Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10](=O)[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>O1CCOCC1>[C:1]([O:5][C:6]([NH:8][NH:9][C:10](=[S:31])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[F:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc([N+](=O)[O-])cc1F
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NNC(=S)c1ccc([N+](=O)[O-])cc1F
Yield: 110.3 %

Procedure:
N′-(2-Fluoro-4-nitro-benzoyl)hydrazinecarboxylic acid tert-butyl ester (Step 1, 2.32 g, 7.75 mmol) and Lawesson's reagent (2.35 g, 5.81 mmol) in dioxane (50 ml) are heated at 85° C. overnight. The mixture is evaporated under vacuum and the residue purified by flash column chromatography (70% dichloromethane/hexane) to give the title compound as a bright orange solid (2.02 g, 82%), [M+H]+=316.
Reaction SMILES: [N:1]([C@@:4]1(/[CH:32]=[CH:33]/[P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[C@@H:11]2[C@@H:7]([O:8]C(C)(C)[O:10]2)[C@H:6]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][C:24](=[O:31])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:5]1)=[N+:2]=[N-:3]>C(O)(C(F)(F)F)=O.O>[N:1]([C@@:4]1(/[CH:32]=[CH:33]/[P:34](=[O:41])([O:38][CH2:39][CH3:40])[O:35][CH2:36][CH3:37])[C@@H:11]([OH:10])[C@@H:7]([OH:8])[C@H:6]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][CH:17]=[N:18][C:19]=3[NH:23][C:24](=[O:31])[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:5]1)=[N+:2]=[N-:3]
Reactant: CCOP(=O)(/C=C/[C@@]1(N=[N+]=[N-])O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(/C=C/[C@@]1(N=[N+]=[N-])O[C@@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)[C@H](O)[C@@H]1O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
Compound 36.4 (122 mg, 0.18 mmol) was dissovled in a mixture of TFA in water (1.5 mL TFA in 0.2 mL water). The solution was stirred at r.t. for 30 min and then concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with EtOAc to 20% MeOH in EtOAc to give compound 36.5 (68 mg, 70% yield).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]([O:15]C)=[O:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1>C(Cl)Cl.B(Br)(Br)Br>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([C:13]([OH:15])=[O:14])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccnc2cc(OC)ccc12
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccnc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a cooled (0° C.) solution of methyl 7-methoxyquinoline-4-carboxylate (378 mg, 1.74 mmol) in CH2Cl2, BBr3 (9 mL, excess) was added and the reaction mixture stirred and warmed to RT. After 4 days, the mixture was poured into ice and the yellow solid collected as the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)[CH:6]=[CH:5][N:4]=1.[Cl-].[Li+].CC(N(C)C)=O>CS(C)=O>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])[CH:6]=[CH:5][N:4]=1
Reactant: COc1c(-c2ccnc(N(C)C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CN(C)c1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Temperature: 60 °C
Yield: 49.3 %

Procedure:
Combined 6-(4-(2-(dimethylamino)pyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide from the above reaction and lithium chloride (42.7 mg, 1.008 mmol) and DMA (1 mL) and heated at 60° C. for 20 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (ammonium hydroxide conditions) to give the title compound (42 mg, 49.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 2H) 1.56-1.67 (m, 2H) 1.81 (ddt, J=14.9, 7.5, 3.8, 3.8 Hz, 1H) 3.05 (s, 6H) 3.17 (t, J=6.4 Hz, 2H) 3.28 (td, J=11.6, 1.8 Hz, 2H) 3.86 (dd, J=11.4, 2.5 Hz, 2H) 7.07 (d, J=4.5 Hz, 1H) 7.35 (br. s., 1H) 7.67 (d, J=6.1 Hz, 1H) 7.90 (s, 1H) 8.10-8.19 (m, 1H) 8.47-8.59 (m, 2H) 8.80 (d, J=2.0 Hz, 1H). MS m/z 423 [M+H]+.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Cl[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=1.O>CN1C(=O)CCC1>[N+:20]([C:17]1[CH:18]=[CH:19][C:14]([O:3][C:4]2[CH:12]=[C:11]3[C:7]([CH:8]=[CH:9][NH:10]3)=[CH:6][CH:5]=2)=[N:15][CH:16]=1)([O-:22])=[O:21]
Reactant: Oc1ccc2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccc3cc[nH]c3c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
