Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[NH2:12][C:13]1[N:28]=[CH:27][C:16]2[N:17]([CH:24]([CH3:26])[CH3:25])[C:18]3[C:23]([C:15]=2[C:14]=1[CH2:29][CH3:30])=[CH:22][CH:21]=[CH:20][CH:19]=3.[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39](O)=[O:40])=[CH:33][CH:32]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[N:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([NH:12][C:13]2[N:28]=[CH:27][C:16]3[N:17]([CH:24]([CH3:26])[CH3:25])[C:18]4[C:23]([C:15]=3[C:14]=2[CH2:29][CH3:30])=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:40])=[CH:33][CH:32]=1
Reactant: CCc1c(N)ncc2c1c1ccccc1n2C(C)C
Reactant: O=C(O)CCc1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CCc1c(NC(=O)CCc2ccncc2)ncc2c1c1ccccc1n2C(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
EDAC (0.035 g, 0.18 mmol) was added to a solution of 3-amino-4-ethyl-9-isopropyl-9H-pyrido[3,4-b]indole (Method 5; 0.03 g, 0.12 mmol), DMAP (0.007 g, 0.06 mmol) and 3-(pyridin-4-yl)propanoic acid (Method 6; 0.027 g, 0.18 mmol) in DMF (10 ml). The mixture was stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The organic layer was separated, washed with brine, dried over magnesium sulphate and then evaporated to dryness in vacuo. The crude product was purified by flash chromatography eluting over a gradient of 0-10% MeOH in DCM. NMR (CDCl3) 8.72 (s, 1H), 8.51 (m, 2H), 8.19 (d, 1H), 7.59 (d, 2H), 7.47 (s, 1H), 7.29 (m, 1H), 7.20 (m, 2H), 5.05 (m, 1H), 3.12 (m, 4H), 2.78 (m, 2H), 1.73 (d, 6H), 1.31 (t, 3H); m/z 388.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[C:9]([F:12])([F:11])[F:10].[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][C:19]([CH3:25])=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1>C[Si](C)(C)N[Si](C)(C)C.O1CCOCC1>[Br:15][C:16]1[C:17]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:9]([F:10])([F:11])[F:12])[CH:4]=2)=[N:18][C:19]([CH3:25])=[C:20]([N+:22]([O-:24])=[O:23])[CH:21]=1
Reactant: Cc1nc(Cl)c(Br)cc1[N+](=O)[O-]
Reactant: Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1nc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(Br)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 18.9 %

Procedure:
In a 50 mL single-necked round-bottomed flask, 0.13 ml of hexamethyldisilazane and 1.21 g of 4-chloro-3-trifluoromethyl-phenol are dissolved and stirred in 3.0 ml of dry dioxane under Argon atmosphere at ambient temperature. To this mixture, 270 mg of 55% sodium hydride suspension is added carefully (gas evolution) and stirring is continued for 30 minutes. After this, a solution of 1.55 g of 3-bromo-2-chloro-6-methyl-5-nitro-pyridine in 4.0 ml of dry dioxane is added dropwise by syringe and stirring is continued for 22 hours at ambient temperature. The reaction is then quenched by the addition of an excess of a dilute aqueous NaOH solution (pH=12 of water phase) and extraction carried out with cyclohexane. The organic phase is dried over sodium sulfate, filtered and concentrated in vacuo to obtain an orange oil. Purification by flash chromatography over a silica gel cartridge (50 g, 150 ml) using heptane/ethyl acetate 95:5 (v:v) as eluent gave 480 mg of the compound in the form of a wet solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]3)[CH:9]=2)[CH:4]=1.C(O)(=O)C.Br>O>[CH2:19]([C@H:16]1[CH2:17][CH2:18][C@H:13]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[CH:4]=[C:3]([OH:2])[CH:12]=[CH:11]3)[CH2:14][CH2:15]1)[CH2:20][CH3:21]
Reactant: CCC[C@H]1CC[C@H](c2ccc3cc(OC)ccc3c2)CC1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CCC[C@H]1CC[C@H](c2ccc3cc(O)ccc3c2)CC1
Temperature: 25 °C

Procedure:
To 28.0 g of 2-methoxy-6-(trans-4-propylcyclohexyl) naphthalene were added 280 ml of acetic acid and 280 ml of 48% hydrobromic acid. The reaction mixture was then heated under reflux for 12 hours. The reaction solution was then allowed to cool to room temperature. To the reaction solution was then added 500 ml of water to cause crystallization. The crystal thus precipitated was then filtered off. The crystal was washed with water, and then dried under reduced pressure to obtain 26.8 g of 6-(trans-4-propylcyclohexyl)-2-naphthol.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14]([NH:35][CH2:34][CH2:32][OH:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: NCCO
Reactant: CS(=O)(=O)O[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@H](NCCO)C3)ccc12

