Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:8]1([N:7]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C1CCOCC1
Solvent: Nc1ccccc1
Product: c1ccc(N2CCCCC2)cc1
Yield: 98 %

Procedure:
Among the cyclic ethers suitable for the practice of this invention are those which contain only carbon and an oxygen atom in an unstrained ring (i.e., the ring contains at least four carbon atoms and an oxygen atom bonded to two separate carbon atoms of the ring). Examples of such cyclic ethers include tetrahydrofuran, 2-methyltetrahydrofuran, 3-methyltetrahydrofuran, tetrahydro-2-furancarbinol, 2-ethoxymethyl tetrahydrofuran, 2-butoxymethyl tetrahydrofuran, tetrahydrofuroic acid, methyl tetrahydrofuroate, tetrahydropyran, 2-methyltetrahydropyran, furan, dihydrofuran, pyran, dihydropyran, and the like. In the case of such cyclic ethers as tetrahydrofuran, tetrahydropyran and their suitably substituted congeners, reaction with primary aromatic amines such as aniline and nuclear alkylanilines (e.g., toluidines, xylidines, o-, m-, p-ethylaniline, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-diethylanilines, etc.) results in gem-dialkylation of the nitrogen atom with high conversions of the aromatic amine and very high product yields. For example, reaction between tetrahydrofuran and aniline at 250° C. using a TiO2 catalyst (LHSV of 0.2 per hour) gave a 98% conversion of aniline with a 97% yield of 1-phenylpyrrolidine. Similarly, tetrahydropyran and aniline when reacted at 300° C. over a TiO2 catalyst (LHSV of 0.2 per hour) resulted in a 74% aniline conversion with a 98% yield of 1-phenylpiperidine.
Reaction SMILES: Br[CH:2]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[N:22]1([C:28](=[S:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.C(Cl)Cl>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:29]=[C:28]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[S:30][C:2]=2[C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: NC(=S)N1CCCCC1
Reactant: CS(=O)(=O)c1ccc(C(Br)C(=O)c2ccc(F)cc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2sc(N3CCCCC3)nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 71.8 %

Procedure:
To a solution of 2-bromo-1-(4-fluorophenyl)-2-(4-methylsulfonylphenyl)ethanone (0.462 g, 1.24 mmol) (Example 26, Step 2) in ethanol (10 mL) in a 25 mL round bottom flask was added piperidine thiocarboxamide (0.198 g, 1.37 mmol) and the solution was heated to reflux for 14 hours. The reaction was cooled to room temperature and concentrated in vacuo yielding a foam. This foam was dissolved in methylene chloride and washed successively with NaHCO3 saturated solution (3 portions) and brine, dried over Na2SO4, filtered and reconcentrated in vacuo yielding 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-piperidinyl)-thiazole (0.371 g, 72%) as a yellow-green fluffy solid: mp 173°-175° C., 1H NMR (CDCl3) 400 mHz δ7.77 (d, J=8.56 Hz, 2H), 7.46 (dd, J=5.60, 8.80), 7.38 (d, J=8.56 Hz, 2H), 6.99 (t, J=8.80 Hz, 2H), 3.53 (s (broad), 4H), 3.05 (s, 3H), 1.70 (s (broad), 6H). MS (EI): m/z 417 (MH+). HRMS Δ=-1.5 mmu.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7](O)=[O:8])[C:5]=1[C:13]([OH:15])=O)([O-:3])=[O:2].P([O-])([O-])([O-])=O.[OH:21][NH3+:22].O[NH3+].O[NH3+]>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:6]2[C:7]([N:22]([OH:21])[C:13](=[O:15])[C:5]=12)=[O:8])([O-:3])=[O:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C(=O)O
Reactant: [NH3+]O
Agent: O=P([O-])([O-])[O-]
Product: O=C1c2cccc([N+](=O)[O-])c2C(=O)N1O

