Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH3:15])[C:11]([Cl:20])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]2[O:42][N:41]=[C:40]([CH3:43])[CH:39]=2)[CH:33]=1)=[O:31])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)CC(C)C)cc3NC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(isobutyl-methyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J27) (328 mg, 1.0 mmol) and 3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K4) (301 mg, 1.0 mmol) according to the general procedure M. Obtained as a light yellow foam (360 mg, 65%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][O:21][CH3:22].[C:23]1([CH3:33])[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>>[NH2:18][C:9]1[C:8]2[N:7]=[C:6]([CH2:19][CH2:20][O:21][CH3:22])[N:5]([CH2:4][CH2:3][CH2:2][NH:1][S:29]([C:26]3[CH:27]=[CH:28][C:23]([CH3:33])=[CH:24][CH:25]=3)(=[O:31])=[O:30])[C:17]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c(N)nc3ccccc3c2n1CCCN
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCCNS(=O)(=O)c1ccc(C)cc1
Yield: 32.4 %

Procedure:
Using the general method of Example 242, 1-(3-aminopropyl)-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-4-amine (1.53 g, 5.11 mmol) was reacted with p-toluenesulfonyl chloride (1.07 g, 5,62 mmol) to provide 750 mg of N-{3-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-4-methylbenzenesulfonamide as a solid, m.p. 189-191° C. Analysis: Calculated for C23H27N5O3S 0.50H2O: % C, 59.72; % H, 6.10; % N, 15.14; Found: % C, 59.73; % H, 5.95; % N, 15.08.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][NH:8][C:5]2=[CH:6][CH:7]=1.[Cl:22][C:23]1[S:27][C:26]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)=[N:25][CH:24]=1.C(N(CC)CC)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:29](=[O:30])[NH:28][C:26]3[S:27][C:23]([Cl:22])=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Br)cc32)C1
Reactant: O=C(Nc1ncc(Cl)s1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
2-Amino-5-chlorothiazole hydrochloride (1.00 g, 5.80 mmol) was dissolved in methylene chloride (50 mL), and the obtained solution was then washed with a saturated aqueous solution of sodium hydrogen carbonate. The resulting solution was dried over anhydrous sodium sulfate and was then filtered. After that, pyridine (0.47 mL, 5.80 mmol) and 4-nitrophenyl chloroformate (1.18 g, 5.80 mmol) were added to the filtrate, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a solid was collected by filtration, was then washed with methylene chloride, and was then dried to obtain 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (980 mg, 56%) in the form of a white solid. t-Butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (65.1 mg, 0.184 mmol) synthesized by a method described in the known method (International Publication WO2009/089454) or a method similar thereto was dissolved in N,N′-dimethylformamide (2 mL). Thereafter, 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (55.2 mg, 0.184 mmol) and triethylamine (13 μL, 0.092 mmol) were added to the above obtained solution, and the obtained mixture was then stirred at 50° C. for 3 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the captioned compound (60.0 mg, 64%) in the form of a white solid.
Reaction SMILES: [OH-:1].[Li+].[CH3:3][C:4]([C:6]1[C:7]([OH:13])=[CH:8][CH:9]=[CH:10][C:11]=1[OH:12])=[O:5].[C:14](Cl)(=[O:24])[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](Cl)=O)[CH:16]=1.Cl>C1COCC1>[OH:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:4](=[O:5])[CH:3]=[C:18]([C:17]1[CH:16]=[C:15]([CH:23]=[CH:22][CH:21]=1)[C:14]1[O:24][C:7]3[C:6]([C:4](=[O:1])[CH:3]=1)=[C:11]([OH:12])[CH:10]=[CH:9][CH:8]=3)[O:12]2
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Reactant: CC(=O)c1c(O)cccc1O
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1cc(-c2cccc(-c3cc(=O)c4c(O)cccc4o3)c2)oc2cccc(O)c12
Temperature: -10 °C
Reaction time: 2 h

