Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[N-:22]=[N+]=[N-].[Na+].O>CN(C)C=O.[C].[Pd]>[CH3:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[NH2:22])=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nn(-c2ccccn2)c2nc3ccccc3c(N)c12
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.44 g, 4.89 mmol) and sodium azide (0.35 g, 5.37 mmol) in N,N-dimethylformamide (10 mL) was heated under reflux at 100° C. for 30 minutes. The solution was cooled to room temperature, poured into water, and the organic matter was extracted with chloroform. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. To a solution of the residue thus obtained in ethanol (70 mL), 10% palladium-carbon (2 g, 50% hydrate) was added and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The solution was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure. The residue thus obtained was purified by basic silica gel column chromatography (ethyl acetate:methanol=95:5) to give the title compound (760 mg, 57% yield).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([CH3:26])[C:7]([N:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21](Br)=[CH:20][C:19]=4Br)=[O:17])[CH2:12][CH2:11]3)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C([N:30]1[CH2:34][CH2:33][NH:32][C:31]1=[O:35])(=O)C>>[O:35]=[C:31]1[NH:32][CH2:33][CH2:34][N:30]1[C:19]1[CH:20]=[C:21]([N:32]2[CH2:33][CH2:34][NH:30][C:31]2=[O:35])[CH:22]=[CH:23][C:18]=1[C:16]([N:13]1[CH2:14][CH2:15][N:10]([C:7]2[C:6]([CH3:26])=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][N:8]=2)[CH2:11][CH2:12]1)=[O:17]
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2Br)CC1
Reactant: CC(=O)N1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2N2CCNC2=O)CC1
Yield: 39.9 %

Procedure:
Using [4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl](2,4-dibromophenyl)methanone (250 mg) described in Preparation Example 238 and 1-acetylimidazolidin-2-one (200 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (102 mg) was obtained.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([OH:41])=O)=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.C(O)(=O)C.[NH2:55][CH2:56][C:57]([N:59]([CH3:61])[CH3:60])=[O:58].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:39]([NH:55][CH2:56][C:57]([N:59]([CH3:61])[CH3:60])=[O:58])=[O:41])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:23]4[CH2:24][CH2:25][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:27][CH2:28]4)=[O:22])=[CH:18][C:17]4[CH:35]=[CH:36][CH:37]=[CH:38][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)C(=O)CN
Reactant: O=C(O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CN(C)C(=O)CNC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)N1CCC(N2CCOCC2)CC1)=Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 48 h
Yield: 49.3 %

Procedure:
To a stirred solution of 13-cyclohexyl-6-[[4-(4-morpholinyl)-1-piperidinyl]carbonyl]-7H-indolo[2,1-a][2]benzazepine-10-carboxylic acid (40 mg, 0.07 mmol) in CH2Cl2 (1.5 mL) were added N,N-diisopropylethylamine (60 μL, 0.34 mmol), 2-amino-N,N-dimethylacetamide monoacetate (16 mg, 0.1 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (19 mg, 0.1 mmol), and 1-hydroxybenzotriazole (14 mg, 0.1 mmol). The suspension was allowed to stir at r.t. for 2 days, then diluted with CH2Cl2, filtered through Celite, and chromatographed on silica gel (gradient elution: 0%→10% MeOH in CH2Cl2) to give the title compound as a yellow solid (22 mg, 48% yield). LC/MS (ESI) retention time: 1.66 min, m/z 638 (MH+); 1H NMR (400 MHz, CDCl3) δ 1.29-1.43 (m, 2 H) 1.47-1.59 (m, 1 H) 1.71-1.80 (m, 2 H) 1.87-1.96 (m, 1 H) 2.34-2.35 (m, 1 H) 2.40-2.51 (m, 3 H) 2.60-2.76 (m, 2 H) 2.77-2.89 (m, 1 H) 3.02 (s, 3 H) 3.04 (s, 3 H) 3.66 (s, 4 H) 4.25 (d, J=3.78 Hz, 2 H) 4.39 (s, 1 H) 5.07-5.08 (m, 1 H) 6.61 (s, 1 H) 6.81 (s, 1 H) 7.33-7.49 (m, 5 H) 7.51-7.59 (m, 1 H) 7.86 (d, J=8.56 Hz, 1 H) 8.02 (s, 1 H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)[CH:2]=1.[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[S:27][CH:28]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[F:16][C:17]1[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=1[C:24]1[N:25]=[C:26]([N:29]2[CH2:34][CH2:33][N:32]([C:8]([NH:7][C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[O:15])[CH2:31][CH2:30]2)[S:27][CH:28]=1
Reactant: O=C(Nc1cccnc1)OCC(Cl)(Cl)Cl
Reactant: Fc1cccc(-c2csc(N3CCNCC3)n2)c1F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: O=C(Nc1cccnc1)N1CCN(c2nc(-c3cccc(F)c3F)cs2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
A mixture of 2,2,2-trichloroethyl pyridin-3-ylcarbamate (211 mg, 0.782 mmol), 1-[4-(2,3-difluorophenyl)-1,3-thiazol-2-yl]piperazine (200 mg, 0.711 mmol) and diisopropylethylamine (0.248 ml, 1.42 mmol) in dimethyl sulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate), and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 157 mg (55.0%) of the desired product as a solid. mp 172-173° C.
Reaction SMILES: N1C=CC=CC=1.[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.[N:34]1([S:40](Cl)(=[O:42])=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.CCCCCC>C(OCC)(=O)C>[Cl:7][C:8]1[C:9]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:10][C:11]([NH:14][S:40]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:42])=[O:41])=[N:12][CH:13]=1
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCC
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1cc(F)ccc1F)c1cc(NS(=O)(=O)N2CCCCC2)ncc1Cl
Temperature: 70 °C
Reaction time: 96 h
Yield: 46.4 %

