Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=2)=[C:4]([Cl:25])[CH:3]=1.[CH3:26][O:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29].C([O-])([O-])=O.[K+].[K+]>COCCOC.CCOC(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:4]1[CH:3]=[C:2]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:28]([O:27][CH3:26])=[O:29])[CH:35]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:12]([C:13]2[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:20])[N:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:9]=1
Reactant: COC(=O)c1cccc(B(O)O)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Br)cc2Cl)n(-c2c(Cl)cccc2Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(-c3cc(C(F)(F)F)nn3-c3c(Cl)cccc3Cl)c(Cl)c2)c1
Temperature: 25 °C
Yield: 88.2 %

Procedure:
To a solution of 5-(4-bromo-2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazole (3.55 g, 7.55 mmol) and 3-(methoxycarbonyl)phenylboronic acid (1.77 g, 9.83 mmol) in 1,2-dimethoxyethane (36 mL) was added K2CO3 (3.126 g, 22.65 mmol) and H2O (4 mL). The resulting biphasic suspension was stirred at ambient temperature and sparged with nitrogen for 10 minutes. The reaction was then treated with dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (600 mg, 0.734 mmol) and heated to 80° C. in an oil bath. The reaction was heated at 80° C. for 10 hours and then allowed to cool to ambient temperature. The cooled reaction mixture was diluted with EtOAc and H2O. The aqueous layer was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford crude product as a dark oil. The crude product was purified by flash-column chromatography eluting with a gradient from 0% to 40% EtOAc/hexane to afford methyl 3′-chloro-4′-(1-(2,6-dichlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)biphenyl-3-carboxylate (3.50 g, 88% yield) solid. MS(ES): 525 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[NH:16][C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24].CC1C=CC(S(O[CH2:36][C@H:37]2[CH2:41][CH2:40][CH2:39][O:38]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]3[C:14]4([C:22]5[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=5)[N:16]([CH2:36][C@H:37]5[CH2:41][CH2:40][CH2:39][O:38]5)[C:15]4=[O:23])[CH2:13][O:12][C:10]3=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:24]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: CN1C(=O)COc2cc3c(cc21)C1(CO3)C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 1-methyl-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1-methyl-1′-[(2R)-tetrahydrofuran-2-ylmethyl]-1H-spiro[furo[3,2-g][1,4]benzoxazine-8,3′-indole]-2,2′(1′H,3H)-dione was obtained (69%) as as an off-white solid: mp 79-81° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) δ7.33 (dd, J=7.8, 7.8 Hz, 1H), 7.16-7.04 (m, 3H), 6.63-6.62 (m, 1H), 6.39-6.32 (m, 1H), 4.96-4.92 (m, 1H), 4.72-4.67 (m, 1H), 4.54 (s, 2H), 4.37-4.26 (m, 1H), 3.98-3.85 (m, 2H), 3.82-3.70 (m, 2H), 3.15 (s, 3H), 2.13-2.00 (m, 1H), 1.98-1.88 (m, 2H), 1.78-1.65 (m, 1H); 13C NMR (75 MHz, CDCl3) δ177.7 (2C), 163.9 (2C), 157.4, 157.3, 146.9 (2C), 143.1, 142.6, 132.2, 131.9, 129.2, 129.1, 124.4 (2C), 123.8 (2C), 123.5, 123.1, 122.8, 109.8, 109.7, 109.6, 100.1 (2C), 80.8, 80.6, 76.9, 76.2, 68.4, 68.2, 67.7, 58.1 (2C), 44.9, 44.6, 29.3, 29.1, 28.5, 28.4, 25.7 (2C); MS (ES+) m/z 429.1 (M+23), 407.1 (M+1).
Reaction SMILES: OC1[C:9]([O:10][CH2:11]CC)=[CH:8]C(C=O)=CC=1[N+]([O-])=O.[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]>>[CH3:27][O:26][C:25]1[CH:24]=[CH:23][C:20]([CH:21]=[O:22])=[CH:19][C:18]=1[O:17][CH2:8][CH2:9][O:10][CH3:11]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Product: COCCOc1cc(C=O)ccc1OC
Yield: 89 %

Procedure:
Followed the procedure described in Step 2 of Intermediate 65 starting from 3-hydroxy-4-methoxybenzaldehyde, isolated 2.4 g, yield 89%.
Reaction SMILES: [C:1]([Li])#[C:2][CH3:3].[O:5]=[C:6]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]>O1CCCC1>[OH:5][C:6]([CH2:3][C:2]#[CH:1])([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]/[CH:8]=[CH:9]/[I:10]
Reactant: [Li]C#CC
Reactant: CCCCC(=O)C/C=C/I
Solvent: C1CCOC1
Product: C#CCC(O)(C/C=C/I)CCCC
Reaction time: 0.5 h

