Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:5]=[C:4]([N:17]2[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]2[CH2:24][OH:25])[N:3]=1.Cl.[CH:27]12[O:34][CH:31]([CH2:32][CH2:33]1)[CH2:30][NH:29][CH2:28]2.C(N(CC)CC)C>C(O)C>[CH:31]12[O:34][CH:27]([CH2:33][CH2:32]1)[CH2:28][N:29]([C:2]1[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)[N:5]=[C:4]([N:17]3[C@@H:21]([CH2:22][OH:23])[CH2:20][CH2:19][C@H:18]3[CH2:24][OH:25])[N:3]=1)[CH2:30]2
Reactant: O=[N+]([O-])c1ccc(-c2nc(Cl)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1
Reactant: C1CC2CNCC1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=[N+]([O-])c1ccc(-c2nc(N3CC4CCC(C3)O4)nc(N3[C@H](CO)CC[C@@H]3CO)n2)cc1

Procedure:
A suspension of ((2S,5R)-1-(4-chloro-6-(4-nitrophenyl)-1,3,5-triazin-2-yl)pyrrolidine-2,5-diyl)dimethanol (1.3 g, 2.7 mmol), 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.51 g, 3.4 mmol) in ethanol (15 mL) was treated with triethylamine (1.35 mL, 10 mmol) and heated with a heat gun briefly to reflux. The reaction mixture was purified by automated flash chromatography (methanol/chloroform) to provide the title compound as a hard peach colored foam. MS (ES+)=443.2 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]([CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:11])=[N+]=[N-].CCOC(C)=O.O>C1COCC1>[NH2:7][CH:10]([C:12]1[S:13][C:14]([CH3:17])=[CH:15][CH:16]=1)[CH3:11]
Reactant: Cc1ccc(C(C)N=[N+]=[N-])s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(C(C)N)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
Add lithium aluminum hydride (29 mg, 0.72 mmol) to a solution of (±)-2-(1-azidoethyl)-5-methylthiophene (100 mg, 0.59 mmol) in anhydrous THF (5 mL). Stir at room temperature overnight. Work-up the mixture with EtOAc and water. Filter the mixture over Celite®. Separate and wash the organic phase with brine. Dry over Na2SO4, filter and concentrate in vacuo. Purify by SCX chromatography. Rinse with DCM/methanol (1:1), load the crude mixture in methanol and elute sequentially with methanol and 1N ammonia in methanol to obtain the title compound as an oil (80 mg, 95%). GC-MS m/z 141 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])(=[O:26])=[O:25]
Reactant: CCCCCCCC(=O)NCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NCCCCOS(C)(=O)=O
Yield: 105.7 %

Procedure:
To a solution of 2.00 g (8.22 mmol) of N-(4-hydroxybutyl)caprylamide and 1.37 ml (9.86 mmol) of triethylamine in 50 ml of methylene chloride was added 0.76 ml (9.86 mmol) of methanesulfonyl chloride under ice-cooling with stirring. The mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 2.55 g of the desired compound (96.5% colorless powder), mp: 59.0°-60.0° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[NH2:36][C:37]1[C:38]([CH3:47])=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([NH:42][CH3:43])=[O:41]>C(O)(C)C>[CH3:43][NH:42][C:40](=[O:41])[C:39]1[CH:44]=[CH:45][CH:46]=[C:37]([NH:36][C:2]2[N:7]=[C:6]([N:8]3[CH2:13][CH2:12][CH:11]([O:14][CH2:15][C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=4)[CH2:10][CH2:9]3)[N:5]=[CH:4][N:3]=2)[C:38]=1[CH3:47]
Reactant: CNC(=O)c1cccc(N)c1C
Reactant: FC(F)(F)Oc1ccc(COC2CCN(c3ncnc(Cl)n3)CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Nc2ncnc(N3CCC(OCc4ccc(OC(F)(F)F)cc4)CC3)n2)c1C
Temperature: 80 °C
Reaction time: 24 h
Yield: 15.1 %

