Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([C:16]2[N:17]=[N:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=2)=[O:15])=[CH:4][CH:3]=1.[Br:40]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>>[Br:40][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]([C:16]2[N:17]=[N:18][N:19]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:20]=2)=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2C(=O)c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Product: O=C(c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1)c1ccccc1-c1ccc(CBr)cc1
Yield: 100.6 %

Procedure:
400 mg of 4'-methyl-2-(2-trityltetrazol-5-ylcarbonyl)biphenyl (prepared as described in Preparation 12), 150 mg of N-bromosuccinimide and 20 mg of benzoyl peroxide were treated in the same manner as described in Preparation 8, to give 465 mg of the title compound as a crystalline powder, melting at 161°-163° C. (with decomposition).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25]O>>[CH3:22][C:23]([CH3:28])([CH3:27])[CH2:24][CH2:25][O:20][C:19](=[O:21])[CH2:18][O:17][C:14]1[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:16][N:15]=1
Reactant: CC(C)(C)CCO
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Product: CC(C)(C)CCOC(=O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Yield: 85 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using 3,3-dimethylbutanol (26 mg, 0.26 mmol) as the coupling partner. Concentration (no chromatography) yielded 54 mg (85%) of the titled compound. ESI-MS m/z 376 (MH+), 374 (M−H−).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.Cl.[NH2:11][OH:12].[OH-].[Na+]>O>[F:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:11]\[OH:12])=[CH:4][CH:3]=1
Reactant: NO
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O/N=C\c1ccc(F)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 95.5 %

Procedure:
To a suspension of 4-fluoro-benzaldehyde (30.4 g, 0.24 mol) in water (50 mL) was added at 0-5° C. within 5 minutes a solution of hydroxylamine hydrochloride (17.7 g, 0.25 mol) in water (30 mL) and the resulting mixture stirred for 15 minutes at 0-5° C. The mixture was then treated at 15-25° C. within 15 minutes with 32% NaOH (24.44 mL, 0.26 mol) and the resulting suspension was stirred for one additional hour and then extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and subsequently concentrated to dryness to afford 31.9 g (95%) of the title compound as a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH:7]=O.[CH3:9][O:10][C:11](=[O:19])[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]=[C:3]1[CH2:7][NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:11]([O:10][CH3:9])=[O:19])=[CH:17][CH:16]=1
Reactant: Cn1ccnc1C=O
Reactant: COC(=O)c1ccc(N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1ccc(NCc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-Methyl-2-imidazolecarboxaldehyde (5.0 mmol) and methyl-4-aminobenzoate (5.0 mmol) were mixed in MeOH (7 mL). Acetic acid (0.3 mL) was added and the mixture stirred for 30 minutes at room temperature. The reaction mixture was cooled, sodium cyanoborohydride (5.0 mmol) was added and the reaction allowed to stir at room temperature for a further 17 h. The reaction mixture was then concentrated under vacuum and partitioned between H2O and EtOAc. The aqueous layer was extracted with EtOAc, and the combined organic layers were washed with H2O, brine, dried over MgSO4 and the solvent removed under vacuum. The residue was purified by flash chromatography (silica gel, 5% MeOH in DCM) to give methyl 4-{[(1-methylimidazol-2-yl)methyl]amino}benzoate: m/z=246 in MS ES+ as a pale yellow solid which was used directly in the subsequent step.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]1(=[O:44])[NH:38][C:37](=[O:39])[C:36]2=[CH:40][CH:41]=[CH:42][CH:43]=[C:35]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:38]1[C:34](=[O:44])[C:35]3[C:36](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:37]1=[O:39])=[C:12]2[O:26][CH2:27][CH2:28][CH2:29][C:30]([F:33])([F:32])[F:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)Cn1c(CCl)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(OCCCC(F)(F)F)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 94.3 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-2-isobutyl-4-(4,4,4-trifluorobutoxy)-1(2H)-isoquinolinone (3.37 g, 7 mmol) and potassium phthalimide (1.94 g, 10.5 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 2-[[6-benzyloxy-2-isobutyl-1-oxo-4-(4,4,4-trifluorobutoxy)-1,2-dihydro-3-isoquinolinyl]methyl]-1H-isoindole-1,3(2H)-dione (3.91 g, 94.4%) as crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=O)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[N:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[C:46]1([NH2:49])[CH2:48][CH2:47]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:33]([C:34]([O:36][CH3:37])=[O:35])=[C:11]3[CH:12]=[C:13]([C:24]4[CH:32]=[CH:31][CH:30]=[C:26]([C:27](=[O:29])[NH:49][C:46]5([C:41]6[CH:42]=[CH:43][CH:44]=[CH:45][N:40]=6)[CH2:48][CH2:47]5)[CH:25]=4)[C:14]([N:16]([CH2:21][CH2:22][OH:23])[S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)O)c3)cc12
Agent: Cl
Product: COC(=O)c1c(-c2ccc(F)cc2)nn2cc(N(CCO)S(C)(=O)=O)c(-c3cccc(C(=O)NC4(c5ccccn5)CC4)c3)cc12

