Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Sn:5](=[O:10])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].[CH2:11]([CH:13]([CH2:16][CH3:17])[CH2:14][OH:15])[CH3:12]>>[CH2:1]([Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[O:10][Sn:5]([CH2:6][CH2:7][CH2:8][CH3:9])([CH2:1][CH2:2][CH2:3][CH3:4])[O:15][CH2:14][CH:13]([CH2:16][CH3:17])[CH2:11][CH3:12])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC[Sn](=O)CCCC
Reactant: CCC(CC)CO
Product: CCCC[Sn](CCCC)(OCC(CC)CC)O[Sn](CCCC)(CCCC)OCC(CC)CC
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A 500 ml recovery flask was charged with 59.8 g (0.15 mol) of dibutyltin oxide (manufactured by Aldrich Chemical Co., U.S.A., 98%) and 122 g (1.2 mol) of 2-ethyl-1-butanol (manufactured by Aldrich Chemical Co., U.S.A., 98%), whereby the flask contained the resulting white slurry mixture. The flask was attached to an evaporator (manufactured by Shibata Scientific Technology Ltd., Japan, R-144) connected to a thermoregulator-equipped oil bath (manufactured by Masuda Corporation, Japan, OBH-24), a vacuum pump (manufactured by ULVAC Inc., Japan, G-50A), and a vacuum controller (manufactured by Okano Works Ltd., Japan, VC-10S). The oil bath temperature was set at 140° C. The flask was immersed in the oil bath, whereupon rotation of the evaporator was started. Rotation was continued for about 30 minutes while stirring and heating under atmospheric pressure with the evaporator purge valve open. The evaporator purge valve was then closed, and the pressure in the system was gradually lowered to about 70 kPa using the vacuum pump and the vacuum controller. This state was maintained for 1 hour, after which the flask was removed from the oil bath. The reactant had turned a transparent liquid. The purge valve was gradually opened to return the system pressure to atmospheric pressure. The distillate was 3.6 g, transparent and had separated into 2 layers. Analysis of the distillate showed a water content of about 2.2 g. The flask was then removed from the oil bath and the purge valve was gradually opened to return the system pressure to atmospheric pressure. The flask yielded 175 g of reaction solution. Results of 119Sn, 1H and 13C-NMR analysis showed that, using dibutyltin oxide as a reference, the reaction solution contained about an 99% yield of 1,1,3,3-tetrabutyl-1,3-bis(2-ethyl-butyloxy)-distannoxane.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24].[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[CH:30])[CH3:26].CCN(CC)CC>C1COCC1.[Cu]I>[CH2:25]([O:27][CH:28]([O:31][CH2:32][CH3:33])[C:29]#[C:30][C:2]1[N:7]=[C:6]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[C:5](=[O:13])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:3]=1[CH3:24])[CH3:26]
Reactant: C#CC(OCC)OCC
Reactant: Cc1c(Br)nc(C(=O)N(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(C#Cc1nc(C(=O)N(C)C)c(=O)n(-c2cccc(C(F)(F)F)c2)c1C)OCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 25.1 %

Procedure:
6-Bromo-N,N,5-trimethyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxamide (0.10 g, 0.247 mmol), propargylaldehyde diethyl acetal (0.48 mg, 0.370 mmol), copper(I) iodide (0.001 mg, 0.005 mmol) and Et3N (1 ml) in THF (1 ml) were placed in a glass tube for microwave synthesis. The mixture was degassed with argon and Pd(Cl2) (PPh3)2 (0.007 g) was added. The tube was sealed and heated with stirring at 60° C. (150 W) in a microwave heater for 20 minutes. The mixture was diluted with EtOAc (5 ml) and filtered. The solution was concentrated in vacuo and was then purified on silica to give the title compound (28 mg, 25%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[O:11][C:12]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:13]=3[C:14]=2[CH3:15])=[CH:4][CH:3]=1.[OH:32]O.N>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:9][C:10]2[O:11][C:12]3[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[C:13]=3[C:14]=2[CH3:15])=[O:32])=[CH:4][CH:3]=1
Reactant: Cc1c(CSc2ccc(F)cc2)oc2cccc(OCCCNCc3cccnc3)c12
Reactant: OO
Agent: N
Solvent: ClCCl
Product: Cc1c(CS(=O)c2ccc(F)cc2)oc2cccc(OCCCNCc3cccnc3)c12
Reaction time: 1 h

