Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C>ClCCl.Cl>[Cl:17][C:15]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH:16]=1
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Cl)cc1NS(C)(=O)=O
Temperature: 2.5 °C
Reaction time: 0.17 h

Procedure:
A solution of methanesulphonyl chloride (6.3 g) in dichloromethane was added to a stirred, cooled (0-5° C.) solution of methyl 2-amino-4-chlorobenzoate (9.5 g) in dichloromethane. Triethylamine (7.1 g) was then added and the mixture was stirred at 0-5° C. for 10 minutes and then at room temperature for 0.5 hours. The mixture was diluted with 2N hydrochloric acid. The organic phase was separated, washed with water, dried and evaporated. The crude product was purified by column chromatography to yield methyl 4-chloro-2-(N-methylsulphonylamino)benzoate as a white solid, (3.6 g) m.p. 125.5-128.1° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:20](OCC1C=CC=CC=1)(=[O:22])[CH3:21]>C1COCC1>[CH3:9][S:8][C:4]1[N:3]=[C:2]([CH2:1][C:20](=[O:22])[CH3:21])[CH:7]=[CH:6][N:5]=1
Reactant: CSc1nccc(C)n1
Reactant: CC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1nccc(CC(C)=O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.5 %

Procedure:
To a solution of 4-Methyl-2-(methylthio)pyrimidine (1) (3 g, 21.40 mmol) in THF (35.7 mL) at −10° C. was added LHMDS (32.1 mL, 32.1 mmol, 1M in THF). The resulting reaction was warmed to rt and stirred for 15 minutes, after which time the reaction was cooled back to −10° C. and Benzyl Acetate (3.21 mL, 23.54 mmol) was added. The reaction was then warmed to rt and stirred for 1 hour, after which time complete conversion to product was observed by LCMS. TLC after 1 hour still showed the presence of some starting material and the reaction was continued stirring for an additional hour. After this time there was no change in TLC and the reaction was worked up. The reaction was quenched by slow addition of saturated ammonium chloride and the volatile solvent evaporated. The mixture was then diluted with EtOAc and water. The organic layer was then washed with brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 8-66% EtOAc in Heptane to give the desired product as a yellow liquid (1.93 g, 50%). MS (ES+): m/z=183.1 (100) [MH+]. HPLC: tR=0.91 minute over 3 minutes. Purity: 76% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C[Si](C)(C)[CH2:13][C:14]([O:16][CH3:17])=[O:15].[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33][C:34]2=O)=[CH:30][CH:29]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C1COCC1>[CH2:20]([O:27][C:28]1[CH:36]=[C:35]2[C:31]([CH2:32][CH2:33]/[C:34]/2=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])=[CH:30][CH:29]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CCc2ccc(OCc3ccccc3)cc21
Reactant: COC(=O)C[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)/C=C1\CCc2ccc(OCc3ccccc3)cc21
Temperature: -78 °C
Yield: 38 %

Procedure:
At −78° C., lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (4 mL, 26 mmol) was added slowly to a solution of methyl 2-(trimethylsilyl)acetate (4 g, 26 mmol) in THF (20 mL). The reaction mixture was maintained at −78° C. for 22 minutes. 1.2 (3.5 g, 15 mmol) in THF (20 mL) was then added slowly to the mixture. The mixture was stirred at −78° C. and allowed to warm to room temperature overnight. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc (300 mL). The organic layers were washed with brine and dried over anhydrous sodium sulfate. After removing solvent by rotary evaporation, the residue was purified by column chromatography (1:4 EtOAc/hexane). The Product 1.3 was obtained in 38% yield as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=1.[F:15][C:16]([F:39])([F:38])[CH2:17][CH2:18][C@@H:19](OS(C(F)(F)F)(=O)=O)[C:20]([O:22]CC1C=CC=CC=1)=[O:21]>>[C:11]([O:10][C:8](=[O:9])[C@H:7]([C@@H:19]([CH2:18][CH2:17][C:16]([F:39])([F:38])[F:15])[C:20]([OH:22])=[O:21])[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(OCc1ccccc1)[C@@H](CCC(F)(F)F)OS(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Cc1cccnc1
Product: CC(C)(C)OC(=O)[C@@H](c1cccnc1)[C@@H](CCC(F)(F)F)C(=O)O

