Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[CH2:39][CH2:40][CH2:41][C:42]([CH2:53][CH3:54])([O:45][Si:46]([CH2:51][CH3:52])([CH2:49][CH3:50])[CH2:47][CH3:48])[CH2:43][CH3:44].[H-].[Na+].C1OCCOCCOCCOCCOC1>O1CCCC1>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:39][CH2:40][CH2:41][C:42]([CH2:53][CH3:54])([O:45][Si:46]([CH2:51][CH3:52])([CH2:47][CH3:48])[CH2:49][CH3:50])[CH2:43][CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CCC(CC)(CCCBr)O[Si](CC)(CC)CC
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(CCCOCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C)O[Si](CC)(CC)CC
Yield: 98.4 %

Procedure:
1α,3β-Bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (400 mg, 0.734 mmol), 1-bromo-4-ethyl-4-(triethylsilyloxy)hexane (475 mg, 1.47 mmol), sodium hydride (60% in oil, 88 mg, 2.20 mmol), 15-crown-5 (162 mg, 0.735 mmol) and tetrahydrofuran (1 ml) were subjected to reaction using a procedure similar to that of Example 5(1) (reflux under heating for 1 hour), worked up and purified by column chromatography (hexane:toluene=3:2) to give the titled compound (569 mg, 98%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[N:5][CH:6]=[C:7](Cl)[N:8]=2)[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH2:41]=[CH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]2[C:4](=[N:5][CH:6]=[C:7]([CH:41]=[CH:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:8]=2)[N:3]=1
Reactant: C=Cc1ccccc1
Reactant: CCCCCOc1nc(N)nc2ncc(Cl)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCCOc1nc(N)nc2ncc(C=Cc3ccccc3)nc12
Yield: 72.9 %

Procedure:
A mixture of 1.5 g (5.6 mmoles) 2-amino-6-chloro-4-n-pentyloxypteridine (e.g. available following the procedure disclosed by Mohr et al. in Helv. Chem. Acta (1992) 75:2317), palladium acetate (63 mg, 0.28 mmoles), tri-o-tolylphosphane (682 mg, 2.24 mmoles), cuprous iodide (53 mg, 0.28 mmoles), styrene (1,3 ml., 11.3 mmoles) and triethylamine 3.1 ml, 22 mmoles) was stirred in dry acetonitrile (50 ml) under reflux for 90 hours. It was evaporated and the residue purified by silica gel column chromatography with chloroform. The product fraction was evaporated to give 1.37 g (yield: 72%) of an orange powder exhibiting, after recrystallization from a EtOAc/hexane mixture, a melting point (m.p.) range of 127–128° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][C:3]=1[C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([O:28][CH3:29])[C:22]([O:30][CH3:31])=[CH:21]2.Cl.[N:33]([O-])=O.[Na+].O>C(O)(=O)C>[CH2:11]([O:10][C:5]1[C:6]([O:8][CH3:9])=[CH:7][C:2]2[N:1]=[N:33][C:19]3[C:18]([C:3]=2[CH:4]=1)=[CH:27][CH:26]=[C:25]1[CH:24]=[C:23]([O:28][CH3:29])[C:22]([O:30][CH3:31])=[CH:21][C:20]=31)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=N[O-]
Reactant: COc1cc2ccc(-c3cc(OCc4ccccc4)c(OC)cc3N)cc2cc1OC
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc2ccc3c4cc(OCc5ccccc5)c(OC)cc4nnc3c2cc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
6-(2-Amino-5-benzyloxy-4-methoxyphenyl)-2,3-dimethoxy-naphthalene 41 (35 mg, 0.084 mmol) was dissolved in acetic acid (0.65 mL) and concentrated hydrochloric acid (0.13 mL). The solution was cooled in an ice bath and diazotized by the dropwise addition of a solution of sodium nitrite (0.052 g in 0.52 mL water). The reaction mixture was allowed to warm slowly to room temperature and left for 1 day. To the resulting red solution containing some precipitate was added 50 mL water and the mixture was extracted with ethyl acetate (30 mL×3). The organic layers were combined and washed with diluted sodium hydroxide solution first, then with water and brine. The organic layer was dried using anhydrous sodium sulfate and evaporated in vacuo. The crude product was purified by column chromatography on silica gel using 20:80 hexanes:ethyl acetate to give the pure 42 (24 mg) in 67% yield; mp 244-246° C.; IR (KBr) 2935, 1621, 1507, 1466, 1307, 1269, 1234, 1206, 1168 cm−1; 1H NMR (CDCl3) δ4.07 (3H, s), 4.14 (3H, s), 4.21 (3H, s), 5.40 (2H, s), 7.25 (1H, s), 7.37-7.60 (5H, m), 7.91 (1H, d, J=9.0), 7.97 (1H, s), 8.01 (1H, d, J=9.0), 9.11 (1H, s); 13C NMR δ56.48, 56.86, 56.91, 71.64, 101.69, 104.43, 107.82, 109.58, 116.84, 118.19, 118.81, 126.95, 127.97, 128.34, 128.90, 129.34, 131.51, 136.31, 141.61, 144.52, 151.00, 151.14, 152.31, 152.93; HRMS (EI) calcd for C26H22N2O4 m/z: 426.1580; found: 426.1577.
Reaction SMILES: C([N:8]1[CH2:13][C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[O:11][CH:10]([C:26]([O:28][CH3:29])=[O:27])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CCO.[Pd]>[O:11]1[C:12]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:13][NH:8][CH2:9][CH:10]1[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)C1CN(Cc2ccccc2)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)C1CNCC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Temperature: 65 °C
Yield: 74 %