Procedure:
To a solution of 2-chloro-4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazine (500 mg, 1.28 mmol) in isopropanol (4 mL, 3 mL/mmol) was added DIPEA (0.4 mL, 1.92 mmol) and 3-amino-N,2-dimethylbenzamide (211 mg, 1.29 mmol) and the reaction was stirred at 80° C. for 24 h. The reaction mixture was concentrated under reduced pressure and extracted with EtOAc (2×30 ml). The organic extracts were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel column chromatography provided N,2-dimethyl-3-((4-(4-((4-(trifluoromethoxy)benzyl)oxy)piperidin-1-yl)-1,3,5-triazin-2-yl)amino)benzamide (100 mg, 16%) as a solid. Observed mass (M+1): 517.1.
Reaction SMILES: [SH:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([OH:11])[N:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl.CCCCCC>C(O)C.[OH-].[Na+].O>[CH2:12]([S:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([OH:11])[N:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: Oc1nc(S)nc2nc[nH]c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCCCCC
Product: Oc1nc(SCc2ccccc2)nc2nc[nH]c12
Yield: 42.9 %

Procedure:
2.00 g (11.9 mmol) of 2-mercapto-6-hydroxypurine was dissolved in a solvent mixture of 10 ml of ethanol, 10.9 ml of 2N sodium hydroxide and 15 ml of water. Under ice cooling with stirring, 2.06 ml (17.9 mmol) of benzylbromide was added to the solution, following stirring at room temperature for 30 minutes. Again under ice cooling, the mixture was neutralized with 2N hydrochloric acid and 30 ml of n-hexane was added to the mixture. A precipitated was collected by filtration, washed with ethyl acetate and dried to afford 1.32 g (yield, 45%) of 2-benzylthio-6-hydroxypurine as a crude product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:24][CH2:25][CH3:26])(=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[CH2:25]([O:24][C:16]([CH:17]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:23])[CH3:26]
Reactant: BrCCCCCCOCc1ccccc1
Reactant: CCOC(=O)CC(=O)OCC
Product: CCOC(=O)C(CCCCCCOCc1ccccc1)C(=O)OCC
Yield: 60 %

Procedure:
Ethyl 2-ethoxycarbonyl-8-benzyloxyoctanoate was prepared from 6-benzyloxyhexyl bromide (3.52 g, 13 mmol) and diethyl malonate (2.29 g, 14 mmol) according to the general procedure given above. Yield 60%, bp 152°-158° C./0.15 torr. 1H-NMR: 1.24 (t, 6H), 1.2-1.9 (m, 10H), 3.43 (t, 2H), 4.18 (q, 4H), 4.45 (s, 2H), 7.27 (m, 5H).
Reaction SMILES: [NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-])=O)=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1.[H][H]>C(OC)(=O)C.O1CCCC1.[Ni]>[NH2:1]/[C:2](/[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19])=[C:3]1\[C:4](=[O:12])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[S:7]\1
Reactant: [H][H]
Reactant: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1[N+](=O)[O-]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: COC(C)=O
Product: N/C(=C1/Sc2ccccc2C1=O)c1ccccc1N

Procedure:
0.5 gm (0.00168 mol) of (E)-2-[(amino)-(2-nitrophenyl)methylene]-benzo[b]thiophen-3(2H)-one was dissolved in a mixture of 10 cc of methyl acetate and 10 cc of tetrahydrofuran, and after adding 0.5 gm of Raney nickel the mixture was hydrogenated at room temperature and a hydrogen pressure of 5 bar until hydrogen uptake was at an end. The catalyst was then filtered off, the solvent was evaporated at reduced pressure, and the residue was recrystallized twice in the presence of activated charcoal from tetrahydrofuran/petroleum ether (1:1). 330 mgm (73% of theory) of yellow crystals were obtained, m.p. 186°-187° C. (petroleum ether/tetrahydrofuran 1:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:15])[CH3:14])=[C:2]2[NH:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([OH:23])[CH2:19][CH2:18]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Product: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](O)CC1