Procedure:
Intermediate S-3 was synthesized from tert-butyl 2-(pyridin-3-yl)acetate (100 mg, 0.517 mmol) and (R)-benzyl 5,5,5-trifluoro-2-(trifluoromethylsulfonyloxy)pentanoate (245 mg, 0.621 mmol) using the procedure described for Intermediate S-2 to give Intermediate S-3 (60 mg, 0.173 mmol) as a white solid containing about 30% of the (R, S) isomer. MS(ES):m/z=483.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[C:9]([O:12][CH3:13])[CH:8]=[CH:7]2.[Li]CCCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][C:29]([OH:32])([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[N:10]=3)[N:5]=[CH:4][CH:3]=2)[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: COc1ccc2nccc(Br)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc2nccc(C3(O)CCN(C(=O)OC(C)(C)C)CC3)c2n1
Temperature: -78 °C
Yield: 66.6 %

Procedure:
To a solution of 8-bromo-2-methoxy-[1,5]naphthyridine (1 g, 4.18 mmol, prepared as in WO 2006/032466) in dry THF (20 mL) at −78° C. was added dropwise n-BuLi (2.5 M in hex, 5 mL, 1.2 eq). The mixture was stirred at −78° C. for 1 h before the dropwise addition of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (0.833 g, 4.2 mmol) in THF (5 mL). The mixture was stirred at −78° C. for another h and then slowly warmed to rt. The mixture was quenched by the addition of sat. aq. NH4Cl solution (10 mL) and extracted with EA. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by CC (hex/EA 1:1 to EA) to give the desired intermediate (1.0 g, 66.5%) as yellow oil.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[C:10]([CH3:16])([CH3:15])[C:11]([O:13][CH3:14])=[O:12]>>[CH3:15][C:10]([O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1)([CH3:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: Cc1cccc(O)c1
Reactant: COC(=O)C(C)(C)Br
Product: COC(=O)C(C)(C)Oc1cccc(C)c1

Procedure:
The title compound was prepared following the same protocol as described in Step 1, Example 36, using the m-cresol instead of the p-cresol and the methyl α-bromoisobutyrate instead of the methyl bromoacetate.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[C:18](=[O:21])([O-])[O-].[Na+].[Na+].CO>C(Cl)Cl.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>[O:21]=[C:18]1[NH:8][CH:7]=[C:6]([C:2]2[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][CH:3]=2)[CH:5]=[CH:4]1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)NCCc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NCCc1ccc(-c2ccc(=O)[nH]c2)cc1
Temperature: 90 °C
Yield: 117.1 %

Procedure:
IMS (600 mL) and water (250 mL) were degassed thoroughly. tert-Butyl 4-bromophenethylcarbamate (32.7 g, 109 mmol), sodium carbonate (46.2 g, 436 mmol), palladium tetrakis (12.6 g, 11.0 mmol) and 2-methoxypyridine boronoic acid (25.0 g, 163 mmol) were added and the reaction mixture heated to 90° C. for 18 hours. The reaction was cooled to room temperature, filtered and the residue washed with IMS (100 mL) and ethyl acetate (1 L). The filtrate was washed with water (500 mL), dried (MgSO4) and concentrated to give a brown solid. The crude residue was subject to column chromatography (0 to 1.5% MeOH in DCM) to give a white solid, tert-butyl 4-(6-oxo-1,6-dihydropyridin-3-yl)phenethylcarbamate (20.95 g, 63.8 mmol, 58% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[C:15]2=[O:29])=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[C:15]2=[O:29])=[CH:11][CH:12]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(N)cc3)c2=O)cc1

Procedure:
3-{4-[3-(4-Nitrophenyl)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}propionic acid ethyl ester (P7, 300 mg, 0.74 mmol) and palladium on charcoal (30 mg) were stirred at room temperature in ethanol (10 mL) under atmospheric pressure of hydrogen for 3 hours, then the reaction mixture was filtered through celite and concentrated. The crude oil was purified by chromatography on silica gel (50% v/v ethyl acetate in petroleum ether) to afford the title compound as an oil.
Reaction SMILES: CS[C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1.[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH2:18]>C(O)C>[F:15][C:16]1[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=1[NH:18][C:3]1[NH:4][C:5](=[O:14])[C:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][N:8]=1
Reactant: Nc1ccccc1F
Reactant: CCOC(=O)c1cnc(SC)[nH]c1=O
Solvent: CCO
Product: CCOC(=O)c1cnc(Nc2ccccc2F)[nH]c1=O
Reaction time: 24 h
Yield: 17.4 %