Procedure:
Prepared according to the method of example 33(b), using N-[6-Chloro-2-[(3R)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 35(a)) (0.2 g) and ethanolamine (0.8 mL) to afford the title compound (0.068 g).
Reaction SMILES: [NH2:1][NH2:2].C([O:5][C:6]([CH:8]([CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH2:15][CH2:14]1)[CH2:9][C:10](=O)[CH3:11])=O)C>C(O)(=O)C>[CH3:11][C:10]1[CH2:9][CH:8]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])[CH2:15][CH2:14]2)[C:6](=[O:5])[NH:1][N:2]=1
Reactant: CCOC(=O)C(CC(C)=O)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: NN
Solvent: CC(=O)O
Product: CC1=NNC(=O)C(C2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Hydrazine (4.72 mL, 148.7 mmol) was added to a solution of benzyl 4-[1-(ethoxycarbonyl)-3-oxobutyl]piperidine-1-carboxylate (2.69 g, 7.44 mmol) in acetic acid (110 mL). The reaction mixture was heated at 50° C. After 1 h, the reaction mixture was concentrated. The residue was diluted with dichloromethane, neutralized by saturated aqueous sodium bicarbonate. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate and concentrated to give the title compound. MS 330.2 (M+1).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:16]=[C:15]([CH3:17])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=4)=[CH:22][N:21]=3)[CH:13]=2)[N:8]=1>O1CCOCC1>[Cl:32][C:29]1[CH:28]=[CH:27][C:26]([C:23]2[CH:24]=[CH:25][C:20]([C:19]#[C:18][C:12]3[CH:13]=[C:14]4[C:9](=[CH:10][CH:11]=3)[N:8]=[C:7]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:16]=[C:15]4[CH3:17])=[N:21][CH:22]=2)=[CH:31][CH:30]=1
Reactant: Cc1cc(Cl)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Cc1cc(N2CCCC2)nc2ccc(C#Cc3ccc(-c4ccc(Cl)cc4)cn3)cc12

Procedure:
77 μL (0.925 mmol) of pyrrolidine is added to a solution of 90 mg (0.231 mmol) of 2-chloro-6-[5-(4-chlorophenyl)pyridin-2-ylethynyl]-4-methylquinoline in 5 mL of 1,4-dioxane and the reaction mixture is refluxed overnight. It is evaporated down in vacuo, and the residue is taken up in DMF and purified by HPLC-MS. The fractions containing the product are combined, evaporated down, and freeze-dried. The product is dissolved in DCM, evaporated down, and the residue is triturated with a little EtOAc, filtered, washed again with a little EtOAc, and dried at 50° C. in the circulating air dryer. Yield: 39 mg (39% of theoretical); C27H22ClN3 (M=423.936); calc.: molpeak (M+H)+: 424/426 (Cl); found: molpeak (M+H)+: 424/426 (Cl); HPLC-MS: 5.8 min (method A).
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[CH2:34][C:35]([N:37]=[C:38]=[O:39])=[O:36]>>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[CH:13][C:14]=3[O:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:38]([NH:37][C:35](=[O:36])[CH2:34][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH3:26])=[O:39])=[CH:20][C:19]=3[F:25])[CH:9]=2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: COc1ccccc1CC(=O)N=C=O
Product: CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5OC)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 308 (370 mg, 1.05 mmol) and (2-methoxy-phenyl)-acetyl isocyanate (240 mg, 1.25 mmoL) [A. J. Hill, et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and eluted with EtOAc, to afford the title compound 309c in 42% yield as a white solid. 1H NMR (d-DMSO) δ (ppm): 10.98(s, 1H), 10.69(s, 1H), 8.41(d, 1H, J=5.3 Hz), 7.94(d, 1H, J=1.2 Hz), 7.81(dd, 1H, J1=13.1 Hz, J2=2.4 Hz), 7.77(d, 1H, J=0.9 Hz), 7.65(s, 1H), 7.45-7.40(m, 2H), 7.26-7.19(m, 2H), 6.97(d, 1H, J=8.0 Hz), 6.89(dt, 1H, J1=0.8 Hz, J2=8.2 Hz), 6.54(d, 1H, J=5.5 Hz), 4.04(q, 2H), 3.75(s, 3H), 3.70(s, 2H), 1.38(t, 3H). MS (m/z): 546.1(M+H) (found).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.C(OC([NH:37][C:38]1[CH:39]=[C:40]([Cl:59])[C:41]([N:44](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:42][CH:43]=1)=O)(C)(C)C>>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][NH:44][C:41]3[C:40]([Cl:59])=[CH:39][C:38]([NH2:37])=[CH:43][N:42]=3)[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: CC(C)(C)OC(=O)Nc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c1
Product: Nc1cnc(NCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)c(Cl)c1

