Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9](=O)[NH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Br:1][C:2]1[C:7]2[N:8]([CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:9]([Cl:22])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)CCCn1c(=O)[nH]c2cccc(Br)c21
Product: CCOC(=O)CCCn1c(Cl)nc2cccc(Br)c21
Temperature: 100 °C
Reaction time: 4 h
Yield: 36 %

Procedure:
A mixture of ethyl 4-(7-bromo-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)butanoate (4.11 g, 12.6 mmol) and phosphoryl chloride (49 g, 320 mmol) was stirred at 100° C. for 4 hr. After cooling, phosphoryl chloride was evaporated in vacuo. The residue was neutralized with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 5-30% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound as a colorless powder (1.57 g, 4.54 mmol, 36%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15]([CH:18]=1)[CH:16]=O.CCO>O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([F:19])=[C:15](/[CH:16]=[N:9]/[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=1
Reactant: NNc1ccc(F)cc1
Reactant: O=Cc1cc(Br)ccc1F
Solvent: O
Solvent: CCO
Product: Fc1ccc(N/N=C/c2cc(Br)ccc2F)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
A 1000 mL round bottom flask was charged with 20.0 g (123 mmol) of 4-fluorophenylhydrazine and 28.4 g (140 mmol) of 5-bromo-2-fluorobenzaldehyde and 400 mL of EtOH and warmed at 90° C. After 2 hours, the mixture was cooled to room temperature and then diluted with 200 mL of water and filtered. The solid were then dissolved in EtOAc and washed with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was passed through a pad of silica gel to afford 37 g (97%) of N-[1-(5-bromo-2-fluorophenyl)meth-(E)-ylidene]-N′-(4-fluorophenyl)hydrazine. MS m/z 312.11 (MH+).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[C:13]([O:17][C:18]([NH:20][C:21]1[C:22]([Cl:43])=[C:23]([CH:29]([OH:42])[CH2:30][N:31]([CH2:39][CH2:40]O)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=[C:25]([C:27]#[N:28])[CH:26]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1>[C:13]([O:17][C:18]([NH:20][C:21]1[C:22]([Cl:43])=[C:23]([CH:29]2[O:42][CH2:40][CH2:39][N:31]([C:32]([O:33][C:34]([CH3:37])([CH3:35])[CH3:36])=[O:38])[CH2:30]2)[CH:24]=[C:25]([C:27]#[N:28])[CH:26]=1)=[O:19])([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C(O)CN(CCO)C(=O)OC(C)(C)C)c1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(C2CN(C(=O)OC(C)(C)C)CCO2)c1Cl
Reaction time: 8 h
Yield: 67.5 %

Procedure:
Diethyl azodicarboxylate (203 μL, 1.28 mmol) was added to a solution of tert-butyl (2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)-2-hydroxyethyl)(2-hydroxyethyl)carbamate (389 mg, 0.853 mmol) and triphenylphosphine (336 mg, 1.28 mmol) in dry toluene (9.0 mL) at room temperature. This was left stirring overnight. Water was added and the reaction was extracted with EtOAc. The organic phase was dried with sodium sulfate and the solvent was removed. Radial silica gel chromatography eluting with hexane containing 0 to 20% EtOAc afforded tert-butyl 2-(3-((tert-butoxycarbonyl)amino)-2-chloro-5-cyanophenyl)morpholine-4-carboxylate (252 mg) as a colorless foam.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[NH:12]1[CH:16]=[N:15][CH:14]=[N:13]1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1nc[nH]n1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(-n2cncn2)ccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 24 h

Procedure:
4-Fluoro-2-methyl-nitrobenzene (2 g, 0.013 mol), 1,2,4-triazole (0.9 g, 0.013 mol), potassium carbonate (1.78 g, 0.013 mol) were dissolved in DMSO (50 ml) and stirred at 90° C. for 24 h under dry conditions. The yellow suspension was poured into water (150 ml), extracted (EtOAc), dried (Na2SO4) and evaporated under reduced pressure to afford an orange solid which was purified by flash column chromatography on silica eluting with n-pentane/ethyl acetate (50-100%) to afford a white solid (2.83 g 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH2:8][C:9]#[CH:10])[CH:2]=1.[I-].[CH3:14][N+]1C=CC=CC=1.[BH4-].[Na+]>>[CH3:14][N:1]1[CH2:6][CH2:5][CH:4]=[C:3]([C:7](=[N:11][OH:12])[CH2:8][C:9]#[CH:10])[CH2:2]1
Reactant: C[n+]1ccccc1
Reactant: C#CCC(=NO)c1cccnc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Product: C#CCC(=NO)C1=CCCN(C)C1

