Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:16][CH3:17])[CH:8]=1)=O.Cl.[OH:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[NH:29])=[CH:23][CH:22]=1.[OH-].[Na+]>CCO.CO>[CH2:16]([N:9]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:15]2[C:7]([C:5]2[CH:4]=[CH:3][N:30]=[C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([OH:20])=[CH:22][CH:23]=3)[N:29]=2)=[CH:8]1)[CH3:17]
Reactant: N=C(N)Nc1ccc(O)cc1
Reactant: CCn1cc(C(=O)/C=C/N(C)C)c2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CCn1cc(-c2ccnc(Nc3ccc(O)cc3)n2)c2cccnc21

Procedure:
A mixture of (E)-3-(dimethylamino)-1-(1-ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)prop-2-en-1-one (5 mmol) in 3 mL EtOH/MeOH (1:2, v/v) was treated with 1-(4-hydroxyphenyl)guanidine hydrochloride (5 mmol) and NaOH (10 mmol). The reaction mixture was microwaved at 150° C. for 25 minutes. The residue was purified by chromatography using EtOAc to elute the titled compound. Recrystallisation from EtOAc yielded white solid. 1H-NMR (DMSO-d6) δ: 1.45 (t, 3H, J=7.2 Hz, CH3), 4.37 (q, 2H, J=7.6 Hz, CH2), 6.74 (d, 2H, J=8.8 Hz, Ph-H), 7.15 (d, 1H, J=5.2 Hz, Pyrimidin-H), 7.20 (q, 1H, J=4.8 Hz, Ar—H), 7.51 (d, 2H, J=8.8 Hz, Ph-H), 8.29 (d, 1H, J=5.2 Hz, Pyrimidin-H), 8.35 (m, 1H, Ar—H), 8.54 (s, 1H, Ar—H), 8.88 (d, 1H, J=6.8 Hz, OH), 9.04 (s, 1H, Ar—H), 9.10 (s, 1H, NH). MS (ESI+) m/z 322.1469 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cccnc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: c1cncc(OC2CCNC2)c1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 30.4 %

Procedure:
To 1.3 gm of 3-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-pyridine was added 10 mL of solution containing 5 mL of TFA and 5 mL of CH2Cl2 at ice-bath temperature. The reaction solution was slowly warmed to room temperature and allowed to stir 50 min at room temperature. After 50 min, solvents were removed in vacuo and the crude product was purified by flash chromatography (9:1:0.05, CHCl3:MeOH:conc. NH4OH) to obtain 120 mg (30.4% yield in two steps) of a clear oil: 1H NMR (300 MHz, CD3OD) δ8.21 (1H, d, J=2.6 Hz), 8.11 (1H, d, J=4.7 Hz), 7.38 (2H, m), 5.00 (1H, m), 3.13-2.88 (4H, m), 2.20-1.95 (2H, m); Mass spectrum (ESI) m/z 165.6 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][CH:21]=1)[NH:15][C:16](=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[C:16]([NH:15][C:14]1[CH:13]=[C:12]([NH:11][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Nc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cccc(Nc2ncccc2[N+](=O)[O-])c1
Yield: 55.9 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (6.12 g), 3′-aminoacetanilide (5.80 g) and potassium carbonate (5.34 g) in toluene (50 ml) was refluxed for 5 hours. The mixture was cooled, and the solids were collected and washed with water, ethanol and isopropyl ether successively to give 2-(3-acetamidophenyl)amino-3-nitropyridine (5.88 g) as an orange solid.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8](=[O:11])[CH:9]=[CH2:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:20]>CN(C=O)C>[CH:1]1([CH2:6][C@H:7]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:8]([C@H:9]2[CH2:10][O:20]2)=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O
Reactant: C=CC(=O)[C@H](CC1CCCC1)NC(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCC1)C(=O)[C@H]1CO1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 43 %