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (480 mg, 2.0 mmol) was reacted with trans-4-aminocyclohexanol (287 mg, 2.5 mmol) to afford the desired product (500 mg, 78%) as an orange-red solid: 1H NMR (500 MHz, CDCl3) δ 10.90 (s, 1H), 8.95 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 5.10 (tdt, J=11.2, 8.0, 3.9 Hz, 1H), 3.76 (tt, J=10.0, 4.3 Hz, 1H), 2.68 (s, 3H), 2.33-2.24 (m, 2H), 2.13-2.04 (m, 2H), 1.63-1.41 (m, 8H); ESI MS m/z 320 [M+H]+
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[NH:6][C:5]1=[O:20].[CH2:22]([C:35]([OH:37])=[O:36])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33]>C(OCC)(=O)C>[OH:1][CH:2]([CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([CH3:17])[C:11]([CH3:19])([CH3:18])[CH2:10]2)[NH:6][C:5]1=[O:20])[CH2:21][O:33][C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:35]([O:37][CH2:21][CH:2]([OH:1])[CH2:3][N:4]1[C:8](=[O:9])[C:7]2([CH2:10][C:11]([CH3:18])([CH3:19])[N:12]([CH3:17])[C:13]([CH3:16])([CH3:15])[CH2:14]2)[NH:6][C:5]1=[O:20])=[O:36])=[O:34]
Reactant: O=C(O)CCCCCCCCCCC(=O)O
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC1CO1)C2=O
Solvent: CCOC(C)=O
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COC(=O)CCCCCCCCCCC(=O)OCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O
Temperature: 180 °C

Procedure:
A mixture of 4.4 g of 3-(2,3-epoxypropyl)-7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 1.6 g of 1,10-decanedicarboxylic acid was heated at 180° C. for 3 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, treated with an aqueous alkaline solution and purified by column chromatography through silica gel eluted first with ethyl acetate, then with a 2:1 by volume mixture of ethyl acetate and methanol. The desired compound was obtained in the form of a white powder, melting point 53°-57° C.
Reaction SMILES: [NH2:1][CH2:2]CCOC1C2C([Cl:16])=CC=CC=2OC(=O)C=1.C(OC(=O)N[CH2:25][CH2:26][CH:27]([O:29][C:30]1[C:35]2[C:36]([Cl:40])=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32](=[O:41])[CH:31]=1)C)(C)(C)C>>[ClH:16].[NH2:1][CH2:2][CH2:25][CH2:26][CH2:27][O:29][C:30]1[C:35]2[C:36]([Cl:40])=[CH:37][CH:38]=[CH:39][C:34]=2[O:33][C:32](=[O:41])[CH:31]=1
Reactant: NCCCOc1cc(=O)oc2cccc(Cl)c12
Reactant: CC(CCNC(=O)OC(C)(C)C)Oc1cc(=O)oc2cccc(Cl)c12
Product: Cl
Product: NCCCCOc1cc(=O)oc2cccc(Cl)c12

Procedure:
Is prepared using the procedure for 4-(3-amino-propoxy)-5-chloro-1-benzopyran-2-one from [3-(5-chloro-2-oxo-2H-1-benzopyran-4-yloxy)-butyl]-carbamic acid tert-butyl ester to afford the title compound as the hydrochloric acid salt. 1H NMR (DMSO-d6, 300 MHz) δ 7.86 (3H, br s), 7.61 (1H, t, J=8.25 Hz), 7.42 (2H, t, J=9.5, 8.75 Hz), 5.96 (1H, s), 4.23 (2H, t, J=5.75 Hz), 2.85 (2H, m), 1.83 (4H, m); MS (ESI, Pos.) calcd for C13H14ClNO3 m/z [M+H]=268.1, found 268.1.
Reaction SMILES: C(N(CC)C[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:28][CH3:29])[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])C.FC1C=CC=CC=1S(CC1C(C(OC)=O)=C(OC)C(C2C=COC=2)=CC=1)(=O)=O.[CH2:65]([N:67](CC)[CH2:68][CH2:69]N)[CH3:66]>>[CH2:65]([N:67]([CH2:68][CH3:69])[CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[S:14]([CH2:17][C:18]1[C:23]([C:24]([O:26][CH3:27])=[O:25])=[C:22]([O:28][CH3:29])[C:21]([C:30]2[CH:34]=[CH:33][O:32][CH:31]=2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:66]
Reactant: CCN(CC)CCN
Reactant: CCN(CC)CCCNc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC
Agent: COC(=O)c1c(CS(=O)(=O)c2ccccc2F)ccc(-c2ccoc2)c1OC
Product: CCN(CC)CCNc1ccccc1S(=O)(=O)Cc1ccc(-c2ccoc2)c(OC)c1C(=O)OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 192, starting from methyl 6-(2-fluorobenzenesulphonylmethyl)-3-(furan-3-yl)-2-methoxybenzoate (Intermediate 96) and N,N,-diethylethylenediamine, as brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH3:19])[C:11]([O:17][CH3:18])=[C:12]([CH:16]=2)[C:13]([OH:15])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(C(Cl)=O)=O.[NH2:26][C:27]1[C:28]([CH3:35])=[C:29]([OH:34])[CH:30]=[CH:31][C:32]=1[F:33].C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1.O>[F:33][C:32]1[C:27]([NH:26][C:13](=[O:15])[C:12]2[CH:16]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)[CH:9]=[C:10]([CH3:19])[C:11]=2[O:17][CH3:18])=[C:28]([CH3:35])[C:29]([OH:34])=[CH:30][CH:31]=1
Reactant: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)O
Reactant: Cc1c(O)ccc(F)c1N
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COc1c(C)cc(-c2cccc(F)c2)cc1C(=O)Nc1c(F)ccc(O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.5 %

