Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=3[N+:27]([O-])=O)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].O1CCC[CH2:33]1.COC(OC)OC>[Zn].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([N:16]3[C:17]4[CH:22]=[C:21]([CH:23]=[O:24])[C:20]([O:25][CH3:26])=[CH:19][C:18]=4[N:27]=[CH:33]3)[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: COc1cc([N+](=O)[O-])c(Nc2nc(-c3cccc(Cl)c3)c(C(N)=O)s2)cc1C=O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: COC(OC)OC
Product: COc1cc2ncn(-c3nc(-c4cccc(Cl)c4)c(C(N)=O)s3)c2cc1C=O
Temperature: 25 °C

Procedure:
To a suspension of 0.100 g (0.23 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-4-methoxy-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.46b), 3 mL of saturated ammonium chloride solution and 3 mL of tetrahydrofuran was added 0.100 g of zinc powder. The mixture was stirred room temperature until the organic layer became straw yellow in color (1 hour). The mixture was filtered, and the filtrate was partitioned between 30 mL of saturated ammonium chloride solution and 30 mL of tetrahydrofuran. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give a red solid. The solid was stirred at room temperature with 5 mL of glacial acetic acid and 0.05 mL of trimethylorthoformate for 1 hour and then concentrated under reduced pressure. The residue was partitioned between 50 mL of ethyl acetate and 50 ml, of potassium carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.053 g of 4-(3-chloro-phenyl)-2-(6-formyl-5-methoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid amide (I.46a) as a yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[S:51]([NH2:55])([NH2:54])(=[O:53])=[O:52].C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14](=[O:38])[CH:15]([C:29]2[CH:34]=[CH:33][C:32]3[O:35][CH2:36][O:37][C:31]=3[CH:30]=2)[O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[O:24])[NH:54][S:51](=[O:53])(=[O:52])[NH2:55])=[CH:19][C:18]=2[CH2:26][CH2:27][CH3:28])(=[O:11])=[O:12])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CCCc1cc(C(=O)O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Reactant: NS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCCc1cc(C(=O)NS(N)(=O)=O)ccc1OC(C(=O)NS(=O)(=O)c1ccc(C(C)C)cc1)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.6 %

Procedure:
A solution of 158 mg (0.293 mmol) of N-(4-iso-propylbenzenesulfonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide (free acid form of the product of Example 58) and 71 mg (0.440 mmol) of 1,1'-carbonyldiimidazole in 1 mL of dry tetrahydrofuran was refluxed for 3.5 hours. The reaction mixture was cooled to room temperature and 141 mg (1.47 mmol) of sulfamide and 110 μL (0.733 mmol) of DBU were added and the mixture was refluxed again. The reaction progress was monitored by analytical HPLC analysis using a Waters 600E HPLC system with a 4.6×250 mm 5 μM Zorbax-RX C8 at 40° C. and eluting isocratically 1.5 mL/min using 60% A (95-5 acetonitrile-water) 40% B (95-5 water-acetonitrile) each with 0.1% TFA where the column effluent was monitored at 254 nM with a Waters model 490 UV-visible detector. After 2.0 hour of additional refluxing, analytical HPLC analysis indicated that the coupling was complete. The reaction mixture was diluted with 2.5 mL of methanol and 2 mL of water, filtered and the filtrate partially purified was purified using a Varian 5500 HPLC by applying the compound in a 4.5 mL total volume (2.5 mL methanol and 2 mL water) onto two in series 21.2×250 mm Zorbax ODS C18 columns and eluting at 15 mL/min with 60% acetonitrile and 40% water both with 0.1% TFA. The column effluent was monitored 254 nM with a Kratos Spectroflow 783 UV detector. Combination and evaporation of the purified fractions afforded 50 mg (28%) of the title compound. The mixed fractions were combined and subjected to a second preparative HPLC chromatography using a linear gradient over 35 minutes from 65% water and 35% acetonitrile both with 0.1% TFA to 65% acetonitrile and 35% water both with 0.1% TFA, holding all other conditions from the previous chromatography. The purified fractions were combined and concentrated to afford 57 mg (31%) of the title compound, which was combined with the previously purified material to provide a total of 107 mg (59%) of the title compound as an amorphous solid.
Reaction SMILES: C1(S([CH2:10][C:11]2[N:15]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=3[F:23])[NH:13][N:12]=2)(=O)=O)C=CC=CC=1.[N:24]1[CH:29]=[CH:28][C:27](/[CH:30]=[CH:31]\[C:32]#[N:33])=[CH:26][CH:25]=1>>[F:23][C:17]1[CH:18]=[C:19]([F:22])[CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]2[CH:10]=[C:30]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)[CH:31]=[C:32]([NH2:33])[N:12]2[N:13]=1
Reactant: N#C/C=C\c1ccncc1
Reactant: O=S(=O)(Cc1n[nH]c(-c2ccc(F)cc2F)n1)c1ccccc1
Product: Nc1cc(-c2ccncc2)cc2nc(-c3ccc(F)cc3F)nn12