Procedure:
Methyl 2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-5-(3-(1-(pyridin-2-yl)cyclopropylcarbamoyl)phenyl)pyrazolo[1,5-a]pyridine-3-carboxylate was prepared from 3-(2-(4-fluorophenyl)-6-(N-(2-hydroxyethyl)methylsulfonamido)-3-(methoxycarbonyl)pyrazolo[1,5-a]pyridin-5-yl)benzoic acid (0.05 g, 0.10 mmol) and 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (0.03 g, 0.15 mmol). LCMS: retention time: 1.473 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters-Sunfire, 5 micron, C18, 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 254 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 3 min, a hold time of 1 min, and an analysis time of 4 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 644 (MH+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[SH:10].Cl[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10][CH2:12][CH2:13][N:14]1[CH2:15][CH2:16][CH:17]([NH:20][C:21]2[N:25]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:24]3[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=3[N:22]=2)[CH2:18][CH2:19]1
Reactant: Sc1nc2ccccc2o1
Reactant: Fc1ccc(Cn2c(NC3CCN(CCCl)CC3)nc3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(Cn2c(NC3CCN(CCSc4nc5ccccc5o4)CC3)nc3ccccc32)cc1
Yield: 50 %

Procedure:
A mixture of 1.5 parts of 2-benzoxazolethiol, 4.6 parts of N-[1-(2-chloroethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine, 4.2 parts of potassium carbonate and 120 parts of 2-propanone was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in water. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 2.5 parts (50%) of N-[1-[2-[(2-benzoxazolyl)thio]ethyl]-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-amine; mp. 174.2° C. (compound 73).
Reaction SMILES: C([O:4][C:5]1[CH:10]=[C:9]([I:11])[C:8]([F:12])=[CH:7][C:6]=1[O:13][CH3:14])(=O)C.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1.CO>[F:12][C:8]1[C:9]([I:11])=[CH:10][C:5]([OH:4])=[C:6]([O:13][CH3:14])[CH:7]=1
Reactant: COc1cc(F)c(I)cc1OC(C)=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(F)c(I)cc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.8 %

Procedure:
To a solution of 64B (680 mg, 2.19 mmol) in THF (3.0 mL) and MeOH (1.0 mL) was added 1.0 N NaOH (2.74 mL, 2.74 mmol). The reaction was stirred at rt for 2.0 h before it was acidified by addition of 5% citric acid. The mixture was extracted with EtOAc, washed with brine and dried over Na2SO4. After evaporation of the solvent, 64C (586 mg, 100% yield) was obtained as a solid and used for next step without further purification. 1H NMR (400 MHz, CDCl3) δ ppm 3.85 (s, 3H) 6.62 (d, J=8.79 Hz, 1H) 7.21 (d, J=6.15 Hz, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F:10][C:11]([F:23])([F:22])[O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:10][C:11]([F:22])([F:23])[O:12][C:13]1[CH:18]=[CH:17][C:16]([C:2]2[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1
Reactant: N#Cc1ccnc(Cl)c1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccnc(-c2ccc(OC(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 96 %