Procedure:
To a solution of {3-[2-(4-fluoro-phenylsulfanylmethyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-amine (16 mg) and bis(2,4-pentanedionato)-vanadium oxide (9.8 mg) in dichloromethane (2 ml) was added 30% hydrogenperoxide aqueous solution (20 μl) at room temperature and the mixture was stirred for 1 hour. After the addition of ammonia solution (2 ml) the whole mixture was vigorously stirred until the sticky precipitation disappeared, then extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. The mixture was separated by silica gel column chromatography developed by dichloromethane and methanol. {3-[2-(4-fluoro-benzenesulfinylmethyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-amine (5 mg) was obtained as a white solid: ESI-MS: m/z 453 (MH+); 1H-NMR (CDCl3): δ 1.98 (3H, s), 2.00-2.09 (2H, m), 2.85 (2H, t, J=6.9 Hz), 4.01 (1H, d, J=13.5 Hz), 4.13 (2H, t, J=5.9 Hz), 4.32 (1H, d, J=13.5 Hz), 6.59 (1H, d, J=7.9 Hz), 6.94 (1H, d, J=8.2 Hz), 7.10-7.25 (4H, m), 7.44-7.49 (2H, m), 7.65-7.69 (1H, m), 8.49-8.59 (2H, m). {3-[2-(4-fluoro-benzenesulfonylmethyl)-3-methyl-benzofuran-4-yloxy]-propyl}-pyridin-3-ylmethyl-amine (11 mg) was obtained as a colorless oil:. ESI-MS: m/z 469 (MH+); 1H-NMR (CDCl3): δ 1.99-2.09 (2H, m), 2.12 (3H, s), 2.86 (2H, t, J=7.3 Hz), 3.84 (2H, s), 4.13 (2H, t, J=5.9 Hz), 4.50 (2H, s), 6.59 (1H, d, J=8.3 Hz), 6.89 (1H, d, J=8.2 Hz), 7.11-7.69 (7H, m), 7.69-8.57 (2H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].CN(C1C=CC=CN=1)C.[CH2:22]([N:29]1[CH2:34][CH2:33][CH:32](O)[CH2:31][CH2:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH3:1][N:2]([CH3:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([O:8][CH:32]1[CH2:31][CH2:30][N:29]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:34][CH2:33]1)=[O:7]
Reactant: CN(C)c1cccc(C(=O)O)c1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: CN(C)c1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Reaction time: 2 h
Yield: 67.1 %

Procedure:
0.33 g (0.002 mol) of 3-dimethylaminobenzoic acid was dissolved in 10 ml of dimethylformamide, treated with 0.122 g (0.001 mol) of dimethylaminopyridine and 0.383 g (0.002 mol) of 1-benzyl-4-hydroxypiperidine and cooled to 0°. 0.422 g (0.0022 mol) of N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride was added and the mixture was stirred at 0° for a further 2 hrs. Subsequently, the mixture was stirred at room temperature for 3 days, the solvent was distilled off and the residue was chromatographed over silica gel with ethyl acetate/hexane (1:2). 0.454 g (67%) of 1-benzyl-piperidin-4-yl 3-dimethylamino-benzoate was obtained as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][S:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:11]O>C(O)(=O)C>[O:4]1[C:5]2([CH2:10][CH2:9][S:8](=[O:11])[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: OO
Reactant: C1COC2(CCSCC2)O1
Solvent: CC(=O)O
Product: O=S1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A room temperature mixture of 13.8 g of product from Example 392 dissolved in 100 ml of acetic acid is treated, dropwise over 20 minutes, with 9.0 ml of 30% hydrogen peroxide. The reaction mixture is stirred at room temperature for 1 hour, concentrated in vacuo at 50° C., and extracted with ethyl acetate. The organic layer is washed 2× with saturated sodium bicarbonate, water and saturated sodium chloride, dried and concentrated in vacuo. The aqueous washes are combined and concentrated in vacuo to about 25 ml. The residue is saturated with solid potassium carbonate and extracted 2× with 200 ml of ethyl acetate. The organic phase is concentrated in vacuo to a solid which is triturated with hexane and collected to give 13.1 g of the desired product.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3Cl)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[NH2:33][C@@H:34]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35]1>C(O)C>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][C@@H:13]([N:15]2[CH:23]=[N:22][C:21]3[C:16]2=[N:17][CH:18]=[N:19][C:20]=3[NH:33][C@@H:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:36][CH2:35]2)[CH2:12][C@@H:11]1[OH:25])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(Cl)ncnc32)C[C@@H]1O
Reactant: N[C@H]1CCc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Yield: 78.2 %