Procedure:
A mixture of 9-tert-butyl 2-methyl 4-benzyl-1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate (670 mg, 1.66 mmol), ammonium formate (623 mg, 9.936 mmol) and palladium, 10 wt. % on activated carbon (353 mg, 3.31 mmol) in EtOH (5 mL) was heated at 65° C. for 50 minutes. The reaction mixture was cooled to room temperature, filtered and partitioned between EtOAc/1M aq. NaOH. The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated in vacuo to yield 9-tert-butyl 2-methyl 1-oxa-4,9-diazaspiro[5.5]undecane-2,9-dicarboxylate as a foam (386 mg, 74%). ESI-MS m/z calc. 314.2. Found 315.5 (M+1); Retention time: 0.99 minutes (3 min run).
Reaction SMILES: [O:1]([C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O:20][C:21](=[O:39])[CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33](Br)[CH:32]=2)=[CH:26][C:25]=1[CH3:38]>>[CH3:38][C:25]1[CH:26]=[C:27]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([O:18][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]([C:14]([F:15])([F:16])[F:17])[C:8]=3[O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:32]=2)[CH:28]=[CH:29][C:24]=1[CH2:23][CH2:22][C:21]([OH:39])=[O:20]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: Oc1cccc(C(F)(F)F)c1Oc1ccccc1
Product: Cc1cc(Oc2cccc(Oc3cccc(C(F)(F)F)c3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared according to Example 85 by using 2-phenoxy-3-trifluoromethyl-phenol and 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester to afford about 111 mg (6%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calcd for C29H23O5F3 508, found 509 (M+1, 100%).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[N:11]2[C:12]=1[C:13]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)=[C:14]3[CH2:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(=O)([O-])O.[Na+]>O1CCCC1>[C:34]([O:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]3=[C:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=[C:10]4[N:11]3[C:15](=[CH:16][CH:17]=[CH:18]4)[C:14]=2[CH2:19][CH3:20])=[CH:22][CH:23]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1c(-c2ccc(O)cc2)c2c(Cc3ccccc3)cc3cccc1n32
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCc1c(-c2ccc(OC(C)=O)cc2)c2c(Cc3ccccc3)cc3cccc1n32
Temperature: 25 °C
Reaction time: 24 h
Yield: 35 %

