Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)[CH2:25][CH2:24]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[O:9])=[CH:6][N:5]=[C:4]([NH:33][C:32]2[CH:31]=[CH:30][C:29]([N:26]3[CH2:25][CH2:24][N:23]([CH3:22])[CH2:28][CH2:27]3)=[CH:35][CH:34]=2)[N:3]=1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2cccc(F)c2)c(N)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: CN1CCN(c2ccc(Nc3ncc(C(=O)c4cccc(F)c4)c(N)n3)cc2)CC1
Temperature: 105 °C
Yield: 62.1 %

Procedure:
A suspension of (4-amino-2-ethanesulfonyl-pyrimidin-5-yl)-(3-fluoro-phenyl)-methanone (20.1 mg, 0.0650 mmol, Example 3), 4-(4-methylpiperazino)aniline (15.8 mg, 0.0826 mmol, Appolo Chemical) and p-toluenesulfonic acid hydrate (15 mg, 0.0777 mmol, Aldrich) in isopropanol (2.5 mL) was placed in a sealed tube and heated at 100 to 110° C. under microwave conditions for 1 hour. The resulting mixture was evaporated in vacuo and the crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(3-fluoro-phenyl)-methanone as a light yellow solid (16.4 mg, 68% yield). HRMS, observed: 407.1994; Calcd for (M+H)+: 407.1990.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH3:34][O:33][C:31]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]2)=[CH:21][CH:20]=3)=[O:23])[CH2:25][CH2:26]1)=[O:32]
Reactant: COC(=O)Cl
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Agent: Cl
Product: COC(=O)N1CCN(C(=O)c2cc3cc(OC4CCN(C(C)C)CC4)ccc3[nH]2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and methyl chloroformate. Light-yellow solid. MS (m/z): 429.3 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]=[C:11]([NH:14][CH2:15][C:16]3[O:17][C:18]([CH3:21])=[CH:19][CH:20]=3)[O:12][CH2:13][C:8]=2[CH:7]=1)=[O:4].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>C(#N)C>[CH3:21][C:18]1[O:17][C:16]([CH2:15][NH:14][C:11]2[O:12][CH2:13][C:8]3[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH:23]=[CH:22][C:9]=3[N:10]=2)=[CH:20][CH:19]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(CNC2=Nc3ccc(NC(=O)CCl)cc3CO2)o1
Solvent: CC#N
Product: Cc1ccc(CNC2=Nc3ccc(NC(=O)CN4CCOCC4)cc3CO2)o1
Yield: 86.7 %

Procedure:
Prepared from the above described 2-chloro-N-{2-[(5-methyl-furan-2-ylmethyl)-amino]-4H-benzo[d][1,3]oxazin-6-yl}-acetamide (100 mg, 0.300 mmol) and morpholine (0.260 ml 2.996 mmol) in acetonitrile (1 ml) according to the procedure described for Example 3 step B. Obtained the title compound as a white solid (100 mg, 87%), MS (ISP) m/e=385.3 [(M+H)+].
Reaction SMILES: CN(C)[CH:3]=[C:4]1[CH2:9][CH2:8][CH2:7][CH:6]([O:10][CH2:11][CH3:12])[C:5]1=O.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:37][C:38]([NH2:40])=[NH:39])[CH:28]=[CH:29][C:30]=1[N:31]1[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]1>>[CH2:11]([O:10][CH:6]1[C:5]2[N:40]=[C:38]([NH:37][C:27]3[CH:28]=[CH:29][C:30]([N:31]4[CH:35]=[C:34]([CH3:36])[N:33]=[CH:32]4)=[C:25]([O:24][CH3:23])[CH:26]=3)[N:39]=[CH:3][C:4]=2[CH2:9][CH2:8][CH2:7]1)[CH3:12]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CCOC1CCCC(=CN(C)C)C1=O
Solvent: O=[N+]([O-])O
Product: CCOC1CCCc2cnc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)nc21