Procedure:
A pyridine (2 ml) solution of the [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amine (101 mg, 0.235 mmol) obtained in Example 196 and piperidine-1-sulfonyl chloride (48 mg, 0.259 mmol) was stirred at 70° C. for 19 hours. To the reaction mixture was added piperidine-1-sulfonyl chloride (48 mg, 0.259 mmol) and the resulting mixture was stirred at 70° C. for 4 days. The reaction mixture was returned to room temperature and then, concentrated under reduced pressure. The residue thus obtained was diluted with ethyl acetate. The diluted solution was washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the hexane:ethyl acetate (=4:1) eluate was concentrated under reduced pressure to yield a white solid. The resulting solid was washed with hexane-ether, and collected by filtration to give the title compound (63 mg, 0.109 mmol, 47%) as a white powder.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1)(=[O:3])[CH3:2].[BrH:10].[Br:11]CC(C1C=C(C)C=CN=1)=O>>[BrH:11].[Br:10][CH2:2][C:1]([C:4]1[N:5]([CH3:9])[CH:6]=[CH:7][N:8]=1)=[O:3]
Reactant: Cc1ccnc(C(=O)CBr)c1
Reactant: CC(=O)c1nccn1C
Agent: Br
Product: Cn1ccnc1C(=O)CBr

Procedure:
* 2-bromoacetyl-1-methylimidazole hydrobromide was prepared from 2-acetyl-1-methylimidazole according to the procedure for preparing 2-bromoacetyl-4-methylpyridine hydrobromide described in step 2 of Example 31.
Reaction SMILES: C([C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])=O.[CH:26]([O:33][CH2:34][CH3:35])([O:30][CH2:31][CH3:32])OCC>C(O)C>[CH2:34]([O:33][CH:26]([O:30][CH2:31][CH3:32])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:22]([F:23])([F:25])[F:24])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1)=[O:7])[CH3:35]
Reactant: CCOC(OCC)OCC
Reactant: COc1c(C=O)cc(C(=O)N2CSc3ccccc32)cc1C(F)(F)F
Solvent: CCO
Product: CCOC(OCC)c1cc(C(=O)N2CSc3ccccc32)cc(C(F)(F)F)c1OC

Procedure:
3-(3-formyl-4-methoxy-5-trifluoromethylbenzoyl)-2,3-dihydro-1,3-benzothiazole (277 mg) was dissolved in ethanol (1.5 mL) and triethyl orthoformate (0.16 mL), Amberlyst-15 (27 mg) was added to the solution, and then the mixture was refluxed for 3.5 hours. The reaction solution was filtered, and then the solvent was distilled off under reduced pressure to obtain the title compound (326 mg) as a yellow oily substance.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][S:26][CH:25]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH2:24][N:23]([CH2:33][C:34]([O:36]C(C)(C)C)=[O:35])[C:22]1=[O:41])[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]([CH:11]([NH:20][CH:21]1[CH2:27][S:26][CH:25]([C:28]2[CH:32]=[CH:31][S:30][CH:29]=2)[CH2:24][N:23]([CH2:33][C:34]([OH:36])=[O:35])[C:22]1=[O:41])[CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN1CC(c2ccsc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CN1CC(c2ccsc2)SCC(NC(CCc2ccccc2)C(=O)OCc2ccccc2)C1=O

