Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[CH:13])=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:4](=[O:21])[CH2:3]1.I[C:24]1[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=1.C(N(CC)CC)C.CN(C)C=O>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][C:8]([C:12]#[C:13][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=3)=[CH:9][CH:10]=2)[N:5]([C:14]2[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=2)[C:4](=[O:21])[CH2:3]1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc2c(c1)N(c1ccc(C)cc1)C(=O)CC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)N(c2ccc(C)cc2)C(=O)CC3(C)C)cc1
Temperature: 50 °C

Procedure:
To a mixture of 0.13 g (0.45 mmol) of 4,4-dimethyl-3,4-dihydro-N-(4-methylphenyl)-7-ethynyl-2(1H)-quinolinone (Compound 20) and 0.29 g (1.0 mmol) of ethyl 4-iodobenzoate were added 2.9 g (4.0 mL, 29 mmol) of triethylamine, 2.0 mL of dimethylformamide, 0.019 g (0.10 mmol) of copper(I)iodide, and 0.067 g (0.10 mmol) of bis(triphenylphosphine)palladium(II) chloride, consecutively. The resulting mixture was heated at 50° C. for 16 hours. Thereafter methylene chloride was added and the reaction mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (15% ethyl acetate in hexanes) to give the title compound as an orange solid. PNMR (300 MHz, CDCl3) d 1.41 (3 H, t, J=7.1 Hz), 1.43 (6 H, s), 1.86 (2 H, t, J=6.0 Hz), 2.44 (3 H, s), 2.48 (2 H, s), 4.37 (2 H, q, J=7.1 Hz), 6.59 (1 H, d, J=1.5 Hz), 7.12 (2 H, d, J=8.3 Hz), 7.20-7.38 (4 H, m), 7.50 (2 H, d, J=8.1 Hz), 7.98 (2 H, d, J=8.1 Hz).
Reaction SMILES: CO[C:3]([O:11]C)([O:9][CH3:10])[CH2:4][CH2:5][CH2:6][C:7]#[CH:8].C([Li])CCC.[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH:36]=[O:37])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>O1CCCC1.CCOCC>[CH2:18]([O:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[CH:36]([OH:37])[C:8]#[C:7][CH2:6][CH2:5][CH2:4][C:3]([O:9][CH3:10])=[O:11])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1ccc2ccccc2c1OCc1ccccc1
Reactant: C#CCCCC(OC)(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: COC(=O)CCCC#CC(O)c1ccc2ccccc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A solution of 1,1,1-trimethoxy-5-hexyne (3.90 g, 0.023 mo)e) in dry tetrahydrofuran (50 mL) was stirred at -78° and treated with n-butyllithium (1.6M in hexane; 15 mL, 0.024 mole). The solution was stirred for 30 minutes, then treated with a solution of 1-benzyloxy-2-naphthaldehyde (4.25 g. 0.016 mole) in dry tetrahydrofuran (12 mL). The reaction mixture was allowed to warm to room temperature, stirred for 4 hours, and poured into water. The crude product was isolated by extraction with ether and chromatographed with 3:1 ether/hexane. This afforded the title compound (6.15 g. 97%) as an oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[F:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][N:40]([CH:43]2[CH2:48][CH2:47][N:46]([C:49]3[C:55]([O:56][CH3:57])=[CH:54][C:52]([NH2:53])=[C:51]([O:58][CH3:59])[CH:50]=3)[CH2:45][CH2:44]2)[CH2:39][CH2:38]1.N>CC(O)C.Cl.CO>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:53][C:52]3[CH:54]=[C:55]([O:56][CH3:57])[C:49]([N:46]4[CH2:45][CH2:44][CH:43]([N:40]5[CH2:39][CH2:38][N:37]([CH2:36][CH2:35][F:34])[CH2:42][CH2:41]5)[CH2:48][CH2:47]4)=[CH:50][C:51]=3[O:58][CH3:59])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1N
Agent: Cl
Agent: N
Solvent: CC(C)O
Solvent: CO