Procedure:
Employing the general method of Example 6 above, 2.95 g (12.2 mmol) of 1-(3-pyridinyl)-3-butyne-1-one oxime were converted to the corresponding 1-methyl pyridinium iodide and subsequently reduced by the action of sodium borohydride to produce 1.2 g of 1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-3-butyne-1-one oxime which was isolated as the ethanedioate salt, mp 55° -57° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[NH:11][C:10]([CH3:15])=[C:9]2[C:16]([OH:18])=O)=[C:4]([F:19])[CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[Br:30].C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Br:30][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([NH:20][C:16]([C:9]3[CH:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=4[F:19])[CH2:13][C:12](=[O:14])[NH:11][C:10]=3[CH3:15])=[O:18])[CH:22]=2)[NH:26][N:25]=1
Reactant: Nc1ccc2[nH]nc(Br)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2F)CC(=O)N1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Br)c3c2)C(c2ccc(Cl)cc2F)CC(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10 %

Procedure:
The product of Example 3, Step 2 (125 mg, 0.441 mmol, 1.00 equiv), 5-amino-3-bromoindazole (94 mg, 0.441 mmol, 1.0 equiv), and EDC (101 mg, 0.529 mmol, 1.20 equiv) were suspended in 1.0 mL DMF. Et3N (0.074 mL, 0.529 mmol, 1.2 equiv) was added and the solution was stirred at room temperature for 18 hrs. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (20-100% EtOAc in Hexanes) to provide 21 mg (10%) of the title compound as an off white solid. MS (ES+) m/e 478 [M+H]+
Reaction SMILES: Cl[CH:2]([CH2:6][O:7][CH3:8])[C:3](Cl)=[O:4].[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:20]2[S:21][CH:22]=[CH:23][N:24]=2)(=[O:18])=[O:17])=[CH:12][C:11]=1[OH:34].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:19]([C:20]2[S:21][CH:22]=[CH:23][N:24]=2)[S:16]([C:13]2[CH:14]=[CH:15][C:10]3[NH:9][C:3](=[O:4])[CH:2]([CH2:6][O:7][CH3:8])[O:34][C:11]=3[CH:12]=2)(=[O:18])=[O:17])=[CH:31][CH:30]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc(N)c(O)c2)cc1
Reactant: COCC(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COCC1Oc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc2NC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
To a solution of 2-chloro-3-methoxypropanoyl chloride (500 mg, 3.18 mmol) and 4-amino-3-hydroxy-N-(4-methoxybenzyl)-N-(thiazol-2-yl)benzenesulfonamide (Intermediate AD; 1.04 g, 2.65 mmol) in DMF (20 mL) was added Cs2CO3 (2.59 g, 7.95 mmol). The reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain the crude material which was further purified by column chromatography (silica gel 100-200 mesh and 0-30% ethyl acetate in hexane) to obtain N-(4-methoxybenzyl)-2-(methoxymethyl)-3-oxo-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (500 mg, 33.1%) as an off white solid. m/z (ESI) 476.1 (M+H)+.
Reaction SMILES: [B][B][B][B][B][B][B][B][B][B].[NH2:11][C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:19]=2[N:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]2)[N:14]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)[N:13]=1.[CH3:49][O:50][C:51]1[CH:64]=[CH:63][C:54]([CH2:55][N:56]2[CH2:60][C:59](=O)[CH2:58][C:57]2=[O:62])=[CH:53][CH:52]=1>CO.C(Cl)Cl>[CH3:48][O:47][C:44]1[CH:43]=[CH:42][C:41]([CH2:40][N:14]2[C:15]3=[N:16][CH:17]=[C:18]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:19]([N:21]4[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:25][CH2:26]4)=[C:20]3[C:12]([NH:11][CH:59]3[CH2:58][C:57](=[O:62])[N:56]([CH2:55][C:54]4[CH:53]=[CH:52][C:51]([O:50][CH3:49])=[CH:64][CH:63]=4)[CH2:60]3)=[N:13]2)=[CH:46][CH:45]=1
Reactant: COc1ccc(Cn2nc(N)c3c(N4CCN(C(=O)OC(C)(C)C)CC4)c(-c4ccccc4)cnc32)cc1
Reactant: COc1ccc(CN2CC(=O)CC2=O)cc1
Agent: [B][B][B][B][B][B][B][B][B][B]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(CN2CC(Nc3nn(Cc4ccc(OC)cc4)c4ncc(-c5ccccc5)c(N5CCN(C(=O)OC(C)(C)C)CC5)c34)CC2=O)cc1
Temperature: 48 °C
Reaction time: 20 h
Yield: 71.4 %

