Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[N:3]1.[CH3:12][N:13]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14](Cl)=[O:15]>>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:4]1[CH:5]=[CH:6][N:2]([O:1][C:14](=[O:15])[N:13]([CH3:12])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1
Reactant: On1ccc(-c2cccs2)n1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)On1ccc(-c2cccs2)n1)c1ccccc1

Procedure:
The title compound was prepared from 1-hydroxy-3-(2-thienyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane) (66%, oil).
Reaction SMILES: O1CCCOC1[CH2:7][CH2:8][C:9]1[C:10]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:17]=[CH:16][C:11]=2[N:12]=[C:13]([NH2:15])[N:14]=1.Cl[C:28]1N=C(C(C)C)C2N=C(C3C=CC(F)=CC=3)C=CC=2N=1>>[F:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:9]([CH:8]([CH3:7])[CH3:28])[C:10]=3[N:19]=2)=[CH:25][CH:24]=1
Reactant: CC(C)c1nc(Cl)nc2ccc(-c3ccc(F)cc3)nc12
Reactant: Nc1nc(CCC2OCCCO2)c2nc(-c3ccc(F)cc3)ccc2n1
Product: CC(C)c1nc(N)nc2ccc(-c3ccc(F)cc3)nc12

Procedure:
The procedure for the synthesis of 4-(2-[1,3]dioxan-2-yl-ethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidin-2-ylamine was repeated, except for the use of 2-chloro-6-(4-fluoro-phenyl)-4-isopropyl-pyrido[3,2-d]pyrimidine instead of 2-chloro-4-(2-[1,3]dioxan-2-yl-ethyl)-6-(4-fluoro-phenyl)-pyrido[3,2-d]pyrimidine. The resulting title compound was characterized as follows: MS (m/z) 283.0 [M+H]+; HPLC Rt=3.42 minutes (Method A).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[C:34](C)=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH:45]=O)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:50][C@@H:51]1[CH2:56][NH:55][CH2:54][C@H:53]([CH3:57])[NH:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:48][CH3:49])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:31][CH2:32][C:33]4[CH:34]=[C:35]([C:39]5[CH:44]=[CH:43][CH:42]=[C:41]([CH2:45][N:55]6[CH2:54][C@H:53]([CH3:57])[NH:52][C@H:51]([CH3:50])[CH2:56]6)[CH:40]=5)[CH:36]=[CH:37][CH:38]=4)=[O:30])[CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(C=O)c3)c2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2cccc(-c3cccc(CN4C[C@@H](C)N[C@@H](C)C4)c3)c2)c1
Yield: 40.1 %

Procedure:
A mixture of N-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-N′-[(3′-formyl-2-methyl-3-biphenylyl)methyl]-1,3-benzenedicarboxamide (100 mg, 0.000152 mol) in 1,2-dichloroethane (4 mL) with (2R,6S)-2,6-dimethylpiperazine (27.4 mg, 0.00024 mol) and sodium triacetoxyborohydride (68 mg., 0.00032 mol) and AcOH (12 μL) was placed on an oscillating shaker overnight at room temperature. The reaction was quenched with sat. aq. NaHCO3, then extracted with 1,2-dichloroethane (2×). Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. Purification was carried out on a Gilson HPLC instrument with acetonitrile-water (0.1% TFA) gradient; C18-RP Column. Fractions containing the clean desired product were combined; diluted with EtOAc; washed with sat. aq. NaHCO3; and the aq. phase was back-extracted with EtOAc. Combined organic extracts were washed with sat. aq. NaCl and dried (Na2SO4) and concentrated to a residue. It was taken up in a small amount of 1,2-dichloroethane and transferred to a vial and pumped down to afford the title compound as a pale brown colored solid [45.3 mg (39%)]. LC-MS m/z 757.5 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.[CH3:14][N:15]=[C:16]=[O:17]>C(Cl)Cl>[CH3:14][NH:15][C:16]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:17]
Reactant: CN=C=O
Reactant: NCCSc1cccc2nccn12
Solvent: ClCCl
Product: CNC(=O)NCCSc1cccc2nccn12
Yield: 0.1 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (1.93 g, 10 moles) in methylene chloride (30 ml) was added methyl isocyanate (0.59 ml, 10 moles) under ice-cooling with stirring and the mixture was stirred under ice-cooling for 1 hour. After the solvent was distilled off, the residue was purified by column chromatography (eluent: ethanol/ethyl acetate=1:5) to obtain 2.15 g of the desired product (86.0%, pale yellow crystals).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]([OH:22])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23]I>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]2[CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]([O:22][CH3:23])[CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CCC(O)CC1c1cccc(OCc2ccccc2)c1
Reactant: CI
Product: COC1CCC(C)C(c2cccc(OCc3ccccc3)c2)C1
Yield: 65 %

