Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][S:5]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[H-].[Na+].[Cl:25][C:26]([CH2:28]Cl)=[CH2:27]>CN(C=O)C>[Cl:25][C:26](=[CH2:27])[CH2:28][N:4]([CH2:3][CH:2]([OH:1])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[S:5]([C:8]1[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=1)(=[O:7])=[O:6]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)NCC(O)c2ccccc2)cc1
Reactant: C=C(Cl)CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CN(CC(O)c1ccccc1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-2), 10.0 g, 31 mmol) was placed in a flame-dried 500 mL round bottom flask and dissolved in anhydrous DMF (100 mL). The resulting solution was cooled to −10° C. and treated with NaH (0.9 g, 37 mmol). The resulting bright orange suspension was stirred 30 min at −10° C. 2,3-dichloropropene (3.9 mL, 40 mmol) was added neat dropwise and the reaction immediately turned dark brown. N-Tetrabutylammonium iodide (100 mg, catalytic) was added and the reaction was removed from the ice/acetone bath and warmed to 25° C. The reaction was stirred overnight prior to, quenching with 5% NH4Cl (200 mL) and extraction with EtOAc (3×100 mL). The combined organic layers were washed with H2O (3×100 mL) and NaCl (sat. aq.) prior to drying with MgSO4 and filtration. Concentration under reduced pressure produced an amber oil that was purified by flash column chromatography (SiO2, 0-60% EtOAc/hexanes gradient over 30 min) to yield N-(2-chloroprop-2-enyl)-N-(2-hydroxy-2-phenylethyl)-4-nitrobenzenesulfonamide (1-3) as a light orange oil. 1H NMR (300 MHz, CDCl3) δ 8.31 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H), 7.34 (m, 5H), 5.36 (s, 2H), 5.01 (dd, J=8.0, 4.0 Hz, 1H), 4.25 (d, J=16.2 Hz, 1H), 4.10 (d, J=16.2 Hz, 1H), 3.42 (m, 2H), 2.80 (br s, 1H); MS 379.3 found 379.8 (M−H2O) required.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]([C:10]1([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=2[F:20])[CH2:12][O:11]1)[CH3:9].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C>[F:20][C:14]1[CH:15]=[C:16]([F:19])[CH:17]=[CH:18][C:13]=1[C:10]1([C@H:8]([OH:7])[CH3:9])[CH2:12][O:11]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2ccc(F)cc2F)CO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: C[C@@H](O)C1(c2ccc(F)cc2F)CO1
Temperature: 55 °C
Reaction time: 1 h

Procedure:
2-[(1R)-1-(3,4,5,6-Tetrahydro-2H-pyran-2-yl)oxyethyl]-2-(2,4-difluorophenyl)oxirane (82 g; manufactured by a method disclosed in Japanese Laid Open Application Hei 04/074168-A) and 6.3 g of pyridinium p-toluenesulfonate were dissolved in 600 ml of ethanol and the solution was stirred at 55° C. for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 1 liter of ethyl acetate and the resulting solution was washed with water (2×200 ml). The aqueous layer was extracted with ethyl acetate (2×100 ml). The organic layers were combined, washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluate; hexane:ethyl acetate=10:1 to 8:1 to 3:1) to give 31.5 g of (1R)-1-[2-(2,4-difluorophenyl)-2-oxiranyl]ethanol as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.C(=O)(OC)OC.[H-].[Na+].[C:20]([OH:23])(=[O:22])[CH3:21]>O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH:7]([CH2:21][C:20]([OH:23])=[O:22])[C:8]2=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCc2ccc(Br)cc21
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(=O)OC
Product: O=C(O)CC1Cc2ccc(Br)cc2C1=O
Temperature: 25 °C