Procedure:
The title compound, MS m/e (%): 323 (M+, 100), 303 (60), was prepared in accordance with the general method of example 1 from 3-benzenesulfonylmethyl-5-(2,4-difluoro-phenyl)-1H-[1,2,4]triazole and (E)/(Z)-3-pyridin-4-yl-acrylonitrile.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]2[N:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:2]1.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([NH:30][C:31]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]3[N:13]=[C:12]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)[CH:11]=[CH:10][N:9]=3)[CH2:2]2)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(C(=O)Nc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.7 %

Procedure:
To a suspension of 15 mg of 2-[(piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (from EXAMPLE 6) in 2 mL of THF was added 7.6 mg of phenyl isocyanate. The mixture was stirred at room temperature overnight. An additional 7.6 mg of phenyl isocyanate was added and the mixture was stirred for an additional 24 h, then concentrated. The residue was purified by flash chromatography, eluting with 1:1 hexanes-acetone, to yield 12 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 8.61 (s, 1H), 8.37 (d, J=5.3, 1H) 8.17 (d, J=7.3 Hz, 1H), 7.36-7.44 (m, 2H), 7.22-7.34 (m, 3H), 7.00 (t, J=7.3 Hz, 1H), 6.78 (d, J=5.3 Hz, 1H), 6.52 (s, 1H), 5.75 (br s, 1H), 3.97 (dd, J=3.4, 13.0 Hz, 1H), 3.77 (dt, J=4.4, 13.0 Hz, 1H), 3.41-3.57 (m, 2H), 3.14 (br t, J=10.5 Hz, 1H), 3.02 (dd, J=8.9, 13.3 Hz, 1H), 1.92-2.08(m, 2H), 1.72-1.84 (m, 1H), 1.53-1.64 (m, 1H), 1.41 (ddt, J=3.9, 9.8, 10.1 Hz, 1H). Mass spectrum (EST) 428.2 (M+1).
Reaction SMILES: O[CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:13](=[O:28])[C:14]2[C:19]([S:20][CH3:21])=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:15]=2[O:26][CH3:27])[CH2:3]1.COCCN(S(F)(F)[F:39])CCOC>>[F:39][CH:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:13](=[O:28])[C:14]2[C:19]([S:20][CH3:21])=[CH:18][C:17]([C:22]([F:25])([F:24])[F:23])=[CH:16][C:15]=2[O:26][CH3:27])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(O)C1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1CCCC1N1CCC(F)C1

Procedure:
The title compound, light yellow solid, MS: m/e=421.1 [(M+H)+], was prepared in accordance with the general method of example 17 from N-[(1RS,2SR)-2-(3-hydroxy-pyrrolidin-1-yl)-cyclopentyl]-2-methoxy-6-methylsulfanyl-4-trifluoromethyl-benzamide (example 63) and bis(2-methoxyethyl)aminosulfur trifluoride. The two diastereomers were not separated.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19]O)=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:44]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][Br:44])=[C:15]([CH:21]([CH3:23])[CH3:22])[CH:14]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C#Cc2ccc(CO)c(C(C)C)c2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C#Cc2ccc(CBr)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of methyl[4-(4-hydroxymethyl-3-isopropyl-phenylethynyl)-phenyl]-acetate (Compound 123, 180.0 mg, 0.56 mmol) and triphenylphosphine (190.0 mg, 0.73 mmol) in 5 mL CH2Cl2 was cooled to 0° C. and N-bromosuccinimide (130.0 mg, 0.73 mmol) was added in 5 portions over 20 minutes. The solution was warmed to 25° C. and stirred for 17 hours. The reaction was quenched by the addition of dilute aqueous NaHCO3. The resulting mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (Na2SO4) and concentrated under reduced pressure. The title compound, 212.0 mg (98%), was isolated by column chromatography (5-10% EtOAc-hexanes) as a pale-yellow oil.
Reaction SMILES: [CH:1]1([N:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][C:16]=3[O:23]C)=[C:13]3[C:8]([C:9]([F:25])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C1CCCCC=1>>[CH:1]1([N:6]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=3[OH:23])=[C:13]3[C:8]([C:9]([F:25])=[CH:10][CH:11]=[CH:12]3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)c(OC)c1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Product: Oc1ccc(-c2c3cccc(F)c3nn2C2CCCC2)c(O)c1
Yield: 44.5 %