Procedure:
Ethyl 1,6-dihydro-2-methylthio-6-oxo-5-pyrimidinecarboxylate (20 g) and 2-fluoroaniline (15.6 g) are added to ethanol (200 ml), and the mixture is refluxed with stirring for 24 hours. After cooling, the precipitate is collected by filtration and recrystallized from DMF to give ethyl 1,6-dihydro-2-(2-fluoroanilino)-6-oxo-5-pyrimidinecarboxylate (4.5 g). M.p. 250°-252° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=1.Cl.O1CCOCC1.C(O)[C@H](O)[C@H]1OC(=O)C(O)=C1O>C1(C)C=CC=CC=1>[OH:12][C:10]1[C:20]2[C:19](=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[N:23]=[C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: COc1cccc(N)c1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Temperature: 280 °C

Procedure:
A solution of ethyl benzoylacetate (b) (100.0 g, 0.52 mol), m-anisidine (a) (128.1 g, 1.04 mol) and 4 N HCl/dioxane (5.2 mL) in toluene (1.0 L) was refluxed for 6.25 h in a Dean-Stark apparatus. The cooled toluene solution was successively washed with aqueous 10% HCl (2×300 mL), 1 N NaOH (2×300 mL), H2O (300 mL) and brine (150 mL). The toluene phase was dried (MgSO4), filtered and concentrated under reduced pressure to give a 1.2:1.0 mixture of ester c and amide d (144.6 g, 45% /38% crude yield) as a dark brown oil. The crude oil was heated to 280 ° C. for 80 min while distilling generated EtOH. The cooled dark solid obtained was triturated with CH2Cl2 (200 mL). The suspension was filtered and the resulting solid washed with CH2Cl2 to give e (22.6 g, 17% from a) as a beige solid: 1H NMR (DMSO-d6) δ8.00 (d, J=9.0 Hz, 1H), 7.81-7.82 (m, 2H), 7.57-7.59 (m, 3H), 7.20 (d, J=2.2 Hz, 1H), 6.94 (dd, J=9.0, 2.2 Hz, 1H), 6.26 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]1[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:10][CH:11]2[CH2:13][CH2:12]2)=[CH:6][N:7]=1
Reactant: Oc1ccc(Br)nc1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccc(OCC2CC2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 91.5 %

Procedure:
A mixture of 6-bromopyridin-3-ol (10.0 g), (bromomethyl)cyclopropane (7.76 g), potassium carbonate (11.9 g), and DMF (100 mL) was stirred at 60° C. overnight. Water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (12.0 g) as a colorless oil.
Reaction SMILES: [C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2].Br[CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]([CH2:5][O:6][CH:7]([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]#[N:32])[CH2:22][CH2:21]1)=[O:19])[CH3:8])([O:3][CH3:4])=[O:2]
Reactant: N#CCCCCBr
Reactant: COC(=O)COC(C)n1c(C(=O)C2CCNCC2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COC(C)n1c(C(=O)C2CCN(CCCCC#N)CC2)nc2ccccc21
Temperature: 90 °C

Procedure:
Mix 1-[(1-carbomethoxy methoxy ethyl)-1H-benzimidazol-2-yl][1-(4-piperidinyl)]methanone (4.45 g, 12.91 mmol), 5-bromovaleronitrile (2.5 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)(=[NH:3])[CH3:2].C(N(CC)CC)C.[C:40](Cl)(=[O:43])[O:41][CH3:42]>ClCCl>[CH3:42][O:41][C:40]([CH2:2][C:1]([NH:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([N:13]2[CH2:18][CH2:17][N:16]([S:19]([C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[C:27]([Cl:32])[CH:28]=4)[CH:23]=3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[O:12])[CH2:7][CH2:6]1)=[NH:3])=[O:43]
Reactant: COC(=O)Cl
Reactant: CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CC(=N)N[C@H]1CC[C@H](C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-(trans-4-acetimidoylaminocyclohexane-1-ylcarbonyl)-4-(6-chloronaphthalene-2-sulfonyl)piperazine (300 mg) and triethylamine (199 mg) in dichloromethane (30 ml) was added methyl chlorocarbonate (192 mg), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was concentrated, and the residue was purified with silica gel column chromatography (ethyl acetate) to give colorless crystals of the title compound (171 mg).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9](Cl)(=[O:11])=[O:10])#[N:2].[CH3:13][NH:14][CH3:15].C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9]([N:14]([CH3:15])[CH3:13])(=[O:11])=[O:10])#[N:2]
Reactant: CNC
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CN(C)S(=O)(=O)c1ccccc1C#N
Yield: 85 %