Procedure:
6-Bromo-1-indanone (142 g, 672 mmol) in tetrahydrofuran (1200 mL) was added slowly to refluxing dimethyl carbonate (143 mL, 1680 mmol), sodium hydride (80.6 g, 2020 mmol, 60% in oil, washed with pentane after weighing) and tetrahydrofuran (1200 mL). After refluxing the mixture for 2.5 hours, acetic acid (240 mL) was added dropwise at 0° C. and then allowed to warm to room temp. The mixture was partitioned between diethyl ether/dichloromethane and dilute aqueous hydrochloric acid. The organic layer was washed with 2N hydrochloric acid, water, aqueous sodium bicarbonate, and brine and was then dried over sodium sulfate to obtain a brown solid after removing solvent under vacuum, (176 g, 97%, crude), 124.5-127.5° C. m.p. 1H-NMR (300 MHz, CDCl3) (a ratio of approximately 3:1 enol to ketone tautomers) 7.91 (d, 0.27H), 7.77 (d, 0.73H, J=1.8), 7.73 (dd, 0.27H), 7.54 (dd, 0.73H, J=8.1, 1.8), 7.39 (d, 0.27H), 7.34 (d, 0.73H, J=7.9), 3.86 (s, 2.19H), 3.83 (m, 0.27H), 3.80 (s, 0.81H), 3.50 (m, 0.27H), 3.47 (s, 1.46H), 3.32 (m, 0.27H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[S:13][CH3:14])=[O:5].C(O)(=O)C.CO[CH:21]1[CH2:25][CH2:24][CH:23](OC)O1>O>[F:12][C:10]1[CH:9]=[CH:8][C:7]([S:13][CH3:14])=[C:6]([C:4](=[O:5])[CH2:3][N:2]2[CH:21]=[CH:25][CH:24]=[CH:23]2)[CH:11]=1
Reactant: COC1CCC(OC)O1
Reactant: CSc1ccc(F)cc1C(=O)CN
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CSc1ccc(F)cc1C(=O)Cn1cccc1
Temperature: 95 °C
Yield: 44.9 %

Procedure:
To a solution of 2-amino-1-[5-fluoro-2-(methylthio)phenyl]ethanone hydrochloride (4.54 g, 19.27 mmol) in water (29 ml), heated at 90° C., were added trihydrated sodium acetate (2.62 g, 19.27 mmol), glacial acetic acid (17 ml) and 2,5-dimethoxytetrahydrofuran (2.40 ml, 18.50 mmol). After 20 seconds at 90-100° C. the mixture was cooled and extracted with ethyl acetate. The organic layers were washed with a 20% solution of sodium bicarbonate and brine, dried and evaporated. The residue was chromatographed (50% petroleum ether 40-60° in dichloromethane) to afford 2.07 g of 22c as white crystals mp 133.2-134.0° C. (50% yield). 1H NMR (CDCl3) δ7.39-7.15 (m, 34); 6.66-6.65 (m, 2H); 6.22-6.20 (m, 2H); 5.20 (s, 2H); 2.42 (s, 3H). MS m/z 252 (M++H), 234, 202 (100), 183, 169, 154, 141, 126, 109, 80.
Reaction SMILES: [CH:1]1([CH:6]=[C:7]2[C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([C:18]([O:20]C)=[O:19])=[CH:13][CH:14]=3)[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH:23]([C:25]1[CH:32]=[CH:31][C:28]([C:29]#[N:30])=[C:27]([C:33]([F:36])([F:35])[F:34])[CH:26]=1)[NH2:24]>>[C:29]([C:28]1[CH:31]=[CH:32][C:25]([N:23]2[CH:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:7]3[CH2:8][O:9][C:10]4[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[CH:13]=[CH:14][C:15]=4[C:16]3=[N:24]2)=[CH:26][C:27]=1[C:33]([F:34])([F:35])[F:36])#[N:30]
Reactant: COC(=O)c1ccc2c(c1)OCC(=CC1CCCC1)C2=O
Reactant: N#Cc1ccc(NN)cc1C(F)(F)F
Agent: Cl
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2CCCC2)cc1C(F)(F)F