Procedure:
Using an analogous procedure to that described in Example 2, (1SR,3RS,4SR)-3-(3-benzyloxyphenyl)-4-methylcyclohexan-l-ol was reacted with methyl iodide to give (1SR,3RS,4SR)-3-(3-benzyloxyphenyl)-1-methoxy-4-methylcyclohexane in 65% yield as an oil.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10](=O)[NH:9][C:8]=2[N:7]=[C:6]1[N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:2]#[C:3][CH3:4].P(Cl)(Cl)([Cl:39])=O>>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]([Cl:39])=[N:9][C:8]=2[N:7]=[C:6]1[N:24]1[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2[nH]c(=O)n(CCc3ccccc3)c(=O)c21
Reactant: O=P(Cl)(Cl)Cl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Cl)n(CCc3ccccc3)c(=O)c21
Temperature: 120 °C
Reaction time: 8 h

Procedure:
A mixture consisting of 290 mg of t-butyl 4-[7-(2-butynyl)-2,6-dioxo-1-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate and 4 ml of phosphorus oxychloride was heated and stirred in an oil bath at 120° C. for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 5 ml of tetrahydrofuran. This solution was added dropwise to a mixture consisting of 250 mg of di-t-butyl dicarbonate, 10 ml of a saturated sodium bicarbonate solution, and 10 ml of tetrahydrofuran while the mixture was being stirred and cooled with ice. The mixture was incubated at room temperature for 4 hours, and then extracted with ethyl acetate. The organic layer was washed with water then with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated under reduce pressure. The residue was purified by silica gel column chromatography using 30 to 50% ethyl acetate/hexane. Then, the material was further purified by reverse-phase column chromatography using 50 to 100% methanol/water to give 60 mg of the title compound.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH2:6][OH:7])=[C:4]([CH3:11])[CH:3]=1.Br[C:13]1[CH:20]=C(C)C(C=O)=C(C)[CH:14]=1>>[CH3:10][C:8]1[CH:9]=[C:2]([CH:13]([CH3:20])[CH3:14])[CH:3]=[C:4]([CH3:11])[C:5]=1[CH2:6][OH:7]
Reactant: Cc1cc(Br)cc(C)c1C=O
Reactant: Cc1cc(Br)cc(C)c1CO
Product: Cc1cc(C(C)C)cc(C)c1CO
Yield: 95 %

Procedure:
4Bromo-2,6-dimethylbenzyl alcohol, from 4-bromo-2,6-dimethylbenzaldehyde (Hjed, H. et al. Acta Chem. Scand. 1965, 19:2166); 95% yield, mp 117-119° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13](Br)=[C:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=[O:6].[N:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2B(O)O)[CH:32]=[CH:31][CH:30]=1>>[OH:1][CH2:2][CH2:3][N:4]([CH3:28])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:38]=2[N:29]=[CH:30][CH:31]=[CH:32]3)=[C:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:9][CH:8]=1)=[O:6]
Reactant: CN(CCO)C(=O)c1ccc(C(Br)=C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reactant: OB(O)c1cccc2cccnc12
Product: CN(CCO)C(=O)c1ccc(C(=C2CCN(C(=O)OC(C)(C)C)CC2)c2cccc3cccnc23)cc1