Procedure:
A solution of (1S,2R,4R)-2-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-(6-chloro-9H-purin-9-yl)cyclopentanol (0.091 g, 0.24 mmol), triethylamine (0.1 mL, 0.72 mmol) and (S)-1-aminoindane (0.0662 g, 0.48 mmol) in ethanol (5 mL) was refluxed at 95° C. for 14 h and then concentrated under reduced pressure. The residue was purified by flash chromatography (0 to 60% EtOAc/DCM) to afford the title compound (0.09 g, 80%).
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]1[N:15]=[N:14][C:13]([C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)=[CH:12][CH:11]=1)[CH2:6]2.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[OH-].[Na+]>ClCCl>[CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH:3]1[CH2:4][N:5]([C:10]1[N:15]=[N:14][C:13]([C:16]#[C:17][C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:22][CH:23]=3)=[CH:12][CH:11]=1)[CH2:6]2
Reactant: CN1C2CCC1CN(c1ccc(C#Cc3ccc(N)cc3)nn1)C2
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN1C2CCC1CN(c1ccc(C#Cc3ccc(NC(=O)c4ccccc4)cc3)nn1)C2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 4-[6-(8-methyl-3,8-diaza-bicyclo[3.2.1]oct-3-yl)-pyridazin-3-ylethynyl]-phenylamine (0.53 g, 1.66 mmol) and dichloromethane (20 ml) was added: benzoylchloride (0.35 g, 2.5 mmol) solved in dichloromethane (20 ml). The mixture was stirred at 0° C. for 2 hours and was then allowed to stir at room temperature for 15 hours. Aqueous sodium hydroxide (20 ml, 1 M) was added and the mixture was extracted with dichloromethane (3×30 ml). The mixture was dried and evaporated. Mp 88-96° C. LC-ESI-HRMS of [M+H]+ shows 424.2145 Da. Calc. 424.213735 Da, dev. 1.8 ppm.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14](O)[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:18]>CCOCC>[CH2:1]([O:3][C:4]([C:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([Cl:18])[C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c[nH]c2c(O)ncnc12
Solvent: CCOCC
Product: CCOC(=O)c1c[nH]c2c(Cl)ncnc12
Temperature: 105 °C
Yield: 83.3 %

Procedure:
4,6-Diazaindole 4 (2.74 g, 13.2 mmol) was slurried in POCl3 (37 mL, 400 mmol) and heated at 105° C. for 3.5 h. The reaction mixture was cooled, diluted with Et2O (150 mL) and the resulting precipitate was collected by filtration, rinsed with EtOAc and Et2O and dried under vacuum to yield 7-chloro-4,6-diazaindole 5 (2.48 g, 11.0 mmol, 83%) as a yellow powder which was used without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([C:19]([OH:21])=[O:20])[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1(O)[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=1>>[C:30]1([O:20][C:19]([C:17]2[N:18]=[C:14]([CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]3)[S:15][CH:16]=2)=[O:21])[C:31]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)O)cs2)CC1
Reactant: Oc1cccc2ccccc12
Product: CC(C)(C)OC(=O)N1CCC(c2nc(C(=O)Oc3cccc4ccccc34)cs2)CC1

Procedure:
A solution of 2-[1-(tert-butoxycarbonyl)piperidin-4-yl]-1,3-thiazole-4-carboxylic acid (VIII-1, 12.0 g) is reacted analogously to Example IX-1 with 1-naphthol (7.20 g). This gives, after chromatographic purification, tert-butyl 4-{4-[(1-naphthyloxy)carbonyl]-1,3-thiazol-2-yl}piperidine-1-carboxylate (12.3 g, 73%)
Reaction SMILES: [C:1]([C:4]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH:16](OC)(OC)OC.Cl>CO>[CH3:16][O:10][C:7]12[CH2:8][CH2:9][C:4]([C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH2:5][CH2:6]1)[C:1](=[O:3])[CH2:2]2
Reactant: CCOC(=O)C1(C(C)=O)CCC(=O)CC1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CO
Product: CCOC(=O)C12CCC(OC)(CC1)CC2=O
Temperature: 5 °C

Procedure:
To a stirred solution of Step 3 product (1 eq) and trimethyl orthoformate (4.00 eq) in MeOH (9.4 v/w) at 5° C. was bubbled HCl gas (approximately 5 eq) over 2 hours, maintaining a pot temperature of 5° C. Upon complete addition, the reaction mixture, under nitrogen, was heated to, and stirred at, reflux for 30 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1.CN1[CH2:30][CH2:29][O:28]CC1.O>ClCCl>[C:29]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[S:6][CH:7]=[C:8]([CH2:9][C:10]3[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=3[O:20][CH3:21])[C:4]=2[CH:3]=1)(=[O:28])[CH2:30][CH2:23][CH2:2][CH2:3][CH3:4]
Reactant: CN1CCOCC1
Reactant: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Solvent: O
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2scc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Reaction time: 1 h
Yield: 75 %