Procedure:
A solution of (S)-tert-butyl (1-cyclopentyl-3-oxopent-4-en-2-yl)carbamate (854 mg, 3.20 mmol) in DMF (70 mL) was cooled to −20° C. and a bleach solution (9.50 mL, 12.8 mmol, 10% active spice) was added dropwise under nitrogen. The reaction mixture was warmed to 0° C. and stirred for 1.5 h. Water (70 mL) was added and the mixture was extracted with EtOAc (2×50 mL). The organic phases were combined, washed with brine (2×50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc=80:1) to afford tert-butyl ((S)-3-cyclopentyl-1-((R)-oxiran-2-yl)-1-oxopropan-2-yl)carbamate as a viscous oil (390 mg, contaminated with some impurities, 43% yield) as a yellow oil.
Reaction SMILES: [C:1]1([C:7]2[N:12](C)[CH2:11][CH:10]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([O:26][C:27](Cl)=[O:28])[CH3:25].[C:30](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]1([C:7]2[N:12]([C:27]([O:26][CH2:24][CH3:25])=[O:28])[CH:11]([CH3:30])[CH:10]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:15]3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CC(N2CCc3ccccc3C2)ON=C1c1ccccc1
Reactant: CCOC(=O)Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)N1C(c2ccccc2)=NOC(N2CCc3ccccc3C2)C1C

Procedure:
To 3.08 g. of 3-phenyl-6-(1,2,3,4-tetrahydro-2-isoquinolyl)-methyl-5,6-dihydro-4H-1,2,4-oxadiazine 50 ml. of absolute acetone, 1.0 ml. of chlorocarbonic acid ethyl ester and 1.0 g. of anhydrous potassium carbonate are added. The reaction mixture is refluxed for 6 hours. The insoluble substances are filtered off while hot and the solvent is evaporated. After recrystallization of the residue from cyclohexane 1.18 g. of 3-phenyl-4-ethoxycarbonyl-6-(1,2,3,4-tetrahydro-2-isoquinolyl)-methyl-5,6-dihydro-1,2,4-oxadiazine are obtained, melting at 114° to 116° C.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([Cl:4])=[O:3].CCN(C(C)C)C(C)C.[CH2:16]([NH:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]>C1COCC1>[CH2:16]([N:20]([C:1](=[O:5])[C:2]([Cl:4])=[O:3])[CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCNCCCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN(CCCC)C(=O)C(=O)Cl
Reaction time: 0.08 h

Procedure:
To a 0° solution of oxalyl chloride (479 mL, 5.49 mmol) in THF (10 mL) under nitrogen was added DIPEA (2.28 mL, 13.07 mmol) and dibutylamine (925 mL, 5.49 mmol). The resulting mixture was stirred at 0° for 5 min, whereby (dibutylamino)oxoacetyl chloride is formed, then transferred via syringe to a solution of 4-(4-aminophenyl)-2-aminothiazole (corresponding to the deprotected title compound of either Example 1(a) or 1(b)). The resulting mixture was stirred under nitrogen for 4 h, after which time another batch of freshly prepared (N,N-dibutylamino)oxalylchloride (prepared in the same manner and with the same amounts as above) was added to the reaction mixture. The stirring was continued for 1 h. The mixture was then diluted with EtOAc and extracted with 10% aqueous HCl. This aqueous extract was washed with EtOAc:Hex (1:1), then filtered. The collected solid, containing the desired product as its hydrochloride salt, was treated with 2N aqueous NaOH and extracted with EtOAc. This latter extract was washed with H2O, dried (MgSO4) and concentrated under reduced pressure to give a solid (398 mg) which was further purified by crystallization from EtOAc/MeOH to give the title compound (240 mg, 12% yield) as a beige solid: M.p. 178-179° C.; 1H NMR (400 MHz, DMSO-d6) δ10.68 (s, 1H), 7.75 (d, 2H, J=8.7 Hz), 7.64 (d, 2H, J=9.0 Hz), 7.02 (s, 2H), 6.92 (s, 1H), 3.33 (m, 4H), 1.50-1.60 (m, 4H), 1.33 (sixt., 4H, J=7.5 Hz), 1.25 (sixt., 4H, J=7.5 Hz), 0.92 (t, 3H, J=7.5 Hz), 0.82 (t, 3H, J=7.5 Hz); MS (FAB) m/z 375 (MH)+. Anal. Calcd for C19H26N4O2S: C, 60.94; H, 7.00; N, 14.96. Found: C, 60.82; H, 6.85; N, 14.95.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22]Br)=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1.[CH2:25]([NH:27][CH2:28][CH2:29][OH:30])[CH3:26]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29][OH:30])=[CH:14][CH:13]=2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(Cl)cc1)c1ccc(OCCCCBr)cc1
Reactant: CCNCCO
Product: CCN(CCO)CCCCOc1ccc(N(C)C(=O)Oc2ccc(Cl)cc2)cc1

