Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([OH:37])([CH3:36])[CH3:35])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:40]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([O:37][CH3:40])([CH3:35])[CH3:36])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CCCc1nc(CC)n(-c2ccc(C(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(C(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 32 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(1-hydroxy-1-methylethyl)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.30 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.049 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.076 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=2[CH3:17])=[N:6][CH:7]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:12][C:11]([NH:13][C:14](=[O:16])[CH3:15])=[N:10][C:9]=3[CH3:17])=[N:6][CH:7]=2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(N)cn2)s1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(-c3sc(NC(C)=O)nc3C)nc2)cc1

Procedure:
Using an analogous procedure to that described in Example 83, N-[5-(5-aminopyridin-2-yl)-4-methyl-1,3-thiazol-2-yl]acetamide was reacted with 4-methoxyphenylsulfonyl chloride to give the title compound; 1H NMR Spectrum: (DMSOd6) 2.13 (s, 3H), 2.47 (s, 3H), 3.81 (s, 3H), 7.09 (d, 2H), 7.55 (m, 2H), 7.73 (d, 2H), 8.26 (m, 1H), 10.42 (s, 1H), 12.05 (s, 1H); Mass Spectrum: M+H+ 419.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([C:7]([SH:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[Cl:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21]Cl.C([O-])([O-])=O.[Cs+].[Cs+].[Na+].[I-]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].O>[Cl:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][S:13][C:7]1[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: FC(F)(F)c1ccc2c(S)ccnc2c1
Reactant: ClCCOCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: FC(F)(F)c1ccc2c(SCCOCCCl)ccnc2c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
7-Trifluoromethyl-4-quinoline-thiol (2 g, 8.7 mmol) and 2-chloroethyl ether (6.2 g, 43.7 mmol) were charged in a 50 ml round-bottomed flask equipped with a magnetic stirrer. Then Cs2CO3 (2.8 g, 8.7 mmol), NaI (1.3 g, 8.7 mmol), TBABr (1.1 g, 3.5 mmol) and water (15 mL) were added and the reaction mixture was stirred for 1 h at 90° C. The reaction mixture was poured in 100 mL of H2O, extracted with CH2Cl2 (2×100 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4, filtered and evaporated to dryness. The crude compound was purified by column chromatography (SiO2; CH2Cl2:MeOH=99:1 to 98:2) to give after evaporation 4-[2-(2chloro-ethoxy)-ethylsulfanyl]-7-trifluoromethyl-quinoline 26 (1.9 g, 65% yield) as a colourless oil.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:23](Cl)(=[O:25])[CH3:24]>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:14][CH2:13][C@H:12]([NH:15][C:23](=[O:25])[CH3:24])[CH2:11]3)[C:4]=2[CH2:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: N[C@H]1CCN(c2cccc3c2CCO3)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(c2cccc3c2CCO3)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-N-(2,3-dihydrobenzofuran-4-yl)-3-(amino)pyrrolidine (0.1 mmol) and triethylamine (0.15 mmol) were dissolved in CH2Cl2. Acetylchloride (0.12 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The organics were then washed with 1 N HCl, NaHCO3, and brine. The organic solution was dried over sodium sulfate, concentrated in vacuo, and purified by silica gel column chromatography eluting with 4% methanol in CH2Cl2 to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17](Br)[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1.[CH3:21][Zn]C>C1COCC1.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>[NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:12]=[C:13]([CH:16]=[C:17]([CH3:21])[CH:18]=2)[C:14]#[N:15])[C:6]([Cl:9])=[CH:7][CH:8]=1
Reactant: C[Zn]C
Reactant: N#Cc1cc(Br)cc(Oc2c(Cl)ccc(CN)c2F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(Oc2c(Cl)ccc(CN)c2F)c1
Temperature: 65 °C
Yield: 14.1 %

