Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([C:10]([C:36](=[O:38])[NH2:37])=[CH:11][N:12]2[CH2:15][C:16]([N:18]2[CH2:22][C@H:21]([F:23])[CH2:20][C@H:19]2[C:24](=[O:35])[NH:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=2[F:34])=[O:17])=[CH:8][CH:7]=1.[Li+].[BH4-]>C1COCC1>[Cl:33][C:29]1[C:28]([F:34])=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][NH:25][C:24]([C@@H:19]1[CH2:20][C@@H:21]([F:23])[CH2:22][N:18]1[C:16](=[O:17])[CH2:15][N:12]1[C:13]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH2:3][OH:2])[CH:14]=2)[C:10]([C:36]([NH2:37])=[O:38])=[CH:11]1)=[O:35]
Reactant: COC(=O)COc1ccc2c(C(N)=O)cn(CC(=O)N3C[C@H](F)C[C@H]3C(=O)NCc3cccc(Cl)c3F)c2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(=O)c1cn(CC(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2cc(OCCO)ccc12
Reaction time: 2 h

Procedure:
To a solution of (3-carbamoyl-1-{2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-1H-indol-6-yloxy)-acetic acid methyl ester Example 592 (30.0 mg, 0.049 mmol) in THF (1 mL) was added LiBH4 (2M in THF; 0.049 mL, 0.098 mmol) and stirring was continued at RT for 2 h. The reaction mixture was partitioned between CH2Cl2 and water, and the aqueous layer was extracted with CH2Cl2 (3×). The combined organics were dried (phase separator) and concentrated under reduced pressure. Purification by preparative HPLC (SunFire C18-ODB, 5 μm, 19×50 mm, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 20 mL/min) afforded after lyophilization of the purified fractions the desired compound as a white solid. MS: 535 [M+H]+; tR (HPLC conditions c): 3.72 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:7]=[CH:6][C:5]=1[C:18]#[C:19][CH2:20][OH:21].N1C=CN=C1.[CH3:28][C:29]([Si:32](Cl)([CH3:34])[CH3:33])([CH3:31])[CH3:30]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:7]=[CH:6][C:5]=1[C:18]#[C:19][CH2:20][O:21][Si:32]([C:29]([CH3:31])([CH3:30])[CH3:28])([CH3:34])[CH3:33]
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1C#CCO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: COC(=O)c1cc(OCc2ccccc2)ccc1C#CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
To a solution of 5-Benzyloxy-2-(3-hydroxy-prop-1-ynyl)-benzoic acid methyl ester (80 g, 270 mmol) in DCM (1.5 L) was added imidazole (36.8 g, 540 mmol) and TBSCl (61 g, 405 mmol). The mixture was stirred at room temperature for 3 hours. The reaction mixture was washed with water, brine, dried over Na2SO4 and concentrated to dryness. The residue was purified by chromatography column on silica gel to afford title product (90 g, 81%).
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]=[C:6]([NH:11][NH2:12])[C:5]=1[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:16][CH:15]=1)[CH2:2][CH3:3].[CH:31](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:9]=[C:8]([CH3:10])[N:7]2[CH:31]=[N:12][N:11]=[C:6]2[C:5]=1[CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]2[NH:30][N:29]=[N:28][N:27]=2)=[CH:18][CH:19]=1)[CH2:2][CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: CCCc1nc(C)nc(NN)c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Product: CCCc1nc(C)n2cnnc2c1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
4.8 g of 6-n-propyl-2-methyl-4-hydrazino-5-{[2'(5-tetrazolyl)-4-biphenylyl]methyl}pyrimidine, prepared in Example 67, are heated to reflux for 4 hours in 40 ml of triethyl orthoformate. The mixture is evaporated under vacuum and the residue is crystallised in an ethyl acetate/isopropyl ether mixture to give 1 g of 7-n-propyl-5-methyl-8-{[2'-(5-tetrazolyl)-4biphenylyl]methyl}-1,2,4-triazolo[4,3-c]pyrimidine in the form of crystals of melting point 182°-184° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[N+:9]([CH2:12][CH3:13])([O-:11])=[O:10].[OH-].[Na+]>CCO.O>[N+:9]([CH:12]([CH3:13])[CH:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)[OH:8])([O-:11])=[O:10]
Reactant: O=Cc1ccncc1
Reactant: CC[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C(O)c1ccncc1)[N+](=O)[O-]