Procedure:
Analogous to Example 4, but from 500 mg (2.37 mmol) of 3-nitrophthalic acid and 187 mg (0.947 mmol) of hydroxylammonium phosphate at a bath temperature of 130° C. The yield was 443 mg (90%).
Reaction SMILES: C([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34]C=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)C.[CH2:40]([N:44]([CH3:49])[C:45](=O)[CH2:46]Cl)[CH2:41][CH2:42][CH3:43]>>[CH2:40]([N:44]([CH3:49])[CH2:45][CH2:46][O:10][C:8]1[CH:7]=[CH:6][C:36]([CH2:37][CH2:32][CH2:31][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=2[CH:14]2[CH2:23][CH2:22][C:21]3[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=3[CH2:15]2)=[CH:35][CH:34]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCCCN(C)C(=O)CCl
Product: CCCCN(C)CCOc1ccc(CCCNc2cc(OC)c(OC)cc2C2CCc3cc(O)ccc3C2)cc1
Yield: 16.4 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and N-butyl-2-chloro-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.6 mg) was obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][N:7]=1)[CH2:4][OH:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Br:12][C:9]1[CH:10]=[CH:11][C:6]([C@@H:3]2[CH2:4][O:5][C:14](=[O:16])[NH:2]2)=[N:7][CH:8]=1
Reactant: N[C@@H](CO)c1ccc(Br)cn1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: O=C1N[C@H](c2ccc(Br)cn2)CO1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 151.1 %

Procedure:
To a suspension of (R)-2-amino-2-(5-bromopyridin-2-yl)ethanol hydrogen chloride (4.97 g, 19.6 mmol) and TEA (9.02 mL, 64.7 mmol) in DCM (60 mL) at 0° C. was added a solution of triphosgene (2.91 g, 9.80 mmol) in DCM (20 mL) during 45 min. The resulting mixture was stirred at 0° C. for 15 min, then warmed to it and stirred for 1 h. The reaction was quenched with NH4Cl (15 mL) and stirred for 15 min. The aqueous layer was separated, basicified with Na2CO3, and extracted with DCM (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was purified by a SiO2 column (0-80% EtOAc/Hexanes, Rf=0.15 in 50% EtOAc) to afford the titled compound as an off-white solid (3.60 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][CH:9]([CH3:20])[C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[C:17]([OH:19])=O)=[O:11])=[O:7])=[CH:4][C:3]=1[Cl:23].[O:24]=[C:25]1[O:29][CH:28]([O:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=CC=2)[CH:27]([NH:39]C(C2CCCN2C(=O)C(NC(=O)C2C=CC(N)=C(Cl)C=2)C)=O)[CH2:26]1>>[CH:31]1([O:30][CH:28]2[CH:27]([NH:39][C:17]([CH:13]3[CH2:14][CH2:15][CH2:16][N:12]3[C:10](=[O:11])[CH:9]([NH:8][C:6](=[O:7])[C:5]3[CH:21]=[CH:22][C:2]([NH2:1])=[C:3]([Cl:23])[CH:4]=3)[CH3:20])=[O:19])[CH2:26][C:25](=[O:24])[O:29]2)[CH2:32][CH2:33][CH2:38][CH2:37][CH2:36]1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OCCc1ccccc1
Reactant: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)O
Product: CC(NC(=O)c1ccc(N)c(Cl)c1)C(=O)N1CCCC1C(=O)NC1CC(=O)OC1OC1CCCCC1
Yield: 47 %

