 1.72 minutes.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C@@H:10]2[C:14]3[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:29](OCC)(=[O:31])C.CCCCCC>C(Cl)(Cl)Cl>[CH:29]([C:18]1[C:13]2[O:12][CH2:11][C@H:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:28])=[C:16]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:17]=1[CH3:19])=[O:31]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: Cc1c(C=O)c2c(c(C)c1NC(=O)CC(C)(C)C)[C@@H](c1ccc(C(C)C)cc1)CO2
Yield: 83 %

Procedure:
Using (+)-N-((3R)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 37, the title compound was synthesized in the same manner as in Example 20. Yield: 83%. Melting point: 179-180° C. (ethyl acetate-hexane). [α]D°=−25.80° (c=0.48, chloroform).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][OH:3].[OH-].[Na+].Cl[C:11]1[N:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13](OCC)=[O:14]>COCCOC>[OH:14][C:13]1[C:12]2[C:11](=[N:21][CH:20]=[CH:19][CH:18]=2)[O:3][C:2]=1[C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)CO
Reactant: CCOC(=O)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CCOC(=O)c1oc2ncccc2c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41 %

Procedure:
Ethyl glycolate (35.5 mL, 375 mmol) is slowly added (over 20 minutes) to a slurry of NaOH (15.8 g, 394 mmol) in 1,2-dimethoxyethane (400 mL) under N2 with the flask being in an ice bath. The mixture is allowed to warm to rt, is stirred for 30 min, and ethyl 2-chloronicotinate (27.84 g, 150 mmol) in 1,2-dimethoxyethane (50 mL) is added over 10 minutes. The reaction is warmed to 65° C. for 15 h in an oil bath. The mixture is concentrated to dryness, the residue is dissolved in H2O (500 mL), washed with hexane (500 mL), acidified to pH 3 with 5% HCl, and extracted with CHCl3 (4×400 mL). The combined organic layer is dried over MgSO4, filtered, and concentrated to a yellow solid. The solid is suspended in ether (200 mL) and heated on a steam bath until concentrated to a volume of 40 mL. The material is allowed to crystallize overnight, then filtered to afford ethyl 3-hydroxyfuro[2,3-b]pyridine-2-carboxylate (C40) as a pale orange solid (41% yield). Additional material is obtained by concentrating the filtrate. Recrystallization in ether a second time afforded (C40) as a pale yellow solid (7.3% yield). MS (EI) for C10H9NO4, m/z: 207 (M)+.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][O:18]C(=O)C1C=CC=CC=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[F:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[C:30]([CH3:35])[CH:29]=1.[OH-].[Na+]>O1CCOCC1.CO>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:32][C:31]1[CH:33]=[CH:34][C:28]([F:27])=[CH:29][C:30]=1[CH3:35])=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][OH:18])(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1cc(F)ccc1N
Reactant: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1Nc1c(C(=O)C(C)C)cnc2c(CO)cccc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 3-isobutyryl-4-chloro-8-(benzoyloxymethyl)quinoline (1.84 g, 5 mmol) and 4-fluoro-2-methylaniline (0.78 ml, 7 mmol) in dioxan (25 ml) was heated at reflux for 2 hours, then the solvent evaporated. A solution of sodium hydroxide (0.8 g, 20 mmol) in methanol (50 ml) was added and the mixture stirred at room temperature for 1.5 hours. The resulting precipitate was filtered off and recrystallised from methanol to give (0.48 g, 27%), m.p. 139°-140°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].Cl[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(OCC)(=O)C>C(Cl)Cl>[CH2:10]([O:9][C:7]([N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNCCO
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(CCO)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To N-methylethanolamine (149 mmol) in methylene chloride (100 ml) at 0° C. was added benzyl chloroformate (70 mmol). The mixture was stirred at 0° C. for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2M HCl, saturated NaHCO3 solution, and brine, then dried over Na2SO4 and evaporated to provide the desired compound. 1H NMR (CDCl3,TMS) δ 7.36 (m, 5H), 5.14 (s,2H), 3.78 (m, 2H), 3.47 (m, 2H), 3.01 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[C:23](Cl)(=[O:25])[CH3:24]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[C:23]([C:10]1[S:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)c1ccc(-c2ccsc2-c2ccc(F)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Titanium (IV) chloride (2.7 ml) was added dropwise to a stirred solution of 2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (5 g) and acetyl chloride (2.2 ml) in benzene (50 ml) at 5° to 10° C. The mixture was stirred at ambient temperature for 4 hours, poured into ice-water, and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was recrystallized from a mixture of ethanol and ethyl acetate to give pale brown crystals of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (3.7 g).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:16][C:17]1[C:18]([O:20][C:21](=O)[C:22]=1[CH3:23])=[O:19].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[F:14][C:12]([F:15])([F:13])[O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([N:1]3[C:18](=[O:19])[C:17]([CH3:16])=[C:22]([CH3:23])[C:21]3=[O:20])[S:3][C:4]=2[CH:10]=1
Reactant: CC1=C(C)C(=O)OC1=O
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CC1=C(C)C(=O)N(c2nc3ccc(OC(F)(F)F)cc3s2)C1=O
Yield: 74.6 %