Procedure:
Decaborane (0.014 g, 0.12 mmol) was added to a solution of tert-butyl 4-(3-amino-1-(4-methoxybenzyl)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.20 g, 0.39 mmol) and 1-(4-methoxybenzyl)pyrrolidine-2,4-dione (0.10 g, 0.47 mmol) in MeOH (3 mL) and DCM (0.5 mL) and stirred at 48° C. (oil bath) for 20 hours. The solvent was removed. The resulting residue was dissolved in ethyl acetate (20 mL), washed with saturated NaHCO3 (10 mL), dried (sodium sulfate) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (hexane:ethyl acetate=1:1) to give tert-butyl 4-(1-(4-methoxybenzyl)-3-(1-(4-methoxybenzyl)-5-oxopyrrolidin-3-ylamino)-5-phenyl-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazine-1-carboxylate (0.20 g, 70%) as a solid. LCMS (APCI+) m/z 718(M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11](S(C)(=O)=O)[S:12]([CH3:15])(=[O:14])=[O:13].[Li+].[OH-]>CCO.O>[I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)N(c1ccc([N+](=O)[O-])cc1I)S(C)(=O)=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Yield: 93.5 %

Procedure:
To a mixture containing N-(2-iodo-4-nitrophenyl)-N-(methylsulfonyl)methanesulfonamide (31 g; 75 mmol) in EtOH (230 ml), water (115 ml) and LiOH (9 g; 375 mmol) were added. The reaction mixture was refluxed for 2 hours, then cooled to room temperature, the solvent evaporated under reduced pressure. NH4Cl (saturated solution, 250 ml) was added and the mixture was stirred until a yellow solid precipitated. The crude product was filtered and dried under vacuum to give N-(2-iodo-4-nitrophenyl)methanesulfonamide (24 g) which was used in the following reaction without any further purification.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.N1C=CC=CC=1.CC(C)=O.C(=O)=O.[C:19]([C:21]1(O)[CH2:27][CH:26]2[N:28]([CH2:29][C:30]([F:33])([F:32])[F:31])[CH:23]([CH2:24][CH2:25]2)[CH2:22]1)#[N:20]>C(OCC)C>[C:19]([C:21]1[CH2:22][CH:23]2[N:28]([CH2:29][C:30]([F:33])([F:32])[F:31])[CH:26]([CH2:25][CH2:24]2)[CH:27]=1)#[N:20]
Reactant: N#CC1(O)CC2CCC(C1)N2CC(F)(F)F
Agent: O=C=O
Solvent: CC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#CC1=CC2CCC(C1)N2CC(F)(F)F
Temperature: 80 °C
Reaction time: 24 h
Yield: 60 %