Procedure:
Prepared from syn-(2-cyclohexyloxy-5-oxo-tetrahydro-furan-3-yl)-carbamic acid allyl ester and 97a following the method used for 98a to give the title compound (153 mg, 47% yield). 1H-NMR (500 MHz, CD3OD) δ 1.06-2.38 (m, 14H), 1.42 (d, 3H), 2.50-2.66 (m, 1H), 2.69-2.82 (dd, 1H), 3.06-3.75 (m, 2H), 3.80-3.94 (m, 1H), 4.40-4.52 (m, 1H), 4.57-4.65 (m, 1H), 4.70-4.80 (m, 1H), 5.72 (d, 1H), 6.71 (m, 1H), 7.50-7.63 (m, 1H), 7.78 (d, 0.6H), 8.42 (d, 0.4H). Analytical HPLC 10.30 min. LC-MS (ES+) m/e=521.2 (MH+).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.[Cl:8][CH2:9][CH2:10][N:11]=[C:12]=[O:13].C1(C)C=CC=CC=1>C1COCC1>[Cl:8][CH2:9][CH2:10][NH:11][C:12]([NH:1][CH:2]1[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1)=[O:13]
Reactant: NC1CCOCC1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C(NCCCl)NC1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A RB flask was charged with 4-aminotetrahydropyran (9.77 g, 97 mmol) in THF (480 mL) and was cooled in an ice bath. To this stirring solution was added 2-chloroethyl isocyanate (11.19 g, 106 mmol) drop-wise and the reaction was brought to RT and stirred at RT overnight. The reaction mixture was concentrated to dryness and the crude product was washed successively with saturated NH4Cl (60 mL) and saturated NaHCO3 (60 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to dryness to afford a white solid. Toluene (20 mL) was added and the residue was concentrated to dryness. The process was repeated a second time (to remove any moisture) to afford 1-(2-chloroethyl)-3-(tetrahydro-2H-pyran-4-yl)urea as a white solid. The product was utilized in the next reaction without purification. 1H NMR (CDCl3): δ 5.34-4.94 (bs, 1 H), 4.93-4.56 (bs, 1 H), 3.94 (dt, J=11.9, 3.2 Hz, 2 H), 3.84-3.71 (m, 1 H), 3.64-3.59 (m, 2 H), 3.49-3.47 (m, 2 H), 1.95-1.83 (m, 2 H), 1.50-1.34 (m, 2 H); MS (ESI) m/z: 207.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]([CH3:16])([CH3:15])[C:12]([OH:14])=O)[N:10]=2)[N:7]=1.Cl.[CH3:18][NH:19][CH3:20].C(N(CC)CC)C>CN(C)C=O>[CH3:18][N:19]([CH3:20])[C:12](=[O:14])[C:11]([C:9]1[N:10]=[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[N:7][N:6]2[CH:8]=1)([CH3:16])[CH3:15]
Reactant: CNC
Reactant: CC(C)(C(=O)O)c1cn2nc(Cl)ccc2n1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)C(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
0.959 g of 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionic acid was dissolved in 6 ml of N,N-dimethylformamide; 0.714 g of N,N′-carbonyldiimidazole was added, followed by stirring at room temperature for 60 minutes. To this mixture, 0.392 g of dimethylamine hydrochloride and 0.665 ml of triethylamine were added under ice cooling conditions, followed by stirring at room temperature for 3 hours. Saline was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol (95:5). The desired fraction was collected and concentrated; the crystal obtained was collected by filtration to yield 0.608 g of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]3)[C:10]2=[O:38])[O:6][CH:7]=1)[CH3:2].[ClH:39]>C(Cl)Cl.O1CCOCC1>[ClH:39].[CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][N:9]2[C:14]3[CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[S:17][C:13]=3[C:12](=[O:24])[N:11]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[C:10]2=[O:38])[O:6][CH:7]=1)[CH3:2]
Reactant: CCc1coc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCc1coc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
A solution of tert-butyl 4-{1-[(4-ethyl-1,3-oxazol-2-yl)methyl]-2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (780 mg; compound B5) in DCM (20 ml) is reacted with a solution of hydrogen chloride in 1,4-dioxane (3 ml, 4.0 M) according to the procedure described in example B28 to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:35])([F:34])[F:33])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[K+].[K+].[CH2:44]([S:46](Cl)(=[O:48])=[O:47])[CH3:45]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:14]([CH:16]3[CH2:21][CH2:20][N:19]([S:46]([CH2:44][CH3:45])(=[O:48])=[O:47])[CH2:18][CH2:17]3)=[O:15])[CH2:11][CH:10]2[N:22]([CH3:37])[C:23](=[O:36])[C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[C:26]([C:32]([F:33])([F:34])[F:35])[CH:25]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)c(Cl)c2)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCS(=O)(=O)N1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)c3ccc(OC)c(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a solution of N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide (50 mg, 0.90 mmol) in acetone (0.5 mL) was added potassium carbonate (finely milled) (19 mg, 0.13 mmol), ethanesulfonyl chloride (13 μL, 0.13 mmol) and acetone (0.5 mL). The suspension was stirred for 18 h at ambient temperature. It was diluted with ethyl acetatec (10 mL) and washed with an aqueous solution of Na2CO3 (1 M, 10 mL) and brine (10 mL). The aqueous layers were extracted with ethyl acetate (10 mL) and the combined organic layers were dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=30:70 to 0:100) afforded the title compound (44 mg, 76%) as an off-white foam. MS m/e: 650.2 [M]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:8][CH2:7][C:6](=[O:9])[NH:5][C:4]2[CH:10]=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:3]1=2.[C:18](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:18][N:5]1[C:6](=[O:9])[CH2:7][CH2:8][C:2]([CH3:17])([CH3:1])[C:3]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:4]1=2
Reactant: CC1(C)CCC(=O)Nc2ccc([N+](=O)[O-])cc21
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CN1C(=O)CCC(C)(C)c2cc([N+](=O)[O-])ccc21
Reaction time: 1 h