Procedure:
The title compound was synthesized by procedure analogous to Step 2 of Example 11 from cis-2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from Step 1 of Example 5 and di-tert-butyl {5-[(tert-butoxycarbonyl)amino]-3-chloropyridin-2-yl}imidodicarbonate from Step 1 of this example.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][N:7]1[CH2:12][CH2:11][NH:10][C:9]2[N:13]=[CH:14][C:15]([C:17]3[CH:25]=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][CH:18]=3)=[CH:16][C:8]1=2.[N:32]1([CH:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33]1>>[N:32]1([CH:37]2[CH2:42][CH2:41][N:40]([C:21]([C:20]3[CH:24]=[CH:25][C:17]([C:15]4[CH:14]=[N:13][C:9]5[NH:10][CH2:11][CH2:12][N:7]([CH2:6][C:5]6[CH:26]=[CH:27][CH:28]=[CH:29][C:4]=6[O:3][C:2]([F:30])([F:31])[F:1])[C:8]=5[CH:16]=4)=[CH:18][CH:19]=3)=[O:23])[CH2:39][CH2:38]2)[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2ccccc2OC(F)(F)F)CCN3)cc1
Reactant: C1CCN(C2CCNCC2)C1
Product: O=C(c1ccc(-c2cnc3c(c2)N(Cc2ccccc2OC(F)(F)F)CCN3)cc1)N1CCC(N2CCCC2)CC1
Yield: 65 %

Procedure:
4-{1-[2-(Trifluoromethoxy)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid (98 mg) was reacted with 4-(1-pyrrolidinyl)piperidine as in General Procedure 8 to give the title compound as a yellow solid (65% yield). LCMS: m/z=565.98 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 1.53 (2H, bs), 2.88 (7H, m), 2.27 (1H, m), 2.57 (4H, s), 2.98 (2H, m), 3.46 (2H, m), 3.63 (2H, m), 3.81 (1H, bs), 4.55 (2H, s), 5.21 (1H, s), 6.71 (1H, s), 7.33 (8H, m), 7.71 (1H, s).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:18]3[S:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[C:35]([NH:42][CH2:43][CH2:44]Br)([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36]>C1COCC1>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:16]=[C:17]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:18]3[S:23][C:22]([CH2:44][CH2:43][NH:42][C:35](=[O:36])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:21][C:19]=3[N:20]=2)[CH:12]=[CH:13][CH:14]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(-c2nc(N3CCOCC3)c3sccc3n2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCc1cc2nc(-c3cccc(O[Si](C)(C)C(C)(C)C)c3)nc(N3CCOCC3)c2s1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
4-(2-(3-(tert-butyldimethylsilyloxy)phenyl)thieno[3,2-d]pyrimidin-4-yl)morpholine (166 mg, 388 μmol, 1.0 eq.) was solved with dry THF (3 ml) under room temperature and added to a round-two-neck flask that was heated under vacuum and flushed with nitrogen. The solution was then cooled to −78° C. and n-BuLi (315 μl, 1.6 M solution in hexanes, 1.3 eq.) was added dropwise. After stirring for 20 min., 2-(boc-amino)ethyl bromide (130 mg, 582 μmol, 1.5 eq.) was added to the reaction mixture and the reaction mixture was stirred at −78° C. for 20 min. and then warmed to room temperature. The reaction mixture was further stirred at room temperature overnight.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([S:18][CH:19]([CH2:22][OH:23])[CH2:20][OH:21])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[Cl:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[CH:32]=O)=[CH:28][CH:27]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[Cl:25][C:26]1[CH:35]=[CH:34][C:29](/[CH:30]=[CH:31]/[C@H:32]2[O:21][CH2:20][C@H:19]([S:18][C@H:16]([CH3:17])[C@:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:24])[CH2:10][N:11]3[CH:15]=[N:14][CH:13]=[N:12]3)[CH2:22][O:23]2)=[CH:28][CH:27]=1
Reactant: O=C/C=C/c1ccc(Cl)cc1
Reactant: C[C@@H](SC(CO)CO)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(Cl)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
In 14 ml of methylene chloride were dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-difluorophenyl)-3-[(1,3-dihydroxy-2-propyl)thio]-1-(1H-1,2,4-triazol-1-yl)-2-butanol as described in Reference example 2 and 191 mg (1.15 mmol) of trans-4-chlorocinnamaldehyde [Bull. Chem. Soc. Japan 52 555 (1979)], and 233 mg (1.23 mmol) of p-toluenesulfonic acid monohydrate and 1.5 g of molecular sieves 4A were added thereto, followed by stirring of the resulting mixture for 1 hour and 15 minutes. An aqueous sodium hydrogencarbonate solution was added to the reaction mixture and the mixture was stirred for 10 minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried to distil off the solvent under reduced pressure. The thus obtained oil was subjected to column chromatography using 15 g of silica gel and eluted with a mixed solvent hexane-ethyl acetate (3:2) to obtain 280 mg (yield: 67%) of the desired title compound, trans isomer (A) as an oil. Further, the oil was eluted with a mixed solvent of hexane-ethyl acetate (1:1) to obtain 35 mg (yield: 8%) of the cis isomer (B) as an oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[S:13][C:14]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[C:15]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[O:10])=[CH:5][N:4]=1.[NH:28]1[CH:32]=[CH:31][N:30]=[CH:29]1.O>CN(C=O)C>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:15]1[N:16]=[C:12]([NH:11][C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[N:4][CH:5]=2)=[O:10])[S:13][C:14]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: c1c[nH]cn1
Reactant: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(CCl)nc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(N2CCOCC2)s1)c1ccc(Cn2ccnc2)nc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
Compound 36 (97.1 mg, 0.240 mmol) was dissolved in DMF (2.5 mL), imidazole (49.0 mg, 0.721 mmol) was added thereto, followed by stirring at 95° C. for 2 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under the reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:3) to afford the entitled Compound 37 (58.0 mg, 55%).
Reaction SMILES: [CH:1]12[O:7][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2]2.[N-:8]=[N+:9]=[N-:10].[Na+]>CC(C)=O.O>[N:8]([CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][CH:1]1[OH:7])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=[N-]
Reactant: C1CCC2OC2C1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC1CCCCC1O
Yield: 10.6 %

