Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([OH:10])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:11]([O:13][CH:14]([O:18][CH2:19][CH3:20])[CH2:15][CH2:16]Cl)[CH3:12].O>CN(C)C=O>[C:2]([O:10][CH2:16][CH2:15][CH:14]([O:18][CH2:19][CH3:20])[O:13][CH2:11][CH3:12])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCOC(CCCl)OCC
Reactant: O=C(O)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(CCOC(=O)c1ccccc1)OCC
Temperature: 25 °C

Procedure:
A stirred solution of 50.0 grams (0.347 mole) of the sodium salt of benzoic acid and 53.0 grams (0.320 mole) of 3-ethoxy-4-oxahexyl chloride in 500 ml of dimethylformamide was heated at reflux for three hours. The reaction mixture was cooled to ambient temperature, and 500 ml of water was added. The mixture was extracted with two 700 ml portions of diethyl ether. The combined extracts were dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 57.5 grams of 3-ethoxy-4-oxahexyl benzoate. The nmr spectrum was consistent with the proposed structure. Further extraction of the aqueous layer with diethyl ether yielded an additional 34.7 grams of the benzoate.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][N:51]([CH3:65])[C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH2:64])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1>CN(C=O)C>[CH3:50][N:51]([CH3:65])[C:52]1[N:57]=[CH:56][C:55]([C:58]2[CH:59]=[C:60]([NH:64][C:23]([C:18]3[C:19](=[O:22])[O:20][C:21]4[C:16]([CH:17]=3)=[CH:15][CH:14]=[CH:13][C:12]=4[O:11][CH3:10])=[O:25])[CH:61]=[CH:62][CH:63]=2)=[CH:54][CH:53]=1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Reactant: CN(C)c1ccc(-c2cccc(N)c2)cn1
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: COc1cccc2cc(C(=O)Nc3cccc(-c4ccc(N(C)C)nc4)c3)c(=O)oc12
Temperature: 25 °C
Yield: 66.7 %

Procedure:
DIEA (0.012 mL, 0.071 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.071 mmol) in 0.5 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-(6-dimethylamino-pyridin-3-yl)-phenylamine (0.014 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.018 g of product in 66% yield: LCMS (ESI) m/z 416 (MH+).
Reaction SMILES: [NH:1]([C:5]1[CH:52]=[CH:51][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]3)=[O:21])=[C:14]([C:30]3[CH2:34][C:33]([CH2:43][C:44]([O:46]C(C)(C)C)=[O:45])([CH2:35][C:36](=[O:42])[O:37]C(C)(C)C)[O:32][N:31]=3)[CH:13]=2)=[O:10])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[NH:3].C(O)(C(F)(F)F)=O>>[NH:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([N:22]3[CH2:27][CH2:26][S:25](=[O:29])(=[O:28])[CH2:24][CH2:23]3)=[O:21])=[C:14]([C:30]3[CH2:34][C:33]([CH2:43][C:44]([OH:46])=[O:45])([CH2:35][C:36]([OH:42])=[O:37])[O:32][N:31]=3)[CH:13]=2)=[O:10])=[CH:51][CH:52]=1)[C:2]([NH2:4])=[NH:3]
Reactant: CC(C)(C)OC(=O)CC1(CC(=O)OC(C)(C)C)CC(c2cc(OC(=O)c3ccc(NC(=N)N)cc3)ccc2CCC(=O)N2CCS(=O)(=O)CC2)=NO1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ccc(C(=O)Oc2ccc(CCC(=O)N3CCS(=O)(=O)CC3)c(C3=NOC(CC(=O)O)(CC(=O)O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A mixture of 3-(5,5-bis(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazol-3-yl)-4-(3-(1,1-dioxidothiomorpholin-4-yl)-3-oxopropyl)phenyl 4-carbamimidamidobenzoate (49.0 mg) and TFA (1 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, and then, the pH of the residue was adjusted to about 4 by the addition of water and subsequently a saturated aqueous solution of ammonium acetate. The obtained mixture was stirred at room temperature for 3 days, and then, the obtained solid was collected by filtration and washed with water and acetone to obtain the title compound (33.1 mg).
Reaction SMILES: [C:1]([CH:3]([CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)C(OCC)=O)#[N:2].[OH-].[Na+].Cl>>[C:16]1([CH2:15][N:12]2[CH2:13][CH2:14][CH:9]([CH2:3][C:1]#[N:2])[CH2:10][CH2:11]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)C(C#N)C1CCN(Cc2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#CCC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
A mixture of 58 parts of ethyl α-cyano-1-(phenylmethyl)-4-piperidineacetate and 125 parts of sodium hydroxide solution 2 N is stirred for 3 hours at room temperature. The mixture is neutralized with concentrated hydrochloric acid while cooling and the solvent is evaporated. The residue is stirred for 4 hours at 150° C. in 180 parts of N,N-dimethylacetamide. The reaction mixture is cooled, filtered and the filtrate is evaporated. The residue is taken up in water and extracted with methylbenzene. The extract is dried, filtered and evaporated. The residue is distilled, yielding 35 parts (82%) of 1-(phenylmethyl)-4-piperidineacetonitrile; bp. 135°-140° C. at 0.2-0.3 mm. pressure.
Reaction SMILES: [C:1]1([O:9][CH3:10])[C:2](=[CH:5][CH:6]=[CH:7][CH:8]=1)[O:3][CH3:4].[CH3:11][C:12]([CH3:17])=[CH:13][C:14](Cl)=[O:15].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[CH3:4][O:3][C:2]1[CH:5]=[C:6]([C:14](=[O:15])[CH:13]=[C:12]([CH3:17])[CH3:11])[CH:7]=[CH:8][C:1]=1[O:9][CH3:10]
Reactant: COc1ccccc1OC
Reactant: CC(C)=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1ccc(C(=O)C=C(C)C)cc1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 98 %

