Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-:1].[Li+].[C:3]([O:11][CH2:12][C@@H:13](OS(C1C=C(Cl)C(Cl)=CC=1Cl)(=O)=O)[C@@H:14]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH:16]=[N:17][O:18][CH3:19])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(OCC)(=O)C>O1CCCC1.CN1CCN(C)C1=O>[C:3]([O:11][CH2:12][C@@H:13]([Br:1])[C@@H:14]([O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:15][CH:16]=[N:17][O:18][CH3:19])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CON=CC[C@H](OC(=O)c1ccccc1)[C@@H](COC(=O)c1ccccc1)OS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Reactant: [Br-]
Agent: [Li+]
Solvent: CN1CCN(C)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CON=CC[C@H](OC(=O)c1ccccc1)[C@H](Br)COC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
1.52 g of lithium bromide was added to a solution of 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate in 17.9 mL of tetrahydrofuran and 16.1 mL of 1,3-dimethyl-2-imidazolidinone, and the obtained mixture was then stirred at 50° C. for 3 hours. Thereafter, ethyl acetate and a 25% lithium bromide aqueous solution were added to the reaction mixture. The organic layer was fractionated, and it was washed with a 13% lithium bromide aqueous solution and was then dried over anhydrous sodium sulfate. After that, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0 to 75/25), so as to obtain 4.84 g of (2R,3S)-2-bromo-5-(methoxyimino)pentane-1,3-diyl dibenzoate in the form of a colorless oily product.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([Br:15])=[CH:8][C:3]=1[C:4](OC)=[O:5].[NH3:16]>CO>[NH2:1][C:2]1[CH:11]=[C:10]([N+:12]([O-:14])=[O:13])[C:9]([Br:15])=[CH:8][C:3]=1[C:4]([NH2:16])=[O:5]
Reactant: COC(=O)c1cc(Br)c([N+](=O)[O-])cc1N
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(Br)c([N+](=O)[O-])cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
25.8 g (93.8 mmol) of methyl 2-amino-5-bromo-4-nitro-benzoate were dissolved in 800 ml of methanol and saturated with ammonia at -40° C. Subsequently, the mixture was stirred at room temperature overnight. The solution was concentrated and the residue was triturated with methylene chloride. The precipitate was filtered off under suction and dried. 18.3 g (75%) of 2-amino-5-bromo-4-nitro-benzamide were obtained as orange coloured crystals;
Reaction SMILES: [CH2:1]([C:3](Cl)=[O:4])[CH3:2].C(Cl)Cl.[N:9]1([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][C:26]=4[CH3:32])[C:23]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH:13]=[CH:12][N:11]=[CH:10]1>N1C=CC=CC=1>[N:9]1([C:14]2[CH:15]=[CH:16][C:17]([C:20]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([NH:31][C:3](=[O:4])[CH2:1][CH3:2])=[CH:27][C:26]=4[CH3:32])[C:23]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[CH:22][CH:21]=3)=[CH:18][CH:19]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CCC(=O)Cl
Reactant: Cc1cc(N)ccc1-n1c(CCC(=O)O)ccc1-c1ccc(-n2ccnc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(=O)Nc1ccc(-n2c(CCC(=O)O)ccc2-c2ccc(-n3ccnc3)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of pyridine (1 mL) and C2H5COCl/DCM (v/v=1/100, 4.2 mL) was added a solution of 20B (see scheme 20) (150 mg, 0.389 mmol) in pyridine (1 mL) at 0° C. The mixture was stirred at room temperature overnight. The solvents were removed under reduced pressure and the resulting solid was acidified with 10% hydrochloric acid to pH=5.0. The resulting precipitate was isolated by centrifuge, rinsed with water, dried under reduced pressure to afford the crude product as a brown powder, After purification by prep-HPLC, 3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(2-methyl-4-propionamidophenyl)-1H-pyrrol-2-yl)propanoic acid (32 mg, 19%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[CH2:12][C:11]([CH3:15])=[N:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:13](=[O:14])[CH:12]([C:31](=[O:32])[NH:30][C:27]3[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=3)[C:11]([CH3:15])=[N:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2N=C(C)CC2=O)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: COc1ccc(N2N=C(C)C(C(=O)Nc3ccc(F)cc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 4.1 g of 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one in 75 ml of benzene and 2.5 g of triethylamine is combined with 2.75 g of p-fluorophenylisocyanate while stirring at ambient temperature. After standing overnight, the mixture is evaporated, the residue taken up in 0.3 N hydrochloric acid, the resulting crystals collected, washed with water, dried, triturated with ethyl acetate and recrystallized from methanol to yield the 1-(p-methoxyphenyl)-3-methyl-4-(p-fluorophenylcarbamoyl)-2-pyrazolin-5-one of Formula II with R=OCH3, R'=H and R"=F, melting at 254°-256° (dec.).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].C(N=[C:41]=[O:42])C.[CH:43](N(C(C)C)CC)(C)[CH3:44].Cl>C(#N)C.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[C:15](=[O:33])[N:16]([CH3:32])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[C:12]([S:34]([NH:37][C:41]([CH2:43][CH3:44])=[O:42])(=[O:36])=[O:35])[CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCN=C=O