Procedure:
Dry, pulverulent lithium hydroxide (19.5 mmol, 3 equivalents) is added in one portion to a well-stirred solution of 2,6-dihydroxyacetophenone (6.6 mmol) in dry THF (5 ml) under an argon atmosphere at −78° C. The reaction mixture is stirred at −78° C. for one hour and subsequently at −10° C. for two hours. After the mixture has been re-cooled to −78° C., a solution of isophthaloyl chloride (3.3 mmol) in THF (10 ml) is added in one portion. The mixture is stirred at −78° C. for one hour and at room temperature for 4 hours until the starting material has disappeared. The reaction mixture is emptied into a mixture of ice (150 g) and concentrated HCl (5 ml) and extracted with chloroform (3×50 ml). The solvents are removed from the dried extracts, and the residue is dried under reduced pressure for 24 hours. Glacial acetic acid (30 ml) and sulfuric acid (0.2 ml) are added to the residue, and the mixture is heated at 95–100° C. for from 30 minutes to one hour under an argon atmosphere. Approximately one third of the acetic acid is stripped off, and the residue is emptied into water. The precipitated product is filtered, washed and dried and recrystallised in methanol, giving 3′-(5-hydroxychromonyl)-5-hydroxyflavone. EI-MS (70 eV) m/e (rel. abund.)=398.
Reaction SMILES: [CH3:1][C:2]1O[CH:4]=[CH:5][C:6](=[O:16])[C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)C.O.Cl.C[C:23]1[NH:24]C=C[C:27](=[O:37])[C:28]=1[O:29]CC1C=CC=CC=1>OCC(CO)O>[CH2:23]([N:24]1[CH:4]=[CH:5][C:6](=[O:16])[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]1[CH3:1])[CH:28]([CH2:27][OH:37])[OH:29]
Reactant: Cc1[nH]ccc(=O)c1OCc1ccccc1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: OCC(O)CO
Solvent: O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CC(O)CO
Yield: 40 %

Procedure:
35.6 g (165 mmol. 1.5 eq.) of 2-methyl-3-benzyloxy-4-pyranone and 10 g (110 mmol) of 1-amino-1-desoxy-glycerol are put into 600 mL of a 50:50 ethanol-water mixture; then 14 mL of an aqueous solution of soda (2N) is added. The reaction medium is then brought under reflux agitation for 48 hours. The reaction medium is left to cool, and then a solution of concentrated HCl is added to reach a pH=1. After evaporation of ethanol, the resifue is extracted using ethyl ether (3×100 mL) in order to eliminate any excess of 2-methyl-3-benzyloxy-4-pyranone. The aqueous phase is brought to neutral pH by addition of an aqueous solution of NaOH and then concentrated under reduced pressure. The residue is retaken up with a minimum of water. By precipitation, 12.7 g (43.9 mmol) of 2-methyl-3-benzyloxypyridine-4(1H)-one of glycerol is isolated, which is pure at chromatographic and NMR analyses. Yield 40%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:14]([CH:17]2[CH2:22][N:21]([CH:23]=[O:24])[CH2:20][CH2:19][O:18]2)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([S:14]([CH:17]2[CH2:22][N:21]([CH:23]=[O:24])[CH2:20][CH2:19][O:18]2)(=[O:16])=[O:15])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[CH:9]=1
Reactant: O=CN1CCOC(S(=O)(=O)c2cc([N+](=O)[O-])cc(C(F)(F)F)c2)C1
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(C(F)(F)F)cc(S(=O)(=O)C2CN(C=O)CCO2)c1
Reaction time: 72 h

Procedure:
To an argon purged solution of (3-nitro-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino) methanone (658 mg, 1.87 mmol) in EtOH (20 mL) was added Pd/C (198 mg, 0.187 mmol, 10%). The resulting mixture was allowed to stir under an atmosphere of hydrogen gas for 3 days. The reaction was purged with argon, filtered through Celite and concentrated under reduced pressure to afford (3-amino-5-(trifluoromethyl)phenyl)-(sulfonylmorpholino)methanone which was used without further purification. MS m/z=323 [M+H]+. Calc'd for C12H13F3N2O3S: 322.
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:48][N:49]1[CH2:54][CH2:53][CH2:52][C:51]([NH2:61])([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:50]1>CN(C=O)C>[Cl:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:61][C:51]1([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[CH2:52][CH2:53][CH2:54][N:49]([CH3:48])[CH2:50]1)=[O:6]
Reactant: CN1CCCC(N)(c2ccccc2)C1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCCC(NC(=O)c2cccc(C(F)(F)F)c2Cl)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 51.9 %

Procedure:
To a solution of 33 mg (0.144 mmol) 2-chloro-3-(trifluoromethyl)benzoic acid (commercial), 75 mg (0.197 mmol) HATU and 90 ul (0.524 mmol) N-ethyldiisopropylamine in DMF (1 ml) was added a solution of 25 mg (0.131 mmol) rac-1-methyl-3-phenyl-piperidin-3-ylamine (Example A.1) in DMF (0.25 ml). The mixture was stirred at room temperature for 22 hours. The solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The solution was washed once with water and twice with a saturated sodium carbonate solution. The aqueous layer was extracted once with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified on silica gel (Eluent: Heptane/ethyl acetate 0 to 100%) to provide 27 mg (52%) of the title compound as a light yellow oil. MS (m/e): MS (m/e): 397.2 (M+H)
Reaction SMILES: [C@@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[NH:14]2)=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.IC.N1[CH2:28]CCN2CCCCCC=12>CN(C=O)C>[C@@H:1]1([NH:10][C:11]([N:13]2[C:21](=[O:22])[C:20]3[C:15](=[N:16][C:17]([Cl:24])=[CH:18][C:19]=3[CH3:23])[N:14]2[CH3:28])=[O:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)N[C@H]3CCc4ccccc43)c(=O)c12
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1cc(Cl)nc2c1c(=O)n(C(=O)N[C@H]1CCc3ccccc31)n2C

