Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH3:12][O:13][CH2:14][CH2:15]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:15][CH2:14][O:13][CH3:12])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: OCc1c(F)cc(O)cc1Cl
Reactant: COCCBr
Product: COCCOc1cc(F)c(CO)c(Cl)c1
Yield: 52 %

Procedure:
This compound was prepared from 3-chloro-5-fluoro-4-hydroxymethyl-phenol and (2-bromoethyl) methyl ether according to the procedure described in Example 179 to give the product as a yellowish oil (209 mg, 52%); MS (EI): 234.1 (M)+.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=[N:10][C:9]=3[NH:8][C:6]2=[O:7])[CH2:3][CH2:2]1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:16][CH2:17][C:18](=[O:20])[CH3:19])[CH:11]=[N:10][C:9]=3[N:8]([CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[C:6]2=[O:7])[CH2:2][CH2:3]1
Reactant: CC(=O)CCn1cnc2[nH]c(=O)n(CC3CC3)c(=O)c21
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)CCn1cnc2c1c(=O)n(CC1CC1)c(=O)n2CC1CCCCC1

Procedure:
The title compound was prepared by stirring 1-cyclopropylmethyl-7-(3-oxobutyl)xanthine, 5 g, with 4.6 mls of bromomethylcyclohexane and 5.2 g of potassium carbonate in 30 ml DMF over 5 hours. After evaporation of the solvent the title compound was purified by column chromatography (ether).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[H-].[Na+].CS([C:16]1[N:21]=[C:20]2[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[N:23]=[CH:24][C:19]2=[C:18]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])[N:17]=1)(=O)=O>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[O:9][C:16]1[N:21]=[C:20]2[N:22]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:30])[CH3:31])[N:23]=[CH:24][C:19]2=[C:18]([NH:33][CH2:34][C@H:35]([OH:37])[CH3:36])[N:17]=1
Reactant: Oc1ccc(F)cc1F
Reactant: C[C@@H](O)CNc1nc(S(C)(=O)=O)nc2c1cnn2COCC[Si](C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@@H](O)CNc1nc(Oc2ccc(F)cc2F)nc2c1cnn2COCC[Si](C)(C)C
Temperature: 100 °C
Reaction time: 0.42 h
Yield: 43.7 %

Procedure:
2,4-Difluorophenol (510 mg, 3.922 mmol) was dissolved in 5 mL dry DMF, and sodium hydride (152 mg of 60% suspension in mineral oil, 3.791 mmol) was added. The reaction mixture was stirred for 25 minutes, and then (R)-1-[6-Methanesulfonyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol (525 mg, 1.307 mmol) was added. The reaction mixture was heated to 100° C. for four hours with stirring, then was stirred for 16 hours at room temperature. The reaction mixture was quenched by addition to water, and was partitioned between water and ethyl acetate. The organic layer was separated, dried over MgSO4, filtered, and evaporated under reduced pressure. The residue was purified by flash chromatography (8% MeOH in methylene chloride) to give 258 mg of (R)-1-[6-(2,4-Difluoro-phenoxy)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-ylamino]-propan-2-ol. Mass Spec. M+H=452.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[N:23][C:22]([CH2:25]Br)=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([O:16][C:17](=[O:27])[NH:18][C:19]1[CH:24]=[N:23][C:22]([CH2:25][NH:5][CH:1]2[CH2:4][CH2:3][CH2:2]2)=[CH:21][N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cnc(CBr)cn1
Reactant: NC1CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnc(CNC2CCC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
In a dried 100 mL round bottom flask was added cyclobutylamine (740 mg, 889 μl, 10.4 mmol, Eq: 3), K2CO3 (480 mg, 3.47 mmol, Eq: 1.00) and THF at rt. under argon. To the mixture was added a solution of (5-Bromomethyl-pyrazin-2-yl)-carbamic acid tert-butyl ester (1 g, 3.47 mmol, Eq: 1.00) in THF dropwise. The resulting reaction mixture was stirred vigorously at room temperature under argon overnight. The reaction was concentrated, diluted with water/DCM and extracted with DCM (2×30 mL). Combined organic extracts were concentrated to give a solid. The crude product was purified by LC chromatography (50 g spherical silica column) eluting with 5 to 10% MeOH in 1/1 EtOAc/Hex to afford 348 mg (36%) of the title compound as a white solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:23]([Li])[CH2:24][CH2:25]C.C(Br)C=C>C1COCC1>[CH2:25]([C:6]1([C:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH:21]=2)[C:7]2[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10][C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2)[CH:24]=[CH2:23]
Reactant: CN1CCC(=C2c3ccccc3CCc3ccccc32)CC1
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC1(C2=CCN(C)CC2)c2ccccc2CCc2ccccc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
Dissolved 4-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine (10 g, 34.6 mmol) in 200 mL of dry THF, and cooled to -78° C. under a nitrogen atmosphere. Added n-butyl lithium (15.2 mL of 2.5M in hexane, 38.0 mmol) dropwise via syringe. Warmed to 0° C, and stirred for 60 mins. Recooled to -78° C, and added allyl bromide (4.6 g, 3.3 mL, 38.0 mmol) dropwise via syringe. Warmed to room temperature slowly, and stirred for 5 hours. Added saturated NH4Cl, and extracted with ether. Dried the combined organic extracts with MgSO4, filtered, and evaporated. Purified the crude product by flash chromatography on silica gel eluting with 5:95:0.1MeOH:EtOAc:NH4OH. Combined appropriate fractions, and evaporated to give 8.0 g (70% yield) of 4-[10,11-dihydro-5-(2-propenyl)-5H-dibenzo[a,d]cyclohepten-5-yl]-1-methyl-1,2,5,6-tetrahydropyridine as an oil. Dissolved free base in ether, and added 19 weight % HCl-EtOH until acidic. Added additional ether, and let stand to precipitate hydrochloride salt. Recrystallized salt from acetonitrile-ether.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:20][N:19]=1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]1[S:22][C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)=[N:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)s2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4O)s2)CC1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 90 %