Procedure:
Combined 5,5-Dimethyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one (231 mg, 0.986 mmol), cesium carbonate (650 mg, 2 mmol), iodomethane (123 uL, 2 mmol) and DMF (6 mL). Stirred at room temp. for 1 hour. Evaporated off solvent, added water and extracted into methylene chloride. Dried organic layer over sodium sulfate, filtered and concentrated under reduced pressure to yield a yellow solid, 1,5,5-Trimethyl-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one. mp 115° C.; LCMS: m/z=249.07 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.32 (d, 1H, J=2.3 Hz), 8.19 (dd, 1H, J=8.7, 2.3 Hz), 7.34 (d, 1H, J=8.6 Hz), 3.37 (s, 3H), 2.34 (m, 2H), 2.14 (m, 2H), 1.43 (s, 6H).
Reaction SMILES: [CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(NC(C)C)(C)C.ClC(OC)=O.[NH2:33][C:34]1[CH:50]=[CH:49][C:37]([CH2:38][S:39]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(=[O:41])=[O:40])=[CH:36][CH:35]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:17][CH:18]2[CH2:20][CH2:19]2)[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([CH2:38][S:39]([CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])(=[O:41])=[O:40])=[CH:49][CH:50]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1cc(N(CC2CC2)C2CCCCC2)ncn1
Reactant: CCOC(=O)CCS(=O)(=O)Cc1ccc(N)cc1
Agent: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCS(=O)(=O)Cc1ccc(NC(=O)c2cc(N(CC3CC3)C3CCCCC3)ncn2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclohexyl(cyclopropylmethyl)amino)pyrimidine-4-carboxylic acid (Intermediate 13, 130 mg; 0.47 mmol) in DCM was treated with diisopropylamine (90 mL; 0.52 mmol) and methyl chloroformate (40 mL; 0.52 mmol). After stirring at 0° C. for 15 minutes, ethyl 3-(4-aminobenzylsulfonyl)propanoate (Intermediate 42, 130 mg; 0.48 mmol) was added. After stirring at 0° C. for 30 minutes and RT for 1 hour, saturated sodium bicarbonate solution was added and the mixture stirred for 15 minutes. DCM was added and the layers separated. The organic extract was filtered through a hydrophobic frit and the solvent removed in vacuo. The residue was purified by column chromatography (silica) eluting with petroleum ether containing increasing amounts of EtOAc to give the title compound as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.Cl[CH2:8][CH2:9][CH2:10][OH:11]>[OH-].[Na+]>[OH:11][CH2:10][CH2:9][CH2:8][N:3]1[C:2]([NH2:1])=[N:6][N:5]=[N:4]1
Reactant: Nc1nnn[nH]1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Product: Nc1nnnn1CCCO