Procedure:
A 100 ml flask was charged with 2-amino-6-trifluoromethoxybenzothiazole (7.03 g), 2,3-dimethylmaleic anhydride (4.16 g) and diphenyl ether (50 ml), and a Dean-Stark separator was attached to the flask. The reaction materials were refluxed for about 5 minutes. After allowing the reaction mixture to cool, it was poured into hexane (200 ml). The resulting crystals were collected by filtration and washed with a small amount of diethyl ether to give N-(6-trifluoromethoxy-2-benzothiazolyl)-dimethymaleimide (7.66 g). m.p. 196°-198° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[N:11]=[CH:12][C:13](=O)[NH:14][CH:15]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:13]1[CH:12]=[N:11][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:15][N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(F)c(-c2c[nH]c(=O)cn2)c1
Product: COc1ccc(F)c(-c2cnc(Cl)cn2)c1

Procedure:
A solution of 5-(2-fluoro-5-methoxyphenyl)-pyrazin-2-one in POCl3 was heated at 100° C. -110° C. in a sealed tube for 16 h. After evaporating the remaining POCl3 under reduced pressure, the brown residue was taken up in EtOAc and washed (3×) with saturated aqueous NaHCO3 solution. The EtOAc solution was then dried (NA2SO4) and concentrated under reduced pressure leaving a brown oil. The oil was filtered through a pad of silica gel (30% EtOAc/hexanes eluent) and the solvents were again evaporated under reduced pressure. The oil was taken up in CH2Cl2, heated for 5 min, with decolorizing charcoal and filtered through celite. Evaporation of the solvent afforded 2-chloro-5-(2-fluoro-5-methoxyphenyl)pyrazine as a light-brown oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:7]=1[F:14])=[O:4].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([NH:26][C:27]([NH:1][C@@H:2]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:3]([NH:5][C:6]1[C:7]([F:14])=[CH:8][C:9]([F:13])=[CH:10][C:11]=1[F:12])=[O:4])=[O:28])[CH2:23][CH2:24][CH3:25]
Reactant: N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F
Reactant: CCCCN=C=O
Product: CCCCNC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1c(F)cc(F)cc1F

Procedure:
Following the procedure of Example 58 only using the product of Example 50 and n-butylisocyanate, the title compound was obtained, mp 217°-218° C.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:18])[NH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:6][CH:7]=1.[C:19](O)(=[O:21])[CH3:20]>C(OC(=O)C)(=O)C>[C:19]([NH:1][C:2]1[C:3](=[O:18])[NH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH2:16][CH3:17])=[N:6][CH:7]=1)(=[O:21])[CH3:20]
Reactant: CCCOc1ccccc1-c1ncc(N)c(=O)[nH]1
Reactant: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCCOc1ccccc1-c1ncc(NC(C)=O)c(=O)[nH]1
Reaction time: 1 h