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(-c2c(S(N)(=O)=O)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCC(=O)NS(=O)(=O)c1cnn(-c2ccc(C#N)cc2)c1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Temperature: 50 °C
Reaction time: 4 h

Procedure:
1-(4-Cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazole-4-sulfonamide (prepared in Example 205) (97 mg) was dissolved in acetonitrile (2 ml) and thereto were added ethyl isocyanate (0.043 ml) and diisopropylethylamine (0.065 ml) and the resulting mixture was stirred at 50° C. for four hours. The mixture was cooled to room temperature, and thereto were then added 1N hydrochloric acid (20 ml) and ethyl acetate (30 ml) such that the intended products were extracted into an organic layer. The organic layer was washed with 1N hydrochloric acid (20 ml) and saturated saline (30 ml) successively, dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol) to afford 1-(4-cyanophenyl)-5-(3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-N-(ethylcarbonyl)-1H-pyrazole-4-sulfonamide (88 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[C:16]2[C:15]3[C:14]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:1][CH2:2][CH2:3][C@H:4]1[C:16]2[C:15]3[C:14]([O:17][CH:18]4[CH2:23][CH2:22][CH:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])[CH2:20][CH2:19]4)=[N:13][CH:12]=[N:11][C:10]=3[S:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCO)CCC4)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)[C@H](CCOS(C)(=O)=O)CCC4)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(13S)-13-(2-hydroxyethyl)-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (490 mg, 1.09 mmol, 1.00 equiv) in DCM (20 mL) was added triethylamine (201 mg, 1.99 mmol, 1.80 equiv) and methanesulfonyl chloride (189 mg, 1.65 mmol, 1.50 equiv) at 0° C. The resulting solution was stirred for 2 h at room temperature and then washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to provide 530 mg of tert-butyl N-(4-[[(13S)-13-[2-(methanesulfonyloxy)ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[C:21]([C:27]#[N:28])=[C:20]([OH:29])[C:19]=1[CH2:30][CH:31]=C)[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH3:17])=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=[O:34].[Na+]>O1CCCC1.O.C(OCC)(=O)C.S([O-])([O-])(=O)=S.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[C:1]([O:5][C:6]([N:8]([C:18]1[N:23]2[N:24]=[CH:25][CH:26]=[C:22]2[C:21]([C:27]#[N:28])=[C:20]([OH:29])[C:19]=1[CH2:30][CH2:31][OH:34])[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:16][CH3:17])=[CH:13][CH:14]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCc1c(O)c(C#N)c2ccnn2c1N(C(=O)OC(C)(C)C)c1ccc(OCC)cc1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(O)c(C#N)c3ccnn23)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
tert-Butoxy-N-[4-cyano-5-hydroxy-6-(2-propenyl)pyrazolo[1,5-a]pyridin-7-yl]-N-(4-ethoxyphenyl)carboxamide (27) (248 mg) was dissolved in a mixture of tetrahydrofuran (4.6 mL) and water (1.1 mL). To this solution, sodium periodate (611 mg) was added and the solution was cooled to 0° C. To this solution, osmium tetroxide (0.58 mL, 2.5 wt. % 2-methyl-2-propanol solution) was added dropwise and the mixture was stirred at room temperature for 2 h. The reaction solution was diluted with ethyl acetate and aqueous sodium thiosulfate solution was added to quench the reaction. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with a mixture of brine and saturated aqueous ammonium chloride solution (9:1) and dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was dissolved in methanol (5.7 mL). Here sodium borohydride (21.6 mg) was added and the solution was stirred at room temperature for 1 h. The reaction solution was diluted with ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure and the resultant crude product was purified with silica-gel column chromatography (hexane/ethyl acetate=2/1 to 1/2) to obtain the title compound (42) (128 mg, Yield 51%).