Procedure:
A still further embodiment is directed to a process for preparing N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide comprising reacting 2-(methylamino)ethanol with 4-((1-(tert-butoxycarbonyl)piperidin-4-ylidene)bromomethyl)benzoic acid to form tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromomethylene)piperidine-1-carboxylate; reacting the tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)bromomethylene)piperidine-1-carboxylate with 8-quinolineboronic acid to form tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinolin-8-yl)methylene)piperidine-1-carboxylate; deprotecting the tert-butyl 4-((4-(N-(2-hydroxyethyl)-N-methylcarbamoyl)phenyl)(quinolin-8-yl)methylene)piperidine-1-carboxylate to form N-(2-hydroxyethyl)-N-methyl-4-((piperidin-4-ylidene)(quinolin-8-yl)methyl)benzamide; and reacting the N-(2-hydroxyethyl)-N-methyl-4-((piperidin-4-ylidene)(quinolin-8-yl)methyl)benzamide with thiazole-4-carbaldehyde to form the N-(2-hydroxyethyl)-N-methyl-4-(quinolin-8-yl(1-(thiazol-4-ylmethyl)piperidin-4-ylidene)methyl)benzamide.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[NH:10][C:9](=[O:11])[C:8]2([CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]2)[N:7]=1)(=[O:3])[CH3:2].C(Cl)Cl.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]>C(Cl)Cl>[O:11]=[C:9]1[C:8]2([CH2:12][CH2:13][NH:14][CH2:15][CH2:16]2)[N:7]=[C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[NH:10]1.[C:27]([OH:33])([C:29]([F:32])([F:31])[F:30])=[O:28]
Reactant: CC(=O)NCC1=NC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCC1=NC2(CCNCC2)C(=O)N1
Reaction time: 0.5 h

Procedure:
For deprotection, 2A (1.0 equivalent) was dissolved in CH2Cl2 at 0° C., and slowly treated with a 1.6:1 solution of CH2Cl2/TFA (2:1 final ratio, 0.15 M). The reaction was completed in 30 minutes at 0° C. as determined by LCMS analysis. The volatiles were removed under reduced pressure to yield N-((4-oxo-1,3,8-triazaspiro[4.5]dec-1-en-2-yl)methyl)acetamide (2B) as TFA salts which were used without further purification. ESI-MS: m/z 225.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[SH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([S:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][N:8]=1)(=[O:4])[CH2:2][CH3:3]
Reactant: CCC(=O)Cl
Reactant: Cc1cccnc1S
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)Sc1ncccc1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
1.21 ml (13.9 mole) of propionyl chloride were added dropwise, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 1.46 g (11.7 mole) of 2-mercapto-3-methylpyridine (prepared as described in Preparation 7) and 1.94 ml (13.9 mmole) of triethylamine in 15 ml of methylene chloride, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was mixed with 50 ml of methylene chloride, and the mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate. It was then dried over anhydrous magnesium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by medium pressure column chromatography through silica gel, using a 5:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 1.89 g (yield 89%) of the title compound as a light yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:6]2[N:5]=[CH:4][C:3]=1[C:16]([N:18]1[CH2:23][CH2:22][C:21]2([C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:25][CH2:24]2)[CH2:20][CH2:19]1)=[O:17].[NH2:32][C:33]1[C:34]([CH3:39])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH2:14]([O:13][C:11]([C:10]1[CH:9]=[N:8][N:7]2[C:2]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[C:3]([C:16]([N:18]3[CH2:19][CH2:20][C:21]4([C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH2:25][CH2:24]4)[CH2:22][CH2:23]3)=[O:17])[CH:4]=[N:5][C:6]=12)=[O:12])[CH3:15]
Reactant: CCOC(=O)c1cnn2c(Cl)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Reactant: Cc1ccccc1N
Product: CCOC(=O)c1cnn2c(Nc3ccccc3C)c(C(=O)N3CCC4(CCc5ccccc54)CC3)cnc12
Yield: 83.3 %