Procedure:
A solution of 5-amino-2-(2-propoxyphenyl)pyrimidin-4(3H)-one (0.90 g) and 10 drops of acetic anhydride in acetic acid (50 ml) was heated on a steam bath for 4 hours. A further 10 drops of acetic anhydride was added and heating was continued for one hour. Acetic acid was removed under reduced pressure and water was added to the residue which afforded a light brown solid, 0.87 g. This was recrystallised from isopropylacetate to give the title compound, 0.32 g, m.p. 195°-197° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@@H:10]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:30][OH:31].C(=O)([O-])O.[Na+]>>[OH:31]/[N:30]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@@H:10]([C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([OH:27])=[O:26])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: NO
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)ccn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@@H](c2ccc(CC(=O)O)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (S)-2-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)acetic acid and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a white foam, MS (ESI+): m/z=389.2 ([M+H]+).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][Si:24]([CH3:52])([CH3:51])[C:25]1[CH:26]=[C:27]([CH:44]=[C:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:46]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])=[CH:33][CH:32]=1)=O>C1(C)C=CC=CC=1>[CH3:23][Si:24]([CH3:52])([CH3:51])[C:25]1[CH:26]=[C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=2)=[S:10])[CH:44]=[C:45]([Si:47]([CH3:50])([CH3:49])[CH3:48])[CH:46]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)CCc1ccc(NC(=O)c2cc([Si](C)(C)C)cc([Si](C)(C)C)c2)cc1
Solvent: Cc1ccccc1
Product: C[Si](C)(C)c1cc(C(=S)Nc2ccc(CCC(=O)O)cc2)cc([Si](C)(C)C)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 131.8 %

Procedure:
Lawesson's reagent (90 mg) was added to a toluene (5 ml) solution of Compound 20a (140 mg). The obtained mixture was stirred at 100° C. in a nitrogen atmosphere for 1 hour. After the reaction was over, the reaction mixture was allowed to cool, and concentrated. The obtained residue was purified by column chromatography (5% ethyl acetate/n-hexane). Fractions containing the ester body of Compound 4 were collected, and concentrated to dryness. As a result, 126 mg of yellow solid was obtained. The obtained yellow solid (90 mg) was, without further purification, dissolved in ethanol (1 ml). A 1N sodium hydroxide aqueous solution (1 ml) was added thereto in a nitrogen atmosphere. The obtained mixture was stirred under heating at 45° C. for 1 hour. After the reaction was over, the mixture was allowed to cool, and a 1N hydrochloric acid aqueous solution was added thereto. The mixture was separated with ethyl acetate and water. The organic layer was washed once with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and as a result, Compound 20 (54 mg, 64%) was obtained as an opalescent solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[CH:15]=1.C(N(CC)CC)C>C(O)CCC>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([NH:20][C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[N:3]=1
Reactant: COc1cccc(N)c1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: COc1cccc(Nc2nc(N)nc3nc[nH]c23)c1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
To a suspension of 2-amino-6-chloropurine (1.69 g; 0.01 mol) and m-anisidine (1.23 g; 0.01 mol) in n-butanol (20 ml), triethylamine (3.5 ml; 0.025 mol) was added. The resulting thick suspension was stirred at 110° C. for 3 hours. The TLC showed the absence of the starting material and the presence of the desired product. The reaction mixture was then cooled to room temperature. The white precipitate was filtered off, rinsed with n-butanol (3×10 ml) and water (3×10 ml) and dried in the drying oven into constant weight. Yield: 2.19 g (85%). The crude product was purified as hydrochloride salt by crystallization from 2.5 M methanolic hydrogen chloride to give 2.17 g of almost white crystals (as hydrochloride). TLC (chloroform-methanol-NH4OH; 4:1:0.05): one single spot, free of starting material. HPLC purity: 99+%.