Reaction SMILES: C(OC(=O)[N:7]([S:34]([NH2:37])(=[O:36])=[O:35])[CH2:8][C@@H:9]1[CH2:13][C@@H:12]([N:14]2[C:18]3[N:19]=[CH:20][N:21]=[C:22]([NH:23][C@@H:24]4[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[CH2:26][CH2:25]4)[C:17]=3[CH:16]=[CH:15]2)[CH2:11][C@@H:10]1[OH:33])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.C1(C)C=CC=CC=1>[C@@H:24]1([NH:23][C:22]2[C:17]3[CH:16]=[CH:15][N:14]([C@@H:12]4[CH2:13][C@@H:9]([CH2:8][NH:7][S:34]([NH2:37])(=[O:36])=[O:35])[C@@H:10]([OH:33])[CH2:11]4)[C:18]=3[N:19]=[CH:20][N:21]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: CC(C)(C)OC(=O)N(C[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O)S(N)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: NS(=O)(=O)NC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Reaction time: 0.25 h

Procedure:
tert-Butyl(aminosulfonyl)[((1S,2S,4R)-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}-2-hydroxycyclopentyl)methyl]carbamate (345 mg, 0.000636 mol) was dissolved in 2:1 methylene chloride:trifluoroacetic acid (20 mL: 10 mL) and left to stand for 15 minutes at room temperature. The mixture was diluted with toluene (30 mL) and evaporated to dryness. The residue was then re-subjected to the same conditions and azeotroped with toluene after completion. The residue was purified by silica gel chromatography, eluting with 5 to 10% Methanol in dichloromethane, to yield the product, 135 mg (48%). 1H-NMR (400 MHz, MeOD) δ 8.16 (s, 1H), 7.19 (m, 5H), 6.62 (d, J=3.6 Hz, 1H), 5.85 (t, J=7.8 Hz, 1H) 5.43 (ddd, J=4.6 Hz, 8.5 Hz, 17.8 Hz, 1H), 4.46 (t, J=3.6 Hz, 1H), 3.15 (dd, J=7.1 Hz, 12.9 Hz, 1H), 3.05 (ddd, J=3.3 Hz, 8.7 Hz, 15.4 Hz, 1H), 2.91 (m, 1H), 2.63 (m, 1H), 2.33 (ddd, J=1.5 Hz, 8.0 Hz, 13.8 Hz, 1H), 2.20 (m, 2H), 2.02 (m, 2H). LC/MS: Rt=1.45 min, ES+ 443 (AA standard).