Product: COc1cc(N2CCC(N3CCN(CCF)CC3)CC2)c(OC)cc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 180 °C
Yield: 32.1 %

Procedure:
In a 5 mL microwave vial with septum cap, 3-[3-(2-chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (0.200 g, 0.433 mmol), 4-{4-[4-(2-fluoroethyl)-1-piperazinyl]-1-piperidinyl}-2,5-bis(methyloxy)-aniline (0.190 g, 0.520 mmol) were taken up in iPrOH (3 mL) and concentrated HCl (4 drops) was added. The vial was sealed and heated in the microwave at 180° C. for 40 min. Reaction was complete by MS, it was cooled rt, neutralized with 7N ammonia in MeOH, and concentrated in vacuo. The resulting residue was taken up in DCM and purified by column chromatography using basic alumina followed by silica gel flash chromatography. The desired fractions were concentrated and the resulting solid was triturated with DCM and hexane, filtered and vacuum dried to give the title compound (0.110 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.24 (s, 1H), 8.52 (s, 1H), 8.33 (s, 1H), 8.24 (d, J=5.1 Hz, 1H), 8.04 (d, J=7.9 Hz, 1H), 7.83 (d, J=7.9 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.26-7.53 (m, 3H), 7.13-7.27 (m, 2H), 6.84-7.08 (m, 1H), 6.66 (s, 1H), 6.50 (d, J=5.1 Hz, 1H), 4.56 (t, J=4.9 Hz, 1H), 4.45 (t, J=4.9 Hz, 1H), 3.76 (s, 3H), 3.64 (s, 3H), 3.36-3.53 (m, 2H), 2.37-2.74 (m, 12H), 2.13-2.36 (m, 1H), 1.70-1.94 (m, 2H), 1.39-1.69 (m, 2H). MS (M+H, ES+) 792.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:17]=[CH:16][C:11]3[B:12]([OH:15])[O:13][CH2:14][C:10]=3[CH:9]=2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1.CCN(CC)CC>C(Cl)Cl>[OH:15][B:12]1[C:11]2[CH:16]=[CH:17][C:8]([O:7][C:6]3[CH:18]=[CH:19][C:3]([CH2:2][NH:1][S:27]([C:24]4[CH:25]=[CH:26][C:21]([CH3:20])=[CH:22][CH:23]=4)(=[O:29])=[O:28])=[CH:4][CH:5]=3)=[CH:9][C:10]=2[CH2:14][O:13]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NCc1ccc(Oc2ccc3c(c2)COB3O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NCc2ccc(Oc3ccc4c(c3)COB4O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 20 mL scintillation vial containing 5-(4-aminomethyl-phenoxy)-3H-benzo[c][1,2]oxaborol-1-ol (144 mg, 0.56 mmol, 1.1 eq.), 4-methyl-benzenesulfonyl chloride (118.4 mg, 0.62 mmol, 1.1 eq.) in DCM (10.0 mL) was added Et3N (160 μL, 1.12 mmol, 2.0 eq.) drop wise. The mixture was stirred at room temperature overnight. The mixture was carefully treated with aqu. NH4Cl (10 mL) and the layers were separated. The aqueous was extracted with DCM (2×5 mL), combined organic phase was washed with H2O (10 mL), brine (10 mL), dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure. The residue was applied to silica chromatography eluting with EtOAc/Heptanes (0:100 to 80:20) to give N-[4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzyl]-4-methyl-benzenesulfonamide as a white solid. LCMS (m/z) 432 (M+23); 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (DMSO-d6) δ: 9.11 (s, 1H), 8.08 (t, J=6.3 Hz, 1H), 7.65-7.74 (m, 3H), 7.38 (d, J=8.0 Hz, 2H), 7.23-7.31 (m, J=8.6 Hz, 2H), 6.95-7.00 (m, 2H), 6.89-6.95 (m, 2H), 4.92 (s, 2H), 3.95 (d, J=6.3 Hz, 2H), 2.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH2:12][C:11]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[O:10][N:9]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([N:35]=[C:36]=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]>C1(C)C=CC=CC=1>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([N:15]2[CH2:16][CH2:17][C:11]3([O:10][N:9]=[C:8]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=4)[CH2:12]3)[CH2:13][CH2:14]2)=[O:37])=[CH:31][CH:30]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: Clc1cccnc1C1=NOC2(CCNCC2)C1