Procedure:
A solution of 19 (2.5 g, 18 mmol) in DME (90 mL) was added 4-trifluoromethoxy phenyl boronic acid (1.1 mol eq, 4.46 g) and NaHCO3 (3 mol eq, 4.66 g) suspended in water (50 mL). The mixture was degassed under vacuum, then Tetrakispalladium was added (catalytic amount) and the reaction stirred at 100° C. under inert atmosphere for 12 h. The solvent was removed under reduced pressure and water was added to the residue (100 mL). The aqueous phase was extracted with EtOAc (3×50 mL) and the combined organic layer was washed with brine (100 mL) and dried over Na2SO4. The solvent was evaporated under vacuum to obtain 20B as a pale yellow crystals (96% Yield, 4.6 g, 17.4 mmol). 1HNMR (DMSO, 200 MHz) δ 7.5 (dd, 2H, J=2), 7.84 (dd, 1H, J=1.8), 8.31 (d, 2H, J=9.8), 8.54 (d, 1H, J=2), 8.93 (dd, 1H, J=1.9).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:7]=1C.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:21]1([N:27]2[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH2:4][S:5][C:6]3[CH:11]=[CH:10][N:9]=[C:8]([CH2:12][S:13][C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[CH:7]=3)[CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: Cc1c(SCCCCl)ccnc1CSc1ccncc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: c1ccc(N2CCN(CCCSc3ccnc(CSc4ccncc4)c3)CC2)cc1
Yield: 79 %

Procedure:
According to the procedure indicated in Example 7, reaction of 4-(3-chloropropylthio)-3-methyl-2-[(4-pyridinylthio)methyl]pyridine with 1-phenylpiperazine and potassium carbonate and subsequent chromatography on silica gel gives, after crystallization from diisopropyl ether, the title compound; m.p. from 210° C. (dec.); yield 79% of theory.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH3:11])[C:4]([CH3:13])([CH3:12])[CH2:3]1.[H-].[Na+].[N:16]1[C:23](Cl)=[N:22][C:20](Cl)=[N:19][C:17]=1Cl>O1CCOCC1>[CH3:11][O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([O:1][C:17]2[N:19]=[C:20]([O:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH3:11])[C:4]([CH3:13])([CH3:12])[CH2:3]3)[N:22]=[C:23]([O:1][CH:2]3[CH2:7][C:6]([CH3:8])([CH3:9])[N:5]([O:10][CH3:11])[C:4]([CH3:13])([CH3:12])[CH2:3]3)[N:16]=2)[CH2:3][C:4]1([CH3:13])[CH3:12]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CON1C(C)(C)CC(O)CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CON1C(C)(C)CC(Oc2nc(OC3CC(C)(C)N(OC)C(C)(C)C3)nc(OC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C

Procedure:
The title compound is prepared by the reaction of 4-hydroxy-1-methoxy-2,2,6,6-tetramethylpiperidine, sodium hydride, and cyanuric chloride in 1,4-dioxane solvent.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:15]2=[C:16]3[C:11](=[CH:12][CH:13]=[CH:14]2)[CH2:10][CH2:9][CH2:8][N:7]3[S:6]1(=[O:18])=[O:17].[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[C:29]1[CH2:30][CH2:31][NH:32][CH2:33][CH:34]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][CH:24]=[C:23]2[C:29]1[CH2:30][CH2:31][N:32]([CH2:2][CH2:3][CH2:4][N:5]2[C:15]3=[C:16]4[C:11](=[CH:12][CH:13]=[CH:14]3)[CH2:10][CH2:9][CH2:8][N:7]4[S:6]2(=[O:18])=[O:17])[CH2:33][CH:34]=1
Reactant: O=S1(=O)N(CCCCl)c2cccc3c2N1CCC3
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=S1(=O)N(CCCN2CC=C(c3c[nH]c4ccc(F)cc34)CC2)c2cccc3c2N1CCC3
Reaction time: 48 h
Yield: 40.4 %