Reaction SMILES: [F:1][CH:2]([F:32])[CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[CH2:10][N:9]1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22].[H-].[Na+].[CH3:35]I>C1COCC1>[F:32][CH:2]([F:1])[CH2:3][N:4]([CH3:35])[CH2:5][CH2:6][CH2:7][C:8]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[CH2:10][N:9]1[C:21]([N:23]([CH3:25])[CH3:24])=[O:22]
Reactant: CN(C)C(=O)N1CC(c2cc(F)ccc2F)=CC1(CCCNCC(F)F)c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(CCCC1(c2ccccc2)C=C(c2cc(F)ccc2F)CN1C(=O)N(C)C)CC(F)F
Reaction time: 1 h

Procedure:
To 35 mg (0.08 mmol) of amine 19-4 in THF was added 22 mg (0.55 mmol) of NaH (60% dispersion in oil) and 24 μL (0.39 mmol) of MeI. After stirring for 1 h, the reaction was quenched with water and partitioned with EtOAc, washed with brine, dried over MgSO4, concentrated by rotary evaporation, and the residue was purified by column chromatography on silica gel with EtOAc/hexanes to provide 19-5 a colorless gum. Data for 19-5: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.2 (s, 1H), 5.8 (m, 1H), 4.9 (m, 1H), 4.7 (m, 1H), 3.0 (m, 1H), 2.8-2.7 (m, 8H), 2.55 (m, 2H), 2.35 (s, 3H), 2.1 (m, 1H), 1.5 (m, 2H) ppm. HRMS (MS) calc'd M+H for C25H29F4N3O: 464.2320. Found: 464.2320.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH:12]=[CH:13][NH:14]3)=[CH:6][CH:5]=1.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(O)(=[O:44])C>CC(O)(C)C.C(O)C.C(O)(=O)C.[Zn]>[F:20][C:2]([F:1])([F:19])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:44])[NH:14]3)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(-c2cccc3[nH]ccc23)cc1
Reactant: CC(=O)O
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(C)(C)O
Solvent: CCO
Product: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Temperature: 27 °C
Reaction time: 3 h
Yield: 39 %

Procedure:
To the suspension of 4-(4-trifluoromethoxy-phenyl)-1H-indole (4.93 g, 17.78 mmol) in t-BuOH-ethanol-acetic acid (3:2:1) (261 mL) was added pyridinium tribromide (17.06 g, 53.34 mmol)) portionwise. The mixture was stirred at 27° C. for 3 hours, and then to the mixture was added acetic acid (105 mL). Zinc dust was added to the reaction mixture portionwise until the color changed from deep red to light yellow, and the reaction mixture was stirred at room temperature for one hour. The unreacted zinc dust was filtered off and washed with ethanol. The filtrate was concentrated, and the syrupy residue was dissolved in ethyl acetate, which was washed with water, 0.5 N HCl, sat. NaHCO3 and brine, and dried over Na2SO4. After filtration and evaporation, the crude product was triturated with diethyl ether to provide product 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (2.05 g, 39%) as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1F.[CH:10]1([CH:13]([OH:25])[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]1.[H-].[Na+].O>CS(C)=O>[CH:10]1([CH:13]([O:25][C:3]2[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:14][CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:12][CH2:11]1
Reactant: CN(CCC(O)C1CC1)C(=O)OC(C)(C)C
Reactant: Fc1cc(Cl)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(CCC(Oc1cc(Cl)ccc1Cl)C1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.8 %

Procedure:
1,4-Dichloro-2-fluorobenzene (165 mg, 1.00 mmol) and (3-cyclopropyl-3-hydroxypropyl)methylcarbamic acid, 1,1-dimethylethyl ester (230 mg, 1.00 mmol) were dissolved in dimethylsulfoxide (10 ml) under nitrogen at room temperature. To the resulting solution was added sodium hydride (60% in oil) (80 mg, 2.00 mmol). The solution was then allowed to stir at room temperature under nitrogen for 24 h. The mixture was then poured into water and extracted with diethyl ether three times. The combined organic fractions were washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue eluted down a flash chromatography column using 10% ethyl acetate/isohexane as eluent to give 175 mg (47%) of the title compound as an oil.