Procedure:
To a solution of 7-oxa-bicyclo[4.1.0]heptane (0.300 g, 3.06 mmol) in acetone (3 mL) was added sodium azide (0.504 g, 7.75 mmol) in water (3 mL). The reaction mixture was refluxed for 12 h. The acetone was removed in vacuo and the product was extracted with ethyl acetate (5 mL). The organic layer was collected, dried over anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (46 mg).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](O)(=[O:18])[C:16]#[CH:17].C1C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:18])[C:16]#[CH:17]
Reactant: OCCCCCCCc1ccccc1
Reactant: C#CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: C#CC(=O)OCCCCCCCc1ccccc1
Yield: 57.9 %

Procedure:
A mixture of 0.5 g of 7-phenylheptanol, 0.27 g of propiolic acid, 0.005 g of p-toluenesulfonic acid and 25 ml of benzene was refluxed with stirring for six hours while water formed was removed by a Dean-Stark water separator. After the reaction was completed, the reaction solution was washed successively with a 5% aqueous sodium bicarbonate solution and a saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After removal of the solvent under reduced pressure, the obtained residue was subjected to silicagel column chromatography to yield 0.368 g of 7-phenylheptyl propiolate (compound 3).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:32][N:33]([CH3:37])[C:34](Cl)=[O:35]>ClCCl>[CH3:32][N:33]([CH3:37])[C:34]([N:2]([CH3:1])[CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:21][CH2:22][CH2:23][CH2:24]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)=[O:35]
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: CN(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N(C)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reaction time: 8 h
Yield: 34.7 %

Procedure:
To a stirred solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}amine (200 mg, 0.60 mmol) and triethylamine (102 μL, 0.72 mmol) in anhydrous dichloromethane (8 mL) under nitrogen atmosphere was added dropwise a solution of dimethylcarbamoylchloride (67 μL, 0.72 mmol) in anhydrous dichloromethane (2 mL). After stirring overnight, the reaction mixture was quenched with a saturated aqueous solution of NaHCO3. The organic layer was separated, washed with a saturated aqueous solution of NaHCO3 and water then dried over magnesium sulfate, filtered, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with DCM:MeOH (95:5) followed by DCM:MeOH:NH3 (90:5:5) to give the title compound (84 mg, 39%). 1H NMR (400 MHz, CDCl3) δ7.19 (d, 2H), 6.90-6.88 (d, 2H), 4.03 (t, 2H), 3.81-3.78 (m, 2H), 3.56-3.52 (m, 4H), 2.70 (s, 6H), 2.66 (t, 2H), 2.29 (s, 3H), 2.05-2.01 (m, 4H), 1.86-1.81 (m, 6H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]#[N:25])[CH:17]=1.[H-].[Na+].S(OC)(O[CH3:33])(=O)=O>>[CH3:33][O:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][C:4](=[O:12])[C:3]=1[C:13](=[O:26])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH2:23][C:24]#[N:25])[CH:17]=1
Reactant: COS(=O)(=O)OC
Reactant: N#CCOc1cccc(C=CC(=O)c2c(O)c3ccccc3oc2=O)c1
Agent: [H-]
Agent: [Na+]
Product: COc1c(C(=O)C=Cc2cccc(OCC#N)c2)c(=O)oc2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.5 %