Procedure:
Prepared according to Method D step C from 2-cyclopentyl-3-(2,4-dimethoxyphenyl)-7-fluoro-2H-indazole (0.062 g, 0.18 mmol), boron tribromide (0.12 mL, 1.2 mmol) and 1.0 mL of cyclohexene to give the product (0.025 g) as a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[C:5](=O)[CH2:6][C:7]#[N:8].O.[NH2:11][NH2:12]>C(O)C>[CH3:1][C@H:2]1[CH2:4][C@H:3]1[C:5]1[CH:6]=[C:7]([NH2:8])[NH:12][N:11]=1
Reactant: NN
Reactant: CC1CC1C(=O)CC#N
Solvent: O
Solvent: CCO
Product: C[C@H]1C[C@H]1c1cc(N)[nH]n1
Temperature: 80 °C
Yield: 27.7 %

Procedure:
3-(2-Methylcyclopropyl)-3-oxopropanenitrile (0.240 g, 1.95 mmol) was dissolved in dry ethanol (3 mL). Hydrazine monohydrate (0.728 mL, 9.75 mmol) was added, and the reaction mixture was heated to 80° C. for 20 minutes. The reaction mixture was then cooled to room temperature and concentrated. Silica gel chromatography (5% MeOH/DCM) provided a mixture of cis and trans isomers which were separated by chiral HPLC providing 3-(cis-2-methylcyclopropyl)-1H-pyrazol-5-amine (74 mg, 28% for two steps) as an oil.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[C:12]([F:13])=[C:11](F)[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].Cl>O>[F:3][C:4]1[C:12]([F:13])=[C:11]([NH:2][CH3:1])[C:10]([N+:15]([O-:17])=[O:16])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(F)c(F)c1F
Agent: Cl
Solvent: O
Product: CNc1c([N+](=O)[O-])cc(C(=O)O)c(F)c1F
Reaction time: 3 h

Procedure:
A mixture of methylamine (40% aq solution, 0.68 mL, 6.7 mmol), 2,3,4-trifluoro-5-nitro-benzoic acid (0.50 g, 2.3 mmol) and 5 mL water is stirred for 3 h in an ice bath. Then the mixture is acidified with 6M aq HCl and the resulting precipitate is collected by filtration washed with water and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]2[N:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[C:10]2=[O:30])[CH:6]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:3]=[N:4][N:5]([CH2:7][CH2:8][N:9]3[N:18]=[CH:17][C:16]4[C:11](=[CH:12][C:13]([C:19]5[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=5)=[CH:14][CH:15]=4)[C:10]3=[O:30])[CH:6]=2)=[CH:35][N:34]=1
Reactant: O=c1c2cc(-c3ccc(OC(F)(F)F)cc3)ccc2cnn1CCn1cc(Br)cn1
Reactant: COc1ncc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ncc(-c2cnn(CCn3ncc4ccc(-c5ccc(OC(F)(F)F)cc5)cc4c3=O)c2)cn1
Temperature: 85 °C