Procedure:
An oven-dried 100 ml 3-necked round bottom flask was fitted with a thermometer, pressure equalised dropping funnel, magnetic stirrer and short path distillation set-up and the apparatus filled with nitrogen. Phosphorous oxychloride (9.09 g, 58.7 mmol) and pyridine (15.7 g) were charged to the flask and the mixture then cooled to −10° C. in an acetone/Drikold™ bath. A solution of 3-cyano-3-hydroxy-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octane in diethyl ether (45 ml, prepared in Step 1) was added dropwise to the reaction mixture keeping the temperature below 10° C. The mixture was then heated to 80° C. and the diethyl ether (about 40 ml) was distilled out. The condenser was re-arranged to reflux and the reaction was held at 80° C. for 24 hours after which it was cooled and stirred at ambient for 18 hours. The reaction mass was poured onto ice/water (50 ml) and sodium carbonate was added portionwise until the mixture was adjusted to pH8. The mixture was extracted with ethyl acetate (3×30 ml) and the combined extracts were washed with water(200 ml) and brine (200 ml). The extracts were dried (Na2SO4), filtered and concentration in vacuo to give 3-cyano-8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]-oct-2-ene (1.16 g, 60% yield from 8-(2,2,2-trifluoroethyl)-8-azabicyclo[3.2.1]octan-3-one; 73:27 exo:endo cyano).
Reaction SMILES: [CH3:1][O:2][SiH:3]([O:6][CH3:7])[O:4][CH3:5].[CH2:8]([O:10][C:11](=[O:29])[C:12](=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]=[CH2:28])=[CH:21][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:9]>C1(C)C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:14])[C:12](=[CH:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][Si:3]([O:6][CH3:7])([O:4][CH3:5])[O:2][CH3:1])=[CH:23][CH:24]=1)[C:11]([O:10][CH2:8][CH3:9])=[O:29])[CH3:17]
Reactant: C=CCOc1ccc(C=C(C(=O)OCC)C(=O)OCC)cc1
Reactant: CO[SiH](OC)OC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=Cc1ccc(OCCC[Si](OC)(OC)OC)cc1)C(=O)OCC
Temperature: 70 °C

Procedure:
A 250 ml round bottom flask, equipped with a reflux condenser and an oil bath with a magnetic stirrer was charged with 10.0 g (82 mmol) trimethoxysilane and 5.0 g (16.4 mmol) of 2-[[4-(prop-2-enyloxy)benzylidene]-malonic acid diethyl ester in 100 ml of toluene under nitrogen atmosphere. The reaction mixture was heated to 70° C. and a catalytic amount of divinyl-tetramethyl disiloxane platinum complex was added. After the reaction mixture was heated for 2 hours, the solution was concentrates and filtrated over Celite to yield 6.2 g (88%) of crude 2-[[4-[3-(trimethoxysilyl)propoxy]benzylidene]-malonic acid diethyl ester as yellow oil. UV (ethanol) 312 nm (24′793).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])C.N[C@H:11](C(O)=O)CCCCN.N[C@H](C(O)=O)CCSC.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@H](C(O)=O)[C@@H](C)O.N[C@H](C(O)=O)C(C)C.C(SSC[C@H](N)C(O)=O)[C@H](N)C(O)=O.CC1[N+](CC2C=NC(C)=NC=2N)=CSC=1CCO.Cl.[Cl-].C1C=NC=C(C(N)=O)C=1.CC1N=CC(CO)=C(CO)C=1O.Cl.OC1[C@@H]([C@@H](O)CO)OC(=O)C=1O>CC1C(C)=CC2N([C@H]3O[C@H](CO)[C@@H](OP(O[C@@H](CNC(CC[C@@]4(C)C5=N[C@@H]([C@]6(C)[N-]C(=C(C)C7[C@](CC(N)=O)(C)[C@H](CCC(N)=O)C(=CC8C(C)(C)[C@H](CCC(N)=O)C(=C5C)N=8)N=7)[C@@H](CCC(N)=O)[C@@]6(CC(N)=O)C)[C@@H]4CC(N)=O)=O)C)([O-])=O)[C@H]3O)C=NC=2C=1.[C-]#N.[Co+3]>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C@H:3]([CH2:4][CH3:6])[CH3:11]
Reactant: NCCCC[C@H](N)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: [Co+3]
Agent: C/C1=C2/N=C(/C=C3\N=C(/C(C)=C4\[N-][C@@](C)([C@@H]5N=C1[C@](C)(CCC(=O)NC[C@@H](C)OP(=O)([O-])O[C@H]1[C@@H](O)[C@@H](n6cnc7cc(C)c(C)cc76)O[C@@H]1CO)[C@H]5CC(N)=O)[C@@](C)(CC(N)=O)[C@@H]4CCC(N)=O)[C@@](C)(CC(N)=O)[C@@H]3CCC(N)=O)C(C)(C)[C@@H]2CCC(N)=O
Agent: CC(C)[C@H](N)C(=O)O
Product: CC[C@H](C)[C@H](N)C(=O)O