Procedure:
Hexanoyl chloridc (0.024 g.) was added to a stirred solution of methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g.), and N-methylmorpholine (0.1 ml.) in dichloromethane (3 ml.). The mixture was stirred for 1 hour and then poured into water (20 ml.). The aqueous mixture was extracted with dichloromethane (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The mixture was recrystallized from a mixture of ethyl acetate and hexane to give the title compound (0.05 g., 75%) as a colorless solid NMR (250 MHz, DMSO-d6): 0.87(t,3H, CH2CH3), 1.28(m,4H, CH2.CH2.CH3), 1.59 (quintet,2H, CH2CH2CON), 2.29(t,2H, CH2CON), 3.84(s, 3H, OCH3), 3.91(s,3H, OCH3), 4.11(s,2H, CH2 -Ar), 7.14 (d,1H), 7.34 (s,1H), 7.49(m,3H), 7.86(d,1H), 8.11(d, 1H), 9.95(s,1H).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[C:10]([CH3:20])[C:9]2[C:8]([OH:21])=[CH:7][C:6]([CH3:22])=[CH:5][C:4]=2[N:3]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH3:34][O:35][C:36](=[O:39])[CH2:37]Br>O>[CH3:34][O:35][C:36](=[O:39])[CH2:37][O:21][C:8]1[CH:7]=[C:6]([CH3:22])[CH:5]=[C:4]2[C:9]=1[C:10]([CH3:20])=[C:11]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:2]([Cl:1])=[N:3]2
Reactant: COC(=O)CBr
Reactant: Cc1cc(O)c2c(C)c(Cc3ccc(Cl)cc3)c(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(C)cc2nc(Cl)c(Cc3ccc(Cl)cc3)c(C)c12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 2-chloro-3-(4-chlorobenzyl)-4,7-dimethylquinolin-5-ol (1.7 g), N,N-dimethylformamide (25 mL), potassium carbonate (2.1 g) and bromoacetic acid methyl ester (1.1 g) was stirred at 60° C. overnight. The mixture was cooled to room temperature, diluted with water and the resulting precipitate collected by filtration, washed with water and then dried to afford title compound, 0.53 g.
Reaction SMILES: [C:1]([C:3](=[CH:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:9]=1)[C:4](O)=[O:5])#[N:2].C(Cl)(=O)C([Cl:26])=O>ClCCl.CN(C=O)C>[CH2:21]([O:20][C:18](=[O:19])[CH2:17][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH:7]=[C:3]([C:4]([Cl:26])=[O:5])[C:1]#[N:2])=[CH:9]1)[CH3:22]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCOC(=O)Cn1cc(C=C(C#N)C(=O)O)c2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(C=C(C#N)C(=O)Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.4 %

Procedure:
To a stirred suspension of 2-cyano-3-(1-ethoxycarbonylmethyl-1H-indol-3-yl)-acrylic acid (3.0 g, 10 mmol) in dry dichloromethane (120 ml), in the presence of a few drops of dry DMF, was added oxalyl chloride (1.7 ml, 20 mmol). After stirring at rt overnight, the volatiles were removed under reduced pressure, the residue azeotoped twice with dry toluene and dried in vacuo, affording crude title compound (3.18 g) in quantitative yield. This material was stored under argon and was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)[CH:5]=[O:6].[N:13]1([C:19](Cl)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CCN(CC)CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:13]1([C:19]([O:1][C:2]2[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[C:4]([CH:5]=[O:6])[CH:3]=2)=[O:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CC(C)c1cc(O)cc(C=O)c1
Reactant: O=C(Cl)N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1cc(C=O)cc(OC(=O)N2CCOCC2)c1
Reaction time: 3 h
Yield: 22.1 %