Procedure:
To a stirred solution of propynyllithium at -25° is added a solution of 4-oxo-1-iodo-trans-1-octene in tetrahydrofuran. After the addition, the solution is stirred at -20° to -15° C. for 30 minutes. The reaction is quenched with a mixture of hexane and ice. The aqueous phase is separated and extracted with additional hexane. The combined hexane extracts are washed successively with water and brine. The solution is dried over magnesium sulfate and concentrated. The residue is subjected to column chromatography on silica gel with toluene to provide the product as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=[N:12]1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1>>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: Cc1ccc(C(=O)O)cc1-n1cc(-c2ccccn2)nn1
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4ccccn4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 3 was prepared by coupling 4-methyl-3-(4-pyridin-2-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 533 [C27H30N6O4S+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:13]>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[C:9]([Cl:13])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc(O)c(Cl)c1
Temperature: 25 °C

Procedure:
4-tert-Butyl-phenol (2.64 g, 17.5 mmol) was dissolved in 1M solution of SO2Cl2 in DCM (17.5 mL, 17.5 mmol) and MeOH (0.71 mL, 17.5 mmol) was added. The reaction was stirred at rt and monitored for progression. Additional 1M SO2Cl2/DCM (10 mL) and MeOH (0.36 mL) were added. The reaction mixture was concentrated in vacuo to yield the target compound. Calculated mass=186. Observed mass=187
Reaction SMILES: C[C:2]([C:5]1[CH:6]=[C:7]([CH2:16][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])(C)C.CC(C1C=C(C=C(C)C=1O)C=O)(C)C.CC(C1C=C(C=C(C(C)(C)C)C=1O)C=O)(C)C>>[CH3:15][C:12]([C:9]1[CH:8]=[C:7]([CH2:16][N:17]2[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]2)[CH:6]=[C:5]([CH3:2])[C:10]=1[OH:11])([CH3:13])[CH3:14]
Reactant: CC(C)(C)c1cc(CN2CCNCC2)cc(C(C)(C)C)c1O
Agent: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cc1cc(C=O)cc(C(C)(C)C)c1O
Product: Cc1cc(CN2CCNCC2)cc(C(C)(C)C)c1O

Procedure:
This was prepared using the general methodology described for the preparation of 1-(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)methylpiperazine except that 3-(1,1-dimethylethyl)-4-hydroxy-5-methylbenzaldehyde replaced the 3,5-bis(1,1-dimethylethyl)-4-hydroxybenzaldehyde.
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:20])[NH:5][C:6](=[O:19])[NH:7][C:8]=1[C:9](=[O:18])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[CH:11]=1)[CH3:2].C1(C)C=CC(S(O[CH2:31][CH:32]2[CH2:35][CH2:34][CH2:33]2)(=O)=O)=CC=1>>[CH:32]1([CH2:31][N:7]2[C:8]([C:9](=[O:18])[C:10]3[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=3)=[C:3]([CH2:1][CH3:2])[C:4](=[O:20])[NH:5][C:6]2=[O:19])[CH2:35][CH2:34][CH2:33]1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC2)cc1
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)[nH]c(=O)[nH]c1=O
Product: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC2CCC2)c(=O)[nH]c1=O
Yield: 52.6 %