Procedure:
To a solution of 5-(3-fluorophenyl)-2-methoxy-3-methyl-benzoic acid (intermediate III(k)) (500 mg, 1.92 mmol, 1.1 eq) in CH2Cl2 (10 mL) was added (COCl)2 (731.6 mg, 5.76 mmol, 3.3 eq) at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The resulting mixture was concentrated under reduced pressure and the residue that remained dissolved in THF (6 mL) and added to a mixture of 3-amino-4-fluoro-2-methylphenol (intermediate X(e)) (246.5 mg, 1.75 mmol, 1.0 eq) and NaHCO3 (733.5 mg, 8.73 mmol, 5.0 eq) in THF (8 mL). After the addition, the reaction mixture was stirred for a further 2 h. Water was added and the aqueous layer extracted with EtOAc. The organic extract was washed with 5% Na2CO3, dried (Na2SO4), filtered and evaporated in vacuo. The residue obtained was purified by column chromatography (petroleum ether: EtOAc, 10:1 to 5:1 then CH2Cl2:MeOH, 20:1) to give the title compound as a white solid (540 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Cl:12]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>ClCCl>[CH3:7][O:6][C:4]([C:3]1[C:2]([CH2:1][Cl:12])=[N:11][CH:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: COC(=O)c1cccnc1C
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Solvent: ClCCl
Product: COC(=O)c1cccnc1CCl
Yield: 45.7 %

Procedure:
A solution of methyl 2-methylnicotinate (20.0 g, 0.132 mol) and trichloroisocyanuric acid (46.0 g, 0.198 mol) in dichloromethane (100 mL) was stirred at room temperature overnight. The reaction mixture was then washed with saturated aqueous sodium carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and the solvent evaporated in vacuo to provide the title compound as a yellow liquid (11.2 g), which is used as such in the next step.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=1.O>CO.[OH-].[K+]>[O:12]([C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=1[O:10][CH3:11])[C:3]([OH:19])=[O:2])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc(OC)c(Oc2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C(=O)O)cc1Oc1ccccc1
Reaction time: 2 h
Yield: 92.5 %