Procedure:
3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-bromobenzonitrile (0.200 g, 0.562 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.065 g, 0.056 mmol) were combined in THF (4 mL) and treated with dimethylzinc (1 M in heptane) (1.125 mL, 1.125 mmol) with stirring under an inert atmosphere. The reaction mixture was heated to 65° C. and stirred for 1 h. The reaction mixture was concentrated to dryness, partitioned between EtOAc and saturated aqueous NaHCO3, the organic phase was isolated, dried over MgSO4, filtered and concentrated to dryness. The residue was dissolved in CH3OH and gravity filtered through a StratoSpheres™ PL-Thiol MP SPE+ cartridge. The filtrate was cooled in an ice bath and the resultant precipitate filtered off to give 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.023 g, 0.079 mmol, 14.07% yield) as a white solid. The mother liquor was concentrated to dryness and purified on 40 g silica gel eluted successively with EtOAc and 10% CH3OH/DCM to give a second batch of 3-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-5-methylbenzonitrile (0.072 g, 0.248 mmol, 44.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.45-7.53 (m, 2H), 7.42 (s, 1H), 7.19 (s, 1H), 7.10 (s, 1H), 3.76 (s, 2H), 2.33 (s, 3H), 1.99 (br. s., 2H). LC-MS (ES−) m/z 289.99, 291.15 [M−1]. LC-MS (ES+) m/z 290.98, 293.00 [M+H].
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[CH2:3][C:4]#[CH:5].[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13](Br)[C:10]=1[C:11]#[N:12]>C(N(CC)CC)C.[Cu]I.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>[NH2:8][C:9]1[CH:16]=[CH:15][CH:14]=[C:13]([C:5]#[C:4][CH2:3][Si:2]([CH3:7])([CH3:6])[CH3:1])[C:10]=1[C:11]#[N:12]
Reactant: C#CC[Si](C)(C)C
Reactant: N#Cc1c(N)cccc1Br
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CC#Cc1cccc(N)c1C#N
Yield: 125.2 %

Procedure:
To a stirred solution of trimethyl(prop-2-ynyl)silane (1.12 g, 10 mmol), 2-amino-6-bromobenzonitrile (Klaubert, D. H.; Sellstedt, J. H.; Guinosso, C. J.; Capetola, R. J.; Bell, S. C. J. Med. Chem. 1981, 24, 742) (1.0 g, 5 mmol), CuI (0.01 equiv.) in triethylamine (50 mL) was added Pd(PPh3)4 (0.1 equiv.) at room temperature under nitrogen. The reaction mixture was then refluxed under nitrogen overnight. The solvent was evaporated, and the residue was titrated with EtOAc/water. The organic layer was separated, were washed with brine, and dried over Na2SO4. After evaporation of the solvent, the residue was purified by chromatography on silica gel eluting with 15% EtOAc in hexanes to give the title compound (1.43 g, 63%) as a as a liquid. MS 229 (MH+).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([O:23][NH:24][CH:25]([C:36]([OH:38])=O)[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.ON1C(=O)CCC1=O.Cl.[NH2:48][C@H:49]([C:52]([O:54][CH3:55])=[O:53])[CH2:50][OH:51]>O1CCOCC1.C(OCC)(=O)C.C(N(CC)CC)C>[CH2:16]([O:23][NH:24][CH:25]([C:36]([NH:48][C@H:49]([C:52]([O:54][CH3:55])=[O:53])[CH2:50][OH:51])=[O:38])[CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C(O)C(Cc1c[nH]c2ccccc12)NOCc1ccccc1
Reactant: COC(=O)[C@@H](N)CO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CO)NC(=O)C(Cc1c[nH]c2ccccc12)NOCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
1.24 g of dicyclohexylcarbodiimide was added to 30 ml Of a solution of 1.77 g of N-benzyloxy-DL-tryptophane and 0.70 g of N-hydroxysuccinimide in anhydrous dioxane, with ice-cooling. The mixture was stirred at room temperature for 2 hours. The reaction mixture was filtered to remove the insoluble materials, whereby a light brown solution was obtained. Separately, 0.8 ml of triethylamine was added to 20 ml of a suspension of 0.89 g of methyl L-serinate hydrochloride in anhydrous dioxane. The mixture was stirred at room temperature for 2 hours. Thereto was added the above light brown solution. The resulting mixture was stirred at room temperature for 66 hours. The reaction mixture was diluted with 200 ml of ethyl acetate. The resulting solution was washed with 1N hydrochloric acid and an aqueous solution saturated with sodium chloride, then dried with anhydrous magnesium sulfate, and subjected to distillation to remove the solvent, to obtain 2.07 g of methyl (N-benzyloxy-DL-tryptophyl)-L-serinate as a brown oily substance.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[SH:37].C(N(C(C)C)CC)(C)C.O>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][C:31]=1[S:37][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]3([NH:24][C:25](=[O:27])[CH3:26])[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17]3)=[CH:10][CH:9]=2)=[C:4]([F:28])[CH:3]=1
Reactant: CC(=O)NC1(CCc2ccc(-c3ccc(Br)cc3F)cc2)COC(C)(C)OC1
Reactant: Cc1ccc(S)c(C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)NC1(CCc2ccc(-c3ccc(Sc4ccc(C)cc4C)cc3F)cc2)COC(C)(C)OC1
Yield: 102.6 %