Procedure:
A solution of 1.0 eq. of 4-pyridinecarboxaldehyde (63, Aldrich, cat. no. P6,240-2) and 1.5 eq of nitroethane (Aldrich, cat. no. 22,787-0) in absolute EtOH was stirred at 0° C. as a solution of 2.0 eq. of NaOH in water was added. After a time sufficient for reaction completion, the reaction mixture was concentrated by rotary evaporation and neutralized (pH 7-8) with conc. HCl. A white precipitate formed. The mixture was extracted with EtOAc. The organic layer was dried over MgSO4, filtered and the solvent removed by rotary evaporation. The material was purified by flash chromatography on silica gel using a mixture of MeOH—CH2Cl2 as eluant to afford 64 as a mixture of diastereomers.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17](=O)[C:16](=O)[CH:15]=1.C1C2C(=NC3C(N=2)=CC=CC=3)C=CC=1.IC>C(O)(=O)C.C(O)C>[CH3:13][C:14]1[C:19]([CH3:20])=[CH:18][C:17]2[N:1]=[C:2]3[C:11](=[N:12][C:16]=2[CH:15]=1)[CH:10]=[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=[CH:3]3
Reactant: CC1=CC(=O)C(=O)C=C1C
Reactant: Nc1cc2ccccc2cc1N
Agent: c1ccc2nc3ccccc3nc2c1
Solvent: CCO
Solvent: CI
Solvent: CC(=O)O
Product: Cc1cc2nc3cc4ccccc4cc3nc2cc1C

Procedure:
The 2,3-dimethylbenzo(B)phenazine was prepared by the condensation of 2,3-diaminonapthalene with 4,5-dimethyl-1,2-benzoquinone in 4:1 ethanol to acetic acid at reflux for 2 hours. The phenazine was alkylated by the procedure of Synthesis Example 8, using iodomethane. Electrochemical analysis was consistent with an N,N'-dialkylated phenazine.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH:14]([OH:16])[CH2:13][N:12]1[C:17](=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)Cc2ccc(F)cc2)N(C(=O)OCc2ccccc2)C1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)N1CC(O)CN1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
2-[2-(4-Fluorophenyl)acetyl]-4-oxo-pyrazolidine-1-carboxylic acid benzyl ester, 11, (1.0 g, 2.81 mmol) is dissolved in THF (30 mL) and the solution cooled to −78° C. A 5.0 M solution of borane-dimethyl sulfide complex in ether (1.2 mL, 5.61 mmol) is added dropwise. After 1 hour at −78° C., the reaction is quenched by slow addition of NH4Cl (sat. aq.) (10 mL). The cooling bath is then removed, and the mixture allowed to warm to room temperature with vigorous stirring. The THF is removed in vacuo and the residue diluted with water (50 mL). The mixture is extracted with ethyl acetate (2×100 mL), dried, filtered and concentrated in vacuo to give a yellow oil which is purified over silica (1:1 to 1:2 hexane/ethyl acetate to 100% ethyl acetate) to afford 731 mg (73% yield) as a clear, viscous oil.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].Br[CH2:8][CH2:9][C:10]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:11]#[N:12]>C1COCC1>[C:13]1([C:10]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:9][CH2:8][NH:12][CH2:11]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(C2(c3ccccc3)CCNC2)cc1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
A suspension of LiAlH4 (560 mg, 14.75 mmol) in THF (50 mL) is cooled at 0° C. and a solution of 4-bromo-2,2-diphenylbutyronitrile (1.50 g, 5 mmol) in THF (20 mL) is slowly added. The mixture is stirred at r.t. for 15 h, carefully quenched with MeOH and NaHCO3 and filtered. The filtrate is evaporated, the residue taken up in CH2Cl2 (100 mL) and washed with sat. aq. Na2CO3. (50 mL). The aq. phase is re-extracted with CH2Cl2 (2×50 mL) and the combined organic extracts are dried (Na2SO4), filtered and evaporated. The residue is purified by reversed phase MPLC to provide the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]2[N:4]([C:14]([SH:17])=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1.Br[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[N:25]=[CH:24][CH:23]=[CH:22]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:1][C:2]1[C:3]2[N:4]([C:14]([S:17][C:19]3[CH:20]=[C:21]4[C:26](=[CH:27][CH:28]=3)[N:25]=[CH:24][CH:23]=[CH:22]4)=[N:15][N:16]=2)[CH:5]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:7]=1
Reactant: Brc1ccc2ncccc2c1
Reactant: Cn1cc(-c2cc(F)c3nnc(S)n3c2)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(-c2cc(F)c3nnc(Sc4ccc5ncccc5c4)n3c2)cn1
Temperature: 120 °C
Yield: 33.2 %