Procedure:
L-leucine (2.4 g); L-lysine (1.5 g); L-methionine (1.4 g); L-phenylalanine (2.0 g); L-threonine (1.4 g); L-valine (1.5 g); L-cystine (0.2 g); vitamin A 5000 I.U.; vitamin B1 (1.6 mg); vitamin B12 (2.5 mg); vitamin PP (18 mg); vitamin B6 (2.4 mg) and vitamin C (100 g).
Reaction SMILES: CSC1SC(C(OC)=O)=CC=1N[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:15][CH:14]=1.[NH2:25][C:26]1[CH:27]=[C:28]([C:32]([O:34][CH3:35])=[S:33])[S:29][C:30]=1[CH3:31].C1(C2C=CC(B(O)O)=CC=2)C=CC=CC=1>>[C:16]1([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]3[CH:27]=[C:28]([C:32]([O:34][CH3:35])=[S:33])[S:29][C:30]=3[CH3:31])=[CH:23][CH:24]=2)[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=S)c1cc(N)c(C)s1
Reactant: COC(=O)c1cc(Nc2ccc(-c3ccccc3)cc2)c(SC)s1
Agent: OB(O)c1ccc(-c2ccccc2)cc1
Product: COC(=S)c1cc(Nc2ccc(-c3ccccc3)cc2)c(C)s1
Yield: 19.1 %

Procedure:
Methyl 5-methylthio-4-[(4-phenylphenyl)amino]thiophene-2-carboxylate: Using a procedure similar to Example 208, step (a), 74.4 mg (0.36 mmol) of methyl 4-amino-5-methylthiothiophene-2-carboxylate was allowed to react with 142.5 mg (2 equiv, 0.72 mmol) of 4-phenylphenyl boronic acid to give 24.5 mg (19.1%) of methyl 4-[(4-phenylphenyl)amino]-5-methylthiothiophene-2-carboxylate. 1H NMR (CDCl3, 400 MHz) δ 2.45 (s, 3H), 3.92 (s, 3H), 6.38 (bs, 1H), 7.08-7.14 (m, 2H), 7.33 (m, 1H), 7.43-7.46 (m, 211), 7.54-7.60 (m, 4H), 7.82 (s, 1H).
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH3:19][C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([CH3:27])[C:21]=1[CH2:28][C:29](O)=[O:30]>>[N:12]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3](=[O:18])[N:2]([NH:1][C:29](=[O:30])[CH2:28][C:21]3[C:20]([CH3:19])=[CH:25][C:24]([CH3:26])=[CH:23][C:22]=3[CH3:27])[N:11]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Product: Cc1cc(C)c(CC(=O)Nn2nc(N3CCOCC3)c3ccccc3c2=O)c(C)c1