Procedure:
In analogy to example 17.1, reaction of [4-(4-Bromo-butoxy)-phenyl]-methyl-carbamic acid 4-chloro-phenyl ester with 2-ethylaminoethanol yielded (4-{4-[Ethyl-(2-hydroxy-ethyl)-amino]-butoxy}-phenyl)-methyl-carbamic acid 4-chloro-phenyl ester, MS: 421 (MH+).
Reaction SMILES: CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:25]1([S:28]([C:31]2[CH:36]=[CH:35][C:34](/[C:37](=[CH:41]\[CH:42]3[CH2:47][CH2:46][O:45][CH2:44][CH2:43]3)/[C:38](O)=[O:39])=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH2:27][CH2:26]1.[NH2:48][C:49]1[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=1>C(Cl)Cl>[CH:25]1([S:28]([C:31]2[CH:32]=[CH:33][C:34](/[C:37](=[CH:41]\[CH:42]3[CH2:43][CH2:44][O:45][CH2:46][CH2:47]3)/[C:38]([NH:48][C:49]3[CH:54]=[CH:53][C:52]([F:55])=[CH:51][N:50]=3)=[O:39])=[CH:35][CH:36]=2)(=[O:29])=[O:30])[CH2:27][CH2:26]1
Reactant: O=C(O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: Nc1ccc(F)cn1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(F)cn1)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reaction time: 0.5 h

Procedure:
TFFH (283 mg, 1.07 mmol) and DIPEA (373 μmol, 2.14 mmol) were added to a stirred solution of (E)-2-(4-cyclopropanesulfonylphenyl)-3-(tetrahydropyran-4-yl)acrylic acid (Preparation 23, 300 mg, 0.89 mmol) in anhydrous CH2Cl2 (18 mL). After 30 min, the solution was treated portionwise with 2-amino-5-fluoropyridine (200 mg, 1.78 mmol) over 30 min, before being stirred further for 16 h. Solvent evaporation and purification by RP-HPLC furnished the title compound: RTA=3.34 min; m/z (ES+)=431.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:16].[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][O:16][C:3]2[CH:4]=[CH:5][C:6]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)=[CH:7][C:2]=2[Cl:1])=[CH:20][CH:19]=1
Reactant: Oc1ccc(Oc2cccc(F)c2)cc1Cl
Reactant: OCc1ccc(Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(Oc2ccc(OCc3ccc(Cl)cc3)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 62 %

Procedure:
A mixture of 0.88 g of 2-chloro-4-(3-fluorophenoxy)phenol, 0.54 g of p-chlorobenzyl alcohol, 1.01 g of triphenylphosphine, 0.65 g of diethylazadicarboxylate and 90 ml of tetrahydrofuran was stirred at room temperature. After 48 hours, the reaction mixture was concentrated, and 50 ml of diethyl ether was added thereto. The precipitates were removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel chromatography to give 0.83 g of 4-chloro-1-[2-chloro-4-(3-fluorophenoxy)phenoxy]methylbenzene. Yield, 62%. m.p., 47.3° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[OH-:16].[K+].[CH3:18]O>>[CH3:18][O:16][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: [OH-]
Reactant: CO
Reactant: O=C(O)CCCCCCCCCCCBr
Agent: [K+]
Product: COCCCCCCCCCCCC(=O)O
Yield: 39 %