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(NC(=O)N2CCC3(CC2)CC(c2ncccc2Cl)=NO3)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 83 %

Procedure:
Compound K (0.130 g, 0.451 mmol) was dissolved in toluene (15 ml) and triethylamine (0.12 ml, 0.867 mmol) and 4-tert-butylphenyl isocyanate (0.08 ml, 0.451 mmol) were successively added. The reaction mixture was heated to boiling point and boiled under reflux for 3 h. After cooling of the reaction mixture to RT, the mixture was stirred for 36 h. The reaction mixture was extracted with EtOAc (3×20 ml). The combined organic phases were washed with sat. Na2HCO3 solution (10 ml), dried over Na2SO4 and concentrated to dryness under vacuum. After purification of the residue by column chromatography (hexane:EtOAc1:1), the product was obtained in a yield of 83% (0.160 g).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CCN(C(C)C)C(C)C.[CH2:41]([O:43][C:44](=[O:49])[CH2:45][CH:46]([NH2:48])[CH3:47])[CH3:42]>C1COCC1>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[CH3:28])=[C:18]([CH2:29][O:30][CH3:31])[CH:17]=3)[O:13][N:12]=2)[CH:8]=[CH:7][C:3]=1[C:4]([NH:48][CH:46]([CH3:47])[CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:49])=[O:5]
Reactant: COCc1cc(-c2nc(-c3ccc(C(=O)Cl)c(F)c3)no2)ccc1-c1ccccc1C
Reactant: CCOC(=O)CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)NC(=O)c1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(COC)c3)n2)cc1F
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoyl chloride, prepared as in example 116 (75 mg; 0.17 mmol) in dry THF, DIEA (103 μl; 0.60 mmol) was added followed by ethyl-3-aminobutyrate (45 mg; 0.34 mmol) and the reaction mixture stirred for 2 h30 at RT. The solvent was then removed under vacuum and the crude material purified by flash chromatography (EtOAc/cHex) to afford the title compound as a colorless oil (82 mg, 89%). 1H NMR: (CDCl3, 300 MHz) δ 8.42 (m, 1H), 8.23 (t, J=8 Hz, 1H), 8.16 (dd, J=1.9, 8 Hz. 1H), 8.09 (dd, J=1.5, 8.1 Hz, 1H), 7.96 (dd, J=1.3, 12.4 Hz, 1H), 7.47 (m, 1H), 7.38-7.22 (m, 5H), 7.12 (m, 1H), 4.62 (m, 1H), 4.21 (m, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.33 (s, 3H), 2.65 (m, 2H), 2.07 (s, 3H), 1.37 (d, J=6.8 Hz, 3H), 1.28 (t, J=7.1 Hz, 3H). UPLC/MS: 532.3 (M+H)+ 530.3 (M−H)−. HPLC (Method A) Rt: 5.52 min (purity: 98.5%).
Reaction SMILES: [CH3:1][C:2](O)([CH3:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1.[C:16](#[N:18])[CH3:17].S(=O)(=O)(O)[OH:20].[OH-].[Na+]>C(O)(=O)C>[CH3:1][C:2]([NH:18][C:16](=[O:20])[CH3:17])([CH3:14])[CH2:3][C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1
Reactant: CC(C)(O)Cc1ccc2ccccc2c1
Reactant: CC#N
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NC(C)(C)Cc1ccc2ccccc2c1

Procedure:
To 2-methyl-1-(naphthalen-2-yl)-2-propanol (500 mg) obtained in Step 7 were added acetonitrile (0.5 ml) and acetic acid (0.5 ml) in this order. After ice-cooling the mixture, sulfuric acid (0.5 ml) was added dropwise. The mixture was stirred under ice-cooling for 20 min and poured into a 1N aqueous sodium hydroxide solution, and the mixture was extracted with diethyl ether. The organic layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to recrystallization from ethyl acetate-n-hexane to give the title compound (303 mg).