Procedure:
180 mg of isomer B of t-butyl α-[6-(1-benzyloxycarbonyl-3-phenylpropylamino)-5-oxo-2-(3-thienyl)perhydro-1,4-thiazepin-4-yl]acetate were treated with trifluoroacetic acid by the procedure described in Example 43, to remove the t-butyl group and give 140 mg of the title compound as a powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[Si:44](Cl)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]>C1COCC1.CN(C=O)C>[Si:44]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[C:9]=2[C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][N:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:22][CH:21]=2)=[O:19])=[CH:4][CH:3]=1)([C:47]([CH3:50])([CH3:49])[CH3:48])([CH3:46])[CH3:45]
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2sc3cc(O)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution was prepared consisting of 10 g (21.1 mmol) of [2-(4-hydroxyphenyl)-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone and 6 g (49.1 mmol) of dimethylaminopyridine in 700 mL of THF-DMF (6:1)(v/v). This solution was stirred for one hour at ambient temperature and then cooled to 0° C. in an ice bath. To this solution was added 2.9 g (19.3 mmol) of tert-butyl-dimethylsilylchloride. The reaction mixture was stirred under a nitrogen atmosphere and allowed to warm to ambient temperature. After seventy-two hours, the reaction was quenched with the addition of a saturated solution of aqueous NH4Cl. The organic layer was separated and washed with water, brine, and finally dried by filtration through anhydrous Na2SO4 and evaporated to dryness The crude product was triturated with CH2Cl2, allowed to stand for three hours, and filtered to remove unreacted starting material. This resulting product is a mixture of isomers, which are separated by chromatography on a silica gel column eluted with a linear gradient beginning with CHCl3 and ending with CHCl3 --MeOH (19:1)(v/v). The desired fractions were determined by tlc, combined, and evaporated to dryness. This yielded 5.1 g of the title compound, isolated as a yellow crystalline solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][O:10][C@@H:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13].Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[N:20][OH:21])[CH2:9][O:10][C@@H:11]([CH:16]=[CH2:17])[C:12]([F:15])([F:14])[F:13]
Reactant: C=C[C@H](OCC(=O)c1ccccc1F)C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C=C[C@H](OCC(=NO)c1ccccc1F)C(F)(F)F
Temperature: 50 °C

Procedure:
(S)-1-(2-Fluorophenyl)-2-((1,1,1-trifluorobut-3-en-2-yl)oxy)ethanone (41.22 g) was dissolved in anhydrous methanol (400 mL) and hydroxylamine hydrochloride (14.0 g) and sodium acetate (19.0 g) were added. The reaction mixture was heated to 50° C. for 90 min, then cooled to RT, concentrated in vacuo and the residue purified by silica gel chromatography (2% to 15% EtOAc in hexanes) to afford the title compound as a mixture of geometric isomers (40.54 g). 1H-NMR (400 MHz, CDCl3) δ (ppm): 4.04-4.15 (m, 0.8H), 4.18-4.26 (m, 0.2H), 4.44-4.57 (m, 0.4H) 4.79-4.90 (m, 1.6H) 5.37-5.56 (m, 2H) 5.64-5.78 (m, 1H) 7.03-7.26 (m, 2H) 7.33-7.54 (m, 2H), 7.90 (br s, 0.2H), 8.51 (br s, 0.8H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH:19][C:20]2[C:21](=[O:40])[N:22]([C:27]3[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=3[CH3:39])[C:30]([NH:32][CH:33]3[CH2:35][CH2:34]3)=[O:31])[CH:23]=[C:24](Br)[N:25]=2)[CH2:18][CH2:17][CH2:16]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[CH:33]1([NH:32][C:30](=[O:31])[C:29]2[CH:36]=[CH:37][C:38]([CH3:39])=[C:27]([N:22]3[CH:23]=[CH:24][N:25]=[C:20]([NH:19][C:15]4([C:10]5[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=5[OH:8])[CH2:18][CH2:17][CH2:16]4)[C:21]3=[O:40])[CH:28]=2)[CH2:34][CH2:35]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(Br)nc(NC2(c3ccccc3OCc3ccccc3)CCC2)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(NC2(c3ccccc3O)CCC2)c1=O
Temperature: 75 °C
Yield: 79.2 %