Procedure:
A mixture of Intermediate F (40 mg, 0.160 mmol), 6-bromoquinoline (33.4 mg, 0.160 mmol), xantphos (18.57 mg, 0.032 mmol), Pd2(dba)3 (14.69 mg, 0.016 mmol) and DIPEA (0.111 ml, 0.642 mmol) in DMF (5 ml) was bubbled with N2 for 15 min and then was heated to 120° C. for 5 h under MW radiation. The solvent was removed under reduced pressure. The residue was purified with by silica gel chromatography eluted with DCM/MeOH (from 100% to 90%) to afford the title compound as a brownish solid (20 mg, 29.8% yield). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.87 (s, 1H), 8.50 (s, 1H), 8.35 (s, 1H), 8.29 (d, 1H), 8.04 (m, 1H), 7.98 (d, 1H), 7.91 (d, 1H), 7.85 (d, 1H), 7.65 (d, 1H), 7.53 (m, 1H), 3.84 (s, 3H). LCMS (method B): [M+H]+=377, tR=1.95 min.
Reaction SMILES: C(S[N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16])(C)(C)C.SC1SC2C=CC=CC=2N=1>C1C=CC=CC=1>[C:10]1(=[O:11])[NH:6][C:7](=[O:16])[C:8]2=[CH:15][CH:14]=[CH:13][CH:12]=[C:9]12
Reactant: CC(C)(C)SN1C(=O)c2ccccc2C1=O
Agent: Sc1nc2ccccc2s1
Solvent: c1ccccc1
Product: O=C1NC(=O)c2ccccc21
Yield: 96.5 %

Procedure:
11.8 Grams (0.05 mole) of N-(tert-butylthio)phthalimide and 8.5 grams (0.05 mole) of 2-mercaptobenzothiazole in 200 ml of benzene are stirred at 70° C. for six hours. The reaction mixture is cooled and filtered to obtain 7.1 grams of phthalimide (white solid, m.p. 231° C.). The benzene is stripped from the filtrate by evaporation to give a solid residue. The residue recrystallized from methanol gives 9.3 grams of 2-(tert-butyldithio)benzothiazole, m.p. 80.0°-80.5° C. Another 3.0 grams of product are obtained upon concentration of the alcoholic filtrate.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[C@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][C:5](=[O:14])[CH2:4]1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[Si:15]([O:1][CH2:2][C@@H:3]1[CH2:4][C:5](=[O:14])[CH2:6][C@H:7]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: O=C1C[C@@H](CO)[C@H](c2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1CC(=O)C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 129.3 %