Procedure:
The product of Example 1B and 2-(2,4,6-trimethylphenyl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.30 (d, J=7.3 Hz, 1H), 8.02 (d, J=8.0 Hz, 1H), 7.96-8.00 (m, 1H), 7.88-7.92 (m, 1H), 6.84-6.85 (bs, 2H), 3.77-3.85 (m, 4H), 3.66 (s, 2H), 3.08-3.13 (m, 4H), 2.31 (s, 6H), 2.21 (s, 3H); MS (ESI+) M/Z 407 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[CH:38]=[CH:37][C:14]3[N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=5)=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1.ClC1C=C(C=CC=1)C(OO)=[O:44]>C(Cl)Cl>[O-:44][N+:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[CH:38]=[CH:37][C:14]3[N:15]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:34])[F:35])=[CH:28][CH:27]=5)=[CH:20][CH:19]=4)[CH:16]=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc[n+]([O-])c1)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-Pyridin-3-ylmethyl-1-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-1H-benzimidazole-5-carboxamide (EXAMPLE 35, 31 mg, 0.060 mmol) was dissolved in DCM (3 mL) and treated with m-chloroperoxybenzoic acid (18 mg, 0.72 mmol) and the mixture stirred at rt for 4 h. After this time the mixture was concentrated in vacuo and the crude product purified by preparative HPLC to give the title compound. 1H NMR (CD3OD, 400 MHz): δ 4.63 (s, 2H), 5.21 (s, 2H), 7.24 (d, 2H, J=9.2 Hz), 7.31 (d, 2H, J=8.4 Hz), 7.51-7.60 (m, 6H), 7.66 (d, 1H, J=8.0 Hz), 7.90 (dd, 1H, J=8.8, 1.6 Hz), 8.25 (d, 1H, J=6.0 Hz), 8.31 (s, 1H), 8.38 (s, 1H), 8.46 (s, 1H). MS (ES+); m/z 535 (100) [MH+], 536 (25) [MH+2].
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1.Cl.[NH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31].N1C=CC=CC=1>CC(O)=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:25][N:26]1[CH2:30][CH2:29][CH2:28][C:27]1=[O:31])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]2[N:15]([C:17]([CH:20]([CH3:22])[CH3:21])=[N:18][N:19]=2)[N:16]=1
Reactant: NN1CCCC1=O
Reactant: CC(C)c1nnc2ccc(CC(=O)c3ccc(F)cc3F)nn12
Agent: Cl
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CC(C)c1nnc2ccc(CC(=NN3CCCC3=O)c3ccc(F)cc3F)nn12
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A mixture of 1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (0.20 g, 0.63 mmol, Preparation #K.1), 1-aminopyrrolidin-2-one hydrochloride (0.13 g, 0.95 mmol, prepared according to WO02/094833 Preparation #38), pyridine (0.15 mL, 1.9 mmol), and HOAc (1.2 mL) was sonicated to give a solution in a sealed vial. After stirring for about 16 h, additional 1-aminopyrrolidin-2-one hydrochloride (0.086 g, 0.632 mmol) was added and the resulting solution was stirred at ambient temperature for about 2 d. The reaction was then concentrated under reduced pressure and purified via silica gel chromatography eluting with a gradient of 0-5% MeOH in DCM to give impure 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.16 g) as an oil that was carried on without further purification. A 10 mL round-bottomed flask equipped with reflux condenser and outfitted with a nitrogen inlet adapter was charged with 1-(1-(2,4-difluorophenyl)-2-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethylideneamino)pyrrolidin-2-one (0.060 g, 0.15 mmol) in toluene (1.5 L) to give a yellow solution. Sodium ethoxide (0.020 g, 0.30 mmol) was added in one portion to give a yellow suspension. The reaction mixture was heated to reflux for about 5 h. The reaction mixture was allowed to cool to ambient temperature and continued stirring for about 2 d. The reaction mixture was diluted with water (5 mL) adjusted to about pH 2 with 6 N HCl. The aqueous layer was extracted with EtOAc. The combined organic extracts were dried with MgSO4, filtered, and concentrated under reduced pressure. The resulting residue was purified via silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM. The product-containing fractions were concentrated under reduced pressure and the resulting material was crystallized from EtOAc/heptane to give the title compound (0.031 g, 54%) as orange needles: LC/MS (Table 1, Method b) Rt=2.44 min; MS m/z: 381.4 (M+H)+.
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=3)=[CH:10][C:5]=2[CH2:4][O:3]1.[CH3:21][N:22]([CH2:24][CH2:25]O)[CH3:23].CCN=C=NCCCN(C)C>CN(C=O)C>[CH3:21][N:22]([CH3:23])[CH2:24][CH2:25][O:17][C:16](=[O:18])[C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][C:6]3[B:2]([OH:1])[O:3][CH2:4][C:5]=3[CH:10]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Reactant: CN(C)CCO
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: CN(C)CCOC(=O)c1ccc(Oc2ccc3c(c2)COB3O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a clear solution of 4-(1-hydroxy-1,3-dihydro-benzo[c][1,2]oxaborol-5-yloxy)-benzoic acid ((C38), 0.5 g, 1.75 mmol) in DMF (20 mL) were added N,N-dimethylamino ethanol (0.37 mL, 3.7 mmol) and EDCI (0.71 g, 3.7 mmol). The reaction was stirred at room temperature overnight. Then DMF was evaporated under vacuum. The residue was purified over sililca gel, eluting with 5% MeOH/DCM, to afford the 0.35 g of the title compound in 56% yield. 1H NMR 400 MHz (DMSO-d6) δ: 7.97 (d, J=8.9 Hz, 2H), 7.76 (d, J=7.8 Hz, 1H), 7.15-7.07 (m, 4H), 4.95 (s, 2H), 4.33 (t, J=5.5 Hz, 2H), 2.58 (t, J=5.9 Hz, 2H), 2.20 (s, 6H); MS (ES) m/z: 342 (M+H)'; HPLC purity: 91.90% (220 nm), 94.99% (254 nm).