Procedure:
To 3-(3-(1-(2-(benzyloxy)phenyl)cyclobutylamino)-5-bromo-2-oxopyrazin-1(2H)-yl)-N-cyclopropyl-4-methylbenzamide (Example 268e, 1.537 g) in ethanol (16 mL) was added ammonium formate (2.263 g) and 5% Pd/C (0.546 g) and the reaction heated at 75° C. for 1 h. The mixture was filtered through celite and the solid washed through with ethanol and dichloromethane. The filtrate was collected and the volatiles removed in vacuo. The residue was purified (SiO2 chromatography eluting with 0-30% diethyl ether in dichloromethane) to afford the subtitle product (0.874 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:27][CH2:28][N:29]([CH2:2][C:3]4[CH:12]=[CH:11][C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[N:4]=4)[CH2:30][CH2:31]3)[CH2:22][CH:21]=2)=[CH:16][CH:15]=1
Reactant: ClCc1ccc2ccccc2n1
Reactant: Fc1ccc(C2=CCC(N3CCNCC3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(C2=CCC(N3CCN(Cc4ccc5ccccc5n4)CC3)CC2)cc1
Yield: 53 %

Procedure:
A mixture of 2-chloromethylquinoline (4.7 mmole), and 1-[4-(4-fluorophenyl)-3-cyclohexen-1-yl]piperazine (4.7 mmole) and excess powdered K2CO3 was heated at reflux for 18 hr. The insolubles were removed by filtration, the solution concentrated in vacuo, and the residue crystallized from hexane to give the product (53%, mp: 111-114° C.). Calc'd for C26H28FN3: C, 77.78%; H, 7.03%; N, 10.47%. Found: C, 77.61; H, 6.91%; N, 10.72%.
Reaction SMILES: [NH:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2.S(OCC)(O[CH2:18][CH3:19])(=O)=O>[OH-].[K+]>[CH2:18]([N:1]1[C:9]2[C:4]3[C:5](=[CH:10][CH:11]=[CH:12][C:3]=3[C:2]1=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH3:19]
Reactant: CCOS(=O)(=O)OCC
Reactant: O=C1Nc2cccc3cccc1c23
Agent: [K+]
Agent: [OH-]
Product: CCN1C(=O)c2cccc3cccc1c23
Reaction time: 16 h
Yield: 46 %

Procedure:
A mixture of benz[cd]indol-2(1H)-one (15.0 g, 88.8 mmole) in 20% aqueous potassium hydroxide (200 ml) was heated at 55°-60° C. while 60 ml of diethyl sulfate was added dropwise over a three hour period. After 16 hours at room temperaure and an additional hour at 55°-60° C., the mixture was partitioned between dichloromethane and water. The organic phase was concentrated and purified by chromatography on silicon dioxide with 5% acetone/dichloromethane to give the desired product (8.0 g, 46%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:11]=[C:12](\[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)/[C:13]([OH:15])=[O:14])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.COC1C=C(C=C(C2C=CC(O)=CC=2)C(O)=O)C=C(OC)C=1.C(OC(=O)C)(=O)C.C(N(CC)CC)C.Cl>C(OCC)(=O)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5](/[CH:11]=[C:12](/[C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)\[C:13]([OH:15])=[O:14])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: COc1cc(/C=C(/C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: COc1cc(C=C(C(=O)O)c2ccc(O)cc2)cc(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)=O
Product: COc1cc(/C=C(\C(=O)O)c2ccc(O)cc2)cc(OC)c1
Temperature: 125 °C
Reaction time: 1.5 h