Procedure:
A solution of N-{5-[2-(4′-bromo-2′-fluorobiphenyl-4-yl)ethyl]-2,2-dimethyl-1,3-dioxan-5-yl}acetamide (225 mg) of Reference Example 10, 2,4-dimethylbenzenethiol (69 mg), diisopropylethylamine (129 mg), tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (12.9 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (14.9 mg) in 1,4-dioxane (2 mL) was heated under reflux for 7 hr under a nitrogen atmosphere. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.26 g) as a colorless oil.
Reaction SMILES: [C:1]1([CH2:7][C:8]([N:10]2[CH2:19][CH2:18][CH2:17][C:16]3[N:15]=[CH:14][C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[C:11]2=3)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>O1CCCC1>[C:1]1([CH2:7][CH2:8][N:10]2[CH2:19][CH2:18][CH2:17][C:16]3[N:15]=[CH:14][C:13]4[CH:20]=[CH:21][CH:22]=[CH:23][C:12]=4[C:11]2=3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(Cc1ccccc1)N1CCCc2ncc3ccccc3c21
Agent: B
Solvent: C1CCOC1
Product: c1ccc(CCN2CCCc3ncc4ccccc4c32)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 39.4 %

Procedure:
A stirred solution of 1-(phenylacetyl)-1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine (5.11 g) in sieve dried tetrahydrofuran (300 ml) was treated rapidly with 1M borane in tetrahydrofuran (68 ml). The resultant solution was stirred overnight under a nitrogen atmosphere with exclusion of moisture and thereafer allowed to stand 24 hours. The reaction was quenched by dropwise addition of 10% sodium hydroxide solution (60 ml) and then concentrated to remove the tetrahydrofuran. The oil-aqueous phase mixture was further diluted with water (100 ml) and extracted with dichloromethane (2×200 ml). The combined and dried (Na2SO4) organic phase was filtered and concentrated to a viscous oil (a borane complex of the product). A solution of the oil in glacial acetic acid (30 ml) was cautiously treated with concentrated hydrochloric acid (15 ml) under nitrogen (vigorous gas evolution noted). After stirring for 1 hour at ambient temperature the solution was decanted over crushed ice (500 ml), diluted with water (200 ml) and basified with 50% sodium hydroxide solution. The mixture was extracted with CH2Cl2 (2×250 ml) and the combined and dried (Na2SO4) organic phase was filtered and concentrated to an oil (4.72 g). A TLC analysis (silica gel, ethyl acetate) indicated the oil was a mixture of the desired product and 1,2,3,4-tetrahydrobenzo[c]-1,5-naphthyridine. The mixture was separated by preparative HPLC (silica gel, eluted with ethyl acetate, overlap fractions repurified using new columns) to give 1.92 g of the product as a viscous oil which was combined with a similarly prepared material to give 2.52 g of pure product.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH:6]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:6]([N:19]1[CH2:22][C:21]([CH:1]2[CH2:3][CH2:2]2)([OH:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Br[Mg]C1CC1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
To a 0.5 M cyclopropylmagnesium bromide in THF (4.72 mL, 2.36 mmol), 1-benzhydryl-azetidin-3-one (200 mg, 0.843 mmol) in THF (3 mL) was added dropwise at −78° C. The reaction mixture was stirred at −78° C. for 2 hr. Then it was added saturated NaHCO3 solution and extracted with ether (3×20 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a light yellow oil. The crude product was purified by Prep. HPLC column using CH3CN—H2O-ammonium acetate solvent system. Fractions were collected and concentrated. Then it was extracted with ethyl acetate. The organic layers were combined, dried (MgSO4) and concentrated to give a colorless oil as Grignard reaction product. (63 mg, 27% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][C:15]([F:18])([F:17])[F:16].[CH3:19][N:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]2[CH:35]=[CH:36][O:37][C:22]=2[C:21]1=[O:38].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.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]>[CH3:19][N:20]1[CH:25]=[C:24]([C:2]2[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=2[O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:23]2[CH:35]=[CH:36][O:37][C:22]=2[C:21]1=[O:38]
Reactant: CS(=O)(=O)Cc1ccc(OCC(F)(F)F)c(Br)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)c2ccoc2c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cc(CS(C)(=O)=O)ccc2OCC(F)(F)F)c2ccoc2c1=O
Temperature: 70 °C
Yield: 33.2 %