Procedure:
3-Benzyl-1-ethyl-2-(4-hydroxyphenyl)pyrrolo[2,1,5-cd]indolizine (143 mg, 0.66 mmol) was dissolved in 10 ml of dry tetrahydrofuran and -.10 ml of dry pyridine and acetic anhydride (0.6 ml, 5.43 mmol) was added. The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 100 ml of saturated sodium hydrogen carbonate and stirred for 20 minutes. The organic material was extracted into dichloromethane (4×50 ml), and the combined organic layers were washed with brine, dried over magnesium sulfate and the solvent was evaporated. The crude product was purified by column chromatography over silica gel 60, using 5% of diethyl ether in petroleum ether as the eluent to afford 91 mg (35%) of 2-(4-acetoxyphenyl)-3-benzyl-1-ethylpyrrolo[2,1,5-cd]indolizine as a solid. MS(SP): m/z 393 (M+). 1H-NMR (CDCl3, 300 MHz) δ: 1.39 (t, 3H); 2.37 (s, 3H); 3.10 (q, 2H); 4.29 (s, 2H); 6.94 (s, 1H); 7.05-7.25 (m, 7H); 7.52 (d, 2H); 7.61 (dd, 1H); 7.80 (d, 1H), 7.89 (d, 1H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([N:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.CN([CH:28]=[O:29])C>>[CH2:6]([N:13]1[C:19]2[CH:20]=[CH:21][C:22]([CH:28]=[O:29])=[CH:23][C:18]=2[CH:17]=[CH:16][CH:15]=[CH:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1=Cc2ccccc2N(Cc2ccccc2)C=C1
Reactant: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1ccc2c(c1)C=CC=CN2Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Phosphorus oxychloride (1.9 ml, 20.4 retool) was added to DMF (10 ml) at ambient temperature and the mixture was stirred for 30 minutes under nitrogen atmosphere. To the mixture was added crude 1-benzyl-1H-1-benzazepine (3.23 g, 13.6 mmol) in DMF (5 ml) at ambient temperature. The mixture was stirred at ambient temperature for 1 hour and at 70° C. for 2 hours. Water (35 ml) was added and the mixture was stirred for 10 minutes. The mixture was extracted with EtOAc (2×100 ml) and the combined extracts were washed with H2O (2×50 ml), saturated NaHCO3 solution (50 ml) and brine (50 ml). The solution was dried over MgSO4 and concentrated in vacuo affording the title compound as a brown oil (3.42 g).
Reaction SMILES: Br[C:2]1[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=1>C(N(CC)CC)C.[Cu]I>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:2]2[C:7]([CH:8]=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: C#Cc1ccc(OC)cc1
Reactant: O=Cc1cccnc1Br
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: COc1ccc(C#Cc2ncccc2C=O)cc1
Temperature: 50 °C
Yield: 99.1 %

Procedure:
To a solution of 2-bromo-3-pyridinecarboxaldehyde (1.86 g, 10 mmol) and 4′-methoxy phenylacetylene (1.58 g, 12 mmol) in triethylamine (40 mL) were added dichlorobis(triphenylphosphine) palladium(II) (140 mg, 2 mol %) and copper (I) iodide (20 mg, 1 mol %). The reaction mixture was heated at 50° C. under nitrogen for 3 h, then cooled to room temperature. The ammonium salt was removed by filtration. The filtrate was concentrated under reduced pressure leaving 2-(4-methoxy phenylethynyl)pyridine-3-carboxaldehyde (2.35 g, 99%) as yellow solid. 2-(4-Methoxyphenylethynyl)pyridine-3-carboxaldehyde (2.28 g, 9.60 mmol) and tert-butylamine (3.83 g, 60 mmol) were stirred under nitrogen for 24 h at rt. The resulting mixture was extracted with ether and dried over anhydrous Na2SO4. Removal of solvent gave the imine (2.72 g, 97%) which was used in next step without further purification. To a solution of this imine (2.7 g, 9.23 mmol) in 50 mL anhydrous DMF was added (0.190 g, 0.1 mmol) copper (I) iodide. The reaction mixture was heated at 100° C. for 4 h, then cooled to room temperature and diluted with ether (200 mL). The organic layer was washed with sat. aqueous ammonium chloride solution (3×100 mL). The organic layer was dried over anhydrous Na2SO4. Removal of solvent gave the crude compound as a dark colored solid. Purification by column chromatography (Silica Gel 230-400 mesh; 30% ethyl acetate in hexanes as eluent) afforded 7-(4-methoxy phenyl) [1,6]naphthridine (0.730 g, 33%) as a brown solid. To a solution of 7-(4-methoxy phenyl) [1,6]naphthridine (0.485 g, 2.05 mmol) in anhydrous N-methyl-2-pyrrolidinone (5 mL) was added thiophenol (0.25 g, 2.26 mmol) and potassium carbonate (0.028 g, 0.205 mmol). The reaction mixture was stirred at 190° C. for 1 h under nitrogen. The reaction mixture was cooled to room temperature. The crude compound was adsorbed onto silica gel and purified by column chromatography (Silica Gel 230-400 mesh; 20-70% ethyl acetate in hexanes as fluent) to give 4-(1,6-naphthyridin-7-yl)phenol (0.33 g, 71%) as a pale yellow solid. MS (ES) m/z: 223.95 (M+1), 222.95 (M); Mp. 219-221° C.
Reaction SMILES: C(O[C:6]([N:8]([CH2:17][C:18]#[C:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[O:27][CH2:28][C@@H:29]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:30]=2)[CH:21]=1)[O:9]C(OC(C)(C)C)=O)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+].C[Si]([N:53]=C=O)(C)C>ClCCl>[C:31]1([C@@H:29]2[CH2:28][O:27][C:26]([C:22]3[CH:21]=[C:20]([C:19]#[C:18][CH2:17][N:8]([OH:9])[C:6]([NH2:53])=[O:7])[CH:25]=[CH:24][CH:23]=3)=[N:30]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)ON(CC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1)C(=O)OC(C)(C)C
Reactant: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)N(O)CC#Cc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.1 %