Reaction SMILES: C(N=C=NCCCN(C)C)C.[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16]([NH:18][C:19](=S)[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17].[NH2:36][C:37]1[CH:38]=[C:39]([OH:43])[CH:40]=[N:41][CH:42]=1.CN(C)C=O>C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([CH:32]=[CH:33][C:34]=1[F:35])[C:16](/[N:18]=[C:19](\[NH:36][C:37]1[CH:42]=[N:41][CH:40]=[C:39]([OH:43])[CH:38]=1)/[NH:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1)=[O:17]
Reactant: Nc1cncc(O)c1
Reactant: O=C(NC(=S)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(/N=C(\Nc1cncc(O)c1)Nc1cccc(C(F)(F)F)c1)c1ccc(F)c(F)c1
Temperature: 65 °C

Procedure:
N1-((Ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (43 mg, 0.278 mmol), 3,4-difluoro-N-((3-(trifluoromethyl)phenyl)carbamothioyl)benzamide (100 mg, 0.278 mmol) and 5-aminopyridin-3-ol (31 mg, 0.278 mmol) and were combined in a glass vial and dry dimethylformamide (1.5 mL) was added. The vial was capped and the mixture was heated at 65° C. for 2 h. After cooling the mixture to room temperature, the mixture was diluted with ethyl acetate and washed with water then brine. The organic layer was evaporated onto silica gel and the product was purified by chromatography eluting with 50-100% ethyl acetate in hexanes to give (Z)-3,4-difluoro-N-(((5-hydroxypyridin-3-yl)amino)((3 (trifluoromethyl)phenyl)amino)methylene)benzamide as a colorless oil.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][NH2:13]>O.Cl>[CH3:12][NH:13][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: Cl
Solvent: O
Product: CNc1cc(O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 95 %

Procedure:
The solution of 3-fluoro-4-nitrophenol (1 g, 6.37 mmol) in aqueous MeNH2 solution (5 mL) was stirred at 85° C. for 5 h. After cooling to room temperature, the solution was diluted with water (30 mL) and concentrated HCl added to adjust to pH 1. The resulting precipitate was collected by filtration and the solid dried under vacuum to give the crude product which was used without further purification (1.1 g, 95% yield). LCMS (m/z): 169.1 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:18])[CH2:9][C:10]([N:12]([CH2:14][C:15]([OH:17])=O)[CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[N+:43]([C:46]1[CH:54]=[C:53]2[C:49]([CH:50]=[CH:51][NH:52]2)=[CH:48][CH:47]=1)([O-:45])=[O:44]>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:18])[CH2:9][C:10](=[O:11])[N:12]([CH3:13])[CH2:14][C:15]([N:52]1[C:53]2[C:49](=[CH:48][CH:47]=[C:46]([N+:43]([O-:45])=[O:44])[CH:54]=2)[CH:50]=[CH:51]1)=[O:17])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: CN(CC(=O)O)C(=O)CN(C)C(=O)OC(C)(C)C
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(CC(=O)n1ccc2ccc([N+](=O)[O-])cc21)C(=O)CN(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 30 %

Procedure:
To a mixture of {[2-(tert-butoxycarbonyl-methyl-amino)-acetyl]-methyl-amino}-acetic acid (13.8 g, 53 mmol) and TFFH (21.0 g, 79.5 mmol) in anhydrous THF (125 mL) was added DIEA (27.7 mL, 159 mmol) at room temperature under nitrogen. The solution was stirred at room temperature for 20 min. A solution of 6-nitroindole (8.6 g, 53 mmol) in THF (75 mL) was added and the reaction mixture was heated at 60° C. for 18 h. The solvent was evaporated and the crude mixture was re-partitioned between EtOAc and water. The organic layer was separated, washed with water (×3), dried over Na2SO4 and concentrated. Diethyl ether followed by EtOAc was added. The resulting solid was collected via filtration, washed with diethyl ether and air dried to yield methyl-({methyl-[2-(6-nitro-indol-1-yl)-2-oxo-ethyl]-carbamoyl}-methyl)-carbamic acid tert-butyl ester (6.42 g, 30%). 1H NMR (400 MHz, DMSO-d6) δ 1.37 (m, 9H), 2.78 (m, 3H), 2.95 (d,J=1.5 Hz, 1H), 3.12 (d,J=2.1 Hz, 2H), 4.01 (d,J=13.8 Hz, 0.6H), 4.18 (d,J=12.0 Hz, 1.4H), 4.92 (d,J=3.4 Hz, 1.4H), 5.08 (d,J=11.4 Hz, 0.6H), 7.03 (m, 1H), 7.90 (m, 1H), 8.21 (m, 1H), 8.35 (d,J=3.8 Hz, 1H), 9.18 (m, 1H); HPLC ret. time 3.12 min, 10-99% CH3CN, 5 min run; ESI-MS 405.5 m/z (MH+).