Procedure:
The operation is as in Example 3, starting with 1-(3-chloropropyl)-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (3.8 g), 4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydropyridine (2.9 g) and sodium bicarbonate (3.3 g) in a mixture of dimethylformamide (40 cc) and tetrahydrofuran (25 cc). The mixture is heated to boiling for 48 hours and is then cooled to a temperature close to 20° C. After purification by flash chromatography on a silica column, under a stream of argon at moderate pressure (0.5-1.5 bars) with ethyl acetate as eluent and recrystallization from boiling acetonitrile (200 cc), 1-[3-(4-(5-fluoro-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl)propyl]-5,6-dihydro(1H,4H)-1,2,5-thiadiazolo[4,3,2-ij]quinoline 2,2-dioxide (2.5 g) is obtained, melting at 178° C.
Reaction SMILES: [CH:1]1([C:6]([OH:8])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C=O)C>[CH:1]1([C:6]([O:8][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: BrCc1ccccc1
Reactant: O=C(O)C1CC=CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)C1CC=CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of cyclopent-3-ene-1-carboxylic acid (9.63 g, 85.88 mmol) in 143 mL of degassed DMF was added potassium carbonate (14.24 g, 103.06 mmol) and benzyl bromide (11.24 mL, 94.47 mmol). The mixture was stirred for 2 hours at ambient temperature, and then poured into 150 mL of water and extracted with ethyl acetate. The extracts were washed with water and brine, and dried over sodium sulfate. Filtration and concentration under vacuum afforded benzyl cyclopent-3-ene-1-carboxylate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH:18]=[O:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[C:11](=[O:20])[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(C=O)cc2c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(-c2ccc(F)cc2)c2ccc(CO)cc2c1=O
Yield: 56.8 %

Procedure:
To compound H (335 mg, 0.99 mmol) in ethanol (5 mL) cooled to 0° C. was added sodium borohydride (18.7 mg, 0.49 mmol). After ten minutes, the reaction was diluted with EtOAc and washed well with water. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 192 mg (57%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.25 (s, 1H), 7.76-7.72 (m, 2H), 7.61 (d, J=6 Hz, 1H), 7.54 (t, J=8.64, 8.68 Hz, 2H), 6.94 (d, J=8.68, 1H), 5.42 (t, J=5.68, 5.64 Hz, 1H), 4.62 (d, J=5.48 Hz, 2H), 4.23 (q, J=7.08 Hz, 2H), 1.27 (t, J=7.12, 7.04 Hz, 3H); ES-MS [M+1]+: 342.3.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][N:15]=1>CN1CCCC1=O>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][N:15]=[C:14]2[N:1]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: c1ccc2c(c1)CCCCCN2
Solvent: CN1CCCC1=O
Product: COc1cc2ncnc(N3CCCCCc4ccccc43)c2cc1OC
Yield: 67 %

Procedure:
Utilizing a procedure analogous to that described in Example 47, this product was prepared in 67% yield from 1,2,3,4,5,6-hexahydro-benzo[b]azocine (1.1 eq.), and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in N-methyl-pyrrolidinone. (M.P. 204°-207° C.; GC-MS: 349 (M+); anal. RP18-HPLC RT: 5.25 min.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](F)=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:3])=[O:2].[NH2:13][NH2:14]>>[N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:11]=1[NH:14][N:13]=[C:9]2[NH2:10])([O-:3])=[O:2]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1F
Reactant: NN
Product: Nc1n[nH]c2c([N+](=O)[O-])cccc12
Temperature: 120 °C
Yield: 438.5 %