Procedure:
To a solution of N,O-di(tert-butoxycarbonyl)-[3-[3-(4,5-dihydro-4(R)-phenyl-oxazol-2-yl)phenyl]-2-propyn-1-yl]hydroxylamine (1.99 g, 4 mmol) in dichloromethane (30 ml) cooled to 0° C. was slowly added trifluoroacetic acid (10 ml). The reaction mixture was allowed to warm to room temperature, stirred an additional 30 min., and then poured into a saturated aqueous NaHCO3 solution (100 ml). The mixture was extracted with dichloromethane (3×30 ml) and the organic phase washed with brine (20 ml), dried (MgSO4) and evaporated. The resulting residue was dissolved in tetrahydrofuran (20 ml) and trimethylsilyl isocyanate (0.84 ml, 6.3 mmol) added. After stirring for 10 min. precipitation of product occurred. Methanol (1 ml) was added and solvent was removed by evaporation. The resulting solids were recrystallized from ethyl acetate to afford the title compound (0.98 g, 72 %) as white solids.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[C:20]([C:22]1([OH:27])[CH2:26][CH2:25][O:24][CH2:23]1)#[CH:21]>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:21]#[C:20][C:22]1([OH:27])[CH2:26][CH2:25][O:24][CH2:23]1)[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC1(O)CCOC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC3(O)CCOC3)nc21

Procedure:
A suspension of 0.3 g (2.24 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 17 ml of a dimethylformamide/triethylamine mixture (V/V; 2/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.319 g (2.79 mmol) of (±)-3-ethynyltetrahydro-3-furanol, 0.043 g of CuI (0.23 mmol) and 0.079 g of bis(triphenylphosphine) palladium(II)dichloride (0.11 mmol) are successively added.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1.[CH2:28](O)[CH3:29]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][C:11]2[CH:12]=[C:13]([NH:16][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:23][CH:24]=3)=[O:18])[NH:14][N:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C(=O)O)nc3)[nH]n2)c1
Reactant: CCO
Product: CCOC(=O)c1ccc(C(=O)Nc2cc(CCc3cccc(OC)c3)n[nH]2)cn1
Yield: 15 %

Procedure:
Preparation was analogous to that described for Example 67, except using 5-[[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]pyridine-2-carboxylic acid (55 mg, 0.15 mmol, 1 eq) in ethanol (0.5 mL) to give title compound as a white solid (9 mg, 15% yield); 1H NMR (400.13 MHz, DMSO) δ□ 1.40 (3H, t), 2.97 (4H, s), 3.79 (3H, s), 4.44 (2H, q), 6.54 (1H, s), 6.8 (1H, m), 6.87 (2H, m), 7.25 (1H, t), 8.19 (1H, d), 8.52 (1H, m), 9.25 (1H, s), 11.17 (1H, s), 12.3 (1H, s) MS m/z 395 (MH+)
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[CH2:6]([O:13][C:14]1[CH:24]=[CH:23][C:17]2[CH:18]=[C:19]([CH2:21]O)[S:20][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>ClCCl>[CH2:6]([O:13][C:14]1[CH:24]=[CH:23][C:17]2[CH:18]=[C:19]([CH2:21][Cl:4])[S:20][C:16]=2[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: OCc1cc2ccc(OCc3ccccc3)cc2s1
Solvent: ClCCl
Product: ClCc1cc2ccc(OCc3ccccc3)cc2s1
Temperature: 25 °C