Procedure:
The title compound was prepared from methyl 3-(cyclopentylmethylene)-4-oxochroman-7-carboxylate (Preparation 31; 286 mg, 1.0 mmol) and 4-hydrazinyl-2-(trifluoromethyl)benzonitrile hydrochloride (Preparation 3; 298 mg, 1.3 mmol) according to Method B and Method C. The title compound was largely present as a mixture of cis and trans diastereomers:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:34]=[CH:33][C:18]([NH:19][CH2:20][C:21]3[CH:30]=[C:29]4[C:24]([CH:25]=[CH:26][C:27]([C:31]#[N:32])=[CH:28]4)=[CH:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([N:19]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[C:29](=[CH:28][C:27]([C:31]#[N:32])=[CH:26][CH:25]=4)[CH:30]=3)[C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:33][CH:34]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NCc3ccc4ccc(C#N)cc4c3)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N(Cc3ccc4ccc(C#N)cc4c3)C(=O)c3ccccc3)cc2)CC1

Procedure:
Starting compound: 7-[[4-[(1-t-butoxycarbonyl-4-piperidyl)oxy]anilino]methyl]-2-naphthalenecarbonitrile, benzoyl chloride.
Reaction SMILES: O(CC)CC.[H-].[Al+3].[Li+].[H-].[H-].[H-].[F:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=2[C:21](O)=[O:22])=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>O>[F:12][C:13]1[CH:29]=[CH:28][C:16]([CH:17]([C:19]2[C:20]([CH2:21][OH:22])=[CH:24][CH:25]=[CH:26][CH:27]=2)[OH:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: OCc1ccccc1C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 1190 parts of 1,1'-oxybisethane were added at once 50 parts of lithium aluminium hydride. Then there was added dropwise a solution of 213.7 parts of 2-(4-fluorobenzoyl)benzoic acid in 875 parts of 1,1'-oxybisethane so that the mixture was kept at reflux temperature. Upon completion, stirring was continued first for 30 minutes at room temperature, then for 2 hours at reflux and further overnight at room temperature. The reaction mixture was cooled to 0° C. and there were added dropwise successively 50 parts of water, 50 parts of a 15% sodium hydroxide solution and 150 parts of water all at 0° C. The reaction mixture was filtered over Hyflo and washed thoroughly with 1,1'-oxybisethane. The organic phase was separated, washed with water, dried, filtered and evaporated. The residue was crystallized from a mixture of benzene and hexane, yielding 170.4 parts of α-(4-fluorophenyl)-1,2-benzenedimethanol; mp. ±75° C. (intermediate 91).
Reaction SMILES: [C:1]([N:3]=[C:4]([N:21]([CH3:30])[N:22]=CC1C=CC=CC=1)[NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]2[O:20]CCO2)[CH:11]=1)#[N:2].[ClH:31].C(N(CC)CC)C.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[ClH:31].[CH3:30][N:21]1[C:4]([NH:5][CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][OH:20])[CH:13]=[CH:14][CH:15]=2)=[N:3][C:1]([NH2:2])=[N:22]1
Reactant: CN(N=Cc1ccccc1)C(=NC#N)NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cn1nc(N)nc1NCCCOc1cccc(CO)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
N'-Cyano-N-[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1-methyl-2-(phenylmethylene)hydrazinecarboximidamide (18.2 g) in tetrahydrofuran (150 ml) was treated with 5 N hydrochloric acid (30 ml) at 30° C. for 30 mins. Triethylamine (20 ml) was added followed by sodium borohydride (8.0 g). The resulting mixture was stirred at room temperature for 14 hrs, diluted with ethyl acetate (150 ml) and evaporated to a red oil which was dissolved in ethyl acetate, washed with sodium bicarbonate solution and evaporated to leave an oil. This oil was treated with etheral hydrogen chloride to give the title compound as a white solid (8 g). m.p. 148°-9°. TLC silica, ethyl acetate, water, isopropanol 0.88 ammonia (25:8:15:2) Rf 0.56.
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([O:22]C)=O)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].O.[NH2:25][NH2:26]>CCO>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([NH:25][NH2:26])=[O:22])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: NN
Reactant: COC(=O)c1c[nH]c2ccc(-c3cncc(OC(C)C)n3)cc12
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)NN)c3c2)n1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a stirred solution of methyl 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carboxylate (10 g, 30 mmol) in EtOH (50 mL) was added hydrazine hydrate (30 mL) and the reaction was heated at reflux for 48 h. The reaction was cooled to RT and a white precipitate was formed. The suspension was filtered and dried to afford 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carbohydrazide (9.0 g, 90.9%) as a white solid. MS (ESI, pos. ion) m/z: 312 (M+1); 1H-NMR (DMSO-d6) δ ppm; 11.71 (s, 1H), 9.2 (s, 1H), 8.8 (d, J=1.6 Hz, 1H), 8.71 (s, 1H), 8.1 (s, 1H), 8.0 (s, 1H), 7.90 (dd, J=8.4, 1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 5.4 (m, 1H), 4.35 (d, J=2 Hz, 1H), 1.4 (d, J=6.0 Hz, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH2:25].CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:20][N:21]([CH3:26])[CH2:22][CH2:23][CH2:24][NH:25][S:16]([C:14]1[S:15][C:11]([C:7]2[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Reactant: CN(C)CCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)NCCCN(C)C)s2)s1