Procedure:
A round bottom flask equipped with a stir bar and nitrogen inlet was charged with veratrole (2.5 mL, 20 mmol), 3,3-dimethyl acryloyl chloride (2.2 mL, 20 mmol) and dry CH2Cl2, (100 mL). The solution was cooled to 0° C. and AlCl3 (2.6 g, 20 mmol) was added portionwise. On completion of addition, the cooling bath was removed and the reaction was allowed 3 h. TLC showed consumption of SM. It was added to saturated NH4Cl (100 mL) and stirred vigourously for 15 min. The phases were separated and the CH2Cl2 phase was washed with saturated Na2CO3 (100 mL), washed with brine, (100 mL), dried (Na2SO4) and the solvent was evaporated under reduced pressure. The material was used as is in the next step. Amount obtained: 4.3 g, 19.5 mmol, 98% yield. LC-MS (ESI) m/e 221 (M+H). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.02 (s, 3H) 2.20 (s, 3H) 3.96 (s, 6H) 6.73 (s, 1H) 6.89 (d, J=8.20 Hz, 1H) 7.53-7.60 (m, 2H). Step 2
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]([C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=1)([F:29])[C:11](=[O:28])[N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)(C)(C)C>C(Cl)Cl.Cl.CCOCC>[ClH:36].[ClH:36].[NH2:7][CH2:8][CH2:9][C:10]([C:30]1[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=1)([F:29])[C:11]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH2:14][CH2:13]1)=[O:28]
Reactant: CC(C)(C)OC(=O)NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: NCCC(F)(C(=O)N1CCN(c2ncnc3ccccc23)CC1)c1ccc(Cl)cc1

Procedure:
A solution of [3-(4-chlorophenyl)-3-fluoro-4-oxo-4-(4-quinazolin-4-yl-piperazin-1-yl)-butyl]-carbamic acid tert-butyl ester (226 mg, 0.43 mmol) in DCM (2 mL) and 2.0 M HCl in Et2O (1 mL) was stirred for 12 hours. The mixture was concentrated in vacuo and chromatographed (SiO2) using 10% MeOH/DCM followed by 10% (7N NH3 in MeOH)/DCM as eluent. The purified material was dissolved in MeOH followed by the addition of 2.0N HCl in Et2O, and then concentrated in vacuo. The resulting glass was heated at reflux in isopropyl alcohol and concentrated in vacuo. The resulting solid was suspended in acetonitrile and concentrated in vacuo (repeated twice) to give 4-amino-2-(4-chlorophenyl)-2-fluoro-1-(4-quinazolin-4-yl-piperazin-1-yl)-butan-1-one dihydrochloride as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 8.86 (s, 1H), 8.18 (m, 4H), 8.01 (m, 2H), 7.69 (m, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.40 (d, J=8.6 Hz, 2H), 4.23 (m, 2H), 4.09 (m, 1H), 3.80 (m, 4H), 3.47 (m, 1H), 2.86 (m, 1H), 2.67 (m, 2H), 2.41 (m, 1H). LCMS (APCI+) m/z 428, 430 [M+H]+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH2:11]O.S(Cl)([Cl:23])=O.O>C1(C)C=CC=CC=1>[Cl:8][C:9]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]([N+:18]([O-:20])=[O:19])[C:10]=1[CH2:11][Cl:23]
Reactant: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CO
Reactant: O=S(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)c(Cl)c1CCl
Temperature: 47.5 °C