Procedure:
In the same manner as in Example 19, step 5 and using 7-chloro-3-ethoxycarbonyl-6-(spiro[indane-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine (0.15 g, 0.33 mmol) obtained in step 2 and o-toluidine (0.053 g, 0.5 mmol), the title compound (0.14 g, 85%) was obtained.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH2:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)(Cl)Cl>[CH2:16]([CH:13]1[CH2:12][CH2:11][N:10]([CH2:9][CH2:8][NH2:7])[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCN1CCC(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: NCCN1CCC(Cc2ccccc2)CC1

Procedure:
[2-(4-Benzyl-piperidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (1.34 g, 4.2 mmol) is dissolved in CHCl3 (3 mL) and treated with TFA (3 mL) for 2 h at 20° C. The solvent is evaporated, the residue dissolved CH2Cl2 (100 mL) and washed with 1M aqueous NaOH (2×30 mL). The organic layer is dried (Na2SO4), filtered and concentrated to provide the title compound.
Reaction SMILES: [NH2:1][CH:2]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH:3]([NH:9][CH:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:26]([NH:1][CH:2]([CH2:22][CH:23]([CH3:24])[CH3:25])[CH:3]([NH:9][CH:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])[CH3:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(NC(C)C(=O)N1CCC[C@H]1C(=O)O)C(N)CC(C)C
Reactant: O=C(Cl)c1ccccc1
Product: CCOC(=O)C(NC(C)C(=O)N1CCC[C@H]1C(=O)O)C(CC(C)C)NC(=O)c1ccccc1

Procedure:
By treating a solution of N-(2-amino-1-ethoxycarbonyl-4-methylpentyl)-D,L-alanyl-L-proline (prepared as described in Example 79) in organic solvent with benzoyl chloride, one can obtain N-(2-benzamido-1-ethoxycarbonyl-4-methylpentyl)-D,L-alanyl-L-proline.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Br:12][CH2:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[C:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:15][CH2:14][CH2:13][Br:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(O)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)Oc1ccc(OCCCBr)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 9.9 %

Procedure:
A mixture of 1.52 g (10 mmol) of 4-acetoxyphenol, 2.22 g (11 mmol) 1,3-dibromopropane, and 2.98 g (21 mmol) of anhydrous potassium carbonate in dimethylformamide was stirred rapidly at room temperature for 4 hours. Ethyl acetate was added, and the salts present were removed by filtration. The solvent was removed under reduced pressure, and the residue chromatographed over silica gel. Elution with 15% ethyl acetate-hexane gave 270 mg of the title compound, which was homogeneous by thin layer chromatography (15% by volume of ethyl acetate/hexane on silica gel plates).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:8]([CH3:19])=[CH:9][N:10]2[CH:14]([CH2:15][C:16]([OH:18])=O)[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[CH:1]([O:4][C:5]([C:7]1[C:8]([CH3:19])=[CH:9][N:10]2[CH:14]([CH2:15][C:16]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[O:18])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:2])[CH3:3]
Reactant: Cc1cn2c(c1C(=O)OC(C)C)SCC2CC(=O)O
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: Cc1cn2c(c1C(=O)OC(C)C)SCC2CC(=O)N1CCOCC1
Yield: 54.8 %