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (280 mg; 0.84 mmol; 1 eq), is dissolved in DCM (10 ml). N,N-dimethylpropane-1,3-diamine (0.89 ml; 8.4 mmol; 10 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After one night reaction, water (1 ml) is added and the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (10) as a white solid (105 mg; 28%).
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][C:7]1[C:8](=[O:18])[C:9]2[C:14]([C:15](=[O:17])[CH:16]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.[CH2:19](O)[CH2:20][OH:21]>[Zn].C1(C)C=CC=CC=1>[OH:21][CH2:20][CH2:19][O:17][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:18])=[C:7]([CH3:6])[CH:16]=1
Reactant: OCCO
Reactant: CC1=CC(=O)c2ccccc2C1=O
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: Cc1ccccc1
Product: Cc1cc(OCCO)c2ccccc2c1O
Temperature: 100 °C
Reaction time: 5 h
Yield: 70 %

Procedure:
4.9g of concentrated sulfuric acid were added dropwise, with stirring, to a mixture of 4.75 g (27.6 mmole) 2-methyl-1,4 naphthoquinone, 2.71 g (41.4 mmole) of zinc powder, 15 mL of ethylene glycol and 15 mL of toluene in an ice bath. After the addition was complete, the reaction mixture was stirred for 5 hours at 100° C. The reaction product was extracted with ethyl acetate, washed with water, brine, dried over sodium sulfate, filtered, then evaporated under reduced pressure to give 4.21 g (70% yield) of the above product. That product had a melting point of 136.3-136.8° C. and an 1HNMR as follows: (300 MHz, DMSO-d6) δ 2.37 (s, 3H), 3.86 (m, 2H), 4.10 (t, 2H, J=4.8 Hz), 4.98 (t, 1H, J=5.4 Hz), 6.76 (s, 1H), 7.42 (m, 2H), 8.14 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=9.0 Hz), 8.51 (s, 1H). The mass spectrum showed a molecular ion at m/z 218.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:19])[C:9]2[N:10]=[N:11][N:12]([CH2:14][Si](C)(C)C)[CH:13]=2)[N:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]([F:19])[C:9]2[N:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[N:3]=1
Reactant: C[Si](C)(C)Cn1cc(C(F)c2cccc(Br)n2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1cc(C(F)c2cccc(Br)n2)nn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-6-(fluoro{1-[(trimethylsilyl)methyl]-1H-1,2,3-triazol-4-yl}methyl)pyridine (500 mg, 1.46 mmol) in THF (10 mL) was added TBAF (1.0 M in THF, 4.37 mL, 4.37 mmol). The reaction was stirred at room temperature for 2 h. It was then diluted with water and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), filtered, and evaporated. Flash chromatography (30-100% EtOAc/hexanes) provided the title compound as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([OH:22])=O)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[CH:4][N:3]=1.[CH3:24][NH2:25]>>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([C:20]([NH:25][CH3:24])=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:23])=[N:6][CH:7]=1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3C(=O)O)cc2F)cn1
Reactant: CN
Product: CNC(=O)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step C of Example 504 using 4′-(2-aminopyrazin-5-yl)-3′-fluoro-[1,1′-biphenyl]-2-carboxylic acid and methylamine. MS (ESI): mass calcd. for C18H15FN4O, 322.12; m/z found, 323.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.35 (dd, J=2.3, 1.6, 1H), 8.15 (d, J=4.7, 1H), 8.00 (d, J=1.5, 1H), 7.84 (d, J=8.1, 1H), 7.52-7.41 (m, 4H), 7.27 (s, 1H), 7.24 (dd, J=5.5, 1.7, 1H), 6.68 (s, 2H), 2.59 (d, J=4.6, 3H).
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:34]1([CH:46]=O)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCOCC>[C:2]1([CH2:8][CH:9]=[CH:46][CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=CC1CCCCCCCCCCC1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: C(=CC1CCCCCCCCCCC1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 88.2 %