Procedure:
5-Aminotetrazole (2.1 g.) and 3-chloropropanol (2.1 ml.) were added to aqueous sodium hydroxide (1 g. in 20 ml.) and the mixture heated at 90° for 18 hours. The resulting solution was evaporated and the residue extracted with hot EtOH. The EtOH extracts were evaporated and the residue extracted with EtOAc to give a colourless oil which was a mixture of isomers. These were separated on a column of silica gel using EtOAc/MeOH/aqueous ammonia (s.g. 0.880) 6:1:1 v/v/v as eluant to give 1-(3-hydroxypropyl-5-aminotetrazole as a white solid (0.2 g.) and 2-(3-hydroxypropyl-5-aminotetrazole as a gum (1.0 g.).
Reaction SMILES: C([NH:4][CH:5]([C:11]([O:13]CC)=[O:12])[C:6](OCC)=O)(=O)C.[O-]CC.[Na+].[Na].BrC[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[NH2:4][CH:5]([CH2:6][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:11]([OH:13])=[O:12]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Product: NC(CCCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
Diethyl acetamidomalonate (220 g) in 1 L of absolute ethanol was added to a stirred solution of sodium ethoxide in ethanol, prepared by dissolving sodium (24 g) in absolute ethanol (500 mL), under nitrogen. The reaction mixture was refluxed under nitrogen for 30 minutes and then 1-bromo-3-phenylpropane (200 g) was added. The reaction mixture was refluxed overnight, cooled to ambient temperature, the precipitate removed by filtration and the solvent removed in vacuo. Concentrated hydrochloric acid (800 mL) was added to the residue and the reaction mixture was refluxed for 14 hours. The cooled aqueous solution was washed with ether (2×200 mL). The residual ether in the aqueous phase was removed by nitrogen bubbling through the solution. The pH of the aqueous phase was adjusted to 7-8 by the addition of ammonium hydroxide. The title compound was collected by filtration, air dried and recrystallized from ethanol-water to afford 150 g (83%). m.p. 255°-257° C. MS (FAB) m/e 194 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1C=C[C:6]2[C:7](C)=[N:8][O:9][C:5]=2[C:4]=1[CH:13]=[O:14].[CH3:15][O-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([CH:13]=[O:14])=[C:5]([O:9][CH3:15])[CH:6]=[CH:7][N:8]=1
Reactant: C[O-]
Reactant: COc1ccc2c(C)noc2c1C=O
Agent: [Na+]
Solvent: CO
Product: COc1ccnc(OC)c1C=O

Procedure:
Reaction of the commercially available 2-chloro-4-methoxy-pyridine-3-carbaldehyde (23) with NaOMe in MeOH affords 2,4-dimethoxy-pyridine-3-carbaldehyde (24).
Reaction SMILES: [CH2:1]([NH:19][CH:20]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:31](Cl)(=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>>[CH:20]1([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:31](=[O:49])[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[O:28][C@H:27]([CH2:29][OH:30])[C@@H:25]([OH:26])[C@H:23]([OH:24])[C@H:21]1[OH:22]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCNC1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Product: CCCCCCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCCCCCCCC)C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O