Procedure:
The title compound was prepared from 2-[1-dimethylamino-methylidene]-6-ethoxy-cyclohexanone (232 mg, 1.0 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (223 mg, 0.60 mmol) using in analogous manner the procedure described in example 45b). Obtained as a white solid (50 mg, 22%). MS ISP (m/e): 380.4 (100) [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Cl.[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:14][N:15]([CH3:19])[CH2:16][CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(OCCN(C)C)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
To a solution of ethyl 4-hydroxybenzoate (15.3 g) in N,N-dimethylformamide (150 mL) is added successively 2-dimethylaminoethyl chloride hydrochloride (15.9 g) and potassium carbonate (43.2 g) and the mixture is stirred at 110° C. overnight. To the reaction mixture is added water and the mixture is extracted with ethyl acetate. The organic layer is washed successively with a saturated sodium hydrogencarbonate solution and water, dried over anhydrous sodium sulfate, and concentrated in vacuo. The resultant crude product is purified by flash column chromatography on silica gel (Solvent; chloroform:methanol=10:1) to give ethyl 4-[2-(dimethylamino)ethoxy]benzoate (14.1 g, yield; 65%) as a brown oil. MS (APCI) m/z: 238 [M+H]+
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])[CH:5]=[C:6]([OH:8])[CH:7]=1.C(P(CCCC)CCCC)CCC.[CH2:34](O)[CH2:35][CH2:36][OH:37].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:18])([F:19])[F:20])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:34][CH2:35][CH2:36][OH:37]
Reactant: OCCCO
Reactant: Cc1cc(O)cc(OCc2ccccc2C(F)(F)F)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OCc2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
To a solution of 5-methyl-3-(2-trifluoromethylbenzyloxy)phenol (1.41 g, 5.0 mmol), as prepared in the preceding step, tri-n-butylphosphine (1.62 g, 8.0 mmol) and 1,3-propanediol (1.90 g, 25 rnmol) in anhydrous tetrahydrofuran (50 mL) was added 1,1'-(azodicarbonyl) dipiperidine (2.01 g, 8.0 mmol). The mixture was stirred at ambient temperature overnight. Hexane (100 mL) was added to the mixture and the precipitates were removed by filtration. The filtrate was evaporated in vacuo, and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (1.50 g, 84%). 1H-NMR (300 MHz, CDCl3) δ 7.74 (d, J=7.8 Hz, 1 H), 7.69 (d, J=7.8 Hz, 1 H), 7.56 (t, J=7.6 Hz, 1 H), 7.41 (t, J=7.7 Hz, 1 H), 6.41 (s, 1 H), 6.37 (s, 2 H), 5.23 (s, 2 H), 4.08 (t, J=6.0 Hz, 2 H), 3.85 (t, J=6.0 Hz, 2 H), 2.29 (s, 3 H), 2.02 (t, J =6.0 Hz, 2 H), 1.76 (s, 1 H).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21](=[O:25])[N:22]([CH3:24])[CH3:23])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.[OH-].[Li+]>C1COCC1.O>[C:30]([O:29][C:27]([NH:26][CH:20]([C:21](=[O:25])[N:22]([CH3:24])[CH3:23])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:34])=[O:2])=[CH:7][CH:8]=2)=[CH:14][CH:15]=1)=[O:28])([CH3:32])([CH3:31])[CH3:33]
Reactant: COC(=O)CCc1ccc(Oc2ccc(CC(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)C(Cc1ccc(Oc2ccc(CCC(=O)O)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.1 %

Procedure:
Amide 5 (8.4 g, 17.0 mmol) was dissolved in THF (60 mL) and diluted with water (60 mL). Lithium hydroxide (1.66 g, 69.0 mmol) was added and the reaction mixture was stirred at room temperature for about 2 h. The THF was evaporated and the resulting aqueous layer was acidified with 2.0 M HCl and extracted into EtOAc (2×100 mL). The organic layer was washed with water (1×100 mL) and brine (1×100 mL), dried and concentrated to yield the desired acid compound 6 (8.0 g, 97%). 1H NMR (400 MHz, DMSO-d6): 12.15 (br, 1H), 7.22 (overlapped d, J=8.4 Hz, 4H), 7.06 (d, J=8.4 Hz, 1H), 6.88 (d, J=8.4 Hz, 2H), 6.86 (d, J=8.4 Hz, 2H), 4.53 (m, 1H), 2.91 (s, 3H), 2.73-2.83) (m, 9H), 1.31 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH2:8])[CH:7]=1.Cl[C:17]1[CH:26]=[CH:25][N:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH2:27][CH3:28])=[N:22]2>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([NH:8][C:17]2[C:18]3[C:23](=[N:22][C:21]([CH2:27][CH3:28])=[CH:20][CH:19]=3)[N:24]=[CH:25][CH:26]=2)[CH:7]=1
Reactant: CCc1ccc2c(Cl)ccnc2n1
Reactant: Nc1cc(Cl)ccc1Oc1ccccc1
Product: CCc1ccc2c(Nc3cc(Cl)ccc3Oc3ccccc3)ccnc2n1