Procedure:
To 11.4 g (25.5 mmol) of phenylethyl triphenylphosphonium bromide in 50 mL of dry ether at 0° C. is added 10.2 mL (25.5 mmol) of 2.5M butyllithium. The suspension is stirred at 0° C. for 1 hour followed by the addition of 5.0 g (25.5 mmol) of cyclododecane carboxaldehyde. The mixture is stirred at room temperature for 3 hours after which time no starting material is evident by TLC. The reaction mixture is quenched with 1N HCl. The layers are separated and the aqueous layer is washed twice with ethyl ether. The combined organic layers are dried over a MgSO4 and the ether is evaporated. The residue is flash chromatographed on silica gel using hexanes to give 6.4 g of a colorless oil: NMR (CDCl3) δ 1.0-1.6 (m, 10H), 2.6 (m, 1H), 3.4 (d, 2H, J=8 Hz, ), 5.3 (t, 1H, J=7 Hz), 5.45 (q, 1H, J=7 Hz), 7.2 ppm (m, 5H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl[CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].C1CCN2C(=NCCC2)CC1>C(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[CH2:10][CH2:11][CH2:12][S:13]2(=[O:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: Nc1cccc(Br)c1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: O=S1(=O)CCCN1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-bromoaniline (1.0 mL, 9.18 mmol) and TEA (2.60 mL, 18.5 mmol) in CH2Cl2 (20 mL) was added 3-chloro-1-propanesulfonyl chloride (1.40 mL, 11.5 mmol) at 0° C. After stirring at room temperature for 16 hr, 3-chloro-1-propanesulfonyl chloride (1.40 mL, 11.5 mmol) and TEA (2.6 mL, 18.5 mmol) was added and the solution stirred at room temperature for 2 hr. The solution was then washed with HCl (1.0 N, aq) and brine, dried over Na2SO4 then concentrated in vacuo. The residue was then taken up in DMF (40 mL) and DBU (4.10 mL, 27.6 mmol) was added. The mixture was stirred at room temperature for 64 hr, diluted with EtOAc, then washed with 1N HCl and brine then concentrated. The residue was purified by silica gel chromatography (EtOAc/hexanes) to give 2-(3-bromophenyl)isothiazolidine 1,1-dioxide as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 2.50-2.54 (m, 2H), 3.37 (t, J=7.5 Hz, 2H), 3.74 (t, J=7.5 Hz, 2H), 7.22-7.24 (m, 3H), 7.33 (s, 1H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][NH:9][CH2:8][CH2:7][C:6]=2[C:5]=1[CH:14]=[O:15].CN(C)C=O.Cl[C:22]1[S:23][C:24]([C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[O:29])=[C:25]([CH3:27])[N:26]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:2][O:3][C:4]1[CH:13]=[CH:12][C:11]2[CH2:10][N:9]([C:22]3[S:23][C:24]([C:28]([N:30]4[CH2:31][CH2:32][O:33][CH2:34][CH2:35]4)=[O:29])=[C:25]([CH3:27])[N:26]=3)[CH2:8][CH2:7][C:6]=2[C:5]=1[CH:14]=[O:15]
Reactant: COc1ccc2c(c1C=O)CCNC2
Reactant: Cc1nc(Cl)sc1C(=O)N1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2c(c1C=O)CCN(c1nc(C)c(C(=O)N3CCOCC3)s1)C2
Temperature: 0.11999999731779099 °C
Reaction time: 3.5 h
Yield: 25.6 %