Procedure:
Preparation in analogy to Example 6 from N-octadecylglucopyranosylamine and stearoyl chloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=O)[CH:5]=[CH:4][C:3]1=2.[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH2:28]>ClCCl>[OH:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][NH:28][C:17](=[O:19])[CH2:16][CH2:15][C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:1])([CH3:21])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]=2[CH:7]=1)=[O:20]
Reactant: NCCOCCO
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)O)ccc21
Solvent: ClCCl
Product: CC1(C)CCC(C)(C)c2cc(C(=O)CCC(=O)NCCOCCO)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.6 %

Procedure:
A suspension of 2.88 g (10 mmoles) of 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-oxo butyric acid, described in Example III, and 1.95 g (12 mmoles) of N,N'-carbonyl diimidazole in 50 cm3 of anhydrous dichloromethane is stirred for 2 hours at ambient temperature. The resulting solution is cooled to a temperature between +5° and +10° C. and 1.26 g (12 mmoles) of N-2-hydroxyethoxyethylamine are added. Stirring is continued for 3 hours while permitting the reaction mixture to return to ambient temperature. The reaction mixture is transferred to a separatory funnel and diluted to 100 cm3. After washing with 0.1N HCl and then with water, the dichloromethane phase is dried on sodium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica 60 gel in a 40/25/25/10 dichloromethane/toluene/ethyl acetate/isopropanol eluant mixture. After evaporation and drying, there are obtained 2.5 g of N-(2-hydroxyethoxyethyl) 4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-oxo butyramide in the form of a thick colorless oil kept out of contact with light.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][CH2:8][CH2:9][CH2:10]Br.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1>CC(C)=O>[Br:7][CH2:8][CH2:9][CH2:10][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: BrCCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=Cc1ccc(OCCCBr)cc1
Yield: 61 %

Procedure:
K2CO3 (1.82 g, 13 mmol) and 1,3-dibromopropane (3.05 mL, 30 mmol) were added to a solution of 4-hydroxy-benzaldehyde (1.22 g, 10 mmol) in acetone (30 mL). The mixture was heated under reflux for 8.5 hrs. Then the reaction mixture was filtered and the solvent was removed by evaporation. The resulting residue was mixed with ether and then washed consecutively with 5% NaOH, water, and brine. After drying with MgSO4 and evaporation of the solvent, flash column chromatography (silica gel, hexane 100%>EtOAc:hexane=10:90>20:80) gave the desired compound as a pale yellow oil: Rf=0.71 (silica gel, EtOAc:hexane=35:65); yield 61%; 1H-NMR (300 MHz, CDCl3) δ9.86 (1H, s), 7.82-7.79 (2H, dd, J=6.9 and 1.8 Hz), 7.00-6.97 (2H, dd, J=7.1 and 1.6 Hz), 4.19-4.15 (2H, t, J=5.8 Hz), 3.61-3.56 (2H, t, 6.4 Hz), 2.37-2.28 (2H, qui, 6 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[C:15]([N+:17]([O-])=O)[C:14]([F:20])=[CH:13][C:5]=1[O:6][CH2:7][C:8](OCC)=[O:9])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[F:20][C:14]1[C:15]([NH2:17])=[CH:16][C:4]2[NH:1][C:8](=[O:9])[CH2:7][O:6][C:5]=2[CH:13]=1
Reactant: CCOC(=O)COc1cc(F)c([N+](=O)[O-])cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc2c(cc1F)OCC(=O)N2
Yield: 82.8 %

Procedure:
A suspension of ethyl 2,4-dinitro-5-fluorophenoxyacetate (1.3 g) and 5% palladium-carbon (0.35 g) in ethanol (30 ml) was subjected to catalytic reduction at room temperature under an ordinary pressure until 600 ml of hydrogen was absorbed. The reaction mixture was filtered, and the filtrate was concentrated to give 7-fluoro-6-amino-2H-1,4-benzoxazin-3(4H)-one (0.68 g; yield, 82.8%).