Procedure:
A mixture of 2-bromo-4-(methylsulfonylmethyl)-1-(2,2,2-trifluoroethoxyl)benzene (100 mg, 0.29 mmol), 6-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)furo[2,3-c]pyridin-7-one (96 mg, 0.35 mmol), K3PO4 (184 mg, 0.87 mmol), Pd(dppf)Cl2 (22 mg, 10%) in dioxane/H2O (2 mL/1 mL) was bubbled with nitrogen for 5 min. The sealed vial was heated to 70° C. for 2 h. The reaction mixture was filtered through a short plug of celite; the celite plug was washed with EtOAc (15 mL). The filtrate was washed with water and brine; the organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by prep-HPLC to afford the title compound (40 mg, 33%) as an off-white solid. 1H NMR (CDCl3, 400 MHz) δ 7.76 (d, J=2.0 Hz, 1H) 7.53 (d, J=2.0 Hz, 1H) 7.41-7.38 (m, 1H) 7.37 (s, 1H) 7.02 (d, J=8.4, 1 H) 6.72 (d, J=2.0 Hz, 2H) 4.37 (q, J=8.0 Hz, 2H) 4.27 (s, 2H) 3.73 (s, 3H) 2.89 (s, 3H). LCMS (M+H)+=416.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([CH3:10])[CH:3]=1.N1C=CC=CC=1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28]>O1CCCC1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>[Br:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH:6][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([F:17])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=2)=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)cc(C)c1N
Reactant: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(Br)cc(C)c1NC(=O)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67 %

Procedure:
To a mixture of 4-bromo-2,6-dimethylaniline (15 g, 75 mmol) (commercially available) and pyridine (16.1 ml, 200 mmol) in anhydrous tetrahydrofuran (150 ml) under an atmosphere of nitrogen was added the solution of 4-fluoro-3-nitrobenzoyl chloride (Step A). The reaction mixture was stirred at ambient temperature for 8 hours. The reaction mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate (saturated). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent: cyclohexane/ethyl acetate 2:1) to give N-(4-bromo-2,6-dimethyl-phenyl)-4-fluoro-3-nitro-benzamide (27.54 g, 67% yield) which was used without further purification. LC/MS (Method A): 369 (MH+), 410 (MH++CH3CN).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)=[CH:4][CH:3]=1.CN(C(O[N:21]1N=N[C:23]2C=CC=C[C:22]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N)C>C1COCC1.CN(C=O)C>[CH2:22]([NH:21][C:9](=[O:11])[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH3:12])[CH3:23]
Reactant: CC(C(=O)O)c1ccc(O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CCN
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCNC(=O)C(C)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To 4.00 g (24.1 mmol) 2-(4-hydroxyphenyl)propionic acid in 50 mL THF and 5 ml DMF are added 6.76 g (66.1 mmol) TEA and 8.50 g TBTU. The reaction mixture is stirred at r.t. for 5 min, then 36.1 ml (2 mold solution; 72.2 mmol) ethylamine are added. The reaction mixture is stirred at r.t. 5 h. The solvent is removed in vacuo and the crude product is purified by prep. HPLC-MS (ACN/H2O/NH4OH).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1.P(Br)(Br)([Br:21])=O.C([O-])(O)=O.[Na+]>>[Br:21][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=2)[C:4](=[O:18])[CH:3]=1
Reactant: O=P(Br)(Br)Br
Reactant: CS(=O)(=O)c1ccc(-n2ccc(O)cc2=O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CS(=O)(=O)c1ccc(-n2ccc(Br)cc2=O)cc1
Temperature: 100 °C
Yield: 46.2 %