Procedure:
To a solution of (+)-trans-3-hydroxymethyl-4-phenylcyclopentan-1-one from Example 11, Step F (3.3 g, 16 mmol) in methylene chloride (100 mL) was added t-butyldimethylsilyl chloride (11 g, 49 mmol) and DIPEA (22 mL, 74 mmol). The reaction was stirred at rt for 16 h, poured into dilute aq. hydrochloric acid and extracted twice with ether. The organic layers were washed with brine, dried over sodium sulfate, combined and concentrated. The residue was purified by FC (5% ethyl acetate in hexanes) to afford of (+)-trans-1-t-butyldimethylsilyloxymethyl-4-oxo-2-phenylcyclopentane (6.3 g) as a oil.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:26]([F:29])([F:28])[F:27])[CH2:24][OH:25])=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][O:25][CH2:24][CH:23]([C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:22][CH:21]=1)[C:26]([F:27])([F:28])[F:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(c1ccc(Cl)cc1)C(F)(F)F
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: FC(F)(F)C(COCc1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
Under a nitrogen atmosphere, a solution of 12.58 g of 3-phenoxybenzyl bromide and 10.74 g of 2-(4-chlorophenyl)3,3,3-trifluoropropanol in 30 ml of toluene was slowly added to the mixture of 1.00 g of benzyltriethylammonium chloride, 12.76 g of 45% aqueous sodium hydroxide solution and 15 ml of toluene with ice-cooling. The reaction solution was stirred at room temperature for 14 hours. Thereafter, the reaction solution was poured into dilute hydrochloric acid-ice water and extracted with toluene. The toluene layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under a reduced pressure, and the residue was subjected to column chromatography on silica gel [eluted with n-hexane/toluene (2:1) mixture] to obtain 16.06 g of the desired compound.
Reaction SMILES: S(=O)(=O)(O)O.O[C:7]([CH:10]1[CH2:14][C:13]2[CH:15]=[C:16]([OH:21])[C:17]([O:19][CH3:20])=[CH:18][C:12]=2[O:11]1)([CH3:9])[CH3:8]>>[OH:21][C:16]1[C:17]([O:19][CH3:20])=[CH:18][C:12]2[O:11][C:10]([CH:7]([CH3:9])[CH3:8])=[CH:14][C:13]=2[CH:15]=1
Reactant: COc1cc2c(cc1O)CC(C(C)(C)O)O2
Agent: O=S(=O)(O)O
Product: COc1cc2oc(C(C)C)cc2cc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 43.5 %

Procedure:
To a solution of conc. sulfuric acid (1 ml) was added 2,3-dihydro-2-(1-hydroxy-1-methylethyl)-6-methoxy-5-benzofuranol (50 mg) in several portions during a period of few minutes. The mixture was stirred for 10 minutes at ambient temperature and poured into ice water. The separated oil was extracted with methylene chloride. The organic layer was washed with water, dried, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane/methylene chloride =1/1) to yield 5-hydroxy-6-methoxy-2-(1-methylethyl)benzofuran (20 mg) as crystals.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=[CH:19][C:20]#[N:21])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH:8]1[CH2:9][CH2:10][CH2:11][C:12]2[CH:13]=[C:14]([CH:18]=[CH:19][C:20]#[N:21])[CH:15]=[CH:16][C:17]1=2
Reactant: CC(C)(C)OC(=O)NC1CCCc2cc(C=CC#N)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#CC=Cc1ccc2c(c1)CCCC2N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of [6-(2-cyano-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-yl]-carbamic acid tert-butyl ester (2.7 g, 9.05 mmol) in DCM (40 mL) was added TFA (15 mL). The resulting mixture was stirred at RT for 1 h. Solvent was removed. The residue was redissolved in EtOAc. The organic layer was washed with sat. NaHCO3, H2O, brine, dried over MgSO4 and removed solvent. The crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH (2M NH3) mixture (97:3) gave final compound (1.6 g, 89%). MS m/z: 199.3 (M+H). Calc'd. for C13H14N2-198.26.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.[N:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[O:20]=[C:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]2[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[CH:7]=[CH:6][CH:5]=3)[CH:21]=[C:11]2[NH:12]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCN1CCCCC1)Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1