Procedure:
5-Ehtyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and (cyclobutyl)methyl para-toluenesulfonate were reacted by the same way with the example 1 to obtain the titled compound (179 mg, yield: 52.6%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH3:9])=[C:7]([S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][C:18]3[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=3)[N:20]=2)[CH:6]=[CH:5][N:4]=1.[SH:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.C(N(CC)CC)C>C(O)(C)C>[CH3:9][C:8]1[C:3]([CH2:2][S:27][C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:4][CH:5]=[CH:6][C:7]=1[S:10][CH2:11][CH2:12][CH2:13][S:14][C:15]1[CH:16]=[CH:17][C:18]2[N:19]([C:21]([N+:24]([O-:26])=[O:25])=[CH:22][N:23]=2)[N:20]=1
Reactant: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CCl
Reactant: Sc1ncccn1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1c(SCCCSc2ccc3ncc([N+](=O)[O-])n3n2)ccnc1CSc1ncccn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 6-[3-(2-chloromethyl-3-methylpyridin-4-ylsulfanyl)propylsulfanyl]-3-nitroimidazo[1,2-b]pyridazine (1.23 g, 3.0 mmol), 2-mercaptopyrimidine (330 mg, 2.9 mmol) and triethylamine (335 mg, 3.3 mmol) in isopropanol (100 ml) is heated under reflux for 4.5 h. After cooling, the suspension is stirred at room temperature for a further 18 h and then at 0° C. for 0.5 h. The precipitate is filtered off, washed with isopropanol and dried at 40° C. in vacuo. The crystalline solid is then suspended in water (50 ml) and sodium carbonate solution (10 ml). After filtration and drying in vacuo at 40° C., the title compound is isolated as a pale beige solid. Yield 1.40 g (93%), m.p. 143-147° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][NH:28][CH2:27][CH2:26]4)[N:21]=2)[CH:16]=[CH:17][CH:18]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:10])[F:11])=[CH:5][C:4]=1[C:13]1[C:14]2[N:15]([N:19]=[C:20]([NH:22][C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH2:29][N:28]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:27][CH2:26]4)[N:21]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCNC4)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(CC(=O)N(C)C)C4)nc12

Procedure:
2-{6-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-3,4-dihydro-1H-isoquinolin-2-yl}-N,N-dimethyl-acetamide was prepared from [8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(1,2,3,4-tetrahydro-isoquinolin-6-yl)-amine (0.150 g, 0.341 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.053 mL, 0.512 mmol) in a manner analogous to Example 313 to give product (0.060 g, 34%). MP=99-102° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.51 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.80 (d, 1H), 7.62 (d, 1H), 7.38 (m, 3H), 7.05 (t, 1H), 6.90 (d, 1H), 3.85 (s, 3H), 3.52 (s, 2H), 3.28 (s, 2H), 3.05 (s, 3H), 2.82 (s, 3H), 2.70 (br m, 4H): MS=525 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:16]4[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=4[Cl:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]3[C:6]=2[C:5]([N+:24]([O-])=O)=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:24])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:12][CH2:13][CH2:14][CH2:15][N:7]21
Reactant: O=[N+]([O-])c1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c2nc3n(c12)CCCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 65.1 %

Procedure:
A mixture of 10-chloro-1-(2,4-dichlorophenyl)-7-nitro-2,3,4,5-tetrahydro-1H-[1,3]diazepino[1,2-a]benzimidazole (53 mg, 0.129 mmol) and 10% palladium on carbon (6 mg) in acetic acid (5.0 mL) was stirred under hydrogen atmosphere at room temperature for 6 hr. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (32 mg, 0.084 mmol, 65%) as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([C:14](OC)=[O:15])[CH:10]=[C:9]2[CH3:18])([CH3:3])[CH3:2].CCCCCC.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+]>O1CCCC1.O>[CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[C:11]([CH2:14][OH:15])[CH:10]=[C:9]2[CH3:18])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(C)c2cccc(C(C)C)c2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(CO)nc2c(C(C)C)cccc12
Reaction time: 2 h