Procedure:
12-bromododecanoic acid (2.0 g, 7.16 mmol) was added to a solution of potassium hydroxide (1.61 g, 28.65 mmol) in methanol (30 mLs) and refluxed for 20 hrs. After cooling and acidification with HCl, solvent was removed under reduced pressure. The sample was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, and the solvent removed under reduced pressure. The product was purified by silica column chromatography in 1% diethyl ether/0.3% formic acid/methylene chloride to yield 12-(methoxy)dodecanoic acid (640 mg, 39%): mp 45-47° C.; 1H NMR (300 MHz, CDCl3) δ1.20-1.45 (bm, 15H, methylene envelope), 1.51-1.69 (bm, 4H, 0--CH2 --CH2, CH2 --CH2 --COOH), 2.34 (t, 2H, J=7.4, CH2 --COOH), 3.34 (s, 3H, 0--CH3), 3.38 (t, 2H, J=6.7, 0--CH2), 10.99 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3) δ24.75, 26.16, 29.10, 29.27, 29.38, 29.44, 29.53, 34.12, 58.50, 72.97, 179.70; m/z 231 (M+H+).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C@H:9]([CH2:10][N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])[C@H:8]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:7]1=[O:28].OP([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[O:28]=[C:7]1[C@@H:8]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C@@H:9]([CH2:10][N:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])[NH:6]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2CCOC2=O)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: O=C(N[C@@H]1C(=O)N[C@@H]1CN1CCOC1=O)OCc1ccccc1
Temperature: 90 °C
Yield: 61.6 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((3S,4R)-1-(2,4-dimethoxybenzyl)-2-oxo-4-((2-oxooxazolidin-3-yl)methyl)azetidin-3-yl)carbamate (3.84 g, 8.18 mmol), K2S2O8 (3.10 g, 11.5 mmol) and K2HPO4 (1.852 g, 10.6 mmol) in ACN:water (2:1, 136 mL) while heating for 40 min at 90° C. More K2S2O8 (663 g, 2.45 mmol) and K2HPO4 (370 mg, 2.13 mmol) were added and it was heated for another 3 h. More K2S2O8 (332 mg, 1.23 mmol) and K2HPO4 (185 mg, 1.06 mmol) were added, and it was heated for an additional 2 h, whereupon it was concentrated in vacuo, removing most of the ACN. The mixture was diluted with brine/EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-100% then MeOH-DCM, 10%) to afford the title compound (1.61 g, 62%) as a beige foam. LCMS: Rt=0.51 min, m/z=320.0 (M+1) Method 2m_acidic.
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])[CH2:18][CH3:19])[CH:13]=[CH:14][CH:15]=1)=[N:5]2.[H-].[Na+].[CH3:23]N(C)C=O.CI>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])[CH2:18][CH3:19]
Reactant: CCC(=O)Nc1cccc(-c2ccc3nncn3n2)c1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CCC(=O)N(C)c1cccc(-c2ccc3nncn3n2)c1
Reaction time: 1 h

Procedure:
A mixture of 3.58 g of N-[3-(1,2,4-triazolo(4,3-b]pyridazin-6-yl)phenyl]propanamide, 0.71 g of sodium hydride (50% in oil) and 200 ml of dimethylformamide was stirred under argon, for 1 hour. A 0.92 ml portion of methyl iodide was added and the mixture was stirred overnight. A 0.355 g portion of sodium hydride (50% in oil) and 0.46 ml of methyl iodide were added and stirring was continued overnight. The mixture was poured into 200 ml of water and extracted with 150 ml portions of dichloromethane. The extracts were combined dried and evaporated in vacuo. The residue was crystallized from ehtyl acetate-hexane, giving 1.60 g of the desired product as light orange crystals, mp 140°-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:4]=1[CH:5]=[CH:6][CH2:7]Cl.[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23][C:24]=2[N:25]=1.CCOCC>C(Cl)(Cl)Cl>[NH2:15][C:16]1[S:17][C:18]2[CH2:19][CH2:20][N:21]([CH2:7][CH:6]=[CH:5][C:4]3[CH:9]=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:3]=3[O:2][CH3:1])[CH2:22][CH2:23][C:24]=2[N:25]=1
Reactant: Nc1nc2c(s1)CCNCC2
Reactant: COc1cccc(C=CCCl)c1OC
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COc1cccc(C=CCN2CCc3nc(N)sc3CC2)c1OC
Yield: 39 %