Procedure:
A mixture of 5-nitro-2-fluoro-benzonitrile (Aldrich, 1.00 g, 6.02 mmol) in 30% aqueous hydrazine (5.00 mL, 18.1 mmol) was heated to about 120° C. in a sealed tube for about 40 minutes. The mixture was cooled to ambient temperature and the precipitate was filtered off, washed with water (10 mL) and dried under reduced pressure to yield 7-nitro-1H-indazol-3-ylamine (0.470 g, 26.4 mmol); (DMSO-d6, 400 MHz) δ 12.16 (br, 1H), 8.90 (m, 1H), 8.05 (dd 1H), 7.35 (d, 1H), 5.98 (br, 2H); RP-HPLC (Table 1, Method j) Rt 8.07 min.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.FC(F)(F)S(O[CH2:21][C:22]([F:25])([F:24])[F:23])(=O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:21][C:22]([F:25])([F:24])[F:23])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: Brc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: FC(F)(F)CN1CCC(c2ccc(Br)cc2)CC1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a mixture of 4-(4-bromophenyl)piperidine hydrochloride (5 g, 18.1 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (4.62 g, 19.9 mmol) in ACN (250 mL) was added N,N-diisopropylethyl amine (11 mL, 63.2 mmol). The reaction mixture was heated at 45° C. for 50 min. 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.46 g, 2.0 mmol) was added and heating continued for 1 h. Another 0.46 g of 2,2,2-trifluoroethyl trifluoromethanesulfonate (2.0 mmol) was added and heating continued for 1 h. The reaction mixture was concentrated, diluted with brine and extracted twice with a mixture of hexanes-EtOAc-DCM. The organic layers were combined, concentrated, diluted with toluene and concentrated again. Purification by flash chromatography on silica gel (0 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 322.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J=8.4 Hz, 2 H),7.08 (d, J=8.4 Hz, 2 H),3.06 (m, 2 H),3.00 (q, J=9.7 Hz, 2 H),2.45 (m, 3 H).1.77 (m, 4H).
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:35][CH2:36][CH2:37][F:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:38][CH2:37][CH2:36][CH2:35][N:4]1[CH2:5][CH2:6][CH2:7][N:1]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH2:25][C@@H:26]5[CH2:30][CH2:29][CH2:28][O:27]5)[CH:20]=4)[C:15]3=[O:31])=[CH:10][C:9]=2[O:32][CH3:33])[CH2:2][CH2:3]1
Reactant: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCNCC1
Reactant: FCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(-n2ccc3cc(OC[C@@H]4CCCO4)ccc3c2=O)ccc1N1CCCN(CCCF)CC1
Reaction time: 8 h

Procedure:
To a solution of 2-(4-[1,4]Diazepan-1-yl-3-methoxy-phenyl)-6-[(S)-1-(tetrahydro-furan-2-yl)methoxy]-2H-isoquinolin-1-one (50 mg) and 1-Bromo-3-fluoro-propane (18 mg) in DMF (1 mL) was added cesium carbonate (54 mg) and the mixture was stirred overnight. The crude mixture was purified by preparative HPLC. The product with the molecular weight of 509.63 (C29H36FN3O4) was obtained in this way; MS (ESI): 510 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:20]3[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[O:29][CH2:30][CH3:31])=[CH:11][CH:10]=1)#[N:2].C[Sn]([N:36]=[N+:37]=[N-:38])(C)C>C1(C)C=CC=CC=1>[CH2:30]([O:29][C:17]1[N:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[C:1]3[NH:38][N:37]=[N:36][N:2]=3)=[CH:14][CH:13]=2)[C:20]2[C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1)[CH3:31]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Solvent: Cc1ccccc1
Product: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.8 %

Procedure:
A mixture of methyl 1-((2′-cyanobiphenyl-4-yl)methyl]-2-ethoxybenzimidazole-7-carboxylate (1.85 g) and trimethyltin azide (2.80 g) in toluene (15 ml) were heated under reflux for one day. The reaction mixture was concentrated to dryness. To the residue were added methanol (50 ml) and 1N-HCl (20 ml) and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was adjusted to about pH 3-4 with 1N-NaOH. After removal of the solvent, the residual syrup was purified by column chromatography on silica gel to give crystals. Recrystallization from ethyl acetate-benzene gave colorless crystals (1.16 g, 56%), m.p. 191-193° C. (decomp.).