Procedure:
To a stirring solution of 91.9 mg (0.634 mmol) of 3-hydroxy-5-isopropylbenzaldehyde in 5 mL of CH2Cl2 at r.t. was added 220 μL (1.92 mmol) of 4-morpholinecarbonyl chloride and 0.5 mL (3.59 mmol) of Et3N. After 3 h, sat. NaHCO3 (15 mL) was added, and the aqueous layer was extracted with CHCl3. The organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. Purification by flash silica gel chromatography (20% EtOAc/hexanes) provided 38.8 mg of 3-formyl-5-isopropylphenyl morpholine-4-carboxylate as a yellow oil in 24% yield.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:23][O:24][CH:25]1[CH2:30][CH2:29][N:28]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:27][CH2:26]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Reactant: COC1CCNCC1
Product: COC1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with 4-methoxypiperidine (1.2 equiv) to give 215 (19.6 mg, M+1 411.1)
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([O:10][CH3:11])=[C:5]([CH3:12])[C:4]=1[CH3:13].[CH3:14][O:15][CH3:16]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[C:4]([CH3:13])=[C:5]([CH3:12])[C:6]([O:10][CH3:11])=[C:7]([CH3:9])[C:8]=1[CH:3]=[O:2]
Reactant: COC
Reactant: COc1cc(C)c(OC)c(C)c1C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(C)c(C)c(OC)c(C=O)c1C

Procedure:
1,4-Dimethoxy-2,3,5-trimethylbenzene, 9.00 g (50 mmole), was dissolved in CH2Cl2 (60 ml) and stirred with ice-cooling. After addition of 14.4 g (50×2.5 mmole) of dichloromethyl, methyl ether, 13.8 ml (50×2.5 mmole) of titanium tetrachloride dissolved in CH2Cl2 (30 ml) was added dropwise over 15 minutes. After stirring for further 15 minutes with ice-cooling, the ice bath was removed and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into crashed ice (about 200 g) and stirred vigorously for 30 minutes. The CH2Cl2 layer was washed with water (3 times), and dried (MgSO4), from which CH2Cl2 was evaporated off. The residue was recrystallized from isopropyl ether/hexane (1:1), to give 6.18 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde. The mother liquor was concentrated, and the residue was purified with silica gel (60 g) column chromatography (eluted with isopropyl ether), to give 3.70 g of 2,5-dimethoxy-3,4,6-trimethylbenzaldehyde.
Reaction SMILES: [CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]3[O:20][CH2:19]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7].[C:22]1([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO.[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38]>CC(C)=O>[C:36]([OH:41])(=[O:40])[C:37]([OH:39])=[O:38].[CH3:1][CH:2]([CH3:21])[CH2:3][CH2:4][N:5]1[C:15]2[C:10](=[C:11]([O:16][CH2:17][CH:18]([OH:20])[CH2:19][N:31]3[CH2:32][CH2:33][N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:29][CH2:30]3)[CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][C:6]1=[O:7]
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CC(C)CCN1C(=O)CCc2c(OCC3CO3)cccc21
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)CCN1C(=O)CCc2c(OCC(O)CN3CCN(c4ccccc4)CC3)cccc21
Yield: 38.7 %

Procedure:
2.9 grams of 1-(3-methylbutyl)-5-(2,3-epoxypropoxy)-3,4-dihydrocarbostyril and 1.7 g of 4-phenylpiperazine are mixed with 50 ml of methanol and reacted at 50°-60° C. for 3 hours. The reaction mixture is concentrated under reduced pressure and the residue thus obtained is dissolved in 50 ml of acetone. Into this solution, 20 ml of an acetone solution containing 1.1 g of oxalic acid are added, then the precipitate thus formed is collected by filtration, washed with acetone and dried. Recrystallization from ethanol-ether to obtain 2.1 g of 1-(3-methylbutyl)-5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril monooxalate in the form of colorless crystals. This product is confirmed as a single compound by a silica-gel thin layer chromatography-(developing solvent; chloroform:methanol=9:1).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH2:36])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][C@@H:32]([NH:36][C:2]2[N:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[N:6][CH:7]=2)[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: N[C@@H]1CCCN(Cc2ccccc2)C1
Reactant: CCOC(=O)/C=C/c1cnc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCCN(Cc3ccccc3)C2)cn1
Temperature: 85 °C
Reaction time: 18 h
Yield: 24.2 %

Procedure:
To a solution of ethyl (2E)-3-(5-chloro-2-pyrazinyl)acrylate (300 mg) and potassium carbonate (4.94 mg) in DMF (15 mL) was added (3R)-1-benzyl-3-piperidinamine dihydrochloride (668 mg) under nitrogen at ambient temperature and the mixture was stirred at 85° C. for 18 hrs. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated in vacuo. The residue was purified by silica gel column chromatography (chloroform-MeOH=97-3) to give ethyl (2E)-3-(5-{[(3R)-1-benzyl-3-piperidinyl]amino}-2-pyrazinyl)acrylate (125 mg) as an oil.