Procedure:
Prepared from 2,3-dimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 39% of theory, Melting point: 87°-9 1° C. (ether).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].CO.Cl.[H][H]>[Pd].CC(O)C>[ClH:1].[Cl:1][CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH:11]([CH3:15])[CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:16]
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CC(C)O
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCCl)C(C)CCC2
Yield: 86 %

Procedure:
A mixture of 9.5 parts of 3-(2-chloroethyl)-2,6-dimethyl-4H-pyrido[1,2-a]-pyrimidin-4-one, 160 parts of methanol and 40 parts of 2-propanol saturated with hydrogen chloride was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo and the filtrate was evaporated, yielding 9.5 parts (86%) of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2,6-dimethyl-4H-pyrido[1,2-a]pyrimidin-4-one monohydrochloride (intermediate 175).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O[N:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.O>[N:34]1([O:29][C:28](=[O:30])[C:27]2[CH:26]=[CH:25][C:24]([N:21]3[CH2:22][CH2:23][N:18]([C:15]4[CH:14]=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][CH3:3])=[CH:17][CH:16]=4)[CH2:19][CH2:20]3)=[CH:32][CH:31]=2)[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[N:36]=[N:35]1
Reactant: On1nnc2ccccc21
Reactant: COCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)On4nnc5ccccc54)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.4 %

Procedure:
A mixture of 4-[4-[4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic acid dihydrochloride (2.00 g) and 1-hydroxybenzotriazole (0.84 g) in methylene chloride (40 ml) was treated with triethylamine (1.44 ml) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride, and the mixture was stirred for 24 hours at ambient temperature. The reaction mixture was added to water. The organic layer was taken, washed with saturated sodium hydrogen carbonate aqueous solution, water and saturated sodium chloride aqueous solution successively, and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure. To the residue was added diisopropyl ether, and the resulting precipitate was filtered, washed with diisopropyl ether and dried under reduced pressure to give 4-[4-(4-(6-methoxyhexyloxy)phenyl]piperazin-1-yl]benzoic acid benzotriazol-1-yl ester (2.30 g) as a dark yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:18]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[C:12]([OH:19])=[CH:11][CH:10]=1)([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:2].Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][O:31]1.C(=O)([O-])[O-:37].[K+].[K+].CN(C)C=O>CCOCC>[O:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH:30]1[O:29][CH2:28][CH2:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][O:19][C:12]1([OH:37])[CH:11]=[CH:10][C:9]([C:1]([CH2:4][C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:2])[CH3:3])=[CH:18][CH:13]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: ClCCOCCOCCOC1CCCCO1
Reactant: COC(=O)c1cc(C(C)(C)CC(C)(C)C)ccc1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)C1C=C(C(C)(C)CC(C)(C)C)C=CC1(O)OCCOCCOCCOC1CCCCO1
Temperature: 140 °C
Yield: 64.5 %