Procedure:
Methyl 8-isopropyl-4-methyl-2-quinolinecarboxylate was dissolved in 10 ml of tetrahydrofuran, followed by the dropwise addition of a 1M hexane solution of diisobutyl aluminum hydride at 0° C. under a nitrogen gas atmosphere. After stirring for 2 hours, saturated aqueous ammonium chloride was added to terminate the reaction. Water was added to the reaction mixture and the precipitate so formed was filtered. The filtrate was concentrated under reduced pressure, whereby 107 mg of 8-isopropyl-4-methylquinoline-2-methanol were obtained in the form of a colorless oil. Under a nitrogen gas stream, a solution of 210 μl of dimethyl sulfoxide in 0.5 ml of dichloromethane was added dropwise to a solution of 172 μl of oxalyl chloride in 1 ml of dichloromethane at −60° C. under a nitrogen gas stream, followed by stirring for 5 minutes. To the reaction mixture, a solution of 107 mg of 8-isopropyl-4-methyl-2-quinolinemethanol in 2 ml of dichloromethane was added dropwise, followed by stirring for 15 minutes, dropwise addition of 1 ml of triethylamine and stirring for 5 minutes. The reaction mixture was raised to room temperature and stirred for one hour. Water was added to the reaction mixture and the resulting solution was extracted with dichloromethane. The organic layer was successively washed with water and saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue so obtained was subjected to chromatography on a silica gel column (developing solvent:: 3% ethyl acetate/n-hexane), whereby 87 mg of the title compound were obtained in the form of a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:14][C:13]=2[C:24]2[CH:29]=[C:28]([C:30](=[O:43])[NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=3)[CH:27]=[CH:26][N:25]=2)=[O:10])[CH:6]=[CH:5][CH:4]=1.[NH:44]1[CH2:49][CH2:48][CH:47]([NH:50][C:51](=[O:53])[CH3:52])[CH2:46][CH2:45]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O>[C:51]([NH:50][CH:47]1[CH2:48][CH2:49][N:44]([CH2:2][C:3]2[N:8]=[C:7]([C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[CH:14][C:13]=3[C:24]3[CH:29]=[C:28]([C:30](=[O:43])[NH:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[F:40])[CH:34]=4)[CH:27]=[CH:26][N:25]=3)=[O:10])[CH:6]=[CH:5][CH:4]=2)[CH2:45][CH2:46]1)(=[O:53])[CH3:52]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CCl)n2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NC1CCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)n2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 6-(chloromethyl)-N-(4-(piperidin-1-yl)-2-(4-(3-(trifluoromethyl)benzylcarbamoyl)pyridin-2-yl)phenyl)picolinamide (100 mg, 0.16 mmol, 1.00 equiv) in N,N-dimethylformamide (2 mL), N-(piperidin-4-yl)acetamide (35 mg, 0.25 mmol, 1.50 equiv), potassium carbonate (70 mg, 0.51 mmol, 3.00 equiv), and potassium iodide (6 mg, 0.04 mmol, 0.20 equiv). The resulting solution was stirred overnight at 60° C. The reaction progress was monitored by LCMS. The solids were filtered out. The mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 70.8 mg (51%) of a yellow solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 12.49 (s, 1H), 9.86 (m, 1H), 9.54 (m, 1H), 9.06 (m, 1H), 8.37-8.19 (d, J=9 Hz, 1H), 8.24-8.19 (m, 3H), 7.97-7.95 (d, J=6 Hz, 1H), 7.86-7.83 (m, 2H), 7.70-7.49 (m, 5H), 7.26 (m, 1H), 4.64-4.51 (m, 4H), 3.82 (m, 1H), 3.54-3.24 (m, 8H), 1.95-1.58 (m, 13H). MS (ES, m/z): 714 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH:4]=[N:3]1.Cl.[NH2:14][OH:15].C(=O)(O)[O-].[Na+]>CO>[OH:15][N:14]=[C:11]([C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[CH:4]2)[NH2:12]
Reactant: Cn1ncc2cc(C#N)ccc21
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cn1ncc2cc(C(N)=NO)ccc21
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A solution of 1-methyl-1H-indazole-5-carbonitrile (205 mg, 1.304 mmol), hydroxylamine hydrochloride (363 mg, 5.22 mmol) and sodium bicarbonate (548 mg, 6.52 mmol) in Methanol (6 mL) was heated to 60 degrees for 90 min. The reaction mixture was cooled to ambient temperature and partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc, and the combined organics washed with brine, dried (Na2SO4) and concentrated to afford the crude N′-hydroxy-1-methyl-1H-indazole-5-carboximidamide (174 mg, 0.915 mmol, 70% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15-1.38 (m, 6H) 2.13 (s, 3H) 4.18 (dq, J=19.59, 7.15 Hz, 4H) 4.98 (br. s., 1H) 8.90 (br. s., 1H). LC/MS (m/z) ES+=191 (M+1).
Reaction SMILES: CC(C)([O-])C.[K+].[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1/[C:12](=[N:16]/[OH:17])/[C:13]([OH:15])=[O:14].Cl[CH2:19][C:20]([NH:22][O:23][CH3:24])=[O:21].[Cl-].[Na+]>CS(C)=O.O>[O:7]1[CH:11]=[CH:10][CH:9]=[C:8]1/[C:12](=[N:16]/[O:17][CH2:19][C:20](=[O:21])[NH:22][O:23][CH3:24])/[C:13]([OH:15])=[O:14]
Reactant: O=C(O)/C(=N\O)c1ccco1
Reactant: CONC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CONC(=O)CO/N=C(\C(=O)O)c1ccco1
Reaction time: 1 h