Procedure:
To a mixture of 5 ml of hexamethylphosphoramine and 0.40 g of 4-hydroxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one was added 52 mg of sodium hydride (60% oily), and the mixture was stirred at room temperature for 1 hour. Then, 0.17 g of dimethyl sulfate was added, and the mixture was stirred at room temperature overnight. Thereafter, the reaction mixture was added to ice water, and the mixture was extracted with ethyl acetate. The organic layer washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 81 mg of 4-methoxy-3-[3-[3-(cyanomethoxy)phenyl]-1-oxo-2-propenyl]-2H-1-benzopyran-2-one [Compound No. (15d)] as a pale yellow crystal.
Reaction SMILES: [CH:1]1([CH2:4][C@@H:5]([OH:9])[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C>[CH:1]1([CH2:4][C@@H:5]([OH:9])[C:6]([O:8][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)[C@H](O)CC1CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H](O)CC1CC1
Temperature: 25 °C

Procedure:
A solution of 3.95 g of 3-cyclopropyl-2(R)-hydroxypropionic acid in 50 ml of ethyl acetate was treated with 5.32 ml of triethylamine and 3.8 ml of benzyl bromide. The mixture was stirred and heated under reflux for 3 hours, then allowed to cool to room temperature overnight. The suspension was washed with 2M hydrochloric acid, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the solvent was evaporated. The residue was purified by flash chromatography on silica gel using hexane/ethyl acetate (2:1) for the elution to give 3.36 g of benzyl 3-cyclopropyl-2(R)-hydroxypropionate in the form of a yellow oil.
Reaction SMILES: [CH2:1]([C:4]1([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)[O:9][CH2:8][CH2:7][N:6]([CH3:10])[C:5]1=[O:11])[CH:2]=[CH2:3]>CO>[CH3:19][O:18][C:14]1[CH:13]=[C:12]([C:4]2([CH2:1][CH2:2][CH3:3])[O:9][CH2:8][CH2:7][N:6]([CH3:10])[C:5]2=[O:11])[CH:17]=[CH:16][CH:15]=1
Reactant: C=CCC1(c2cccc(OC)c2)OCCN(C)C1=O
Solvent: CO
Product: CCCC1(c2cccc(OC)c2)OCCN(C)C1=O

Procedure:
2-Allyl-2-(-3-methoxy-phenyl)-4-methyl-morpholine-3-one, as described above in Step C, (0.400 g, 1.53 mmol) was dissolved in MeOH (20 mL), the solution purged with Ar, treated with 10% Pd/C (0.060 g), and hydrogenated under a H2 balloon. After 2 h the reaction mixture was filtered through a celite pad and concentrated to dryness to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C@:10]1([OH:29])[C:22]2[CH:21]=[C:20]3[N:16]([CH2:17][CH2:18][C:19]43OCC[O:23]4)[C:15](=[O:27])[C:14]=2[CH2:13][O:12][C:11]1=[O:28])[CH3:9]>C(OCC)(=O)C>[CH2:8]([C@:10]1([OH:29])[C:22]2[CH:21]=[C:20]3[N:16]([CH2:17][CH2:18][C:19]3=[O:23])[C:15](=[O:27])[C:14]=2[CH2:13][O:12][C:11]1=[O:28])[CH3:9]
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC12OCCO2
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)CCC1=O
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To 90 ml of 90% trifluoroacetic acid, 3.5 g of (4S)-4-ethyl-6,6-(ethylenedioxy)-7,8-dihydro-4-hydroxy-1H-pyrano[3,4-f]indolizine-3,10(4H)-dione were added at room temperature over 5 minutes, followed by stirring at the same temperature for 30 minutes. After completion of the reaction, the solvent was removed under reduced pressure, followed by the thorough removal of the solvent by a vacuum pump. To the residue so obtained was added 20 ml of ethyl acetate. The crystals precipitated were collected by filtration, whereby 2.4 g of the title compound were obtained.