Reaction SMILES: [S:1]1[C:5]([CH:6]([O:11][CH3:12])[C:7](OC)=[O:8])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2.O.[NH2:18][NH2:19]>C(O)C>[S:1]1[C:5]([CH:6]([O:11][CH3:12])[C:7]([NH:18][NH2:19])=[O:8])=[CH:4][C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]1=2
Reactant: COC(=O)C(OC)c1cc2ccccc2s1
Reactant: NN
Solvent: CCO
Solvent: O
Product: COC(C(=O)NN)c1cc2ccccc2s1
Temperature: 50 °C
Yield: 104.1 %

Procedure:
To a solution of methyl 2-(benzo[b]thiophen-2-yl)-2-methoxyacetate (0.174 g, 0.74 mmol) in absolute ethanol (3 mL) was added hydrazine hydrate (0.14 mL, 2.87 mmol) and the mixture was heated at 50° C. for 20 hours. After cooling to room temperature, the solution was concentrated in vacuo. The residue was dissolved in EtOAc and washed with water and brine, dried over Na2SO4 and concentrated in vacuo to give 2-(benzo[b]thiophen-2-yl)-2-methoxyacetohydrazide as a colorless oil (0.182 g, quantitative yield).
Reaction SMILES: [CH:1]([NH:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].C([Li:15])CCC.C(N(CC)C(=O)C=C(C)C)C.BrC1(OC)C=CC(Br)=CC1>C1COCC1>[CH:1]([N-:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].[Li+:15]
Reactant: CC(C)NC1CCCCC1
Reactant: [Li]CCCC
Agent: CCN(CC)C(=O)C=C(C)C
Agent: COC1(Br)C=CC(Br)=CC1
Solvent: C1CCOC1
Product: CC(C)[N-]C1CCCCC1
Product: [Li+]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
In a 250 mL round bottomed flask a solution of lithiumisopropylcyclohexylamide was prepared from isopropylcyclohexylamine (6.21 g, 7.23 mL, 44 mmol) in THF (50 mL) and butyllithium (2.5M in hexane, 17.6 mL, 44 mmol). The solution was cooled to -78° C. under nitrogen and N,N-diethyl-3,3-dimethylacrylamide [109] (3.10 g, 20 mmol) in THF (20 mL) was added. After stirring for 30 min at -78° C., the solution was warmed to room temperature and stirred for 5 h. The reaction mixture was then cooled to -78° C., and 1,4-dibromoanisole [112] (5.852 g, 22 mmol) in THF (30 mL) was added via syringe. The solution was stirred at 0° C. for 24 h and then quenched with saturated aqueous ammonium chloride (100 mL) and diluted with ether (30 mL). The organic layer was separated and the aqueous layer was extracted with ether (3×40 mL). The combined organic layers were washed with brine (40 mL), dried with sodium sulfate and concentrated in vacuo to give 4.60 g of crude material. Flash chromatography of the crude material (hexane/ethyl acetate; 9:1) yielded product 113 (1.17 g, 22%) as a light yellow oil.