NaH (1.1 equivalents) is added to a solution of 6-hydroxyindole (1.0 equivalent) in NMP. The resulting mixture is stirred for 2 hours at room temperature. 2-Chloro-5-nitropyridine (1.1 equivalents) is added and the solution is heated to 100° C. for 2 hours. The solution is cooled and poured into water. The aqueous layer is extracted with EtOAc three times. The organic layers are combined and concentrated to yield the titled compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=1[O:17][CH2:18][CH:19]1[CH2:21][O:20]1.[CH3:26][NH:27][CH3:28]>O1CCCC1>[CH3:26][N:27]([CH3:28])[CH2:21][CH:19]([OH:20])[CH2:18][O:17][C:16]1[CH:22]=[CH:23][CH:24]=[CH:25][C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: CNC
Reactant: c1ccc(OCC2CO2)c(CCCCc2ccc3ccccc3c2)c1
Solvent: C1CCOC1
Product: CN(C)CC(O)COc1ccccc1CCCCc1ccc2ccccc2c1
Yield: 84 %

Procedure:
Following a procedure similar to that described in Example 1(b), 291 mg of 2-{2-[4-(2-naphthyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] dissolved in 5 ml of tetrahydrofuran were treated with 1 ml of 50% by volume aqueous dimethylamine. The crude product thus obtained was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 279 mg (yield 84%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[C:14]1[N:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][N:15]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][NH:12][C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: CC(C)c1cnc(Cl)nc1
Reactant: COc1ccc(CCN)cc1Br
Product: COc1ccc(CCNc2ncc(C(C)C)cn2)cc1Br

Procedure:
Similarly prepared from 2-(3-bromo-4-methoxyphenyl)ethanamine and 2-chloro-5-isopropyl-pyrimidine (see below).
Reaction SMILES: [NH2:1][C:2]1[C:29]([NH2:30])=[CH:28][CH:27]=[CH:26][C:3]=1[O:4][CH2:5][CH2:6][N:7]([CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].O.[O:32]1CCC[CH2:33]1>>[F:12][C:9]([F:10])([F:11])[C:8]([N:7]([CH2:14][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[CH2:6][CH2:5][O:4][C:3]1[C:2]2[NH:1][C:33](=[O:32])[NH:30][C:29]=2[CH:28]=[CH:27][CH:26]=1)=[O:13]
Reactant: Nc1cccc(OCCN(CCCc2c[nH]c3ccccc23)C(=O)C(F)(F)F)c1N
Reactant: C1CCOC1
Solvent: O
Product: O=C(N(CCCc1c[nH]c2ccccc12)CCOc1cccc2[nH]c(=O)[nH]c12)C(F)(F)F
Temperature: 23 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
A mixture of N-[2-(2,3-diamino-phenoxy)-ethyl]-2,2,2-trifluoro-N-[3-(1H-indol-3-yl)-propyl]-acetamide (0.5 g, 1.19 mmol) and diimidazole carbonyl (0.39 g, 2.38 mmol) in anhydrous tetrahyrofuran (50 ml) was stirred at 23° C. for 5 hours. The reaction mixture was poured into water and extracted with ethyl acetate (2×250 ml). The organic layer was washed with water (2×250 ml) and brine (200 ml) and dried over anhydrous magnesium sulfate. The resulting product was concentrated to give the crude product. Purification by chromatography (60% ethyl acetate-hexanes) followed by crystallization from ethyl acetate-hexanes afforded 0.44 g (82.9%) of product as yellowish colored solid: mp 180-181° C.; MS EI m/e 446 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[CH:16]=NC=C[N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Br[C:18]1[N:19]=NC=C[CH:23]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[N:12]=[N:19][CH:18]=[CH:23][CH:16]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Reactant: Brc1cccnn1
Product: Cc1ccc(-c2cccnn2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting with 3-bromopyridazine. ESI-MS (m/z): 215 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[C:17]1([S:23]([CH:26]2[CH2:30][CH2:29][NH:28][CH2:27]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:28]2[CH2:29][CH2:30][CH:26]([S:23]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)(=[O:25])=[O:24])[CH2:27]2)=[O:15])=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: O=S(=O)(c1ccccc1)C1CCNC1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(S(=O)(=O)c3ccccc3)C2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 3-(benzenesulfonyl)pyrrolidine hydrochloride (12.7 mg, 0.051 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.5 mg). Calcd for C21H20N2O4S: 396.1144, found 396.1142.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[CH:5][CH:4]=1)#[N:2].[OH:39]O.[OH-].[Na+]>CS(C)=O>[C:1]([C:3]1[S:7][C:6]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[CH:5][CH:4]=1)(=[O:39])[NH2:2]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)s2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C(N)=O)s2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