Procedure:
In analogy to example 2, 50 mg (0.146 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid (S)-indan-1-ylamide were reacted with 31 mg (0.22 mmol) of iodomethane in DMF with 2,3,4,6,7,8,9,10-octahydro -pyrimido[1,2-a]azepin (DBU). Yield: 6 mg (12%), M+H+: 357.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[N:18]1([CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>>[ClH:1].[N:18]1([CH2:23][CH2:24][CH:25]2[CH2:26][CH2:27][N:28]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=4)=[CH:4][N:3]=3)[CH2:29][CH2:30]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: FC(F)(F)c1ccc(-c2ccc(Cl)nc2)cc1
Reactant: C1CCN(CCC2CCNCC2)C1
Product: Cl
Product: FC(F)(F)c1ccc(-c2ccc(N3CCC(CCN4CCCC4)CC3)nc2)cc1

Procedure:
The title compound was prepared by a similar procedure to that described in Example 1, starting from 2-chloro-5-(4-trifluoromethylphenyl)pyridine and 4-(2-pyrrolidinoethyl)piperidine.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[NH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15])=[N+]=[N-].[Cl:16][C:17]1[CH:18]=[C:19]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[Cl:23].[H][H]>N1C=CC=CC=1.CCO.[Pd]>[NH2:1][CH2:4][C@H:5]1[N:14]([S:24]([C:19]2[CH:20]=[CH:21][C:22]([Cl:23])=[C:17]([Cl:16])[CH:18]=2)(=[O:26])=[O:25])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:15]
Reactant: [N-]=[N+]=NC[C@H]1Nc2ccccc2NC1=O
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: c1ccncc1
Product: NC[C@@H]1C(=O)Nc2ccccc2N1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3R)-3-(azidomethyl)-3,4-dihydroquinoxalin-2(1H)-one (122 mg, 0.60 mmol) in pyridine (3 mL) was added 3,4-dichlorobenzenesulfonyl chloride (300 uL, 1.92 mmol). After stirring at room temperature overnight, the reaction mixture was concentrated under reduced pressure and purified using silica gel chromatography eluting with CH2Cl2-3% MeOH in CH2Cl2. The resulting product (137 mg, 0.33 mmol) was dissolved in EtOH (3 mL) and Pd/C (93 mg, 0.087 mmol) was added. A hydrogen balloon was placed over the reaction mixture for 5.5 hours before it was filtered through celite and concentrated to give (3R)-3-(aminomethyl)-4-[(3,4-dichlorophenyl)sulfonyl]-3,4-dihydroquinoxalin-2(1H)-one, which was used without further purification. LCMS (ES) 385.9.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([CH2:16]Cl)=O.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH3:36])=[CH:29][CH:28]=2)[C:22]([C:45]#[N:46])=[C:21]([SH:47])[N:20]=1>CN(C=O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH2:34][CH:35]([O:37][Si:38]([C:41]([CH3:42])([CH3:43])[CH3:44])([CH3:39])[CH3:40])[CH3:36])=[CH:31][CH:32]=2)[C:22]([C:45]#[N:46])=[C:21]([S:47][CH2:16][C:14]2[N:11]=[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[S:10][CH:13]=2)[N:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)Nc1ccc(F)cc1
Reactant: CC(COc1ccc(-c2c(C#N)c(N)nc(S)c2C#N)cc1)O[Si](C)(C)C(C)(C)C
Solvent: CN(C)C=O
Product: CC(COc1ccc(-c2c(C#N)c(N)nc(SCc3csc(Nc4ccc(F)cc4)n3)c2C#N)cc1)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 78.6 mg (0.46 mmol) of 4-fluorophenylthiourea and 56.0 mg (0.44 mmol) of 1,3-dichloroacetone in 2 ml of dry DMF is stirred at +80° C. for 3 h. After cooling to RT, 370 mg (0.42 mmol) of the compound from Example 42A are added, and the mixture is then stirred at RT for 20 h. The reaction mixture is purified directly by two preparative HPLCs (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+]>CO.ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)=[CH:14][CH:13]=2)=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(-c2ccc(NC(=O)c3nc(Cl)c(CC)[nH]3)cc2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3ncc(C(=O)O)s3)cc2)nc1Cl
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 80.8 %