Procedure:
The product from Example 42b (100 mg, 0.46 mmol) was reacted with the product from Example 3f (88 mg, 0.46 mmol) following the procedure from Example 1g giving the title compound which was triturated with 2:1 ether/THF giving the product as a hydrochloride salt (134 mg, 70%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.34 (t, J=7.35 Hz, 3H) 3.02 (q, J=7.35 Hz, 2H) 6.69 (d, J=6.99 Hz, 1H) 6.97 (d, J=8.82 Hz, 2H) 7.10 (dd, J=7.35 Hz, 1H) 7.15 (d, J=8.82 Hz, 2H) 7.30 (dd, J=8.09 Hz, J=7.72 Hz, 2H) 7.56 (dd, J=2.94 Hz, J=9.19 Hz, 1H) 7.71 (d, J=2.57 Hz, 1H) 7.88 (d, J=8.82 Hz, 1H) 8.52 (d, J=6.99 Hz, 1H) 9.02 (d, J=8.45 Hz, 1H) 11.16 (br s, 1H) 14.56 (br s, 1H); MS (ESI+) m/z 376 (M−Cl)+; (ESI−) m/z 374 (M−HCl)−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.Cl[CH2:26][C:27]([NH:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=1)=[O:28].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[N:15]([CH2:26][C:27]([NH:29][C:30]4[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][CH:31]=4)=[O:28])[N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: O=C(CCl)Nc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cn1nc2c(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3)cnn2c1=O)Nc1ccc(C(F)(F)F)cc1
Temperature: 80 °C
Yield: 81 %

Procedure:
A solution of 7,8-bis(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, (30 mg, 0.084 mmol), prepared as described in Example 1, 2-chloro-N-(4-(trifluoromethyl)phenyl)acetamide (22 mg, 0.092 mmol), K2CO3 (35 mg, 0.25 mmol) in DMF (1 ml), was heated at 80° C. for 1 hour. After this time, the solution was cooled to RT and diluted with ethyl acetate. The resultant solution was then washed with water. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was purified by preparative HPLC to give the title compound, 2-(7,8-bis(4-chlorophenyl)-3-oxo-[1,2,4]triazolo[4,3-b]pyridazin-2(3H)-yl)-N-(4-(trifluoromethyl)phenyl)acetamide (38 mg, 81%) as a yellow solid. MS M+H=558; 1H NMR (CDCl3) δ 8.26 (1H), 7.60 (2H), 7.38-7.20 (8H), 7.11 (2H), 5.07 (2H).
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]#[N:10])=[C:7]([O:11]C)[C:6]([O:13]C)=[C:5]([O:15]C)[C:4]=1[O:17]C.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(C)C=CC=CC=1>[OH:2][C:3]1[C:8]([C:9]#[N:10])=[C:7]([OH:11])[C:6]([OH:13])=[C:5]([OH:15])[C:4]=1[OH:17]
Reactant: COc1c(C#N)c(OC)c(OC)c(OC)c1OC
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#Cc1c(O)c(O)c(O)c(O)c1O
Yield: 66 %

Procedure:
Four and three-tenths grams of pentamethoxybenzonitrile were refluxed in 12.5 g. of anhydrous aluminum chloride and 125 ml. of toluene for three hours after which time the suspension was poured into a mixture of 50 ml. of 12N aqueous hydrochloric acid and 200 g. of ice. The toluene layer was separated and the product recovered from the aqueous layer by filtration. Recrystallization from an ethyl acetate/toluene solvent mixture yielded pentahydroxybenzonitrile decomposing at 238° C. with a prior slight decomposition at 220° C.; yield=66%
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)[NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH2:18][CH2:17]1)(C)(C)C>ClCCl>[F:30][C:28]([F:29])([F:31])[C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([CH2:15][NH2:14])[CH2:17][CH2:18]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 123.5 %