Procedure:
3-Phenoxy-4-methoxybenzoic acid methyl ester (0.8 g, 3.1 mmol) was stirred in a mixture of methanol (8 mL) and 4N potassium hydroxide (10 mL) and heated to reflux. After 2 hours, the mixture was stirred into water (60 mL) and extracted with ether (25 mL). The aqueous solution was stirred and acidified with 4N HCl, and the resulting precipitate was filtered off, rinsed with water, and dried to afford the product (0.7 g); m.p. 186-187° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:17]([O-:20])([O-:19])=O.[K+].[K+].Br[CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27]>O.C(#N)C>[C:4]([OH:27])(=[O:8])/[CH:5]=[CH:15]/[C:17]([OH:20])=[O:19].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][C:25]([CH3:29])([CH3:28])[CH2:26][OH:27])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: CC(C)(CO)CBr
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(CO)CN1CCC(c2noc3cc(F)ccc23)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (3.0 g, 13.6 mmol), K2CO3 (12.5 g, 17.5 mmol), 3-bromo-2,2-dimethyl-1-propanol (3 g, 21 mmol, 1.5 eq.) tetra-butylammonium hydrogen sulfate (1 g, phase transfer catalyst) in water (5 ml) and acetonitrile (150 ml) was heated at reflux for 43 days. TLC showed a small spot for the expected product. The mixture was diluted with EtOAc (400 ml) and washed with brine. The organic solution was dried and concentrated to a dark brown mixture. The crude mixture was purified carefully by flash chromatography (SiO2, 95 g to afford the dried pure product; 260 mg, (6%) as an oil. This oil was converted to the fumarate salt by treatment with fumaric acid (98.5 mg, 1.0 eq.) in ethanol. Recrystallization from ethanol:ether yielded 210 mg of white crystals, m.p.=144°-145° C.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=1)[CH2:2][CH3:3].[N+:20]([C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27])([O-:22])=[O:21].Cl.[OH-].[Na+]>O1CCCC1.N1C=CC=CC=1.O>[O:10]=[C:8]1[N:7]([C:11]2[C:16]([Cl:17])=[CH:15][C:14]([Cl:18])=[CH:13][C:12]=2[Cl:19])[N:6]=[C:5]([N:4]([CH2:1][CH2:2][CH3:3])[C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[C:23]([N+:20]([O-:22])=[O:21])[CH:24]=2)[CH2:9]1
Reactant: CCCNC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCN(C(=O)c1cccc([N+](=O)[O-])c1)C1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1
Reaction time: 19 h

Procedure:
4,5-Dihydro-3-propylamino-5-oxo-1-(2,4,6-trichloro-phenyl)-1H-pyrazole (21.9 g, 68.3 mmol) was dissolved in a mixture of tetrahydrofuran (170 ml) and pyridine (34 ml) and the solution was cooled in an ice-bath. m-Nitrobenzoyl chloride (25.35 g, 136.7 mmol) was dissolved in tetrahydrofuran (40 ml) and the solution was added dropwise to the stirred, cooled mixture. Stirring was continued at room temperature for 19 hrs. A further quantity of m-nitrobenzoyl chloride (10%) was added and the mixture was stirred for 2 hrs to complete the reaction. The mixture was poured into dilute hydrochloric acid (31) and the oily solid was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4). The solvent was removed by evaporation and replaced with ethanol (300 ml). A solution of sodium hydroxide (13.7 g, 324 mmol) in water (40 ml) was added dropwise and the mixture was stirred for 1 hr. The mixture was poured into dilute hydrochloric acid (21) and the resulting oil was extracted with ethyl acetate. The extract was washed with water and dried (MgSO4). The solvent was evaporated under reduced pressure to give a resin, 33.0 g, ca 100%. This was used in the next stage without purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([NH2:11])=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[O:14][CH3:15])[CH3:2].[C:17](OCC)(=[O:19])C.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([N:11]=[C:17]=[O:19])=[CH:6][C:5]=1[NH:12][C:13](=[O:16])[O:14][CH3:15])[CH3:2]
Reactant: CCOc1c(Cl)cc(N)cc1NC(=O)OC
Reactant: CCOC(C)=O
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CCOc1c(Cl)cc(N=C=O)cc1NC(=O)OC
Temperature: 25 °C