Procedure:
A mixture of tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (180 mg, 0.36 mmol) and 10% Pd(OH)2 (1.8 g) in THF (10 mL) was stirred under H2 at rt for 8.5 hrs. The reaction mixture was then filtered and concentrated to give tert-butyl 4-(5-((2S,5R)-6-hydroxy-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (133 mg, 90%) as a white solid. ESI-MS (EI+, m/z): 411.17 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5](O)=[O:6].S(Cl)([Cl:16])=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([Cl:16])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Product: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Yield: 99 %

Procedure:
A stirred solution of 3-fluoro-4-nitro-benzoic acid (1.65 g, 8.91 mmol) in thionyl chloride (10 mL) was heated at reflux for 2 h. Excess thionyl chloride was evaporated in vacuo and the residue azeotroped with toluene to afford 3-fluoro-4-nitro-benzoyl chloride (1.7 g, 99%) as a brown oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([C:9](=O)[CH3:10])[CH:6]=[CH:7][CH:8]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(c1cccc(C(F)(F)F)c1)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
A suspension of 1-(3-(trifluoromethyl)phenyl)ethanone (0.100 g, 0.532 mmol), tert-butyl piperazine-1-carboxylate (0.148 g, 0.797 mmol), acetic acid (0.046 mL, 0.797 mmol) and sodium cyanoborohydride (0.050 g, 0.797 mmol) in ethanol (0.5 mL) was heated under nitrogen at 75° C. After stirring overnight the reaction was concentrated, saturated sodium bicarbonate (0.7 mL) was added, and the product was extracted into ethyl acetate (2×0.7 mL). The combined organic layers were concentrated, dissolved in a minimal amount of dichloromethane, loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 2% to 20% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute).
Reaction SMILES: [CH3:1]I.[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15](=[S:21])[NH:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[CH2:3]([O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([S:21][CH3:1])=[N:16][CH:17]=[N:18]2)=[CH:13][CH:12]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: S=c1[nH]cnc2cc(OCc3ccccc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CSc1ncnc2cc(OCc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.6 %

