Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OO.NC(N)=[O:19].FC(F)(F)C(OC(=O)C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[C:10]([C:11]([F:14])([F:12])[F:13])=[N+:9]([O-:19])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: NC(N)=O
Reactant: O=C(O)c1ccnc(C(F)(F)F)c1F
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cc[n+]([O-])c(C(F)(F)F)c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-fluoro-2-(trifluoromethyl)isonicotinic acid (2.00 g, 9.56 mmol, Oakwood) and urea hydrogen peroxide addition compound (5.00 g, 53.2 mmol, Aldrich) in methylene chloride (50 mL) at 0° C. was added trifluoroacetic anhydride (7.51 mL, 53.2 mmol). The bath was removed and the reaction was allowed to warm to room temperature and stir overnight. The precipitate was filtered off. The filtrate was diluted with a small amount of water and ethyl acetate, the layers were separated and the aqueous was extracted with two further portions of ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated. The solvent was removed in vacuo to afford a yellow solid which was used without further purification. LC-MS: 225.9 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 8.20 (d, 1H), 8.04 (dd, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([P:8](=[O:15])([O:12]CC)[O:9]CC)=[CH:4][CH:3]=1>Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([P:8](=[O:9])([OH:15])[OH:12])=[CH:6][CH:7]=1
Reactant: CCOP(=O)(OCC)c1ccc(F)cc1
Agent: Cl
Product: O=P(O)(O)c1ccc(F)cc1

Procedure:
Diethyl 4-fluorophenylphosphonate (600 mg, 2.55 mmol) was combined with 8M HCl (10 mL, excess) and the mixture refluxed overnight. The reaction was cooled and filtered to remove dark specks. The solvent was removed under vacuum until a solid began to form. The mixture was then put in the refrigerator for several hours. The solid was dried to yield an off-white powder (P80 mg). 1H NMR (400.14 MHz, DMSO) δ 7.71 (ddd, J=12.49, 8.52, 5.99 Hz, 2H), 7.28 (ddd, J=9.02, 9.02, 2.65 Hz, 2H). 31P{1H} NMR (161.97 MHz, DMSO): δ 12.81. Analysis calculated (found) %: C, 40.93 (40.33), H, 3.43 (3.49).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:13]=[N:14][NH:15][CH:16]=3)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22]Br>CN(C)C=O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:12]3[CH:16]=[N:15][N:14]([CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2ncc(-c3cn[nH]c3)nc2c1
Reactant: CN(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
To a solution of 7-bromo-2-(1H-pyrazol-4-yl)quinoxaline (0.225 g, 0.808 mmol) in dry N,N-dimethylformamide (5 mL) under a nitrogen atmosphere was added 60 wt % sodium hydride (92 mg, 2.27 mmol) portionwise. After 5 minutes of stirring with purging, 2-dimethylaminoethylbromide (0.37 g, 0.908 mmol) was added and the reaction mixture stirred at rt for 30 min, concentrated in vacuo and taken into dichloromethane. The organic solution was washed with water (2×), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-5% methanol in ethyl acetate to furnish the title compound (0.183 g, 66% yield). ESMS m/e: 345.9; 347.8 [M]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([OH:20])=O)=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH:25]([CH3:37])[CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:38][S:39]([NH2:42])(=[O:41])=[O:40]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH3:38])(=[O:41])=[O:40])=[O:20])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH:25]([CH3:37])[CH2:24]1)=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: CC1CN(C(=O)c2cnc3c(C(=O)O)cnn3c2NCc2ccccc2)CCC12C=Cc1ccccc12
Product: CC1CN(C(=O)c2cnc3c(C(=O)NS(C)(=O)=O)cnn3c2NCc2ccccc2)CCC12C=Cc1ccccc12
Yield: 78.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(3′-methylspiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.049 g, 0.0825 mmol) obtained in step 2 and methanesulfonamide (0.039 g, 0.413 mmol), the title compound (0.037 g, 79%) was obtained.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:7][N:8]1[S:13](=[O:15])(=[O:14])[NH:12][C:11]([O:16][CH2:17][CH3:18])=[N:10][C:9]1=O.P(Cl)(Cl)([Cl:22])=O>ClCCCl>[Cl:22][C:9]1[N:8]([CH3:7])[S:13](=[O:15])(=[O:14])[N:12]=[C:11]([O:16][CH2:17][CH3:18])[N:10]=1
Reactant: CCOC1=NC(=O)N(C)S(=O)(=O)N1
Reactant: O=P(Cl)(Cl)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCOC1=NS(=O)(=O)N(C)C(Cl)=N1
Yield: 96.5 %