To the solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-cyano-thiophen-2-yl)-amide (0.1 g, 0.18 mmol) prepared in Example 187 in DMSO (2 mL) at 0° C. was added an aqueous solution (30% Aldrich) of H2O2 (0.3 g, 2.6 mmol), then aqueous solution (1N) of NaOH (0.9 mL, 0.9 mmol) was added dropwise. The reaction mixture was stirred at 0° C. for 1 h. The mixture was partitioned between ethyl acetate and saturated aqueous Na2SO3 solution. The organic layer was separated, washed with water, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (50-100% EtOAc in dichloromethane) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (5-carbamoyl-thiophen-2-yl)-amide as a white solid (Yield 40 mg, 39%)
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH:7]=[O:8].[Cl:10][C:11]1[CH:12]=[C:13]([Mg]Br)[CH:14]=[CH:15][CH:16]=1>C1COCC1.CCOCC>[Br:1][C:2]1[S:3][C:4]([Cl:9])=[CH:5][C:6]=1[CH:7]([C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:10])[CH:16]=1)[OH:8]
Reactant: O=Cc1cc(Cl)sc1Br
Reactant: Clc1cccc([Mg]Br)c1
Solvent: C1CCOC1
Solvent: CCOCC
Product: OC(c1cccc(Cl)c1)c1cc(Cl)sc1Br
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-bromo-5-chlorothiophene-3-carbaldehyde from Example 1, Step 3 (2.50 g, 11.1 mmol) in THF/ether at −78° C. was added 3-chlorophenylmagnesium bromide (26.6 mL, 0.5M in THF) in 2 min. and the mixture was stirred at −78° C. for 5 min., quenched with saturated NH4Cl/water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and filtered. The filtrate was concentrated and the residue was purified by flash chromatography (10-20% EtOAc/hexanes) to give the desired product.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([CH3:11])=[C:6]([CH3:10])[C:7]=1[C:8]#[N:9].[S-2:12].[Na+].[Na+]>C(O)(C)(C)C.CC(O)C>[CH3:10][C:6]1[C:5]([CH3:11])=[N:4][NH:3][C:2](=[S:12])[C:7]=1[C:8]#[N:9]
Reactant: [S-2]
Reactant: Cc1nnc(Cl)c(C#N)c1C
Agent: [Na+]
Solvent: CC(C)O
Solvent: CC(C)(C)O
Product: Cc1n[nH]c(=S)c(C#N)c1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-chloro-5,6-dimethylpyridazine-4-carbonitrile (100 mg, 0.60 mmol) and sodium sulfide was stirred in tert-butanol (2.0 mL) in a microwave reaction vial. The vial was sealed and irradiated at 100° C. for 10 minutes. LC/MS indicated product and no remaining starting material. The reaction solution was diluted with IPA (˜10 mL) and stirred at ambient temperature for about 15 minutes, then filtered. The solids on the filter were washed with IPA. The solute was concentrated in vacuo, and the resulting solid was dried overnight at 60° C. in a vacuum oven to give the product. LC/MS: RT=0.24 min., m/z=166 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]([NH2:23])=[N:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[CH3:10][C:11]1[CH:16]=[C:15]([C:17]2[C:18]3=[N:23][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:19]3[CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][C:12]=1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1cc(-c2cccnc2N)ccc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C2=CC=CN3CCS(=O)(=O)N=C23)ccc1-c1ccccc1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 1.163 g) in THF (dry) (30 mL) was added 2-chloroethanesulfonyl chloride (1.22 ml.) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(2-methylbiphenyl-4-yl)pyridin-2-amine (1.51 g) in THF (dry) (50 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water at 0° C. carefully. Water and EtOAc were added and the precipitates were collected and washed with water and EtOAc, dried in vacuo to give the title compound (339 mg) as a white solid. A part of this was recrystallized from MeCN-THF/IPE.