Procedure:
Methyl N-(2-ethoxy-3-chloro-5-aminophenyl)carbamate (2.67 g) in toluene (20 ml) was dropwise added to an ethyl acetate solution containing 10 g of phosgene at 10° to 20° C. The resultant mixture was gradually heated and, after being refluxed for 30 minutes, cooled to room temperature. The solvent was removed by distillation under reduced pressure to give methyl N-(2-ethoxy-3-chloro-5-isocyanatophenyl)carbamate. The thus obtained crude substance was added to a toluene solution (50 ml) containing triethylamine (1.0 g) and 3-buten-2-ol (0.79 g). The resultant mixture was allowed to stand at room temperature for 12 hours, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography using a mixture of toluene and ethyl acetate as the eluent to give 1-methyl-2-propenyl N-(3-chloro-4-ethoxy-5-methoxycarbonylaminophenyl)carbamate (Compound No. 3) (3.57 g) in a yield of 95.6 %. nD25.0 1.5383.
Reaction SMILES: [N:1]#[N:2].O.Cl.Cl.C[O:7][C:8](=[O:34])[C@H:9]([CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])[NH:10][S:11]([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:22])[CH3:21])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[CH2:35]([NH2:37])[CH3:36]>O1CCCC1>[N:1]#[N:2].[OH2:7].[S:11]([NH:10][C@H:9]([C:8]([NH:37][CH2:35][CH3:36])=[O:34])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:33])[NH2:32])([C:14]1[C:26]2[CH:25]=[CH:24][CH:23]=[C:19]([N:20]([CH3:21])[CH3:22])[C:18]=2[CH:17]=[CH:16][CH:15]=1)(=[O:12])=[O:13]
Reactant: COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reactant: CCN
Agent: Cl
Agent: N#N
Solvent: C1CCOC1
Solvent: O
Product: CCNC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Reaction time: 72 h
Yield: 93 %

Procedure:
To a suspension of 1.0 gram of N2 -dansyl-L-arginine methyl ester dihydrochloride monohydrate in 1 ml of tetrahydrofuran was added 3 ml of ethylamine with cooling. The mixture was allowed to stand in a sealed tube at room temperature for 3 days. After the excess amine was removed by evaporation, the residue was poured into 50 ml of water to give a precipitate. Recrystallization from 50% aqueous methanol afforded N2 -dansyl-N-ethyl-L-argininamide monohydrate in 93% yield; mp. 220°-222°C.
Reaction SMILES: ClC1N=C(NC2C=CC3OCCOC=3C=2)C(F)=CN=1.[Cl:20][C:21]1[N:26]=[C:25](Cl)[C:24]([F:28])=[CH:23][N:22]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]2[O:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=2[N:39]=1>>[Cl:20][C:21]1[N:26]=[C:25]([NH:29][C:30]2[CH:31]=[CH:32][C:33]3[O:34][CH2:35][C:36](=[O:40])[NH:37][C:38]=3[N:39]=2)[C:24]([F:28])=[CH:23][N:22]=1
Reactant: Nc1ccc2c(n1)NC(=O)CO2
Reactant: Fc1cnc(Cl)nc1Cl
Agent: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: O=C1COc2ccc(Nc3nc(Cl)ncc3F)nc2N1

Procedure:
In a manner similar to the preparation of 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine, 2,4-dichloro-5-fluoropyrimidine and 6-amino-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one were reacted to yield 2-chloro-5-fluoro-N4-[2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one-6-yl]-4-pyrimidineamine. 1H NMR (DMSO-d6): δ 4.63 (s, 2H), 7.34 (d, J=8.7 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 8.33 (d, J=3.3 Hz, 1H), 10.14 (s, 1H, NH), 11.19 (s, 1H, NH); 19F NMR (282 MHz, DMSO-d6): δ −152.35; LCMS: ret. time: 26.74 min.; purity: 85.90%; MS (m/e): 296.13 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1.[C:20]1(C)C(S(O)(=O)=O)=CC=C[CH:25]=1>C(O)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][CH2:20][CH3:25])[CH2:12][CH2:11][N:10]([CH2:15][CH2:16][CH:17]=[CH2:18])[C:9]2=[O:19])=[N:5][N:4]=1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: C=CCCN1CCC(O)N(c2nnc(OC)s2)C1=O
Solvent: CCO
Product: C=CCCN1CCC(OCC)N(c2nnc(OC)s2)C1=O

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6-hydroxy-2(1H)-pyrimidinone (7 grams), ethyl alcohol (50 ml) and toluenesulfonic acid (0.2 grams) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermomater and reflux condenser. The reaction mixture is then heated at reflux for a period of about 24 hours. After this time the mixture is stripped of unreacted alcohol under reduced pressure to yield a solid product. This product is then recrystallized to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-but-3-enyl-6 -ethoxy-2(1H)-pyrimidinone.