Procedure:
50 parts of phosphorus pentachloride were introduced into a stirred mixture of 41.4 parts of 6-methyl-3-ethoxy-6H-1,2,4,6-thiatriazin-5-one-1,1-dioxide in 100 parts of 1,2-dichloroethane and 100 parts of phosphorus oxychloride at room temperature. The reaction mixture was stirred under reflux for 12 hours and then evaporated down under reduced pressure, giving 43.5 parts (96.5% of theory) of 5-chloro-6-methyl-3-ethoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide, of melting point 75°-80° C.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH3:25])=[N:23][N:24]=[C:20]3[C@H:19]([CH3:26])[CH2:18][NH:17][C:16]=2[CH:27]=1.C([O-])(C)(C)C.[K+]>CS(C)=O.O>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:21]3[C:22]([CH3:25])=[N:23][N:24]=[C:20]3[C@H:19]([CH3:26])[CH2:18][N:17]([C:2]3[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=3)[C:16]=2[CH:27]=1
Reactant: Cc1nnc2n1-c1ccc(Br)cc1NC[C@H]2C
Reactant: O=[N+]([O-])c1ccc(F)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nnc2n1-c1ccc(Br)cc1N(c1ccc([N+](=O)[O-])nc1)C[C@H]2C
Temperature: 120 °C
Yield: 77.1 %

Procedure:
To a solution of 5-fluoro-2-nitropyridine (284 mg, 2 mmol) and (R)-8-bromo-1,4-dimethyl-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (292 mg, 1 mmol) in dimethyl sulfoxide (5 mL) was added potassium tert-butanolate (223 mg, 2 mmol). The reaction mixture was heated at 120° C. for 1 hour under microwave (pressure: 3.2 bar, equipment power: 150 W). The mixture was diluted with water (50 mL), extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated to give a residue which was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=2:1) to give (R)-8-bromo-1,4-dimethyl-6-(6-nitropyridin-3-yl)-5,6-dihydro-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]diazepine (320 mg, 77%) as a light yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2.[O:13]1[C@@H:15]([CH2:16][CH3:17])[CH2:14]1.[F-].[Cs+].CN(C=O)C>O>[OH:13][C@@H:15]([CH2:16][CH3:17])[CH2:14][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[O:7][CH:6]=[CH:5]2
Reactant: O=c1occc2cc(O)ccc12
Reactant: CC[C@H]1CO1
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CN(C)C=O
Product: CC[C@H](O)COc1ccc2c(=O)occc2c1
Temperature: 130 °C
Reaction time: 4 h

Procedure:
A mixture of 6-Hydroxy-isochromen-1-one (405 mg), (S)-(−)-1,2-epoxybutane (361 mg), cesium fluoride (1.1 g) and DMF (5 mL) was stirred for 4 h at 130° C. After adding water it was extracted with dichloromethane, dried over magnesium sulfate and concentrated. The residue was purified by preparative HPLC. In this way the product was obtained with molecular weight 234.25 (C13H1404); MS (ESI): 235 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16]([OH:18])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.Cl.Cl.[CH3:55][C:56]1([CH3:78])[CH2:61][CH2:60][CH2:59][N:58]([CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:71]=[CH:70][C:69]([CH:72]3[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]3)=[CH:68][CH:67]=2)[CH2:57]1>CN(C=O)C>[CH3:55][C:56]1([CH3:78])[CH2:61][CH2:60][CH2:59][N:58]([CH2:62][CH2:63][CH2:64][O:65][C:66]2[CH:67]=[CH:68][C:69]([CH:72]3[CH2:73][CH2:74][N:75]([C:16]([C:9]4[C:10]5[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=5)[C:6]([CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:19])=[CH:7][CH:8]=4)=[O:18])[CH2:76][CH2:77]3)=[CH:70][CH:71]=2)[CH2:57]1
Reactant: COC(=O)CCc1ccc(C(=O)O)c2ccccc12
Reactant: CC1(C)CCCN(CCCOc2ccc(C3CCNCC3)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCc1ccc(C(=O)N2CCC(c3ccc(OCCCN4CCCC(C)(C)C4)cc3)CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 66.2 %