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH2:7])[S:5][CH:6]=1.[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24](O)=[O:25])=[CH:15][N:14]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[C:3]([C:8]2[NH:12][CH:11]=[N:10][N:9]=2)=[C:4]([NH:7][C:24](=[O:25])[CH2:23][C:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[N:14][CH:15]=2)[S:5][CH:6]=1
Reactant: Nc1scc(Br)c1-c1nnc[nH]1
Reactant: O=C(O)Cc1cncc2ccccc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cc1cncc2ccccc12)Nc1scc(Br)c1-c1nnc[nH]1
Reaction time: 3 h
Yield: 15 %

Procedure:
To a solution of 4-bromo-3-(4H-1,2,4-triazol-3-yl)thiophen-2-amine (50 mg, 0.2 mmol) and 2-(isoquinolin-4-yl)acetic acid (56 mg, 0.3 mmol) in methylene chloride (2 mL) were added Hunig's base (i.e., N,N-diisopropylethylamine) (71 uL, 0.4 mmol) and HBTU (133 mg, 0.35 mmol). The heterogeneous reaction mixture was homogenous after 3 h. The reaction was quenched with saturated aqueous ammonium chloride and the aqueous was extracted with methylene chloride. The organic phase was washed with brine and dried over sodium sulfate. The resulting solution was concentrated to provide a pale red solid, which was purified by column chromatography using 3.5% MeOH/CH2Cl2. LCMS: retention time 1.955 min using analytical method [7] with an M+Na of 414.0. 19.0 mg (15% yield): white solid. 1H-NMR (300 MHz, CDCl3) δ 9.34 (s, 1H), 8.66 (s, 1H), 8.07 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz, 1H), 7.75 (m, 1H), 7.65 (m, 2H), 6.88 (d, J=0.5 Hz, 1H), 4.30 (s, 2H). 13C-NMR (75 MHz, CDCl3) δ 168.3, 153.2, 144.8, 142.8, 135.0, 131.5, 128.7, 128.4, 127.8, 123.5, 122.9, 116.2, 104.7, 38.7.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:3]#[C:2][CH2:1][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: C#CCN1CCCCC1
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCCCC3)c21

Procedure:
Using Method C above, 1-(2-propynyl)-piperidine (41.3 mg, 0.34 mmol) (prepared according to Kano et al. supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and Cul (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(1-piperidinyl)-1-propynyl]-2H-indol-2-one. (Yield 15 mg, 31%).