Procedure:
Under nitrogen, 27.9 mL of triethylamine was added to the concentrated solution of 2,3-dichloro-6-nitrobenzylalcohol (compound XI) prepared in the previous step. To this solution, 14.6 mL of thionyl chloride was added via an addition funnel over 15 minutes. Following addition, the solution is heated to 45-50° C. for 18 hours, then cooled to room temperature under nitrogen. Water and toluene are added to the reaction mixture and the mixture filtered. The filtrate is diluted with water, and the aqueous layer removed. The organic layer is washed with water (4×40 mL), and dried by azeotropic distillation. The solution is concentrated to give 1,2-dichloro-3-chloromethyl-4-nitrobenzene (compound (VIII), which could be used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH:6]=[CH:7][CH2:8][N+:9]([O-:27])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Clc1ccc2c(c1)C(c1ccccc1)=NCC=C2
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2)c2cc(Cl)ccc2C=CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 10.7 g (42 mmole) of 8-chloro-1-phenyl-3H-2-benzazepine, 10.7 g (53 mmole) of 85% metachloroperbenzoic acid and 100 ml of methylene chloride was stirred at room temperature or 16 hr. The mixture was washed with cold dilute aqueous sodium hydroxide and brine. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to dryness. The residue was crystallized with ether to give crude product, mp 130°-131° C. Recrystallization from ether gave tan prisms, mp 122°-123° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2].Cl.[NH2:25][OH:26].N1C=CC=CC=1>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[N:25][OH:26])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=O
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1=NO
Temperature: 25 °C
Yield: 79.8 %

Procedure:
6-Methoxy-1-oxo-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (1.6 g, 5.19 mmol) obtained in Example 1 was dissolved in ethanol (100 mL), hydroxylamine hydrochloride (1.08 g, 15.57 mmol) and pyridine (1.64 g, 1.68 mL, 20.76 mmol) were added thereto, refluxed for 1 hr, and cooled to RT. The resulting mixture washed with saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by flash chromatography to obtain 1.34 g of the titled compound (yield: 80%).
Reaction SMILES: [OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([O:5]CC)=[O:4].Cl>[OH-].[Na+]>[OH:1][CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4]
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 80 %

Procedure:
A mixture of racemic ethyl 2-hydroxy-3-(4-benzyloxyphenyl)propionate of the formula (10) (100 g) obtained according to the procedure described in step (iii) above and 10% aq. sodium hydroxide solution (500 ml) was stirred at room temperature for a period of 1-2 h. The progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mixture was acidified with dil. hydrochloric acid at 15-20° C. and the solid thus obtained was filtered and washed with water to afford racemic 2-hydroxy-3-(4-benzyloxyphenyl)propionic acid (72-77 g, 80-85%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28](O)(=[O:30])=[O:29])=[CH:23][C:22]=2[CH3:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(#N)C.P(Cl)(Cl)([Cl:44])=O>CN(C)C(=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:18]=[C:17]([N:19]=[N:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24]([S:28]([Cl:44])(=[O:30])=[O:29])=[CH:23][C:22]=2[CH3:32])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:10]=1[OH:38])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(S(=O)(=O)O)c(C)cc1N=Nc1cc(S(=O)(=O)NC(C)(C)C)c(O)c2cccc(NS(C)(=O)=O)c12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CC(=O)N(C)C
Product: Cc1cc(S(=O)(=O)Cl)c(C)cc1N=Nc1cc(S(=O)(=O)NC(C)(C)C)c(O)c2cccc(NS(C)(=O)=O)c12
Temperature: 0 °C