Procedure:
A solution of 4-[3-(methyloxy)-3-oxopropyl]-1-naphthalenecarboxylic acid (for example as prepared for Intermediate 6) (0.197 g, 0.76 mmol) in anhydrous DMF (2 ml) was treated with HBTU (0.29 g 0.77 mmol), diisopropylethylamine (0.6 ml, 3.82 mmol), the mixture was stirred at room temperature for 20 minutes, 3,3-dimethyl-1-(3-{[4-(4-piperidinyl)phenyl]oxy}propyl)piperidine dihydrochloride (for example as prepared for Intermediate 4) (250 mg, 0.63 mmol) was added and the mixture stirred at room temperature for 4 h. The mixture was evaporated to dryness and purified on a SCX-2 cartridge (5 g) eluting with MeOH, followed by 2M ammonia solution in methanol to afford the title compound (238 mg). LCMS RT=2.79 min, ES+ve m/z 571.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]([NH:13][NH:14][C:15](=[O:34])[C@H:16]([CH2:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[CH2:17][N:18]([O:21]C3CCCCO3)[CH:19]=[O:20])[C:6]=2[F:35])[CH2:4][CH2:3][CH2:2]1>CC(O)=O.O>[N:1]1([C:5]2[N:10]=[C:9]([S:11][CH3:12])[N:8]=[C:7]([NH:13][NH:14][C:15](=[O:34])[C@H:16]([CH2:28][CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH2:17][N:18]([OH:21])[CH:19]=[O:20])[C:6]=2[F:35])[CH2:2][CH2:3][CH2:4]1
Reactant: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OC2CCCCO2)c(F)c(N2CCC2)n1
Solvent: O
Solvent: CC(=O)O
Product: CSc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCC2)n1
Temperature: 25 °C
Yield: 45.1 %

Procedure:
[(2R)-3-{2-[6-(1-Azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (68 mg, 0.13 mmol) was dissolved in a mixture of AcOH/H2O (20 mL, 4:1) and stirred at RT until LCMS indicated completion of the deprotection (overnight). The reaction mixture was concentrated to dryness under vacuum and purified by RP-HPLC to provide [(2R)-3-{2-[6-(1-azetidinyl)-5-fluoro-2-(methylthio)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (25 mg, 44%). LCMS: (M+H)+: 427.2.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:39])[NH2:38])[CH:33]=2)[CH:28]=1)(=O)=O>N1C=CC=CC=1>[C:1]([O:6][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([C:37](=[NH:38])[NH2:39])[CH:33]=2)[CH:28]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)O
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CCCC(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reaction time: 0.5 h
Yield: 38.7 %

Procedure:
To a solution of 1.6 g of n-butyric acid in 50 ml of anhydrous pyridine, while being cooled in ice, was added 4.4 g of DCC. After stirring for 30 minutes, 5.0 g of 6-amidino-2-naphthol methane-sulfonate was added to the mixture and further stirred overnight at room temperature. The precipitate was collected by filtration, washed successively with a small volume of pyridine, ethyl ether, and acetone, and dissolved in methanol at room temperature. The insolubles were collected by filtration and washed with a small volume of methanol. The filtrate and the washings were concentrated under reduced pressure and admixed with ethyl ether. The precipitated crystals were recrystallized from ethanol to obtain 1.8 g of colorless flaky crystals of 6-amidino-2-naphthyl butyrate methanesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][OH:21])[CH3:2].[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][CH:9]([C:14]([O:16][CH3:17])=[O:15])[C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[CH2:20][O:21][C:31]([NH:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)=[O:32])[CH3:2]
Reactant: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1CO
Reactant: COc1ccc(N=C=O)cc1
Product: CCOc1ccc(CC(C(=O)OC)C(=O)OC)cc1COC(=O)Nc1ccc(OC)cc1