Procedure:
Methyl iodide (0.97 ml, 15.4 mmol) was added dropwise to a solution of 7-benzyloxy-3,4-dihydroquinazolin-4-thione (3.45 g, 12.9 mmol) in THF (13 ml) containing 1M sodium hydroxide (25.7 ml). After stirring for 30 minutes at ambient temperature, the mixture was adjusted to pH7 with 2M hydrochloric acid. After dilution with water, the solid was collected by filtration, washed with water and dried under vacuum to give 7-benzyloxy-4-methylsulphanylquinazoline (3.3 g, 92%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[NH:26][C:25]2[C:27]([O:31][CH3:32])=[CH:28][CH:29]=[CH:30][C:24]=2[N:23]=1>CC(O)C.O>[CH3:32][O:31][C:27]1[C:25]2[NH:26][C:22]([NH:18][C:17]3[CH:16]=[CH:15][C:14]([O:13][C:8]4[C:7]([CH:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:12][CH:11]=[CH:10][N:9]=4)=[CH:20][CH:19]=3)=[N:23][C:24]=2[CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(Oc2ncccc2C2CCOCC2)cc1
Reactant: COc1cccc2nc(Cl)[nH]c12
Solvent: O
Solvent: CC(C)O
Product: COc1cccc2nc(Nc3ccc(Oc4ncccc4C4CCOCC4)cc3)[nH]c12
Temperature: 170 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)aniline (0.1130 g, 0.418 mmol) and 2-chloro-7-methoxy-1H-benzo[d]imidazole (0.092 g, 0.502 mmol) in IPA. The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 170° C. for 30 min. The reaction mixture was diluted with water and extracted with DCM. The organic extract was washed with water, brine, dried with magnesium sulfate, filtered, and concentrated. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in DCM, to provide 7-methoxy-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 417.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:3]1.[F:17][C:18]([F:34])([F:33])[C:19]1[O:23][N:22]=[C:21]([C:24]2[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=2)[C:27](O)=[O:28])[N:20]=1>>[CH3:1][CH:2]1[N:7]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[C:24]([C:21]3[N:20]=[C:19]([C:18]([F:34])([F:33])[F:17])[O:23][N:22]=3)[CH:25]=2)[CH:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][N:10]=2)[CH2:3]1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC1CN(c2ccc(C#N)cn2)CC(C)N1
Product: CC1CN(c2ccc(C#N)cn2)CC(C)N1C(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 18 %

Procedure:
This compound was synthesized from 6-(3,5-dimethylpiperazin-1-yl)nicotinonitrile and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described for example 37 step 3 (35 mg, yield 18%). 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=1.8 Hz, 1H), 8.22 (dt, J=7.2 Hz, J=1.7 Hz, 1H), 8.16 (s, 1H), 7.68-7.62 (m, 3H), 6.66 (d, J=9.0 Hz, 1H), 4.46 (m, 2H), 4.29 (d, J=13.8 Hz, 1H), 3.36 (m, 2H), 1.16 (d, J=6.3 Hz, 6H). MS (ESI) m/z: Calculated for C22H19F3N6O2: 456.15. found: 457.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH2:8][CH2:9][CH2:10][N:11]([CH2:12][C:13]([OH:15])=O)[C:6]2=[CH:5][C:4]([O:16][CH2:17][C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=2)=[N:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[O:30]1[CH2:31][CH2:32][N:27]([C:13](=[O:15])[CH2:12][N:11]2[CH2:10][CH2:9][CH2:8][N:7]3[C:2](=[O:1])[N:3]=[C:4]([O:16][CH2:17][C:18]4[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[CH:19]=4)[CH:5]=[C:6]23)[CH2:28][CH2:29]1
Reactant: C1COCCN1
Reactant: O=C(O)CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O
Product: O=C(CN1CCCn2c1cc(OCc1cc(F)c(F)c(F)c1)nc2=O)N1CCOCC1

Procedure:
The title compound was prepared by a procedure similar to that described for E13 starting from 2-(6-oxo-8-((3,4,5-trifluorobenzyl)oxy)-2,3,4,6-tetrahydro-1H-pyrimido[1,6-a]pyrimidin-1-yl) acetic acid and morpholine.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:13])[CH2:5][C@H:4]([NH:14]C(=O)OC(C)(C)C)[C:3]1=[O:22].[ClH:23]>O1CCOCC1>[ClH:23].[NH2:14][C@@H:4]1[C:3](=[O:22])[N:2]([CH3:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH3:13])[CH2:5]1
Reactant: CN1C[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CN1C[C@H](N)C(=O)N(C)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
206.8 mg of 17 (0.677 mmol) are taken up in a 25 mL round-bottomed flask and 5 mL of a solution of hydrochloric acid in dioxane (4M) are added. The medium is stirred overnight at RT under argon. A precipitate forms. After having evaporated the solvent under vacuum, 213 mg of expected product 18 (white solid) are obtained in hydrochloride form.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)S[C:6]=1[C:17]([O:19][CH3:20])=[O:18])(=[O:3])[CH3:2]>[Ni]>[CH3:20][O:19][C:17](=[O:18])[CH2:6][CH:5]([CH2:9][CH2:8][C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=1)[NH:4][C:1](=[O:3])[CH3:2]
Reactant: COC(=O)c1sc(-c2ccc(C)cc2)cc1NC(C)=O
Agent: [Ni]
Product: COC(=O)CC(CCc1ccc(C)cc1)NC(C)=O
Yield: 99 %