Procedure:
A solution of EXAMPLE 12 (0.1 g, 0.4 mmol), 3-piperidinopropionic acid (60 mg, 0.4 mmol), 1-hydroxybenzotriazole (0.098 g, 0.7 mmol), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (0.377 g, 0.7 mmol) and diisopropylethylamine (0.4 mL, 2.2 mmol) in N,N′-dimethylformamide (4 mL) was heated in a microwave at 100° C. for 15 minutes. The mixture was concentrated and purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (CD3OD) δ 8.23-8.27 (m, 3H), 7.89 (td, J=7.8, 1.5 Hz, 1H), 7.68 (d, J=8.3 Hz, 1H), 7.59 (dd, J=7.1, 2.2 Hz, 1H), 7.48-7.56 (m, 1H), 7.42 (t, J=8.0 Hz, 1H), 6.33 (s, 1H), 3.62 (s, 2H), 3.51 (t, J=6.6 Hz, 2H), 3.04 (s, 2H), 2.96 (t, J=6.8 Hz, 2H), 1.98 (d, J=3.4 Hz, 2H), 1.82 (s, 3H), 1.58 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([O:21][CH2:22][CH2:23][O:24][CH3:25])[CH:20]=1)(OC(C)(C)C)=O.[ClH:26]>C(Cl)Cl.CCOCC>[ClH:26].[ClH:26].[CH3:25][O:24][CH2:23][CH2:22][O:21][C:19]1[CH:20]=[C:15]([O:14][CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)[CH:16]=[N:17][CH:18]=1
Reactant: COCCOc1cncc(OC[C@@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COCCOc1cncc(OC[C@@H]2CCCN2)c1
Reaction time: 2 h

Procedure:
To 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-methoxyethoxypyridine from step 197e (480 mg, 1.36 mmol) in CH2Cl2 at 0° C. was added a solution of HCl in Et2O, and the solution was stirred for 2 h. The solvent was removed and the residue was recrystallized from EtOH/Et2O to afford the title compound (215 mg): mp 182-184° C.; [α]25D +22.8 (c 0.56, MeOH); 1H NMR (D2O, 300 MHz) δ 1.98 (m, 1H), 2.00-2.06 (m, 2H), 2.25 (m, 1H), 3.00 (m, 1H), 3.05 (s, 3H), 3.65 (t, 2H, J=6.0 Hz), 3.85 (t, 2H, J=6.0 Hz), 4.15 (m, 1H), 4.30-4.35 (m, 2H), 4.52 (m, 1H), 7.15 (t, 1H, J=3.0 Hz), 8.02 (br s, 2H); MS (CI/NH3) m/z 253 (M+H)+, 279 (M+NH4)+; Anal. Calcd for C13H20N2O3.2.1 HCl: C, 47.48; H, 6.77; N, 8.52. Found: C, 47.56; H. 6.83; N, 8.51.
Reaction SMILES: [F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].I[CH2:30][CH2:31][CH3:32]>>[F:1][C:2]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:30][CH2:31][CH3:32])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(O)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: CCCI
Product: CCCOc1ccc(CN(Cc2ccc(F)cc2F)c2cccc([N+](=O)[O-])c2C)cc1

Procedure:
The product from Example 33A and 1-iodopropane were processed as described in Example 33B to provide the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17](=[O:18])[CH2:16][CH:15]3[C:10]([C:11]4[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:12]=4[CH2:13][CH2:14]3)=[N:9]2)=[CH:4][CH:3]=1)(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(N2N=C3c4cc(Cl)ccc4CCC3CC2=O)cc1
Product: CC(=O)Nc1ccc(N2N=C3c4cc(Cl)ccc4CCC3CC2=O)cc1