Procedure:
Using dimethyl 2-[4-ethoxy-3-(hydroxymethyl)benzyl]malonate and 4-methoxyphenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[N:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:21]=[C:22]([C:26]2[O:30][CH:29]=[N:28][C:27]=2[C:31](O)=[O:32])[CH:23]=[CH:24][CH:25]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[N:17]=[C:16]([NH:18][C:31]([C:27]3[N:28]=[CH:29][O:30][C:26]=3[C:22]3[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=3)=[O:32])[CH:15]=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)c1ncoc1-c1cccc(Cl)c1
Reactant: CC1(c2csc(Cn3ncc(N)n3)n2)OCCO1
Product: CC(=O)c1csc(Cn2ncc(NC(=O)c3ncoc3-c3cccc(Cl)c3)n2)n1

Procedure:
Following general procedure A followed by B, starting from 2-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-2H-[1,2,3]triazol-4-ylamine and 5-(3-chloro-phenyl)-oxazole-4-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:55])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:32][C:27]=4[S:26][C:25]=3[CH:54]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].C1C=C(Cl)C=C(C(OO)=[O:64])C=1>C(Cl)Cl.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:55])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]3[C:28]4[CH:29]=[CH:30][C:31]([C:33]5[NH:34][C:35]([CH:38]6[CH2:42][CH2:41][CH2:40][N:39]6[C:43](=[O:53])[CH:44]([NH:48][C:49]([O:51][CH3:52])=[O:50])[CH:45]([CH3:47])[CH3:46])=[N:36][CH:37]=5)=[CH:32][C:27]=4[S:26](=[O:64])[C:25]=3[CH:54]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:7])[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)sc2cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc23)[nH]1)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)S(=O)c2cc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)ccc2-3)[nH]1)C(C)C
Temperature: -40 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
(1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (0.0041 mmol., 4 mg) was dissolved in 1 mL DCM and cooled to −40° C. mCPBA (0.4 mg, 0.9 eq.) was added. The reaction mixture was stirred at −40° C. for 2 hours and warmed up to 0° C. over 2 hours, then warmed up to room temperature overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give a yellow powder (1-{2-[5-(7-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-5-oxo-5H-5λ4-dibenzothiophen-3-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (Example DD) (0.6 mg).
Reaction SMILES: Br[CH:2]([C:4]1[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)=[N:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:9]=1[CH3:10])[CH3:3].[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)(C)C>[CH3:10][C:9]1[N:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:4]=1[CH:2]([N:30]1[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]1)[CH3:3]
Reactant: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)Br
Reactant: CN1CCNCC1
Solvent: CC(C)O
Product: Cc1nc(-c2ccccc2)nc(-c2cccc([N+](=O)[O-])c2)c1C(C)N1CCN(C)CC1
Yield: 32.4 %

Procedure:
A mixture of 5-(1-bromoethyl)-6-methyl-4-(3-nitrophenyl)-2-phenylpyrimidine (1.5 g) and N-methylpiperazine (1.13 g) in isopropylalcohol (15 ml) was refluxed for 1.5 hours. The reaction mixture was evaporated in vacuo. The residue was chromatographed on allumina eluting with a mixture of ethyl acetate and n-hexane (1:20). The fractions containing the desired product were combined and concentrated in vacuo. The residue was crystallized from a mixture of n-hexane and diethyl ether to give 6-methyl-5-[1-(4-methylpiperazin-1-yl)ethyl]-4-(3-nitrophenyl)-2-phenylpyrimidine (0.51 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.C([BH3-])#N.[Na+].[F:14][C:15]1[C:16]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:17]([CH:25]=[C:26]([CH:29]=O)[C:27]=1[F:28])[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19]>CO>[F:14][C:15]1[C:16]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([I:38])=[CH:34][C:33]=2[F:39])=[C:17]([CH:25]=[C:26]([CH2:29][N:2]2[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[C:27]=1[F:28])[C:18]([NH:20][O:21][CH2:22][CH2:23][OH:24])=[O:19]
Reactant: COC(=O)CCCN
Reactant: O=Cc1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NOCCO)c1cc(CN2CCCC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
Methyl 4-amino-butyrate hydrochloride (commercially available, 48 mg, 0.312 mmol) and sodium cyanoborohydride (20 mg, 0.312 mmol) were added to a solution of 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-5-formyl-N-(2-hydroxy-ethoxy)-benzamide (50 mg, 0.104 mmol) obtained in Step F of Example 1 in methanol (2.0 mL). The mixture was stirred at room temperature for 18 hours. Then, the reaction vessel was equipped with a reflux condenser, and the mixture was heated at 80° C. for 2 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate, and the organic layer was washed sequentially with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resultant residue was purified by silica gel flash chromatography (Mega Bond Elut, Varian, 5% methanol/methylene chloride as an eluent) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(2-oxo-pyrrolidin-1-ylmethyl)-benzamide (Compound H-3, 26.8 mg, 47%) as a white solid.
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH2:10]([O:12][C:13]([N:15]=[C:16]=[S:17])=[O:14])[CH3:11].C1(C)C=CC=CC=1>CO>[CH3:8][C:6]1[N:7]=[C:2]2[S:17][C:16]([NH:15][C:13](=[O:14])[O:12][CH2:10][CH3:11])=[N:9][C:3]2=[N:4][CH:5]=1
Reactant: CCOC(=O)N=C=S
Reactant: Cc1cnc(N)c(Br)n1
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)Nc1nc2ncc(C)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 63.1 %