Procedure:
A mixture of 4-hydroxy-1-(4-(methylsulfonyl)phenyl)pyridin-2(1H)-one (106.1 mg, 0.4 mmol) and phosphorous oxybromide (573.4 mg, 2.0 mmol, Alfa Aesar) was heated at 100° C. for 45 min and then cooed to room temperature. To the above residue was added saturated NaHCO3 aqueous solution at 0° C. followed by extraction with CH2Cl2 (3×). The combined extracts were washed with saturated NaHCO3 aqueous solution and brine, dried Na2SO4) and evaporated. The residual was purified by flash chromatography (0 to 100% EtOAc/hexanes) to yield 60.7 mg (46%) of the product as a yellow solid. MS (ESI) 328 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([C:14]1([CH3:17])[CH2:16][CH2:15]1)[CH:7]=[C:6]([C:18]([OH:20])=[O:19])[C:5]2=[O:21].C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C>C(#N)C>[NH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:11]2[C:10]([F:13])=[C:9]3[C:4]([C:5](=[O:21])[C:6]([C:18]([OH:20])=[O:19])=[CH:7][N:8]3[C:14]3([CH3:17])[CH2:16][CH2:15]3)=[CH:3][C:2]=2[F:1])[CH2:31]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(F)c32)CC1
Solvent: CC#N
Product: CC1(n2cc(C(=O)O)c(=O)c3cc(F)c(N4CCC(N)C4)c(F)c32)CC1

Procedure:
To 1.24 g (4.27 mmol) of 6,7,8-trifluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid in 10 ml of acetonitrile was added 0.77 (4.27 mmol) of 3-[(t-butoxycarbonyl)amino]pyrrolidine and 0.63 g (4.27 mmol) of 1,8-diazobicyclo[5.4.0]undec-7-ene. The mixture was refluxed for one hour, cooled, filtered, and the solids washed with ether. The solids were dissolved in 10 ml of acetic acid at 100° C. and 2 ml of 3N hydrochloric acid was added. This mixture was heated at 100° for four hours, concentrated, triturated with 2-propanol, and the solid filtered, washed with ether, and dried (24 hours, 80° C., 125 mmHg) to give 0.90 g of 7-(3-amino-1-pyrrolidinyl)-6,8-difluoro-1,4-dihydro-1-(1-methylcyclopropyl)-4-oxo-3-quinolinecarboxylic acid as the hydrochloride salt, mp >300° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[CH:5]=[C:4]([CH3:19])[CH:3]=1.[H-].[Na+].[Cl:22]/[CH:23]=[CH:24]/[CH2:25]Cl>C(#N)C.CN(C=O)C.CCCCC.C(OCC)(=O)C>[CH3:14][N:13]1[C:9]([O:8][C:6]2[CH:5]=[C:4]([CH3:19])[CH:3]=[C:2]([O:1][CH2:25]/[CH:24]=[CH:23]/[Cl:22])[N:7]=2)=[CH:10][C:11]([C:15]([F:18])([F:17])[F:16])=[N:12]1
Reactant: Cc1cc(O)nc(Oc2cc(C(F)(F)F)nn2C)c1
Reactant: Cl/C=C/CCl
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OC/C=C/Cl)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
A mixture of 6-hydroxy-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methylpyridine (0.9 g, 3.3 mmol) and NaH (60% in oil, 0.16 g, 4 mmol) in acetonitrile (20 ml) and DMF (1 ml) is stirred for 10 min at ambient temperature and (E)-1,3-dichloropropene (0.4 g, 3.6 mmol) is added. After stirring for 60 h at ambient temperature, the remaining NaH is deactivated and the resulting mixture is diluted with pentane/ethyl acetate (by volume ration 1/1) and filtered through a bed of silica gel. The filtrate is washed with water. The organic layer is dried with anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields the title compound (0.6 g, 52% yield) as an colorless oil.