Procedure:
A solution of 2-cyanobenzensulfonylchloride (2.0 g, 10 mmol), dimethyl amine (1.18 g, 10 mmol, 40 wt % in water) and triethylamine (1.5 mL, 10 mmol) were stirred together at room temperature for 30 min. The resulting slurry was diluted with ethyl acetate and filtered. The filter cake was washed with ethyl acetate and the combined filterate was washed with water, dried (Na2SO4) and concentrated to give the title product as orange plates (1.78 g, 85% yield). 1HNMR (300 MHz, CDCl3) δ: 8.02 (1H, dd, J=8.05, 1.46 Hz), 7.87 (1H, dd, J=7.32, 1.47 Hz), 7.79–7.76 (2H, m), 2.86 (6H, s). LCMS calcd for C9H11N2O2S (M+H): 211.05; found: 211.09.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([N:20]=[N+:21]=[N-:22])=[CH:16][C:15]=2[OH:23])=[CH:8][N:7]=1.[I-:26].[Na+].CC1C=CC(S(NCl)(=O)=O)=CC=1.O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[C:18]([I:26])[C:17]([N:20]=[N+:21]=[N-:22])=[CH:16][C:15]=2[OH:23])=[CH:8][N:7]=1
Reactant: [I-]
Reactant: COC(=O)COc1ccc(NC(=O)c2ccc(N=[N+]=[N-])cc2O)cn1
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccc(NC(=O)c2cc(I)c(N=[N+]=[N-])cc2O)cn1
Reaction time: 0.17 h

Procedure:
To a suspension of (5-(4-azido-2-hydroxybenzoylamino)pyridin-2-yloxy)acetic acid methyl ester (22 mg, 0.064 mmol) in DMF (1 mL) was added sodium iodide (11 mg, 0.07 mmol) and chloramine T (51 mg, 0.22 mol). The reaction mixture turned homogeneous and after 10 minutes, the mixture was poured into water and was extracted with ethyl acetate (3×25 mL). The combined extracts were washed with water and brine and dried over magnesium sulfate. Filtration and concentration in vacuo gave a residue that was purified via radial chromatography (1 mm plate, 10% ethyl acetate/hexanes as eluant). This gave 7.8 mg (26%) of (5-(4-azido-2-hydroxy-5-iodo-benzoylamino)-pyridin-2-yloxy)-acetic acid methyl ester as an off-white solid: 1H NMR (300 MHz, acetone-d6) δ 9.92 (bs, 1H) 8.40 (m, 1H), 8.33 (s, 1H), 8.05 (m, 1H), 6.92 (m, 1H), 6.87 (s, 1H), 4.90 (s, 2H), 3.69 (s, 3H); MS (EI) m/z 467.97 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N+:23]([O-])=O)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:29]1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([Br:26])[C:22]([N:23]3[CH2:32][CH2:31][C@H:30]([NH:33][C:34](=[O:40])[O:35][C:36]([CH3:37])([CH3:39])[CH3:38])[CH2:29]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc3c([N+](=O)[O-])c(Br)cc(c23)C(=O)N1OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2c(Br)cc3c4c(cccc24)C(=O)N(OCc2ccccc2)C3=O)C1
Yield: 80.8 %

