Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8].ClC1C=CC=C(C(OO)=[O:17])C=1>C(Cl)(Cl)Cl>[N+:1]1([O-:17])[CH:6]=[CH:5][CH:4]=[C:3]([CH3:7])[C:2]=1[CH3:8]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cccnc1C
Solvent: ClC(Cl)Cl
Product: Cc1ccc[n+]([O-])c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a stirred solution of 2,3-lutidine (5.00 g, 46.7 mmol) in chloroform (100 mL) at 0° C. was added m-chloroperbenzoic acid (12.0 g of a 77% max reagent) portionwise over 5 min. The reaction mixture was stirred for an additional 30 min at 0° C. and then allowed to warm to room temperature. After 16 h, the reaction mixture was concentrated to dryness, water (20 mL) was added and the pH of the mixture was adjusted to 8 (saturated NaHCO3). The mixture was concentrated and the residue was extracted with dichloromethane/methanol (4:1). The extracts were concentrated to a white solid. Subsequent column purification (SiO2; dichloromethane/methanol, 9:1) gave 2,3-lutidine-N-oxide as a white solid (4.80 g, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[NH:13][N:12]=1.[H-].[Na+].I[CH2:24][CH2:25][CH3:26]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[C:14](=[C:15]([F:20])[CH:16]=[CH:17][CH:18]=2)[N:13]([CH2:24][CH2:25][CH3:26])[N:12]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)c(OC)c1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2OC)c2cccc(F)c21
Yield: 99.2 %

Procedure:
Prepared according to Method D step B from 3-(2,4-dimethoxyphenyl)-7-fluoro-1H-indazole (0.300 g, 1.10 mmol), sodium hydride (60% in oil, 0.058 g, 1.50 mmol) and iodopropane (0.195 mL, 2.00 mmol) to give the title compound (0.343 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[CH3:23])=[O:11])=[CH:4][CH:3]=1.NC1N=CC(/C=C/C(N(C)CC2N(C)C3C(C=2)=CC=CC=3)=O)=CC=1.[C:49]1(=O)[O:54][C:52](=[O:53])[CH2:51][CH2:50]1>O1CCOCC1>[O:53]=[C:52]1[CH2:51][CH2:50][C:49](=[O:54])[N:1]1[C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([N:12]([CH3:24])[CH2:13][C:14]2[S:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:15]=2[CH3:23])=[O:11])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1c(CN(C)C(=O)/C=C/c2ccc(N)nc2)sc2ccccc12
Agent: CN(Cc1cc2ccccc2n1C)C(=O)/C=C/c1ccc(N)nc1
Solvent: C1COCCO1
Product: Cc1c(CN(C)C(=O)/C=C/c2ccc(N3C(=O)CCC3=O)nc2)sc2ccccc12
Yield: 61.4 %

Procedure:
According to the procedure of Example 109, except substituting (E)-3-(6-amino-pyridin-3-yl)-N-methyl-N-(3-methyl-benzo[b]thiophen-2-ylmethyl)acrylamide (2.2 g, 6.6 mmol) for the (E)-3-(6-aminopyridin-3-yl)-N-methyl-N-(1-methyl-1H-indol-2-ylmethyl)acrylamide, and succinic anhydride (0.80 g, 8.0 mmol) in 1,4-dioxane (119 mL) was heated to reflux for 15 h overnight. The title compound (1.7 g, 61%) was prepared as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.01-7.91 (m, 1H), 7.80-7.72 (m, 2H), 7.70-7.63 (m, 1H), 7.43-7.39 (m, 3H), 7.01-6.92 (m, 1H), 5.01-4.85 (m, 2H), 3.21-3.10 (m, 3H), 2.90-2.85 (m, 4H), 2.44 (s, 3H); MS (ESI) m/e 420 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[C:12](=[CH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][CH2:14][C:3]=12.C([O-])=O.[NH4+]>[Pd].C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(=Cc1cccnc1)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1cccnc1)CC2
Yield: 52.1 %

Procedure:
A solution of 8,9-dihydro-10-methyl-7-[(pyridin-3-yl)methylene]pyrido[1,2-a]indol-6(7H)-one (520 mg), ammonium formate (568 mg) and 10% palladium on carbon (200 mg) in acetic acid (20 ml) was stirred at 110° C. for 2 hours. After filtration of the catalyst, the filtrate was evaporated in vacuo. The residue was diluted with 10% methanol-chloroform. The solution was washed with 5% aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel chromatography (5% methanol-chloroform), followed by recrystallization from ethyl acetate-ether, gave 8,9-dihydro-10-methyl-7-[(pyridin-3-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (273 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[N:8][CH:7]=[CH:6]2)#[CH:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.S([C:33]#[N:34])(C1C=CC(C)=CC=1)(=O)=O>C1COCC1>[CH:9]1[C:10]2[C:5](=[CH:4][C:3]([C:1]#[C:2][C:33]#[N:34])=[CH:12][CH:11]=2)[CH:6]=[CH:7][N:8]=1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: C#Cc1ccc2cnccc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CC#Cc1ccc2cnccc2c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 55.4 %