Procedure:
A mixture of 2-(4-aminophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one in acetic anhydride is refluxed under heating for 8 hours. After the acetic anhydride is distilled off, the residue is extracted with chloroform. The extract is washed with water and dried over magnesium sulfate anhydride. The chloroform is distilled off to give 2-(4-acetamidophenyl)-9-chloro-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3(2H)-one.
Reaction SMILES: Br[C:2]1[S:6][C:5]([N:7]2[CH2:12][CH2:11][C:10]([CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]([CH2:28][C:29]([OH:31])=[O:30])[CH:24]=[C:25]([Cl:27])[CH:26]=3)([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:4][CH:3]=1.[F:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CN(C)C=O>[Cl:27][C:25]1[CH:24]=[C:23]([CH2:28][C:29]([OH:31])=[O:30])[CH:22]=[C:21]([O:20][CH2:19][CH2:18][C:10]2([N:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:11][CH2:12][N:7]([C:5]3[S:6][C:2]([C:37]4[CH:36]=[CH:35][CH:34]=[C:33]([F:32])[CH:38]=4)=[CH:3][N:4]=3)[CH2:8][CH2:9]2)[CH:26]=1
Reactant: O=C(O)Cc1cc(Cl)cc(OCCC2(N3CCCC3)CCN(c3ncc(Br)s3)CC2)c1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)Cc1cc(Cl)cc(OCCC2(N3CCCC3)CCN(c3ncc(-c4cccc(F)c4)s3)CC2)c1
Yield: 23.3 %

Procedure:
A mixture of [3-[2-[1-(5-bromothiazole-2-yl)-4-pyrrolidine-1-ylpiperidine-4-yl]ethoxy]-5-chlorophenyl]acetic acid (60 mg), 3-fluorophenyl boronic acid (32 mg), tetrakis (triphenylphosphine) palladium (13 mg), 1M sodium carbonate (0.55 mL) and dimethylformamide (1 mL) was reacted with a microwave reaction device at 180° C. for 5 minutes. The insoluble material was filtrated. To the filtrate was added formic acid. The solvent was evaporated under reduced pressure and the residue was purified by high performance liquid chromatography to give the title compound (14.4 mg). Yield: 24%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.Cl.[CH:28]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38](Cl)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30][N:29]=1>CN(C=O)C>[CH:28]1[C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([S:38]([NH:1][C:2]3[CH:3]=[C:4]([C:8]4[CH:9]=[CH:10][C:11]5[N:12]([CH:14]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=5)[N:13]=4)[CH:5]=[CH:6][CH:7]=3)(=[O:40])=[O:39])[C:32]=2[CH:31]=[CH:30][N:29]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: CC(=O)Nc1cn2nc(-c3cccc(N)c3)ccc2n1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4cccc5cnccc45)c3)ccc2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-(3-aminophenyl)imidazo[1,2-b]pyridazin-2-yl)acetamide (Example 5) (0.032 g, 0.12 mmol), DMF (2.0 mL), pyridine (0.015 mL, 0.180 mmol), and isoquinoline-5-sulfonyl chloride hydrochloride (0.0395 g, 0.150 mmol, Toronto Research Chemicals, Ottawa, Ontario). The mixture was stirred at 25° C. for 5 h then concentrated under reduced pressure. The residue was purified by preparative HPLC (Phenomenex Synergi 4μ MAX-RP 150×21.2 mm, 2 to 100% CH3CN/H2O, 0.1% TFA, over 15 min) (Phenomenex, Torrance, Calif.) to afford the title compound as a light-yellow solid. MS (ESI positive ion) m/z: 459 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 11.03 (s, 1H), 10.91 (s, 1H), 9.50 (s, 1H), 8.75 (d, J=6.5 Hz, 1H), 8.58 (d, J=6.0 Hz, 1H), 8.53 (d, J=7.0 Hz, 1H), 8.45 (d, J=8.0 Hz, 1H), 8.25 (s, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.84 (t, J=7.8 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.56 (d, J=9.5 Hz, 1H), 7.34 (t, J=7.8 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 2.11 (s, 3H).