Procedure:
A mixture of trifluoroacetic acid (10 ml) and dichloromethane (10 ml) was added to tert-butyl({1-[4-(trifluoromethyl)phenyl]piperidin-4-yl}methyl)carbamate (1.36 g). This mixture was stirred at room temperature for 3 h. The sample was concentrated and taken up in dichloromethane (20 ml) and saturated aqueous sodium bicarbonate. The mixture was extracted and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to provide the title compound (1.21 g, 86%). Mass spectrum (ESI) 242.1 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:4].C(C1C2C(=CC=C(OC(F)(F)F)C=2)N([CH2:31][C:32]([OH:34])=[O:33])C=1)(=O)C>>[OH:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:31][C:32]([OH:34])=[O:33])[CH:6]=1)=[O:4]
Reactant: O=C(CO)c1c[nH]c2ccccc12
Reactant: CC(=O)c1cn(CC(=O)O)c2ccc(OC(F)(F)F)cc12
Product: O=C(O)Cn1cc(C(=O)CO)c2ccccc21

Procedure:
was prepared from 2-hydroxy-1-(1H-indol-3-yl)-ethanone [2400-51-3] in a similar manner as described in Scheme A13 (step B and C) for the preparation of (3-acetyl-5-trifluoromethoxy-indol-1-yl)-acetic acid. Colored solid. MS: 234.0 [M+H]+, 489.0 [2M+Na]+; tR (HPLC conditions c): 3.11 min.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[C:27](O)[CH:26]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].IC.O.CN(C)[CH:54]=[O:55]>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[C:27]([O:55][CH3:54])[CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cc(O)cc3occ(CCc4ccccc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Product: COc1cc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c2c(CCc3ccccc3)coc2c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a mixture of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6-hydroxy-3-(2-phenylethyl)benzofuran (25 mg) and potassium carbonate (18 mg) in N,N-dimethylformamide (1 mL) was added iodomethane (0.007 mL), and the mixture was stirred at room temperature for 4 days. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (2 mL). To the solution was added sodium methoxide (28% methanol solution, 0.008 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give the title compound (8 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[NH:8]2)=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1.[CH:31](CS([O-])(=O)=O)([CH3:33])[CH3:32]>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([N:13]3[CH2:18][CH2:17][S:16](=[O:20])(=[O:19])[CH2:15][CH2:14]3)=[O:12])[N:8]2[CH:31]([CH3:33])[CH3:32])=[CH:4][C:3]=1[O:21][CH:22]1[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)[nH]c3cc2Br)CC1
Reactant: CC(C)CS(=O)(=O)[O-]
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCS(=O)(=O)CC4)n(C(C)C)c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 3, the title compound was synthesized from [6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-methanone (Example 6, step 4) and isopropylmethanesulfonate. The desired product was obtained in a yield of 69% as light yellow solid. MS (m/e): 540.3 (M+H, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:15])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Cl[C:17]1[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:17]2[N:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Product: COc1cc(Nc2nccc(C(F)(F)F)n2)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogous manner as described in example 1e) from 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine and 2-chloro-4-trifluoromethyl-pyrimidine. The reaction was refluxed for 16 h. The title compound was obtained as a pale-yellow solid in 43% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:17](=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][Br:11])[CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: O=C(Cl)CCCCCBr
Reactant: COc1cccc(Cl)c1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)CCCCCBr)c(Cl)c1Cl
Temperature: 5 °C
Reaction time: 18 h