Procedure:
Ethyl 2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}phenyl)-1,3-thiazole-5-carboxylate obtained in Example (91c) (89 mg, 0.22 mmol) was dissolved in methanol (15 mL) and dichloromethane (10 mL). A 2 N aqueous lithium hydroxide solution (3 mL, 6 mmol) was added, and the mixture was stirred at 70° C. for 30 minutes. The organic solvent was evaporated under reduced pressure and 1 N hydrochloric acid was added until the pH of the solution was about 4. The resulting solid was collected by filtration and washed with distilled water to obtain 67 mg of the title compound as a light brown solid (80%).
Reaction SMILES: C1(O[C:8](=[O:22])[NH:9][C:10]2[N:11]([O:20][CH3:21])[CH2:12][C:13]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[CH:19]=2)C=CC=CC=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:21][O:20][N:11]1[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:22])=[CH:19][C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH2:12]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: CON1CC2=C(C=C1NC(=O)Oc1ccccc1)CCCC2
Product: COc1ccccc1N1CCN(C(=O)NC2=CC3=C(CCCC3)CN2OC)CC1
Yield: 64 %

Procedure:
Phenyl-N-(2-methoxy-5,6,7,8-tetrahydroisoquinolin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15].O>C(O)C>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[CH2:1]/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCCO
Reactant: ClCC=Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CN(C/C=C/c1ccccc1)CCO

Procedure:
12.5 Grams of cinnamyl chloride and 21 g of 2-methylaminoethanol were dissolved in 100 ml of ethanol, and the solution was refluxed for 5 hours. The solvent was removed by evaporation, to the residue thus obtained was added water and washed with n-hexane. To the water layer was added 3N-sodium hydroxide aqueous solution to adjust its pH to 10-11, and extracted with ether. The ether extract was washed with water and dried with anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was purified by means of a silica gel column chromatography (eluent: chloroform:methanol=25:1) to yield 15 g of 2-[N-methyl-N-(3-phenyl-2(E)-propenyl)amino]ethanol.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][CH:8]([O:16][CH2:17][CH3:18])[CH:9]([CH3:15])[CH:10](OCC)[CH3:11])[CH3:6].C1C2C(=CC=CC=2)C=CN=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:5]([O:7][CH:8]([O:16][CH2:17][CH3:18])[CH3:9])[CH3:6].[CH3:5][O:7][CH:8]=[C:9]([CH3:15])[CH:10]=[CH2:11]
Reactant: CCOC(C)C(C)C(OCC)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccc2cnccc2c1
Product: C=CC(C)=COC
Product: CCOC(C)OCC

Procedure:
According to the present invention, a method for synthesizing 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde comprises the following steps: (1) adding acetaldehyde diethyl acetal (abbreviation: acetal) and ethyl-(1-propenyl)-ether under effects of a catalyst at a temperature of −10° C.˜0° C. to produce 1,1,3-triethoxy-2-methyl-butane; wherein the catalyst is ferric chloride or aluminum chloride; acetaldehyde diethyl acetal is prepared by the Chinese Patent No. ZL97115390.6 of Hoffmann-La Roche Ltd; (2) pyrolysis synthesizing 1,1,3-triethoxy-2-methyl-butane under catalytic effects of isoquinoline and p-Toluenesulfonic acid at a temperature of 180-200° C. to produce 1-methoxy-2-methyl-1,3-butadiene; but the catalyst used in the Chinese Patent ZL97115390.6 of Hoffmann-La Roche Ltd. is silicon-aluminum ball, to pyrolysis produce 1-methoxy-2-methyl-1,3-butadiene at high temperature, its conversion rate is only 41%, and its selectivity is 90%; (3) dissolving 1-methoxy-2-methyl-1,3-butadiene in anhydrous ethanol solvent for synthesis with a phase transfer catalyst and a chlorinating agent at a temperature of −5˜0° C. to generate 4,4-diethoxy-3-methyl-1-chloro-butene; wherein the phase transfer catalyst is cetyl-trimethyl ammonium bromide, the chlorinating agent is trichloroisocyanuric acid; (4) combining 4,4-diethoxy-3-methyl-1-chloro-butene with a triphenylphosphine salt at a temperature of 60˜65° C. to produce a phosphonic salt; and (5) condensing the phosphonic salt under effects of hydrogen peroxide at a temperature of 0˜5° C. in conjunction with sodium carbonate solution to generate 1,1,8,8-tetramethyl-2,7-dimethyl-2,4,6-octatriene at pH=8˜10; and then hydrolyzing under acidic conditions to synthesize 2,7-dimethyl-2,4,6-octatriene-1,8-dialdehyde.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[S:8](Cl)(Cl)=[O:9].O>C(Cl)Cl>[CH3:1][C:2]1([CH3:7])[CH2:5][O:6][S:8](=[O:9])[O:4][CH2:3]1
Reactant: CC(C)(CO)CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CC1(C)COS(=O)OC1
Temperature: 25 °C
Yield: 92 %