Procedure:
To 3-bromo-5-methylpyrazin-2-amine (850 mg, 4.52 mmol) was added ethoxycarbonyl isothiocyanate (0.51 mL, 4.52 mmol) followed by toluene (1 mL). The mixture was placed in a preheated 100° C. oil bath, and within a minute, all the solids had dissolved. After 15 min, all had seized to a solid mass. After an additional 15 minutes, methanol (˜5 mL) was added and the mixture refluxed to digest the solids. The mixture was cooled to rt after 5 minutes and the solids collected by filtration, washing with methanol to give ethyl 6-methylthiazolo[5,4-b]pyrazin-2-ylcarbamate (680 mg, 2.85 mmol, 63.1% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.48 (br. s., 1H) 8.48 (s, 1H) 4.30 (q, J=7.03 Hz, 2H) 2.56-2.65 (m, 3H) 1.31 (t, J=7.15 Hz, 3H). MS (LC/MS) R.T.=2.10; [M+H]+=239.17.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.[N+:32]([C:35]1[CH:36]=[C:37]([OH:41])[CH:38]=[CH:39][CH:40]=1)([O-:34])=[O:33].[C:42]([C:44]1[CH:49]=[CH:48][C:47]([CH2:50][CH2:51]O)=[CH:46][CH:45]=1)#[N:43]>C1COCC1.O>[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH2:51][CH2:50][C:47]2[CH:48]=[CH:49][C:44]([C:42]#[N:43])=[CH:45][CH:46]=2)[CH:36]=1)([O-:34])=[O:33]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: N#Cc1ccc(CCO)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(CCOc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 31.9 %

Procedure:
Triphenylphosphine (11.3 g; 43.1 mmol) and diethylazodicarboxylate (7.5 g; 43 mmol) were dissolved in THF (250 mL) under nitrogen at 0° C. After 5 minutes, 3-nitrophenol (5.00 g; 35.9 mmol) and 2-(4-cyanophenyl)ethanol (6.3 g; 43 mmol) were added. The cooling bath was removed and the mixture stirred for 2 days at room temperature. A new batch was prepared as above and the two were combined before work-up. Water was added and the THF was evaporated. The mixture was extracted with EtOAc, and the organic phase was washed with aqueous 0.2M NaOH and brine, dried (Na2SO4) and the solvent removed in vacuo. Purification by flash chromatography (SiO2; toluene) and recrystallization from CH2Cl2:EtOH afforded 3.07 g (32%) of the sub-title compound.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:7])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)CCC(=O)c1ccc(Br)cc1
Product: O=C(O)CCC(=O)c1ccc(Br)c([N+](=O)[O-])c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Under salt-ice cooling, 3-(4-bromobenzoyl)propionic acid (75.0 g, 291.7 mmol) was added to fuming nitric acid (200 mL) in portions at such a rate that the temperature of the reaction solution could be maintained at −5° C. or lower. After stirring at −12° C. to −10° C. for 1 hour, the reaction solution was poured onto ice. The solid which precipitated was collected by filtration, washed with purified water, and thereafter dried under reduced pressure to obtain 3-(4-bromo-3-nitrobenzoyl)propionic acid (91.0 g).