Procedure:
A mixture of 2-(2-(4-bromo-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one (35 mg, 0.073 mmol), 2-methoxypyrimidin-5-ylboronic acid (13 mg, 0.087 mmol), dppf(Pd)Cl2 (2.7 mg, 0.0037 mmol), potassium carbonate (20 mg, 0.015 mmol) in degassed toluene (1 mL), degassed water (0.5 mL) and degassed isopropanol (0.5 mL) was heated at 85° C. for 3 hours. The layers were separated, the organic layer was concentrated and the residue was purified by reverse phase HPLC to provide 2-(2-(4-(2-methoxypyrimidin-5-yl)-1H-pyrazol-1-yl)ethyl)-7-(4-(trifluoromethoxy)phenyl)phthalazin-1(2H)-one as a white powder. C25H19F3N6O3. 509.2 (M+1). 1H NMR (DMSO) δ 8.74 (s, 1H), 8.38-8.44 (m, 2H), 8.26 (dd, J=2.0, 8.0 Hz, 1H), 8.20 (s, 1H), 8.03 (d, J=8.4 Hz, 1H), 7.94 (d, J=8.8 Hz, 2H), 7.84 (s, 1H), 7.51 (d, J=8.4 Hz, 2H), 4.56 (s, 4H), 3.87 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH2:25][CH3:26])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH3:29])[S:22]([CH2:25][CH3:26])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CCS(=O)(=O)NC1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCS(=O)(=O)N(C)C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Analogously to Example 1f, 8.6 g (23 mmol) of 6-benzyloxy-4-(ethylsulfonyl)amino-2,2-dimethylchroman were introduced in portions into a suspension of 1 g (25 mmol) of sodium hydride (60% dispersion) in 75 ml of DMA at 10° C. After stirring at RT for 2 h, 1.6 ml (25 mmol) of methyl iodide were added dropwise, the temperature rising to 40° C. The mixture was then heated to 35-45° C. for 2 h, and concentrated in vacuo, the residue was treated with water, the resinous product was taken up with EA, the solution was dried and concentrated, and the residue was chromatographed using n-heptane/EA (1:1) on silica gel. 7.4 g of product were crystallized from appropriate fractions using petroleum ether/diisopropyl ether, m.p. 91-93° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12](CC4C=CC=CC=4F)[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[CH:6][CH:7]=1.Br[CH2:34][C:35]1[C:36]([CH3:46])=[N:37][O:38][C:39]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:34][C:35]4[C:36]([CH3:46])=[N:37][O:38][C:39]=4[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[CH2:11]3)[C:9](=[O:24])[N:8]([CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:5]2=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccccc2)c1CBr
Reactant: CC(C)(C)OC(=O)CN1C(=O)C2(CC(=O)N(Cc3ccccc3F)C2)c2cc(Cl)ccc21
Product: Cc1noc(-c2ccccc2)c1CN1CC2(CC1=O)C(=O)N(CC(=O)OC(C)(C)C)c1ccc(Cl)cc12
Yield: 53 %

Procedure:
Following the general method as outlined for Intermediate 33, starting from tert-butyl (5-chloro-2,5′-dioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate (intermediate 32) and 4-(bromomethyl)-3-methyl-5-phenylisoxazole, the title compound was isolated, after purification by chromatography (silica) eluting with cyclohexane containing increasing amounts of ethyl acetate (10 to 50%), as a white solid in 53% yield (HPLC purity 89%). MS (ESI+): 522.4; MS (ESI−):520.1
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH:4]([NH2:27])[CH2:5][NH:6][C:7]([N:9]1[CH2:26][CH2:25][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[CH2:36]([O:43][C:44](Cl)=[O:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(=O)([O-])O.[Na+]>ClCCl>[CH3:1][O:2][C:3](=[O:28])[CH:4]([NH:27][C:44]([O:43][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:45])[CH2:5][NH:6][C:7]([N:9]1[CH2:10][CH2:11][C:12]2([N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:15][N:14]([CH3:23])[C:13]2=[O:24])[CH2:25][CH2:26]1)=[O:8]
Reactant: COC(=O)C(N)CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(CNC(=O)N1CCC2(CC1)C(=O)N(C)CN2c1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.3 %

Procedure:
To a solution of 288 mg (0.74 mmol) of 2-amino-3-((3-methyl-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester in 4 ml of dichloromethane, 0.21 ml (1.48 mmol) of triethylamine and 0.1 ml (0.89 mmol) of benzyloxycarbonyl chloride were added, and the resulting mixture was stirred at room temperature for one day. To the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and the resulting mixture was extracted with chloroform. Organic phases were combined, washed with 10% aqueous citric acid solution and with saturated saline, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (chloroform:methanol=60:1) to obtain 284 mg of 2-benzyloxycarbonylamino-3-((3-methyl-4-oxo-1-phenyl-1,3,8,-triazaspiro[4.5]decane-8-carbonyl)amino)propionic acid methyl ester (yield: 73%)
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50]O)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.P(Br)(Br)[Br:59]>CCOCC>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][CH:10]1[C:40]1[C:48]2[O:47][CH2:46][CH2:45][C:44]=2[C:43]([Cl:49])=[C:42]([CH2:50][Br:59])[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c(c1Cl)CCO2
Solvent: CCOCC
Solvent: c1ccncc1
Product: Clc1c(CBr)cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)c2c1CCO2
Temperature: 25 °C
Reaction time: 20 h
Yield: 212.3 %