Procedure:
To a solution containing 25 g of the naphthol compound obtained in Step (1) above, 180 ml of acetonitrile and 35 ml of phosphorus oxychloride, 15 ml of N,N-dimethylacetamide was added dropwise at a temmperature below 60° C. with stirring. The mixture was stirred at 60° C. for 3 hours and was poured into 800 ml of ice water. The cyrstals thus-precipitated were collected by filtration and washed with 100 ml of acetonitrile.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O-])=O)=[CH:22][CH:21]=1.O>C(O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:27]([CH2:26][C:23]4[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc(CC(=O)[O-])cc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3ccc(OC)cc3)nc(=O)c1-2
Yield: 56.1 %

Procedure:
Sodium spheres (207 mg) were dissolved in ethanol (15 ml) and 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.0 g) was added, followed by 4-methoxyphenylacetate (1.62 g, 9 mmol). The reaction mixture was refluxed for 16 hours, the solvent was stripped, water was added to the residue, and the product was collected by filtration and recrystallized from ether to afford 0.89 g of 1-cyclopentyl-3-ethyl-6-(4-methoxyphenylmethyl)pyrazolo[3,4-d]pyrimidin-4-one, m.p. 172°-173° C.
Reaction SMILES: CNCCNC.[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[NH:11]1)[CH:8]=[CH2:9].I[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[K+].[K+].N>[Cu]I.O1CCOCC1>[CH2:7]([N:10]1[C:18](=[O:19])[C:17]2[C:12](=[N:13][C:14]([S:20][CH3:21])=[N:15][CH:16]=2)[N:11]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)[CH:8]=[CH2:9]
Reactant: C=CCn1[nH]c2nc(SC)ncc2c1=O
Reactant: Ic1ccccn1
Agent: [Cu]I
Agent: CNCCNC
Agent: N
Solvent: C1COCCO1
Product: C=CCn1c(=O)c2cnc(SC)nc2n1-c1ccccn1
Temperature: 95 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
N,N′-dimethylethylenediamine (2.4 mL) was added to a 1,4-dioxane (50 mL) solution of 2-allyl-6-(methylthio)-1,2-dihydro-3H-pyrazolo[3,4-d]pyrimidin-3-one (4.44 g), copper(I) iodide (3.80 g), 2-iodopyridine (5.33 g) and potassium carbonate (3.80 g), and stirred overnight at 95° C. The reaction liquid was cooled, then aqueous ammonia was added thereto and extracted with ethyl acetate, washed with saturated saline water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the residue was crystallized with ethyl acetate to give the entitled compound as a white solid (5.15 g).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+].[CH2:10]([C@@H:12]1[O:14][CH2:13]1)Cl>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH2:1]([O:7][CH2:10][C@@H:12]1[O:14][CH2:13]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCO
Reactant: ClC[C@H]1CO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Product: CCCCCCOC[C@H]1CO1
Reaction time: 3 h

Procedure:
6 ml of n-hexanol was added dropwise to a mixture of 40 g of 50% sodium hydroxide solution, 24 g of (R)-epichlorohydrine as used in the Synthetic Example 1 and 400 mg of tetrabutylammoniumhydrogen sulfate, under cooling at 20° to 25° C. The reaction solution was stirred at the same temperature for 3 hours and added with water, and then the product was extracted into ether. The extracted product was distilled under reduced pressure to obtain 3.35 g of (R)-n-hexylglycidylether.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[S:3]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9](Cl)=[O:10])(=[O:5])=[O:4].[F:16][C:17]1[CH:18]=[C:19]([C:24](=[O:35])[CH:25]=[C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27]2)[CH:20]=[C:21]([F:23])[CH:22]=1.C(N(CC)CC)C.COCCOCCOC>O>[F:16][C:17]1[CH:18]=[C:19]([C:24](=[O:35])[C:25](=[C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[NH:30]2)[C:9]([C:8]2[CH:7]=[C:6]([S:3]([N:2]([CH3:15])[CH3:1])(=[O:5])=[O:4])[CH:14]=[CH:13][CH:12]=2)=[O:10])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C(C=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Reactant: CN(C)S(=O)(=O)c1cccc(C(=O)Cl)c1
Solvent: O
Solvent: COCCOCCOC
Solvent: CCN(CC)CC
Product: CN(C)S(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 25.5 %