Procedure:
25.36 g (0.24 mol) of 2,2-dimethylpropane-1,3-diol was suspended at room temperature in 150 ml of methylene chloride in a 500 ml three-necked flask. 37.36 g (0.31 mol) of thionyl chloride was instilled over 30 minutes. After the end of the addition, the reaction solution was held at reflux for 1.5 hours and then cooled to room temperature. 100 ml of water was added to the reaction. The aqueous phase was discarded; the organic phase was extracted three times with saturated NaHCO3 solution (100 ml), then dried with Na2SO4 and concentrated by evaporation on a rotary evaporator. The residue was distilled at 24 mbars and 78° C. The product was a pure colorless liquid according to GC and weighed 23.4 g, which corresponded to a yield of 92 percent.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:14](#[N:18])[CH2:15][C:16]#[N:17].N1CCCCC1.[CH2:25]([O:27][C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)[CH3:26]>C(O)C>[NH2:17][C:16]1[O:34][C:30]2[C:31]([CH:7]([C:6]3[CH:5]=[C:4]([O:10][CH3:11])[C:3]([O:12][CH3:13])=[C:2]([Br:1])[CH:9]=3)[C:15]=1[C:14]#[N:18])=[CH:32][CH:33]=[C:28]([O:27][CH2:25][CH3:26])[CH:29]=2
Reactant: N#CCC#N
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: CCOc1cccc(O)c1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOc1ccc2c(c1)OC(N)=C(C#N)C2c1cc(Br)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a mixture of 5-bromoveratraldehyde (245 mg, 1 mmol) and malononitrile (66 mg, 1 mmol) in ethanol (2 ml) was added piperidine (0.1 ml, 1 mmol). The mixture was stirred at room temperature for 15 min, then 3-ethoxyphenol (138 mg, 1 mmol) was added and it was stirred overnight. The solvent was evaporated and the residue was purified by chromatography on silica gel (EtOAc/Hexane, 1:2) to yield the title compound. 1H NMR (CDCl3): 6.84-6.82 (m, 2H), 6.70 (s, 1H), 6.61-6.65 (m, 1H), 6.53 (s, 1H), 4.62 (m, 3H), 4.0 (q, J=6.0, 2H), 3.82 (s, 6H), 1.4 (t, J=6.0, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11]I)[C:6]=2[CH:13]=1.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[C:23]([N:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)[CH:24]=1)[N:21]=[CH:20][CH:19]=[CH:18]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][CH2:11][N:28]3[CH2:29][CH2:30][N:25]([C:23]4[CH:24]=[C:15]([Cl:14])[CH:16]=[C:17]5[C:22]=4[N:21]=[CH:20][CH:19]=[CH:18]5)[CH2:26][CH2:27]3)[C:6]=2[CH:13]=1
Reactant: Clc1cc(N2CCNCC2)c2ncccc2c1
Reactant: Clc1ccc2occ(CCI)c2c1
Product: Clc1cc(N2CCN(CCc3coc4ccc(Cl)cc34)CC2)c2ncccc2c1

Procedure:
8-{4-[2-(5-chloro-1-benzofuran-3-yl)ethyl]-1-piperazinyl}-6-chloro-quinoline was prepared by generally following the procedure outlined in example 12, step 6, starting from the 2-(5-chloro-1-benzofuran-3-yl)ethyl iodide (306 mg, 1 mmol) and 6-chloro-8-piperazino quinoline (247 mg, 1 mmol). The product was purified by silica-gel column chromatography by initially eluting it with 80% ethyl acetate:hexane and then with 5% methanol:ethyl acetate, yielding a brown oil. Yield: 110 mg (25%); (M+H): 427; 1HNMR (400 MHz, CDCl3):δ 8.86˜8.85 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 8.03˜8.01 (dd, J1=1.8 Hz, J2=1.8 Hz, 1H); 7.57˜7.10 (m, 7H); 3.51˜2.50 (m, 12H).