Procedure:
Methyl 3-acetamido-5-(4-methylphenyl)thiophene-2-carboxylate (1.4905 g, 5.15 mmol) was reductively desulfurized using Raney nickel to yield the title compound as a white gum (1.3434 g, 5.10 mmol, 99.1%); mp: 50-51° C.; TLC: Rf=0.63 (Solvent I), 0.85 (Solvent L); IR (cm1): 3288 (NH), 2906 (CH aliphatic), 1731 (ester C═O), 1639 (amide C═O), 807 (═CH); 1H nmr (CDCl3): δ 7.07 (s, 4H), 6.08 (br d, 1H, J=8.8 Hz), 4.28 (sextet, 1H, J=5.3 Hz), 3.67 (s, 3H), 2.63 (d, 2H, J=8.2 Hz), 2.55 (m, 2H), 2.30 (s, 3H), 1.96 (s, 3H), 1.84 (quintet, 2H, J=7.9 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[NH:4][C:3]=1[C:12]([O:14]CC)=O.C(O)(=O)C.[CH:21](N)=[NH:22]>C(O)C>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[NH:4][C:3]2[C:12](=[O:14])[NH:22][CH:21]=[N:1][C:2]=2[CH:6]=1
Reactant: N=CN
Reactant: CCOC(=O)c1[nH]c(-c2ccco2)cc1N
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2cc(-c3ccco3)[nH]c12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a solution of ethyl 3-amino-5-(2-furyl)-1H-pyrrole-2-carboxylate (2.58 g) in ethanol (35 mL) was added formamidine acetate (1.83 g), and the mixture was heated under reflux for 18 hrs. After cooling to room temperature, the precipitated solid was collected by filtration, washed with ethanol, and dried under reduced pressure at 60° C. to give the title compound (2.26 g).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].I[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[F-].[K+].Cl>CN(C)C=O>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: CCCCCCCCI
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C#N)c(F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 111.6 %

Procedure:
To dry dimethylformamide (200 mL) were added 2-fluoro-4-hydroxybenzonitrile (13.71 g, 100 mmol), 1-iodooctane (28.82 g, 120 mmol) and potassium fluoride (11.6 g, 200 mmol). This mixture was stirred at room temperature for 16 h, and then at 50° C. for 2 h and then at 90° C. for 2 h. The mixture was then poured into wet-ice (400 g) and 37% HCl (10 mL). The resulting solution was extracted with diethyl ether (3×200 mL). The ether layer was washed with water (2×200 mL) and dried over Na2SO4. After filtration, rotary evaporation gave the crude desired intermediate 2-fluoro-4-n-octyloxybenzonitrile (27.83 g). This liquid intermediate was then added, over a 5-10 min period at 3-13° C., to a flask containing LiAlH(OEt)3 [which had been freshly prepared from LiAlH (5.03 g, 0.1326 mol) and ethyl acetate (15.24 g, 0.1730 mol) at 3-8° C. in diethyl ether (130 mL)]. The reaction mixture was stirred at 5° C. for 75 min and 5 N H2SO4 aqueous solution (120 mL) was added dropwise with cooling. After separation, the aqueous layer was extracted with diethyl ether (2×100 mL) and the combination extracts were washed with water (2×100 mL). Standard work-up procedures afforded crude 2-fluoro-4-n-octyloxybenzaldehyde (26.07 g). The crude material was then mixed with N-tert-butylhydroxylamine (8.6 g, 96.4 mmol), molecular sieves (50 g, 4A) and silica gel (10 g) in chloroform (250 mL). The mixture was stirred at room temperature for 23 h and refluxed for 3 h under argon gas. The mixture was then filtered and rotary evaporated to give a residue which was purified by column chromatography over silica gel eluted with hexanes/ethyl acetate (4:1, v:v). The title compound (12.90 g) was obtained in 39.9% overall yield as a slightly yellowish solid, m.p. 35.6° C. (Rf =0.36 on a silica gel plate using hexanes/EtOAc, 4:1, v:v, as the eluant).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[NH:17][C:16](=O)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:28][O:29][CH2:30][CH2:31][NH2:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[N:17]=[C:16]([NH:32][CH2:31][CH2:30][O:29][CH3:28])[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(=O)[nH]c3cc(Cl)ccc23)CC1
Reactant: COCCN
Agent: [H-]
Agent: [Na+]
Product: COCCNc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)c2ccc(Cl)cc2n1
Yield: 50.5 %