Procedure:
1.54 g of (7-isopropoxycarbonyl-6-methyl-2,3-dihydropyrrolo[2,1-b]thiazol-3-yl)acetic acid, 0.70 g of morpholine and 0.12 g of 4-N,N-dimethylaminopyridine were dissolved in 50 ml of dichloromethane. 1.44 g of N,N'-dicyclohexylcarbodiimide was added thereto under ice-cooling and stirring. Then the mixture was stirred at room temperature for 9 days. After filtering off the insoluble matters, the solvent was distilled off. The oily residue thus obtained was purified by silica gel column chromatography. After crystallizing from ether/n-hexane, 1.05 g of the title compound was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([SH:10])[NH:9][C:5]=2[CH:4]=1.[CH2:13](Cl)/[CH:14]=[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])\[CH3:16].[OH-].[Na+]>CO>[CH3:16]/[C:15](/[CH2:17][CH2:18][CH:19]=[C:20]([CH3:22])[CH3:21])=[CH:14]\[CH2:13][S:10][C:8]1[NH:7][C:6]2[CH:11]=[CH:12][C:3]([O:2][CH3:1])=[CH:4][C:5]=2[N:9]=1
Reactant: COc1ccc2nc(S)[nH]c2c1
Reactant: CC(C)=CCC/C(C)=C/CCl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2[nH]c(SC/C=C(\C)CCC=C(C)C)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the 5-methoxy-2-mercaptobenzimidazole (2.5 g, 0.014M) in methanol (100 mL) was added geranyl chloride (2.4 g, 0.014M). The solution was taken to pH 11 (2N NaOH), stirred overnight at ambient temperature, evaporated, dissolved in CH2Cl2, washed with saturated NaHCO3 +brine, and dried over Na2SO4. The solvent was evaporated to oil which was flash chromatographed (Rf=0.76) (5% MeOH (CH2Cl2)) to give 2-[(3,7-dimethyl-2,6-(E)-octadienyl)thio]-5-methoxy-1H-1,3-benzimidazole (free base) which was converted to its oxalate salt (0.74 g). m.p. 113°-116° C. NMR (DMSO-d6)δ7.8(m,3H), 5.2 (m, 2H), 3.9(d, J=7 Hz, 2H), 3.8(s, 3H), 2.02(m, 4H),1.7(s,3H), 1.6(s, 6H).
Reaction SMILES: BrCC1C=CC2[C:8]3[NH:9][C:10](=[O:17])[C:11]4[C:16]([C:7]=3CC=2C=1)=[CH:15][CH:14]=[CH:13][CH:12]=4>C(O)C.CN(C=O)C>[C:10]1(=[O:17])[C:11]2[C:16]([CH:15]=[CH:14][C:13]3[C:12]=2[CH:10]=[C:11]2[C:16]=3[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][CH:8]=[N:9]1
Reactant: O=c1[nH]c2c(c3ccccc13)Cc1cc(CBr)ccc1-2
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C1N=CC=c2ccc3c(c21)C=c1ccccc1=3
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 9-bromomethyl-5,6-dihydro-5-oxo-11-H-indeno[1,2-c]isoquinoline (0.425 g, 1.3 mmol) or a higher alkylene chain bromo-derivative, an appropriate amine in ethanol or DMF and ethanol and in the presence of base is refluxed for 2 hrs to overnight. The reaction mixture is stirred at room temperature for about 30 minutes and filtered. The resultant solid is washed with ethanol (2×20 mL) and dried in a vacuum oven to provide an Indenoisoquinolinone Analog of Formula IIb or IIIb.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:10][CH:9]=1.O.NN>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][NH2:17])=[CH:10][CH:9]=1
Reactant: O=C1c2ccccc2C(=O)N1CCOc1ccc(-c2ccccc2F)nc1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCOc1ccc(-c2ccccc2F)nc1

Procedure:
189 mg (0.52 mmol) of (2-(2-(6-(2-fluorophenyl)pyridin-3-yloxy)ethyl)isoindole-1,3-dione and 236 mg (4.72 mmol) of hydrazine hydrate (24%) were stirred in 10 ml of ethanol under reflux for 7 h. After cooling the residue was filtered, washed and dried. Yield: 165 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C@H:13]([OH:21])[C@@H:14]3[CH2:18][CH2:17][CH2:16][C:15]3=[N:19]O)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].O>CO.[Ni]>[NH2:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][C@H:14]1[C@H:13]([C:9]1([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][CH2:11][CH2:12]1)[OH:21]
Reactant: ON=C1CCC[C@H]1[C@@H](O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: [Ni]
Solvent: O
Solvent: CO
Product: N[C@@H]1CCC[C@H]1[C@@H](O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 4.71 %