Procedure:
Potassium tert-butoxide (6.73 g) was stirred in dry dimethylsulphoxide (30 ml), then Z-2-(fur-2-yl)-2-hydroxyiminoacetic acid (3.11 g) was added to the suspension, which was cooled in an ice-bath, and the mixture was stirred for 1 hr. Methyl chloroacetohydroxamate (2.35 g) in dimethylsulphoxide (2 ml) was added dropwise. The mixture was stirred for 2 hr at room temperature and the resulting solution was poured into ice and water (125 ml). The pH was adjusted to 1 and the solution was saturated with sodium chloride and extracted with ethyl acetate (50+150+4×200 ml), the pH being kept at 1 by addition of more hydrochloric acid as necessary. The ethyl acetate solution was washed with saturated brine (2×50 ml), then dried (Na2SO4) and evaporated, leaving a pale-brown solid. Washing the solid with dichloromethane left the title-compound, 1.56 g, m.p. 129° (decomp.) λmax (EtOH) 272.5 nm (ε 14,700), νmax (Nujol) 3180 (bonded NH), 1753 (CO2H), 1612 and 1522 cm-1 (bonded CONH), τ(DMSO d6) 2.10, 3.15, 3.30 (α-furyl), ca. 4.45 (NH, CO2H), 5.42 (CH2), 6.35 (OCH3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:16]2([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:12]=[C:13]([F:15])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cc(F)cc(OCc2ccccc2)c1
Reactant: BrCCCCCBr
Product: CCOC(=O)C1(c2cc(F)cc(OCc3ccccc3)c2)CCCCC1

Procedure:
The titled compound was prepared from ethyl 3-benzyloxy-5-fluorophenylacetate according to the procedure described in Example 2F except that 1,5-dibromopentane was used in place of bis(2-chloroethyl) ether.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:18][CH2:17][C:12]3([CH2:16][CH2:15][CH2:14][CH2:13]3)[CH2:11][CH:10]=2)O1.Br[C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:22]=1[CH3:31].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>CC#N.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:31][C:22]1[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[N:24][O:25][C:21]=1[C:9]1[CH2:18][CH2:17][C:12]2([CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:11][CH:10]=1
Reactant: CC1(C)OB(C2=CCC3(CCCC3)CC2)OC1(C)C
Reactant: CCOC(=O)c1noc(Br)c1C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1noc(C2=CCC3(CCCC3)CC2)c1C

Procedure:
To a 2-5 mL microwave vial containing a solution of 4,4,5,5-tetramethyl-2-(spiro[4.5]dec-7-en-8-yl)-1,3,2-dioxaborolane (168 mg, 0.641 mmol) in MeCN (2 mL), ethyl 5-bromo-4-methylisoxazole-3-carboxylate (Intermediate A) (150 mg, 0.641 mmol) was added followed by K2CO3 (266 mg, 1.923 mmol), PdCl2(dppf).CH2Cl2 adduct (Alfa Aesar) (52.3 mg, 0.064 mmol) and water (1 mL). The vial was flushed with nitrogen, sealed and treated in the microwave (Biotage Smith Initiator) at 90° C. for 1 hour. The reaction mixture was partitioned between water (20 mL) and EtOAc (20 mL) and the organic phase was washed with brine (20 mL), dried over MgSO4, filtered and concentrated under reduced pressure to give an orange oil. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-30% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: Cl[C:2]1[C:13]2=[C:14]3[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]2)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]3=[CH:4][CH:3]=1.[OH:20][CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN1CCCC1=O>[OH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:2]2[C:13]3=[C:14]4[N:9]([CH:10]([CH3:15])[CH2:11][CH2:12]3)[CH:8]=[C:7]([C:16]([OH:18])=[O:17])[C:6](=[O:19])[C:5]4=[CH:4][CH:3]=2)[CH2:23][CH2:22]1
Reactant: OC1CCNCC1
Reactant: CC1CCc2c(Cl)ccc3c(=O)c(C(=O)O)cn1c23
Solvent: CN1CCCC1=O
Product: CC1CCc2c(N3CCC(O)CC3)ccc3c(=O)c(C(=O)O)cn1c23
Reaction time: 6 h
Yield: 23.9 %

Procedure:
In a 100 ml flask were placed 6.1 g of 8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 9.5 g of 4-hydroxypiperidine and 60 ml of N-methylpyrrolidone and the mixture was stirred at 150° C. in an argon gas atmosphere. After 6 hours, N-methylpyrrolidone and excessive 4-hydroxypiperidine were removed under reduced pressure. To the residue were added dimethylformamide, ethanol and water and allowed to stand overnight to give 2.3 g of crude crystals which were recrystallized from ethanol-water to give 1.8 g of 8-(4-hydroxy-1-piperidyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid. m.p. 238°-240° C.