Procedure:
4-[4-(tert-Butoxycarbonyl)piperazin-1-yl]-7-chloroquinol-2-one (150 mg, 0.4 mmol), sodium hydride (15 mg, 0.6 mmol), N-phenyl(trifluoromethylsulfon)imide (208 mg, 0.56 mmol), and 2-methoxyethylamine (362 μL, 4.0 mmol) are treated according to method E yielding 85 mg of 4-[4-(tert-butoxycarbonyl)piperazin-1-yl]-7-chloro-2-(2-methoxyethylamino)quinoline. 74 mg thereof are treated with TFA-CH2Cl2 1:1 (0.6 mL) for 1 h and concentrated. The residue is converted into the title product with 4-fluorophenyl isocyanate (30 μL) and triethylamine (230 μL).
Reaction SMILES: [O:1]([CH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[O:25])=[CH:22][C:21]=1[Cl:28])[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[BH4-].[Na+]>C(O)C>[O:1]([CH2:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][OH:25])=[CH:22][C:21]=1[Cl:28])[Si:2]([C:15]([CH3:17])([CH3:18])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)[Si](OCc1ccc(C=O)cc1Cl)(c1ccccc1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)[Si](OCc1ccc(CO)cc1Cl)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.6 %

Procedure:
To a suspension of 4-((tert-butyldiphenylsiloxy)methyl)-3-chlorobenzaldehyde (3.24 g) in ethanol (32 ml) was added sodium borohydride (149 mg) under ice-cooling and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated to about half amount. Water was added and the resulting product was extracted twice with diisopropyl ether. The organic layers were combined, washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to give 4-((tert-butyldiphenylsiloxy)methyl)-3-chlorobenzyl alcohol (3.08 g) as a colorless oil.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1.[NH:15]1[CH:19]=[N:18][CH:17]=[N:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1/[CH:4]=[CH:3]/[CH2:2][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1
Reactant: ClC/C=C/c1ccc2ccccc2c1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C(=C/c1ccc2ccccc2c1)\Cn1cncn1
Reaction time: 14 h
Yield: 10.3 %

Procedure:
A mixture of (E)-1-chloro-3-(2-naphthyl)-2-propene (0.5 g), 1H-1,2,4-triazole (0.5 g) and K2CO3(1.0 g) in DMF (20 ml) was stirred for 14 hours. The mixture was diluted with ethyl acetate and insolubles were filtered off. The filtrate was concentrated in vacuo and the residue was chromatographed on silica gel, eluting with ethyl acetate to give the titled compound (0.06 g) as colorless powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:19])=[CH:5][C:6]([O:16][CH2:17][CH3:18])=[C:7]([CH:15]=1)[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].[Br:20]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:19][C:4]1[C:3]([C:1]#[N:2])=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])=[C:6]([O:16][CH2:17][CH3:18])[CH:5]=1
Reactant: CCOc1cc(C)c(C#N)cc1C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOc1cc(CBr)c(C#N)cc1C(=O)OC(C)(C)C

Procedure:
After dissolving tert-butyl 5-cyano-2-ethoxy-4-methylbenzoate (8.91 g) in carbon tetrachloride, N-bromosuccinimide (6.6 g) and benzoyl peroxide (400 mg) were added and the mixture was heated to reflux for 3 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield a mixture of the title compound and tert-butyl 5-cyano-2-ethoxy-4-methylbenzoate (starting material) (8.80 g) as a white solid.