Procedure:
A stirred mixture of 2,3-dichloroanisole (89 g., 0.50 mole) and 6-bromohexanoylchloride (120 g., 0.59 mole) in methylene chloride (500 ml.) is cooled to 5° C. and treated with aluminum chloride (74 g., 0.56 mole) in portions during a one-half hour period. The reaction mixture is kept at 25° C. for 18 hours then poured into ice water (1 l.) containing hydrochloric acid (100 ml.) the organic phase is separated, washed with water, 2% sodium hydroxide and dilute hydrochloric acid. The methylene chloride is evaporated at reduced pressure. The crude product is dissolved in ether (200 ml.), dried over magnesium sulfate, filtered and treated with hexane (600 ml.) affording 2,3-dichloro-4-(6-bromohexanoyl)anisole which melts at 52°-53° C.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:4]=1[CH2:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.C([O:24][C:25]1[CH:34]=[CH:33][C:28]([O:29][CH2:30][CH2:31]Br)=[CH:27][C:26]=1[CH3:35])C1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:24][C:25]1[CH:34]=[CH:33][C:28]([O:29][CH2:30][CH2:31][N:9]2[CH2:8][CH2:7][CH:6]([CH2:5][C:4]3[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:3]=3[F:2])[CH2:11][CH2:10]2)=[CH:27][C:26]=1[CH3:35]
Reactant: Cc1ccc(CC2CCNCC2)c(F)c1
Reactant: Cc1cc(OCCBr)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(CC2CCN(CCOc3ccc(O)c(C)c3)CC2)c(F)c1

Procedure:
The title compound was prepared from 4-(2-fluoro-4-methylbenzyl)piperidine hydrochloride (311.7 mg, 1.28 mmol), 2-(4-benzyloxy-3-methylphenoxy)ethyl bromide (411 mg, 1.28 mmol) and potassium carbonate (444 mg, 3.2 mmol) in two steps as white-off solid (244 mg), mp 165-167° C. 1H NMR (CD3OD) 1.503 (m, 2 H), 1.848 (m, 3 H), 2.076 (s, 3 H), 2.223 (s, 3 H), 2.560 (m, 2 H), 2.932 (m, 2 H), 3.389 (m, 2 H), 3.526 (m, 2 H), 4.141 (t, J=5.1 Hz, 2 H), 6.758 (s, 1 H), 6.667 (s, 1 H), 6.788-6.858 (m, 3 H), 7.109 (m, 1 H). Anal. Calcd for C22H29ClFNO2 : C, 67.08; H, 7.42; N, 3.98. Found: C, 66.85; H, 7.44; N, 3.46.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].CS(C)=O.[H-].[Na+].S(OCC1CCC=CC1)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=O)=O>O>[CH2:1]([O:11][CH2:25][CH:24]1[CH2:26][CH2:27][CH2:21][CH:22]=[CH:23]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CCC2)cc1
Reactant: CCCCCCCCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCOCC1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 500 mL round bottom flask equipped with a mechanical stirrer was charged with 23.7g (0.15 mol) decyl alcohol, and 150 mL of DMSO. Sodium hydride (4.22 g, 95% in purity; 0.167 mol) was slowly added to above mixture in an ice bath over 20 min. After the above mixture was reacted at room temperature for 3 hrs, the reaction mixture was cooled to room temperature. 3-Cyclohexene-1-methanol tosylate (39.9 g, 0.15 mol) was slowly added to the above mixture over 20 min. The reaction was carried at room temperature overnight, then 80° C. for 3 hrs. The reaction mixture was added to water (150 mL), and then extracted with chloroform (3×150 niL), washed to water (2×100 mL) and dried with sodium sulfate. The solvent was evaporated and the residue distilled to give pure product.
Reaction SMILES: [C:1]1([CH:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].[C:23](#[N:26])[CH:24]=[CH2:25]>O1CCOCC1>[C:23]([CH2:24][CH2:25][C:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[N:26]
Reactant: CCOC(=O)C(c1ccccc1)c1ccccc1
Reactant: C=CC#N
Agent: CC[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)C(CCC#N)(c1ccccc1)c1ccccc1
Temperature: 45 °C

Procedure:
The product of Example 68A (5.58 g) was dissolved in anhydrous dioxane (15 mL). Sodium ethoxide (1.58 g) was added and the mixture was heated to 40-50° C. for 30 minutes. Acrylonitrile (1.44 mL) was added dropwise with stirring. The mixture was heated at 60-70° C. for one hour. The dioxane was removed in vacuo, and the residue was taken up in diethyl ether, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (3-10% ethyl acetate/hexane) to obtain the title compound. MS (DCI+) m/z 311 (M+NH4)+.