Procedure:
Following the procedure of Example W1, 2-benzyloxy-5-bromo-6-nitro-benzo[de]isoquinoline-1,3-dione (0.40 g, 0.94 mmol, from Example S1-A), (S)-pyrrolidin-3-yl-carbamic acid, tert-butyl ester (0.38 g, 2.1 mmol) and triethyl amine (0.18 g, 1.9 mmol) in DMF (5 mL) were reacted at 80° C. for 48 hours to give 0.43 g of the title compound.
Reaction SMILES: Cl[C:2](OCC)=[O:3].[S:7]1[CH:11]=[CH:10][N:9]=[C:8]1[NH:12][S:13]([C:16]1[CH:34]=[CH:33][C:19]([C:20]([NH:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)=[NH:21])=[CH:18][CH:17]=1)(=[O:15])=[O:14]>C1COCC1>[Cl:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[Cl:31])[CH2:24][N:23]1[C:2](=[O:3])[NH:21][C:20]([C:19]2[CH:18]=[CH:17][C:16]([S:13]([NH:12][C:8]3[S:7][CH:11]=[CH:10][N:9]=3)(=[O:15])=[O:14])=[CH:34][CH:33]=2)=[N:22]1
Reactant: N=C(NNCc1ccc(Cl)c(Cl)c1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)Nc3nccs3)cc2)nn1Cc1ccc(Cl)c(Cl)c1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
Ethyl chloroformate (0.05 mL) was added to a solution of 4-(thiazol-2-ylsulfamoyl)-N-(3,4-dichlorobenzylamino)-benzamidine (0.044 mmol) and TEA (0.20 mL) in THF (5 mL) at room temperature and the resulting solution was stirred for 2 h. After concentrating in vacuo 1 N NaOH (4 mL) was added and the solution was heated to 95° C. overnight. After the mixture was cooled to room temperature, the solution was acidified with 1 N HCl and freeze dried. The crude material was purification by reverse phase chromatography to yield 4-[1-(3,4-dichloro-benzyl)-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-N-thiazol-2-yl-benzenesulfonamide (0.002 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][C:9]=2[CH3:24])[CH:5]=[CH:4][N:3]=1.[CH3:25][N:26](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:25]([C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([NH:13][C:14](=[O:23])[C:15]3[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=3[F:22])=[N:10][C:9]=2[CH3:24])[CH:5]=[CH:4][N:3]=1)#[N:26]
Reactant: CN(C)C=O
Reactant: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccnc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1nc(NC(=O)c2c(F)cccc2F)sc1-c1ccnc(C#N)c1
Temperature: 110 °C

Procedure:
A solution of N-[5-(2-Bromo-pyridin-4-yl)-4-methyl-thiazol-2-yl]-2,6-difluoro-benzamide (100 mg, 0.24 mmol), Zn(CN)2 (43.0 mg, 0.36 mmol), and Pd(PPh3)4 (20.0 mg, 0.02 mmol) in DMF (4.0 mL) was degassed by purging with a stream of nitrogen for 10 minutes. The mixture was heated to 110° C. overnight, cooled to room temperature, diluted with CH2Cl2, washed with water, dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified on silica gel to give the title compound (45 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl>CS(C)=O.O.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:9]#[N:10])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: ClCCOCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1(c2ccc(Cl)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 89.1 %

Procedure:
To a stirred suspension of 2-(4-chlorophenyl)acetonitrile (3.06 g, 20.3 mmol) at 0° C. in DMSO (200 mL) was added NaH (1.79 g, 60% in mineral oil, 44.6 mmol). The reaction was stirred at 0° C. for 15 min then at room temperature for 30 min, resulting in a dark purple solution. To this solution was added 1-chloro-2-(2-chloroethoxy)ethane (3.18 g, 22.33 mmol) dropwise. The resulting mixture was stirred at room temperature overnight before diluting with 50 mL water and neutralizing to pH˜7.0 with 1.0 M aq. HCl. The reaction was extracted with Et2O (3×200 mL) and the combined organics were washed with brine (200 mL), dried over Na2SO4, and concentrated. The residue was purified by flash chromatography on silica gel (10-30% EtOAc/hexane eluent) to provide 4-(4-chlorophenyl)tetrahydro-2H-pyran-4-carbonitrile as a yellow crystalline solid (4.01 g, 89% yield) (Note: This compound does not ionize well on LC/MS. It does not have intense UV absorption at 220 nM. The TLC Rf is 0.6 in 30% EA/Hexane).