Procedure:
To a solution of 6-ethynylisoquinoline (0.10 g, 0.65 mmol) in 6.5 mL of THF at −78° C. was added LiHMDS, (0.78 mL, 1.0 M in THF). After 5 minutes, the mixture was warmed to 0° C. The mixture was stirred for 30 minutes and then chilled to −78° C. Tosyl cyanide (0.18 g, 0.98 mmol) was added. After 5 minutes, the reaction was warmed to 0° C. and stirred for 1 hour. The reaction was quenched with 10 mL of aq. NH4Cl. The biphasic mixture was extracted twice with 10 mL of EtOAc and the combined organic extracts were washed with 15 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (5% to 20% EtOAc/hexanes) afforded 3-(isoquinolin-6-yl)propiolonitrile (0.065 g, 0.36 mmol, 56% yield) as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:22][C:23]2[N:28]=[C:27]([N:29](CC)[CH2:30][C:31]3C=CC(OC)=CC=3)[C:26]3=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]3[N:24]=2)[C:6]([F:21])=[C:7]([N:9]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C@H:11]([OH:20])[CH2:10]2)[CH:8]=1)#[N:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[C:1]([C:3]1[CH:4]=[C:5]([NH:22][C:23]2[N:28]=[C:27]([NH:29][CH2:30][CH3:31])[C:26]3=[N:41][CH:42]=[C:43]([C:44]#[N:45])[N:25]3[N:24]=2)[C:6]([F:21])=[C:7]([N:9]2[CH2:14][CH2:13][C@@H:12]([NH:15][C:16](=[O:19])[O:17][CH3:18])[C@H:11]([OH:20])[CH2:10]2)[CH:8]=1)#[N:2]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2F)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OC)[C@H](O)C3)c2F)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 7.8 %

Procedure:
To methyl ((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate (60 mg, 0.098 mmol), in DCE (1.5 mL) was added ANISOLE (0.1 mL, 0.915 mmol) and TFA (1.0 mL, 12.98 mmol); the mixture stirred 2 h at 25° C. and solvent was removed. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: water with 20-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 20-mM ammonium acetate; Gradient: 15-100% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford methyl ((3R,4R)-1-(5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)-2-fluorophenyl)-3-hydroxypiperidin-4-yl)carbamate (3.8 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N(C(C)C)CC)(C)C.Cl[C:32]1[O:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1.O>O1CCCC1>[O:33]1[C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=[C:32]1[NH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:19]=[CH:20][CH:21]=1)[O:8][C:9]([CH3:18])([CH3:17])[C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11]
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCN)c1
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(C)(C)Oc1cccc(CCCNc2nc3ccccc3o2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
tert-Butyl 2-[3-(3-aminopropyl)phenoxy]-2-methylpropionate (167 mg, 0.57 mmol) was dissolved in tetrahydrofuran (3.0 mL). Subsequently, diisopropylethylamine (73.6 mg, 0.57 mmol) and then 2-chlorobenzoxazole (96.2 mg, 0.63 mmol) were added dropwise thereto, and the mixture was stirred for four hours at room temperature. Water was added thereto, and the resultant mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, followed by drying over sodium sulfate, concentration under reduced pressure, and purification by silica gel chromatography (n-hexane/ethyl acetate=3/1), whereby the target compound was obtained (173 mg, 74%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:20])[N:8]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9][CH2:10][CH2:11][C:5]=2[NH:4][C:3]=1[CH:21]=O.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])[CH2:34]3)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[C:33]3[C:37](=[CH:38][CH:39]=2)[NH:36][C:35](=[O:40])/[C:34]/3=[CH:21]\[C:3]2[NH:4][C:5]3[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][N:14]4[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]4)[C:7](=[O:20])[C:6]=3[C:2]=2[CH3:1])=[CH:27][CH:26]=1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CCC2
Reactant: COc1ccc(-c2ccc3c(c2)CC(=O)N3)cc1
Product: COc1ccc(-c2ccc3c(c2)/C(=C/c2[nH]c4c(c2C)C(=O)N(CCN2CCCCC2)CCC4)C(=O)N3)cc1
Yield: 68.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 5 of Example 32 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-1,4,5,6,7,8-hexahydro-pyrrolo[3,2-c]azepine-2-carbaldehyde 32d obtained from step 4 of Example 32 and 5-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as starting materials to obtain (Z)-2-[5-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-methyl-5-(2-piperidin-1-yl-ethyl)-5,6,7,8-tetrahydro-1H-pyrrolo[3,2-c]azepin-4-one 34 (68 mg, yield 68.7%) as a yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][C:17]([O:19]CC)=[O:18])[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].O.[OH-].[Li+]>O1CCCC1.CO.O.O>[CH2:1]([N:4]([CH2:16][C:17]([OH:19])=[O:18])[NH:5][C:6](=[O:15])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)OCC)NC(=O)NCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=CCN(CC(=O)O)NC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.9 %