Procedure:
A mixture of methyl 5-t-octylsalicylate (37.7 g, 0.143 mole), 2-(2-[2-(2-chloroethoxy)ethoxy]ethoxy)tetrahydropyran (54 g, 0.214 mole), potassium carbonate (28 g, 0.217 mole) and N,N-dimethylformamide (250 ml) was heated at 140° C., under nitrogen, for 18 hours, with stirring. The mixture was cooled, diluted with ether, and then washed liberally with saturated sodium chloride solution. The ethereal solution was dried (MgSO4) and evaporated in vacuo to give an oil, which was chromatographed on silica gel to give 46 g of methyl 2-(2-[2-(2-[2-tetrahydropyranyloxy]ethoxy)ethoxy]ethoxy)-5-t-octylsalicylate.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=O)[CH2:5][C:4]2([CH2:12][CH2:11][N:10](C)CC2)O1.C(O)CO.O.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22](S(O)(=O)=O)=[CH:21][CH:20]=1.[Na]>C1(C)C=CC=CC=1>[NH3:10].[CH3:29][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:11][CH2:12][CH2:4][CH2:5][CH2:6][CH2:2][CH3:1]
Reactant: CC1OC2(CCN(C)CC2)CC1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: Cc1ccccc1
Solvent: O
Solvent: OCCO
Product: CCCCCCCCCCCCCC
Product: N

Procedure:
A mixture of 730 mg 2,8-dimethyl-1-oxa-8-azaspiro[4,5]decan-3-one, 2.25 ml ethylene glycol, 836 mg p-toluenesulfonic acid monohydrate and 30 ml toluene was heated under reflux for 3 hours with a Dean-Strak azeotropic dehydration apparatus, and the reaction mixture was poured into 30 ml of an aqueous solution containing 1.26 g sodium becarbonate, the resulting mixture was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on silica gel eluted with a mixted solvent of chloroform/methanol/conc. ammonia (20:1:0.1 by volume) to give 640 mg of 10,14-dimethyl-1,4, 13-trioxa-10-azasprio[4.1.5.2]tetradecane as oil. It was dissolved in isopropanol, and a solution of maleic acid in isopropanol was added to convert it to the corresponding maleate, which was recrystallized from dichloromethane/ether.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[C:10]([OH:13])=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[CH3:14][C:15]([CH3:20])([CH3:19])[CH2:16][CH:17]=O.N1CCCC1>C1COCC1>[CH3:14][C:15]([CH3:20])([CH3:19])[CH:16]=[CH:17][C:9]1[C:7](=[O:8])[C:5]2[C:4]([C:11](=[O:12])[C:10]=1[OH:13])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: CC(C)(C)CC=O
Reactant: O=C1C=C(O)C(=O)c2ccccc21
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)C=CC1=C(O)C(=O)c2ccccc2C1=O

Procedure:
Lawsone (2-hydroxynaphthalene-1,4-dione) (1.4 g) and 3,3-dimethyl-butanal (1.0 g) were dissolved in 20 ml THF at room temperature and 795 μl pyrrolidine added before stirring the reaction for a further 20 minutes. The solvent was removed under vacuum and the residue dissolved in benzene (40 ml) before addition of p-toluenesulphonic acid (2.3 g). The mixture was refluxed for 1 hour, cooled then diluted with ether before the organic phase was washed with sodium bicarbonate solution, followed by one wash with dilute HCl and one wash with water followed by drying under vacuum. The product was purified by chromatograpy using 10% EtOAc/petroleum ether eluant and then crystallised from methanol to yield 260 mg; m.p. 126-128° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=O)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.S(Cl)(Cl)=O.[N:25]1([CH2:30][CH2:31][NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([NH:32][CH2:31][CH2:30][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: NCCN1CCCC1
Reactant: Nc1ncnc2ccc(-c3cccc(C(=O)O)c3)nc12
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: Nc1ncnc2ccc(-c3cccc(C(=O)NCCN4CCCC4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-benzoic acid 14 (100 mg, 0.39 mmol) in DCM (2 mL) was heated with thionyl chloride (0.11 mL, 0.77 mmol) at 80° C. for 1 hour, the mixture was cooled to room temperature and concentrated to dry, 2-pyrrolidin-1-ylethanamine (CAS 7154-73-6) (0.05 mL, 0.58 mmol) was then added, and was stirred overnight. The reaction mixture was purified with prep HPLC to give pure 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)-N-(2-(pyrrolidin-1-yl)ethyl)benzamide 24. LC/MS (ESI+): m/z 363 (M+H).