Procedure:
A mixture of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde hydrochloride (82 mg, 0.36 mmol), anhydrous dimethylformamide (5 mL), (2-chloro-4-methyl-thiazol-5-yl)-morpholin-4-yl-methanone (89 mg, 0.36 mmol) and freshly dried potassium carbonate (149 mg, 1.08 mmol) was stirred under argon at 0.120° C. for 3.5 h and then at 150° C. for 1 h. Water (20 mL) was added and the separated solid product was filtered off. The filtrate was extracted with diethyl ether (5×10 mL) and the combined extracts were washed with water (2×10 mL), dried and concentrated. The residue and the above solid product were combined and triturated repeatedly with diisopropyl ether. In this manner the title compound (37 mg, 0.092 mmol, 26%) was obtained as a beige powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](F)=[CH:4][N+:3]=1[O-:12].[CH3:13][NH2:14].O>C1COCC1>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([NH:14][CH3:13])=[CH:4][N+:3]=1[O-:12]
Reactant: CN
Reactant: O=[N+]([O-])c1cc(Br)[n+]([O-])cc1F
Solvent: C1CCOC1
Solvent: O
Product: CNc1c[n+]([O-])c(Br)cc1[N+](=O)[O-]

Procedure:
2-Bromo-5-fluoro-4-nitropyridine 1-oxide (11.2 g, 47 mmol) and 2 N methylamine (solution in THF) (48 mL, 96 mmol) in 150 mL THF was stirred for 5 min at ambient temperature. Water was poured into the mixture and THF was removed i.vac. The solid was filtered, washed with water and dried at 50° C. i. vac.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:22]3[C:17]([CH:18]=[C:19]([C:27]([OH:29])=O)[N:20]=[CH:21]3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:30]1([NH2:37])[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH2:36].C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[NH:37][C:27]([C:19]1[N:20]=[CH:21][C:22]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]1)[C:23]=2[CH:24]1[CH2:25][CH2:26]1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)O)ncc3c2C2CC2)CC1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3cc(C(=O)Nc4ccccc4N)ncc3c2C2CC2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 109.4 %

Procedure:
To a solution of 7-(4-(tert-butoxycarbonyl)piperazin-1-yl)-8-cyclopropylisoquinoline-3-carboxylic acid (60 mg, 0.15 mmol) and o-Phenylenediamine (16 mg, 0.15 mmol) in DMF (5 mL) was added HOAT (41 mg, 0.3 mmol), EDCI (46 mg, 0.3 mmol), and DIPEA (77 mg, 0.6 mmol). The reaction mixture was stirred at 60° C. overnight. After extraction by EA, the combined organic layers were dried by anhydrous Na2SO4 and concentrated in vacuo to afford tert-butyl 4-(3-(2-aminophenylcarbamoyl)-8-cyclopropylisoquinolin-7-yl)piperazine-1-carboxylate as a yellow solid (80 mg, yield: 99%).
Reaction SMILES: C(OC([NH:8][C@H:9]([CH2:16][CH2:17][S:18][CH3:19])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>Cl.O1CCOCC1>[NH2:8][C@H:9]([CH2:16][CH2:17][S:18][CH3:19])[CH:10]([OH:15])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(O)[C@@H](CCSC)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)C(O)[C@H](N)CCSC

Procedure:
A solution of Example 11C in 4M HCl in dioxane (10 mL) at room temperature was stirred for 4 hours and concentrated to provide the desired product. MS (APCI(+)) m/e 194 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 8.09 (br s, 2H), 7.94 (br s, 1H), 6.58 (m, 0.5H), 6.42 (m, 0.5H), 4.48 (m, 0.5H), 4.30 (m, 0.5H), 3.72 (s, 3H), 2.58 (m, 2H), 2.04 (s, 1.5H), 2.02 (s, 1.5H), 1.82 (m, 2H).