Procedure:
To the solution of ethyl 2-(1-allyl-2-(benzylcarbamoyl)hydrazinyl)acetate (Compound V-1) 1.31 g (4.5 mmol) in tetrahydrofuran/methanol/water (2:3:1) 24 ml, lithium hydroxide monohydrate 377 mg (9.0 mmol) was added and stirred at room temperature for 5 hour. The reaction mixture was diluted with water 25 ml and washed with ether 25 ml. The aqueous phase was acidified with 10%-citric acid 25 ml and extracted with chloroform 30 ml. The organic phase was washed with brine 25 ml and dried with magnesium sulfate then filtered. The filtrate was concentrated in vacuo to obtain the title compound 982 mg (83%).
Reaction SMILES: [CH3:1][C:2](=[N:4][OH:5])[CH3:3].Cl[CH:7]([C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:17]=[C:18]([C:23]3([O:29][CH3:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:19]=[C:20]([F:22])[CH:21]=2)=[CH:11][CH:10]=1)[CH3:8]>>[F:22][C:20]1[CH:19]=[C:18]([C:23]2([O:29][CH3:30])[CH2:24][CH2:25][O:26][CH2:27][CH2:28]2)[CH:17]=[C:16]([S:15][C:12]2[CH:11]=[CH:10][C:9]([CH:7]([O:5][N:4]=[C:2]([CH3:3])[CH3:1])[CH3:8])=[CH:14][CH:13]=2)[CH:21]=1
Reactant: CC(C)=NO
Reactant: COC1(c2cc(F)cc(Sc3ccc(C(C)Cl)cc3)c2)CCOCC1
Product: COC1(c2cc(F)cc(Sc3ccc(C(C)ON=C(C)C)cc3)c2)CCOCC1
Temperature: 60 °C
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 1 except that the reactants were heated to 60° C. for 2 hours, acetone oxime was reacted with 4-{3-[4-(1-chloroethyl)phenylthio]-5-fluorophenyl}-4-methoxytetrahydropyran to give acetone O-{4-[5-fluoro-3-(4-methoxytetrahydropyran-4-yl)phenylthio)-α-methylbenzyl}oxime as an oil in 58% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1[CH2:21][CH2:20][CH2:19][C:18]1=O.C([Mg]Br)CCC>O1CCCC1.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.C/C(/[O-])=C/C(C)=O.[Fe+3]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:18][CH2:19][CH2:20][CH3:21])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1cccc(OCc2ccccc2)n1
Reactant: CN1CCCC1=O
Agent: [Fe+3]
Agent: CC(=O)/C=C(/C)[O-]
Agent: CCCC[Mg]Br
Solvent: C1CCOC1
Product: CCCCc1cccc(OCc2ccccc2)n1
Reaction time: 1 h

Procedure:
To a flask were added 2.0 g 2-(benzyloxy)-6-chloropyridine, 5.0 ml 1-methyl-2-pyrrolidinone and 50 ml of dry tetrahydrofuran. After cooling to 5 C under nitrogen, 0.16 g iron(III) acetylacetonate were added followed by drop wise addition of 8.5 ml of a 2M solution of butylmagnesium bromide in tetrahydrofuran. After stirring for 1 hour at 22 C, the reaction was cooled to 10 C and quenched with 20 ml aqueous ammonium chloride. The mixture was diluted with water and extracted with hexane. After washing with water and removal of solvent, the product was purified by silica gel chromatography using 10% ethyl acetate in hexane to give 1.6 g of an oil.
Reaction SMILES: CC(OC([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=O)(C)C.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]>ClCCl>[NH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([OH:16])[CH2:12][CH2:11]1.[F:17][C:18]([F:23])([F:22])[C:19]([OH:21])=[O:20]
Reactant: CC(C)(C)OC(=O)NCC1CCC(O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC[C@H]1CC[C@H](O)CC1