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=2)[CH:28]=O)[CH:20]=1>>[CH3:18][O:17][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]([O:15][CH3:16])[C:9]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[C:25]([C:21]3[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=3)[CH:26]=2)[C:5](=[O:7])[CH2:4][CH2:3]1
Reactant: O=Cc1cccc(-c2cccnc2)c1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1cccc(-c2cccnc2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available 3-(pyridin-3-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.57 min.; [M+H]+: 389.36 g/mol.
Reaction SMILES: C(OC(=O)C)(=O)C.[O:8]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:9]1=[O:10].C(O)(=O)C.C(O)(=O)C.[I:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(=O)(=O)(O)O.[F:39][P-:40]([F:45])([F:44])([F:43])([F:42])[F:41].[K+]>ClCCl>[F:39][P-:40]([F:45])([F:44])([F:43])([F:42])[F:41].[C:28]1([I+:27][C:16]2[CH:17]=[C:18]3[C:13]([CH:12]=[CH:11][C:9](=[O:10])[O:8]3)=[CH:14][CH:15]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Ic1ccccc1
Reactant: O=c1ccc2ccccc2o1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=c1ccc2ccc([I+]c3ccccc3)cc2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To 80 ml of acetic anhydride was suspended 7.3 g (0.05 mol) of coumarin and 16.1 g (0.05 mol) of iodobenzene diacetate, and 10 g (0.1 mol) of concentrated sulfuric acid was added dropwise thereto at 0 to 7° C. for 1 hour, followed by gradually warming to room temperature and reacting with stirring for 8 hours. After completion of the reaction, the reaction solution was poured in 200 ml of ice water, and 150 ml of dichloromethane was added thereto to dissolve insoluble substance. Then 18.4 g (0.1 mol) of potassium hexafluorophosphate was added to the obtained solution, followed by stirring at room temperature for 2 hours. The dichloromethane layer obtained by fractionation was washed with 100 ml of water twice. The obtained dichloromethane layer was semi concentrated under reduced pressure and the precipitated crystal was filtered off, followed by drying under vacuum at 50° C. for 2 hours to obtain 2.4 g of objective substance as pale yellow crystal (yield: 10%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1.[H-].[Na+].Br[CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>CN(C=O)C>[CH2:19]([O:18][C:16](=[O:17])[CH:15]([O:1][C:2]1[CH:11]=[CH:10][C:5]2[CH2:6][O:7][B:8]([OH:9])[C:4]=2[CH:3]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH3:20]
Reactant: OB1OCc2ccc(O)cc21
Reactant: CCOC(=O)C(Br)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Oc1ccc2c(c1)B(O)OC2)c1ccccc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 59.7 %

Procedure:
H181 (110 mg, 0.73 mmol) was dissolved in DMF (6.0 mL) and cooled to 0° C. with ice bath. To this solution under nitrogen were added in sequence NaH (60% in mineral oil, 117 mg, 2.93 mmol) and ethyl 2-bromo-2-phenylacetate (0.51 mL, 2.93 mmol). The reaction mixture was stirred for 1 d then treated with 1.0 M HCl (10.0 mL). After extraction with ethyl acetate, the organic layer was washed with water and brine, and dried over anhydrous Na2SO4. The residue after rotary evaporation was purified by column chromatography over silica gel to give the title compound (136 mg, 60% yield). 1H NMR (300 MHz, CDCl3): δ 7.62-7.56 (m, 2H), 7.44-7.12 (m, 6H), 5.67 (s, 1H), 5.03 (s, 2H), 4.30-4.10 (m, 2H) and 1.20 (t, J=7.2 Hz, 3H) ppm; Mp: 94-97° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:19][CH:20]1[CH2:22][CH2:21]1.O>CS(C)=O>[CH:20]1([CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][CH:8]=[C:9]3[NH:12][C:13](=[O:15])[CH3:14])=[CH:4][CH:3]=2)[CH2:22][CH2:21]1
Reactant: CC(=O)Nc1cccc2ccc(O)cc12
Reactant: ClCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Nc1cccc2ccc(OCC3CC3)cc12
Reaction time: 2 h
Yield: 59.9 %

Procedure:
17.1 g (0.085 mol) of N-(7-hydroxynaphth-1-yl)acetamide in solution in 50 ml of dimethyl sulphoxide are added under a nitrogen atmosphere to a suspension of 3.4 g (0.085 mol) of sodium hydride in oil, washed beforehand with dry pentane), in 100 ml of dimethyl sulphoxide, while the mixture is cooled with an ice-water bath. Stirring is continued at room temperature for 2 h. 9.05 g (0.1 mol) of (chloromethyl)cyclopropane are added, and the mixture is stirred at room temperature for 4 h and left to stand overnight. The mixture is poured into 1 l of water, stirred for 1 h and left to stand overnight under cold conditions. The solid is separated by filtration, washed with water and dried. 13 g of a product melting point: 154°-155° C., are obtained which is used as it is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](=[S:19])[C:12]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=3)[CH:10]=1)[NH:7][C:6](=[O:20])[CH2:5]2.Cl.[OH-:22].[Na+:23]>O>[OH2:20].[NH2:7][C:8]1[C:9]([C:11](=[S:19])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[CH2:5][C:6]([O-:20])=[O:22].[Na+:23]
Reactant: Cc1ccc(C(=S)c2cc(Cl)cc3c2NC(=O)C3)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(C(=S)c2cc(Cl)cc(CC(=O)[O-])c2N)cc1
Temperature: 100 °C
Reaction time: 22 h
Yield: 39 %

Procedure:
A mixture of 6.4 g (20.0 mmol) of 5-chloro-7-(4-methylthiobenzoyl)indolin-2-one in 110 ml of 3N sodium hydroxide was heated at 100° C. in an oil bath and stirred under a nitrogen atmosphere for 22 hrs. The reaction mixture was diluted to 600 ml with water and then titrated to a pH of 7.5 with concentrated hydrochloric acid. The mixture was then filtered and the filter cake was extracted with 1.5 liter of hot water. The filtrate obtained was concentrated to a solid residue. This residue was dissolved in hot absolute ethyl alcohol and filtered. The filtrate obtained was concentrated to a solid which was dissolved in 300 ml of 2-propanol and filtered. The filtrate obtained was concentrated to 200 ml and cooled to 0° C., whereby a gel was obtained. This gel was left at room temperature and a crystalline solid was collected therefrom by filtration and dried to give 2.9 g (39%) of the titled compound as a yellow solid, m.p. 259°-260° C.