Procedure:
3-[(dimethylamino)sulfonyl]benzoyl chloride (1.97 g) was added to a mixture of 1-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)ethanone (865 mg), triethylamine (1.6 mL) and 2-methoxyethyl ether (10 mL), followed by heating with stirring at 110° C. for 30 minutes. Water (0.06 mL) was added, followed by further heating under reflux for 30 minutes. After cooling, water was added, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1), and recrystallized from ethyl acetate/n-hexane to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-N,N-dimethylbenzenesulfonamide (391 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.Cl.N1C=CNC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: Cl
Agent: O=c1[nH]cc[nH]1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccc(F)nc3)n2)CN1

Procedure:
75 mg (0.17 mmol) of the compound of Example 42A is reacted analogously to the synthesis of the compound of Example 1 with 23 mg (0.19 mmol) of 4-imidazolinone-hydrochloride. 64 mg (74% of theory) of the title compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:28]=[C:27]([N+:29]([O-])=O)[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.FC1C=C(NC(=O)CC(NC2C=CC(F)=CC=2)=O)C=CC=1OC1C2SC=CC=2N=CN=1>>[F:1][C:2]1[CH:28]=[C:27]([NH2:29])[CH:26]=[CH:25][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH3:24])[C:12]([O:14][CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc([N+](=O)[O-])cc3F)c12
Agent: O=C(CC(=O)Nc1ccc(Oc2ncnc3ccsc23)c(F)c1)Nc1ccc(F)cc1
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Yield: 79.9 %

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazine (20 mg, 0.05 mmol) was converted to the title compound (16 mg, 87%) in a manner similar to the preparation of Compound B of Example 28. 1H NMR (CDCl3) δ 7.86-7.83 (m, 1H), 7.50-7.38 (m, 2H), 7.09-7.00 (m, 1H), 6.56-6.45 (m, 1H), 4.14 (t, 2H, J=5.5 Hz), 2.99-2.38 (m, 18H); MS(ESI30 ) m/z 401.4 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([O:13]C)[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([OH:13])[CH:12]=1)[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(c(OC)c1)C(=O)CCC2
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1CCCc2cc(O)cc(O)c21
Temperature: 25 °C

Procedure:
The 6,8-dimethoxy-1-tetralone (3.0 g; 14.0 mmoles) was refluxed overnight with 20 ml of 48% aqueous hydrogen bromide and 20 ml of glacial acetic acid. After cooling to room temperature, the reaction mixture was neutralized with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The combined extracts were dried (brine, magnesium sulfate) and concentrated to afford a red solid which upon trituration with ether gave the desired compound as an off-white solid, 1.77 g (71%); m.p. 209°-210° C.
Reaction SMILES: COC1C=C(OC)C=CC=1C[NH:6][C:7]1[N:8]=[C:9]([CH3:16])[CH:10]=[C:11]2[CH:15]=[CH:14][S:13][C:12]=12>FC(F)(F)C(O)=O>[CH3:16][C:9]1[CH:10]=[C:11]2[CH:15]=[CH:14][S:13][C:12]2=[C:7]([NH2:6])[N:8]=1
Reactant: COc1ccc(CNc2nc(C)cc3ccsc23)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2ccsc2c(N)n1
Temperature: 25 °C

Procedure:
A solution of N-(2,4-dimethoxybenzyl)-5-methylthieno[2,3-c]pyridin-7-amine (235 mg, 0.747 mmol) in trifluoroacetic acid (6 mL) was heated to 40° C. for 1 hour. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. Toluene was added to the flask and the reaction mixture was concentrated under reduced pressure again. The residue was diluted with 10% 2-propanol/chloroform (30 mL), saturated aqueous sodium bicarbonate solution (20 mL), and saturated aqueous sodium carbonate solution (10 mL). The layers were separated, and the aqueous layer was extracted with additional 10% 2-propanol/chloroform (2×10 mL). The combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (1-5% methanol/dichloromethane, linear gradient) to afford 5-methylthieno[2,3-c]pyridin-7-amine. MS ESI calc'd. for C8H9N2S [M+H]+ 165. found 165. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J=5.3 Hz, 1H), 7.23 (d, J=5.3 Hz, 1H), 7.03 (s, 1H), 4.66 (s, 2H), 2.49 (s, 3H).