Procedure:
Sulfonyl chloride (20 ml) is added to a solution of (6-benzyloxy-benzothien-2-yl) methanol (4.20 g, 15.50 mmol) in dichloromethane (40 ml). The mixture was maintained at reflux for 2 h, cooled at room temperature then concentrated under vacuum to give 4.20 g as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.[C:14](#[N:18])[CH:15]([CH3:17])[CH3:16].[Cl-].[Al+3].[Cl-].[Cl-]>>[O:11]1[CH2:12][CH2:13][N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:14](=[NH:18])[CH:15]([CH3:17])[CH3:16])[CH2:9][CH2:10]1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC(C)C#N
Agent: [Al+3]
Agent: [Cl-]
Product: CC(C)C(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine (5.34 g), isobutyronitrile (6 g) and anhydrous aluminium chloride (12 g) was heated at 160°-170° C. for 6 hours to give N-(2-morpholinophenyl)isobutyramidine (m.p. 138° C.) which was recrystallised from a 1:1 mixture of ethylacetate and hexane.
Reaction SMILES: [C:1]1([CH:11]=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:13][C:14]([CH3:16])=[O:15].[OH-].[Na+].O>C(O)C>[C:1]1([CH:11]=[CH:13][C:14](=[O:15])[CH:16]=[CH:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccc2ccccc12)C=Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.7 %

Procedure:
1-Naphthaldehyde (22, 1.36 ml, 10.0 mmol) and acetone (19, 0.37 ml, 5.0 mmol) were combined in ethanol (10 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (0.40 g, 10.0 mmol) and water (10 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethyl acetate to give 0.63 g (38%) of a yellow solid: mp 132-133° C. [expected mp 128° C.]; 1H NMR: δ 7.24 (d, 2H, J=15.7 Hz), 7.57 (m, 6H), 7.92 (m, 6H), 8.28 (d, 2H, J=8.0 Hz), 8.65 (d, 2H, J=15.5 Hz); 13C NMR: δ 123.4, 125.1, 125.4, 126.2, 126.9, 128.1, 128.7, 130.7, 131.7, 132.2, 133.7, 140.3, 188.5.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[C@H:26]1([NH2:33])[CH2:31][CH2:30][C@@H:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][C@H:29]3[CH2:30][CH2:31][C@@H:26]([NH2:33])[CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: N[C@H]1CC[C@@H](N)CC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(N[C@H]3CC[C@@H](N)CC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and cis-cyclohexane-1,4-diamine. MS obsd. (ESI+) [(M+H)+] 451, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.91-7.85 (m, 2 H), 7.79 (s, 1 H), 7.58 (td, J=7.45, 1.26 Hz, 1 H), 7.51-7.44 (m, 1 H), 7.29 (d, J=8.59 Hz, 1 H), 7.21 (dd, J=8.59, 1.52 Hz, 1 H), 6.17 (d, J=7.58 Hz, 1 H), 6.03 (s, 1 H), 5.06 (brs, 2 H), 4.50 (brs, 1 H), 4.11 (d, J=4.55 Hz, 1 H), 3.67 (d, J=4.80 Hz, 1 H), 3.64-3.56 (m, 2 H), 3.16 (m, 2 H), 3.06 (brs, 1 H), 2.35 (s, 3 H), 1.83-1.44 (m, 8 H).
Reaction SMILES: [OH:1][C@H:2]([CH3:39])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][N:14]=2)=[O:11])[C:6](=[O:32])[N:5]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[C:40]([N:50]([CH2:52][C:53](O)=[O:54])[CH3:51])([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:43]([O:42][C:40]([N:50]([CH3:51])[CH2:52][C:53]([O:1][C@H:2]([CH3:39])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10](=[O:11])[NH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][N:14]=2)[C:6](=[O:32])[N:5]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:54])=[O:41])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)O)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Reactant: CN(CC(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN(C)C(=O)OCc5ccccc5)n(-c5ccccc5)c4=O)nc3)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
To a mixture of (R)-1-(2-hydroxypropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (2.0 g, 3.81 mmol), N-Cbz-sarcosine (1.7 g, 7.62 mmol) and DMAP (0.93 g, 7.62 mmol, Aladdin) in 15 mL of CH2Cl2 at 0° C. was added EDC solid (2.19 g, 11.43 mmol, Aladdin) in portions. After stirring at 0° C. for 2 hrs, the mixture was allowed to heat to 40° C. and stirred overnight. The reaction was diluted with 100 mL of CH2Cl2. The resulted solution was washed with 0.1 N HCl (10 mL×2), saturated NaHCO3 (20 mL×2) and followed by water (20 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc/MeOH=4/1) to give the title compound as a yellow solid (2.15 g, 77.3%).