Reaction SMILES: [CH:1]1([O:7][N:8]2[C:13]([CH3:15])([CH3:14])[CH2:12][CH:11]([OH:16])[CH2:10][C:9]2([CH3:18])[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:19]([Cl:22])([Cl:21])=[O:20]>>[ClH:21].[CH:1]1([O:7][N:8]2[C:9]([CH3:17])([CH3:18])[CH2:10][CH:11]([O:16][C:19]([Cl:22])=[O:20])[CH2:12][C:13]2([CH3:15])[CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC1(C)CC(O)CC(C)(C)N1OC1CCCCC1
Reactant: O=C(Cl)Cl
Product: CC1(C)CC(OC(=O)Cl)CC(C)(C)N1OC1CCCCC1
Product: Cl
Yield: 80 %

Procedure:
Following the procedure of Example 1, 1-cyclohexyloxy-2,2,6,6-tetramethyl-4-hydroxypiperidine is reacted with phosgene to form the title compound in a yield of 80%. The product melts at 174°-175° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)(=O)=O.[I-:21].[Na+].O>CC(C)=O>[C:11]1([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][I:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: CS(=O)(=O)OCCCCCc1cccc2ccccc12
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: ICCCCCc1cccc2ccccc12
Yield: 85.9 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 4.1 grams (0.014 mole) of 1-methylsulfonyloxy-5-(naphth-1-yl)pentane, and 4.2 grams (0.028 mole) of sodium iodide in 150 mL of acetone was heated at reflux for 2.5 hours. The reaction mixture was poured into 400 mL of water, and the mixture was extracted with two 100 mL portions of diethyl ether. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 3.9 grams of 5-(naphth-1-yl)pentyl iodide. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[NH:35][C:36]([C:38]1[C:46]2[N:45]=[C:44]([CH2:47][N:48]3C(=O)C4=CC=CC=C4C3=O)[NH:43][C:42]=2[CH:41]=[CH:40][CH:39]=1)=[O:37])[C:6]([N:8]([CH3:31])[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]1)=[O:23])=[O:7].O.NN>C(O)C>[NH2:48][CH2:47][C:44]1[NH:43][C:42]2[CH:41]=[CH:40][CH:39]=[C:38]([C:36]([NH:35][C:34]3[CH:33]=[CH:32][C:5]([C:6]([N:8]([CH3:31])[C:9]4[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=4[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)=[O:23])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])=[O:37])[C:46]=2[N:45]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN3C(=O)c4ccccc4C3=O)nc12
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(CN)nc12
Temperature: 60 °C
Reaction time: 1 h
Yield: 62.6 %

Procedure:
To a solution of 3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]-4-(2-phthalimidomethyl-1 H-benzimidazol-4-yl)carbonylaminobenzamide (383 mg) in ethanol (5 ml) was added hydrazine monohydrate (19 mg) at ambient temperature and the solution was stirred at 60° C. for 1 hour. The reaction mixture was stirred in an ice water bath for 2 hours and the precipitate was filtered off. The filtrate was evaporated in vacuo and the residue was purified by preparative thin-layer chromatography (chloroform-methanol-ammonia solution (28%)=160:32:1) to give 4-(2-aminomethyl-1 H-benzimidazol-4-yl)carbonylamino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (200 mg) as a powder.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][C:12]=1[CH3:13].[F:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.O>CN(C)C=O>[CH3:13][C:12]1[CH:11]=[C:5]2[C:4](=[CH:3][C:2]=1[CH3:1])[C:9](=[O:10])[N:19]([C:18]1[CH:20]=[CH:21][C:15]([F:14])=[CH:16][CH:17]=1)[C:6]2=[O:8]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1cc2c(cc1C)C(=O)OC2=O
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1C)C(=O)N(c1ccc(F)cc1)C2=O
Yield: 77.4 %

Procedure:
4,5-dimethylphthalic anhydride (1.7 g, 9.6 mmol) and 4-fluoroaniline (1.1 g, 9.6 mmol) were stirred with heating in dimethylformamide at 150° C. for 1 hr. After cooling, water was added to the reaction mixture, and the precipitated crystals were collected by filtration, washed with water, and dried. The resulting crystals were purified by silica gel chromatography (chloroform) to give 2.0 g of 5,6-dimethyl-2-(4-fluorophenyl)isoindolin-1,3-dione.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[CH:12][C:13]([OH:17])=[C:14]([Cl:16])[CH:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:18].[Na+].O>CN(C=O)C>[C:1]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([I:18])[CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Oc1ccc(O)c(Cl)c1)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1cc(Cl)c(O)c(I)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3 g of 5-benzoyloxy-1-chloro-2-hydroxybenzene were dissolved in 35 ml of DMF. 2.17 g of sodium iodide and 3.29 g of chloramin T were added. After one hour of stirring at room temperature, about 500 ml of water were added to the mixture, which was then extracted with ethyl acetate. The organic phase was washed with 5% strength sodium thiosulfate solution, dried and concentrated using a rotary evaporator. The resulting product was clean enough for the next reaction. Yield: 3.81 g (84%)