Procedure:
Tert-butyl ((1r,4r)-4-hydroxycyclohexyl)methylcarbamate (1 g) in dichloromethane (10 mL) was treated with trifluoroacetic acid (5 mL) at 0° C. for 10 minutes and at room temperature for 30 minutes. The reaction mixture was concentrated and dried in vacuo to provide the title compound as a trifluoroacetic acid salt.
Reaction SMILES: [CH3:1][N:2]([CH3:42])[C:3](=[O:41])[CH:4]([NH:30][S:31]([C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=1)(=[O:33])=[O:32])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20](=[O:29])[NH:21][O:22]C3C=CC=CC=3)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.[H][H]>CO.[Pd]>[OH:22][NH:21][C:20]([CH2:19][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][CH:4]([NH:30][S:31]([C:34]3[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=3)(=[O:33])=[O:32])[C:3]([N:2]([CH3:42])[CH3:1])=[O:41])=[CH:7][CH:8]=2)=[CH:13][CH:14]=1)=[O:29]
Reactant: Cc1ccc(S(=O)(=O)NC(Cc2ccc(-c3ccc(CCC(=O)NOc4ccccc4)cc3)cc2)C(=O)N(C)C)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)NC(Cc2ccc(-c3ccc(CCC(=O)NO)cc3)cc2)C(=O)N(C)C)cc1
Yield: 28.7 %

Procedure:
Palladium (5% on BaSO4) (0.5 g) was added to a degassed solution of the benzyl hydroxamate 56 (0.8 g) in MeOH (50 mL) and the suspension was treated with hydrogen at atmospheric pressure for 4 h. The suspension was filtered over a Celite® bed and concentrated to yield the desired hydroxamate 57 (0.2 g, 29%). 1H NMR (400 MHz, DMSO-d6): 10.39 (br, 1H), 8.09 (d, J=9.6 Hz, 1H), 7.54 (d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 4.33 (m, 1H), 2.81-2.86 (m, 3H), 2.75 (s, 3H), 2.61-2.67 (m, 1H), 2.53 (s, 3H), 2.28 (s, 3H).
Reaction SMILES: C([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)[CH:10]=[O:11])C1C=CC=CC=1.C1CCC=CC=1>CCO.[Pd]>[OH:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[S:14]1)[CH:10]=[O:11]
Reactant: O=CN(CC1Sc2ccccc2NC1=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCC=C1
Product: O=CN(O)CC1Sc2ccccc2NC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-benzyloxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide (0.17 mmol) in EtOH (12 mL) is added Pd/C (10%) (88.5 mg) followed by cyclohexadiene (1.8 mL). The reaction mixture is stirred at room temperature for 12 hours and the final product N-hydroxy-N-(3-oxo-3,4-dihydro-2H-benzo[1,4]thiazin-2-ylmethyl)-formamide is obtained by preparative LC/MS using 1 to 99% ACN as gradient. 1H NMR (400 MHz, MeOD): δ 8.48 (s, 0.4H), 7.97 (s, 0.6H), 7.49 (m, 2H), 7.19 (m, 2H), 4.03 (m, 2H), 3.5 (dd, 1H). MS: (ES+): 239.1[M+1].
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][NH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl>O1CCOCC1>[O:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CNc1ccc(Oc2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: c1ccc(Oc2ccc(NC[C@H]3CCCN3)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 119.8 %

Procedure:
To the product from step 1 (155 mg, 0.42 mmol) was added 4M HCl in dioxane (6 mL) and the resulting mixture was stirred at rt for 3 h. The solvent was removed in vacuo to obtain the product as a solid (135 mg, 94%). The solid was dried under vacuum oven at 50° C. for 15 h: MS; m/z 269 (M+H): LCMS (UV) 99.6%: Elemental analysis: Calc C, 59.83H, 6.50 N, 8.21. Found C, 59.69H, 6.55 N, 7.97. 1H NMR (400 MHz, DMSO-d6) δ 1.64-1.70 (m, 1H), 1.88-1.98 (m, 2H), 2.07-2.12 (m, 1H), 3.16-3.20 (m, 2H), 3.30-3.37 (m, 2H), 3.57 (s, 1H), 3.66-374 (m, 1H), 6.76 (d, 2H, J=8.8 Hz), 6.88 (t, 4H, J=18 Hz), 7.03 (t, 1H, J=16 Hz), 7.30-7.34 (m, 2H), 9.0 (s, 1H), 9.4 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([O-:38])=[O:37])[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[S:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:5])[CH3:2].C(OCC)(=O)C.[ClH:49]>>[ClH:49].[CH2:1]([O:3][C:4]([C@@H:6]([NH:26][C@@H:27]1[C:33](=[O:34])[N:32]([CH2:35][C:36]([OH:38])=[O:37])[C:31]2[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=2[S:29][CH2:28]1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)[O-])C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](CCCCCCCCN1C(=O)c2ccccc2C1=O)N[C@H]1CSc2ccccc2N(CC(=O)O)C1=O
Reaction time: 3 h