Reaction SMILES: [CH3:1][CH:2]1[NH:7][CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:3]1.C(N(CC)CC)C.[N:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH2:39][CH2:38][CH:37]([C:40](Cl)=[O:41])[CH2:36][CH2:35]2)=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:1][CH:2]1[N:7]([C:40]([CH:37]2[CH2:36][CH2:35][N:34]([C:31]3[CH:30]=[CH:29][N:28]=[CH:33][CH:32]=3)[CH2:39][CH2:38]2)=[O:41])[CH2:6][CH2:5][N:4]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:3]1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Reactant: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CN(S(=O)(=O)c2ccc3ccccc3c2)CCN1C(=O)C1CCN(c2ccncc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
3-Methyl-1-(2-naphthylsulphonyl)piperazine (1.8 g) and triethylamine (3.18 ml) were added in turn to a stirred solution of 1-(4-pyridyl)piperidine-4-carbonyl chloride (1.54 g) in methylene chloride (20 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 89:10:1 mixture of ethyl acetate; methanol and ammonia as eluent. The material so obtained was triturated under diethyl ether to give 3-methyl-1-(2-naphthylsulphonyl)-4-[1-(4-pyridyl)piperidin-4-yl-carbonyl]piperazine (32% yield);
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH3:15])[CH:13]=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C@@H:13]([OH:14])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH3:17])[CH3:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCCCCCCCCCCCBr
Reactant: C[C@@H](C=O)NC(=O)OCc1ccccc1
Product: CCCCCCCCCCCCCCC[C@H](O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 28 (640 mg, 3.1 mmol) and 1-bromopentadecane (5.0 g, 17.2 mmol), alcohol 90 was obtained as a colorless oil (690 mg, 53% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:16]2[C:17]([CH3:27])=[C:18]([CH:24]=[CH:25][CH:26]=2)[O:19][CH2:20][C:21](O)=[O:22])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30]>CN(C)C1C=CN=CC=1.CN(C)C=O>[NH2:1][C:2]1[N:3]([C:16]2[C:17]([CH3:27])=[C:18]([CH:24]=[CH:25][CH:26]=2)[O:19][CH2:20][C:21]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:22])[N:4]=[C:5]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][C:7](=[O:15])[C:6]=12
Reactant: CS(N)(=O)=O
Reactant: Cc1c(OCC(=O)O)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Cc1c(OCC(=O)NS(C)(=O)=O)cccc1-n1nc2c(c1N)c(=O)[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.4 %

Procedure:
A mixture of [3-(3-amino-4-oxo-4,5-dihydro-2H-pyrazolo[4,3-c]quinolin-2-yl)-2-methylphenoxy]acetic acid (64 mg), methanesulfonamide (50 mg), 4-(dimethylamino)pyridine (25 mg), (3-dimethylaminopyropyl)ethylcarbodiimide hydrochloride (40 mg) and N,N-dimethylformamide (6 ml) was stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure. To the residue was added water, and then pH of the residue was adjusted to about 2 by adding a 1N hydrochloric acid. The precipitated solid was collected by filtration, washed with water, and dried to obtain the target compound (29 mg).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([OH:21])[CH2:19][CH2:18][C@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[N+:22]([C:25]1[CH:26]=[CH:27][C:28]([C:29]([O:20][C@H:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C@@:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:21])[CH2:19][CH2:18]2)=[O:30])=[CH:32][CH:33]=1)([O-:24])=[O:23]
Reactant: O[C@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21)c1ccc([N+](=O)[O-])cc1
Reaction time: 8 h

Procedure:
In a 250 mL round-bottom flask was dissolved (6S,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diol (458 mg, 1.572 mmol) (azeotroped with dry benzene) in tetrahydrofuran (8 mL) to give a light orange solution. 4-Nitrobenzoic acid (394 mg, 2.358 mmol) and triphenylphosphine (619 mg, 2.358 mmol) were added under nitrogen. Diisopropyl azodicarboxylate (0.464 mL, 2.358 mmol) was added dropwise. The mixture was allowed to stir overnight. After 15 h, LCMS showed complete conversion, but the desired product was a minor component. It was concentrated to a light yellow oil and directly purified by FCC (5% ethyl acetate/hexanes to 100%) to afford the desired product (125 mg, 18%) as a white solid. MS(ESI)[M+H+]=441.20.