Procedure:
A mixture of Example 220B (200 mg, 0.609 mmol) in MeOH (25 mL) was added to Ra—Ni 2800, (water slurry, 500 mg, 9.93 mmol) in a 50 mL pressure bottle and stirred for 16 hours at 30 psi at room temperature, and filtered through a nylon membrane. The filtrate was concentrated and purified using a Waters C8 OBD SunFire 30 mm×75 mm column eluted with acetonitrile/0.1% TFA to afford Example 220C in 4.71% yield. MS (ESI+) M/Z 314 (M+H)+. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.58 (d, J=8.3 Hz, 1H), 7.52 (d, J=2.1 Hz, 1H), 7.34 (dd, J=8.4, 2.1 Hz, 1H), 5.85 (d, J=4.3 Hz, 1H), 3.74 (dd, J=9.7, 3.5 Hz, 1H), 3.21-3.29 (m, 1H), 2.06-2.38 (m, 5H), 1.10-1.88 (m, 10H);
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH2:11][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:13][C:7]=2[CH:6]=[CH:5][C:4]=1[NH2:19].Cl[C:21]1[N:26]=[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:24]([Cl:39])=[CH:23][N:22]=1>>[Cl:39][C:24]1[C:25]([NH:27][C@@H:28]2[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]2[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])=[N:26][C:21]([NH:19][C:4]2[CH:5]=[CH:6][C:7]3[CH2:13][CH:12]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:11][CH2:10][CH2:9][C:8]=3[C:3]=2[O:2][CH3:1])=[N:22][CH:23]=1
Reactant: COCCNC1CCCc2c(ccc(N)c2OC)C1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Product: COCCNC1CCCc2c(ccc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c2OC)C1

Procedure:
The title compound was prepared from 1-methoxy-N(6)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-2,6-diamine (70 mg, 0.3 mmol) and N-[(1R,2R)-2-(2,5-dichloropyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (90 mg, 0.26 mmol) in an analogous manner to Example 946 to afford a peach foam (47 mg, 31%). Mp: 81-3° C. LCMS (m/e) 567 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.96 (m, 2H), 7.33 (d, J=6 Hz, 1H), 6.92 (d, J=8 Hz, 1H), 5.47 (d, J=8 Hz, 1H), 3.92 (m, 1H), 3.73 (s, 3H), 3.51 (m, 2H), 3.37 (s, 3H), 3.29 (m, 1H), 3.11 (m, 1H), 2.87 (m, 4H), 2.82 (s, 3H), 2.61 (m, 2H), 2.21 (m, 2H), 2.10 (m, 1H), 1.95 (m, 1H), 1.84 (m, 1H), 1.67 (m, 3H), 1.51-1.31 (m, 5H).
Reaction SMILES: [Cl-].C(OC(NCC/C(/N1CCCC1)=C/C(OCC)=O)=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][C:28]1[C:32]2[C:33](=[O:37])[NH:34][CH:35]=[CH:36][C:31]=2[O:30][N:29]=1>>[O:30]([C:31]1[CH:36]=[CH:35][C:27]([C:28]2[C:32]3[C:33](=[O:37])[NH:34][CH:35]=[CH:36][C:31]=3[O:30][N:29]=2)=[CH:28][CH:32]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)/C=C(/CCNC(=O)OCc1ccccc1)N1CCCC1
Reactant: Cc1noc2cc[nH]c(=O)c12
Agent: [Cl-]
Product: O=c1[nH]ccc2onc(-c3ccc(Oc4ccccc4)cc3)c12

Procedure:
The title compound was prepared from 4-phenoxybenzohydroxyiminoyl chloride, prepared using the procedure described in Jones, Raymond C. F. et al, J. Med. Chem. 2003, 46, 87-96, and ethyl (Z)-5-{[(benzyloxy)carbonyl]amino}-3-tetrahydro-1H-1-pyrrolyl-2-pentenoate, prepared using the procedure described in Natale, Nicholas, R. et al, J. Chem. Soc. Perkins Trans. I, 1999, 765-776, using a manner similar to that described in Natale, Nicholas, R. et al, J. Chem. Soc. Perkins Trans. I, 1999, 765-776 for the preparation of 3-methyl-4,5-dihydroisoxazolo[4,5-c]pyridin-4-one. 1H NMR (DMSO-d6, 400 MHz) δ8.31 (d, 2H), 7.66 (d, 1H), 7.46 (t, 2H), 7.22 (t, 1H), 7.1-7.15 (m, 5H), 6.82 (d, 1H); Rt=3.03 min (Conditions a), MS m/e: 303 (M−H)−.