Procedure:
In 5 ml of 5N hydrogen chloride-ethyl acetate solution is dissolved 0.1 g of 3(R)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate, and the solution is left standing at room temperature for 3 hours. Petroleum ether (50 ml) is added to the solution and the deposited precipitate is dried under reduced pressure to give 0.076 g of 3(R)-[1(S)-ethoxycarbonyl-9-phthalimidononyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetic acid hydrochloride as a colorless powder.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[F:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[F:28][C:27]1[CH:26]=[C:25]2[C:16]([N:17]3[C:22]([CH2:23][O:24]2)=[N:21][NH:20][C:19](=[O:29])[CH:18]3[CH3:30])=[CH:15][C:14]=1[O:13][C:10]1([CH3:12])[CH2:9][NH:8][CH2:11]1
Reactant: CC1C(=O)NN=C2COc3cc(F)c(OC4(C)CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1C(=O)NN=C2COc3cc(F)c(OC4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 3-(7-fluoro-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.033 g, 0.078 mmol) in DCM (2 mL) was added TFA (0.5 mL) dropwise and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo to give 7-fluoro 4-methyl-6-(3-methyl-azetidin-3-yloxy)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a white solid (0.017 g, 67%). LC/MS (Table 1, Method 5) Rt=1.806 min; MS m/z: 321 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:1][C:4]1[S:8][C:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)c1ccc([N+](=O)[O-])s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(N)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 76.4 %

Procedure:
To a suspension of tert-butyl 5-nitrothiophene-2-carboxylate (Int. 54) (2.230 g, 9.73 mmol) in a mixture of EtOH (60 ml) and water (30 ml), iron powder (3.26 g, 58.4 mmol) and ammonium chloride (0.364 g, 6.81 mmol) were added. The reaction was stirred at 80° C. for 3 hours and then at RT overnight. The mixture was filtered through a celite pad and the filtrate was evaporated to dryness. The crude was then dissolved in EtOAc and washed with brine; the organic phase was dried over sodium sulfate and the solvent evaporated under vacuum. The residue was purified by filtration through a silica gel cartridge (petroleum ether/EtOAc=9/1 to 6/4) to yield tert-butyl 5-aminothiophene-2-carboxylate (Int. 55) (1.481 g, 7.43 mmol, MS/ESI+200.0 [MH]+).
Reaction SMILES: [CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=O)[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([NH:36][NH2:37])([NH2:35])=[NH:34].[ClH:38].Cl>C(O)C>[ClH:38].[ClH:38].[CH2:1]([N:8]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:9]1[CH:10]=[C:11]2[CH:17]=[C:16]([C:18](=[N:37][NH:36][C:33]([NH2:35])=[NH:34])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:15][C:12]2=[CH:13][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)NN
Reactant: O=C(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Agent: Cl
Solvent: CCO
Product: N=C(N)NN=C(c1ccccc1)c1cc2cc(N(Cc3ccccc3)Cc3ccccc3)ncc2[nH]1
Yield: 69.3 %

Procedure:
A mixture of [5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methanone (Example 55) (129 mg, 0.31 mmol), aminoguanidine hydrochloride (36 mg, 0.32 mmol) and 6 N HCl (0.26 mL) in ethanol (10 mL) was heated to reflux under a nitrogen atmosphere for 2.5 h. TLC analysis showed the remaining ketone, therefore additional aminoguanidine hydrochloride (10 mg, 0.09 mmol) was added. The reaction mixture was refluxed until TLC analysis showed the reaction was completed (2 h). After concentration to dryness, the crude material was triturated with EtOAc. The solid was collected by filtration and dried to provide [[[5-(dibenzylamino)-1H-pyrrolo[2,3-c]pyridin-2-yl](phenyl)methylene]amino]guanidine dihydrochloride (60.6 mg, 36%) as a yellow solid: ESI MS m/z 474 [C29H27N7+H]+; HPLC (Method A) 89.3% (AUC), tR=17.5 min.