Procedure:
E-3-(3,5-dimethoxyphenyl)-2-(4-hydroxyphenyl)-acrylic acid, 7 (10.0 g, 33.3 mmol) was dissolved in a mixture of acetic anhydride (40 mL, 0.42 mole) and triethylamine (40 mL, 0.29 mole) and heated at 125° C. for 24 h. The mixture was cooled to room temperature. Ethyl acetate (150 mL) was added, further cooled to 5° C., acidified with concentrated HCl (30 mL) and stirred at this temperature for 90 min. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layers were washed with water (2×50 mL) and extracted with aqueous NaOH (5M, 3×70 mL). The aqueous alkaline layer was acidified with glacial acetic acid (65 mL) to pH 5.2 and stirred at 0° C. for 30 min. Solid that separated was filtered and mother liquor was acidified with concentrated HCl (90 mL) and stirred at 5° C. for 1 h. Solid that separated was filtered, washed with cold water (2×50 mL) and dried at 45° C. for 6 h to yield, 19, (1.3 g, 13%): mp 135-137° C.; 1HNMR (400 MHz, DMSO-d6) δ 13.28 (br, 1H), 9.70 (br, 1H), 7.32. (d, J=10.4 Hz, 2H), 6.81 (s, 1H, overlapped), 6.79 (d, J=9.7 Hz, 2H), 6.67 (d, J=2.5 Hz, 2H), 6.64 (t, J=2.5 Hz, 1H), and 3.73 (s, 6H); MS (EI) m/z 299[M]−.
Reaction SMILES: Cl[C:2]1[C:3]2[C:11]([CH3:12])=[CH:10][N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[CH2:22]([NH:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH3:23].O>CS(C)=O.Cl>[CH2:25]([N:24]([CH2:22][CH3:23])[C:2]1[C:3]2[C:11]([CH3:12])=[CH:10][N:9]([C:13]3[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[CH3:21])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1)[CH2:26][CH2:27][CH3:28]
Reactant: CCCCNCC
Reactant: Cc1cc(C)c(-n2cc(C)c3c(Cl)nc(C)nc32)c(C)c1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: CCCCN(CC)c1nc(C)nc2c1c(C)cn2-c1c(C)cc(C)cc1C
Yield: 81.2 %

Procedure:
A mixture of 4-chloro-2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]pyrimidine (1.000 g, 3.36 mmol) and N-ethylbutylamine (3.400 g, 33.60 mmol) in 5 ml of dimethylsulfoxide was heated to reflux for 1.5 hours. The mixture was cooled and treated with water and a few drops of 2 N HCl to pH 6.5 and extracted with ethyl acetate. The organic layer was separated, washed with dilute sodium bicarbonate, brine, and dried over sodium sulfate anhydrous and concentrated to dryness. The residue was purified through silica gel column chromatography to give 995 mg (81% yield) of the title compound as an oil. 1H NMR (CDCl3) δ 6 0.90 (t, 3H), 1.23(t, 3H), 1.35(m, 2H), 1.60-1.70(m, 2H), 1.92(s, 6H), 2.30(s, 3H), 2.40(s, 3H), 2.46(s, 3H), 3.58(t, 2H), 3.66(q, 2H), 6.55(s, 1H), 6.95(s, 2H) ppm. The corresponding hydrogen chloride salt was prepared as a white crystals after recrystallization from ethyl acetate. 1H NMR (D2O) δ 0.90(t, 3H), 1.34(m, 5H), 1.75(m, 2H), 1.90(s, 6H), 2.37(s, 3H), 2.48(s, 3H), 2.55(s, 3H), 3.80-3.94(m, 4H), 7.09(s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[NH:8][CH2:7][CH2:6]2.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[N:8]([C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23])[CH2:7][CH2:6]2
Reactant: Cc1ccncc1I
Reactant: COc1cc2c(cc1OC)C(=O)NCC2
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)C(=O)N(c1cnccc1C)CC2
Yield: 24.3 %

Procedure:
Using analogous reaction conditions as described in Example 1, 6,7-dimethoxy-3,4-dihydro-2H-isoquinolin-1-one (I-40d: 100 mg, 0.483 mmol) was reacted with 3-iodo-4-methyl-pyridine (105 mg, 0.483 mmol), 1,4-dioxane (10 mL), copper iodide (9.2 mg, 0.0483 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (21.5 mg, 0.144 mmol) and potassium phosphate (255 mg, 1.207 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 35 mg of the product (24% yield).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:3]=1.FC(F)(F)C(O)=O.[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36])[CH:29]=[CH:28]2>>[ClH:24].[Cl:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[CH:31]=[C:30]([S:35]([N:38]1[CH2:39][CH2:40][N:41]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=4)=[CH:16][CH:15]=3)[CH2:42][CH2:43]1)(=[O:36])=[O:37])[CH:29]=[CH:28]2
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccc(-c2cccnc2)cc1)N1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1

Procedure:
In a similar manner to Example 4 except for the use of 4-(3-pyridyl)benzoic acid hydrochloride and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine trifluoroacetate as the raw materials, the reaction was conducted, whereby the title compound was obtained as a colorless solid.