Procedure:
To a solution of compound 48 (578 mg, 0.81 mmol) in Et2O (14 mL) was added pyridine (0.007 mL, cat.) and phosphorus tribromide (0.038 mL, 0.40 mmol) at 0° C. under an atmosphere of nitrogen. After being stirred for 20 hours at room temperature, the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide the crude product 49 (654 mg) as yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1F.[OH-].[Na+].[O:14]1[CH2:18][CH2:17][CH2:16][CH:15]1[CH2:19][OH:20].Cl>CS(C)=O.O>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:20][CH2:19][CH:15]1[CH2:16][CH2:17][CH2:18][O:14]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: OCC1CCCO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCC2CCCO2)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an ice cold solution of 2-bromo-1-fluoro-4-nitro-benzene (5.0 g, 22.72 mmol) in DMSO (40 mL) was added NaOH (1.36 g, 34.09 mmol) and (tetrahydrofuran-2-yl)methanol (3.47 g, 34.09 mmol) at 0° C. The mixture was stirred at RT for 1 h, then poured into H2O (50 mL), the pH adjusted ˜7 with 1M HCl and extracted with EtOAc (2×250 mL). The combined organics were washed with H2O, brine, dried (Na2SO4), filtered and concentrated in vacuo to obtain i (6.50 g, 95%). 1HNMR (CDCl3, 400 MHz): δ 8.46 (d, J=2.40 Hz, 1H), 8.20 (dd, J=2.40 and 9.20 Hz respectively, 1H), 6.98 (d, J=9.20 Hz, 1H), 4.36 (m, 1H), 4.16 (m, 2H) 3.97 (m, 1H) 3.86 (m, 1H) 2.07 (m 2H) and 1.95 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.OS(O)(=O)=O.[N+:19]([O-])([OH:21])=[O:20].[OH-].[Na+]>>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:19]([O-:21])=[O:20])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: O=[N+]([O-])O
Reactant: CN1CCC(c2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CN1CCC(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To 1-methyl-4-phenylpiperidine (2.663 g, 15.19 mmol) was added carefully H2SO4 (15.2 ml). The reaction was cooled in an ice bath and a solution of H2SO4 (1.66 ml) and fuming HNO3 (0.67 ml, 15.95 mmol) was added dropwise over 45 min. The mix was stirred at 0° C. for 3 h then at RT for 1.5 h before being poured over about 90 g ice and basified with 24 g solid NaOH. The mix was extracted with CH2Cl2. The organic layer was washed with H2O, dried over Na2SO4, and concentrated in vacuo. The crude was eluted on a silica gel column with a MeOH/CH2Cl2 gradient to yield 1-methyl-4-(4-nitrophenyl)piperidine which was hydrogenated under H2 to furnish the title compound.
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]([OH:21])=O)[CH:17]=2)[CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C([O:29][N:30]1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NO>CN(C=O)C.C(OCC)(=O)C>[OH:29][NH:30][C:19]([C:16]1[CH:17]=[C:18]2[C:13]([CH:12]=[CH:11][N:10]2[CH2:9][CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:15]=1)=[O:21]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1ccc2ccn(CCOc3ccccc3)c2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NO)c1ccc2ccn(CCOc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 146.8 %

Procedure:
To a solution of 1(2-phenoxyethyl)-1H-indole-6-carboxylic acid (0.66 g, 1.31 mmol) and TEA (0.92 mL, 6.6 mmol) in DMF (10 mL) was added HATU (0.52 g, 1.37 mmol). The solution was stirred 1 hr at room temperature, then NH2OH (50% wt/wt in H2O; 2 mL) was added and the solution was stirred 1 hr. The reaction solution was then diluted with ethyl acetate (150 mL) and washed with 1N HCl (100 mL) and then aq. NaHCO3 (100 mL). Then organic layer was dried (MgSO4), filtered and then concentrated to provide 0.57 g (93%) of N-hydroxy-1-(2-phenoxyethyl)-1H-indole-6-carboxamide a light yellow solid. 1H NMR (300 MHz, DMSO) δ 11.11 (s, 1H), 8.94 (s, 1H), 8.06 (s, 1H), 7.56 (m, 2H), 7.66 (dd, 1H, J=8.5 Hz, J=1.5 Hz), 7.24 (m, 2H), 6.88 (m, 3H), 6.48 (d, 1H, J=3.0 Hz), 4.61 (t, 2H, J=5.2 Hz), 4.30 (t, 2H, J=5.2 Hz). EM (calc.): 296.12; MS (M+H): 297.06.