Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][C@H:10]([C:13]([NH:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[C:20]([O:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[CH:21]=[CH:22][C:4]=2[N:3]=1.[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1>C(Cl)Cl>[F:33][C:34]1[CH:42]=[CH:41][C:37]([C:38]([N:1]([C:38](=[O:39])[C:37]2[CH:41]=[CH:42][C:34]([F:33])=[CH:35][CH:36]=2)[C:2]2[N:6]([C@H:7]3[CH2:12][CH2:11][C@@H:10]([C:13](=[O:14])[NH:15][CH:16]([CH3:18])[CH3:17])[CH2:9][CH2:8]3)[C:5]3[CH:19]=[C:20]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[CH:21]=[CH:22][C:4]=3[N:3]=2)=[O:39])=[CH:36][CH:35]=1
Reactant: COc1ccc(COc2ccc3nc(N)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(COc2ccc3nc(N(C(=O)c4ccc(F)cc4)C(=O)c4ccc(F)cc4)n([C@H]4CC[C@@H](C(=O)NC(C)C)CC4)c3c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of cis-4-(2-amino-6-(4-methoxybenzyloxy)-1H-benzo[d]imidazol-1-yl)-N-isopropylcyclohexanecarboxamide (424 mg, 0.971 mmol) and 4-fluorobenzoyl chloride (0.172 mL, 1.457 mmol) in DCM was added TEA (0.271 mL, 1.943 mmol), and the resulting mixture was stirred at RT for 10 minutes. The mixture was evaporated, and the residue diluted with DCM, washed with water, brine, and the organic layer dried over Na2SO4. The mixture was purified via flash chromatography using a linear gradient of 0% to 10% MeOH in DCM. The title compound was obtained as a tan foam (442 mg, max 80% yield, mixture of the mono and bis-acylated products).
Reaction SMILES: Cl.Cl.[CH2:3]([N:5]([CH2:30][CH3:31])[CH2:6][CH2:7][O:8][CH:9]1[C:14](OC)([O:15]C)[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10]1)[CH3:4].S(=O)(=O)(O)O>O>[CH2:30]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][O:8][CH:9]1[C:14](=[O:15])[CH2:13][CH2:12][N:11]([CH2:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH2:10]1)[CH3:31]
Reactant: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1(OC)OC
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CCN(CC)CCOC1CN(CCCOc2ccc(F)cc2)CCC1=O
Yield: 75 %

Procedure:
A mixture of 14.07 parts of N,N-diethyl-2-[[1-[3-(4-fluorophenoxy)propyl]-4-,4-dimethoxy-3-piperidinyl]-oxy]ethanamine dihydrochloride, 7.36 parts of a sulfuric acid solution 96% and 500 parts of water was stirred and refluxed for 17 hours. The reaction mixture was allowed to cool and washed with 2,2'-oxybispropane. The aqueous phase was separated and alkalized with sodium carbonate. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) saturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated, yielding 8.0 parts (75%) of 3-[2-(diethylamino)-ethoxy]-1-[3-(4-fluorophenoxy)propyl]-4-piperidinone a residue (intermediate 120).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:13]([C:31](O)=[O:32])=[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[CH3:30])[C:15]=2[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:5]=[CH:6][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[CH:6]=[N:5][N:4]2[C:13]([C:31]([N:44]3[CH2:43][CH2:42][N:41]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:40])[CH2:46][CH2:45]3)=[O:32])=[C:14]([CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=3[CH3:30])[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:3]2[C:2]=1[Cl:1])=[O:9])[CH3:12]
Reactant: CCOC(=O)c1cnn2c(C(=O)O)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cnn2c(C(=O)N3CCN(C(=O)OC(C)(C)C)CC3)c(Cc3cccc(F)c3C)c(-c3ccccc3)c2c1Cl
Yield: 94.8 %

Procedure:
The compound of step 8 (2.335 g, 5.00 mmol), 1-tert-butoxycarbonyl-piperazine (1.024 g, 5.50 mmol), EDIA (2.18 ml, 12.50 mmol) and TBTU (1.766 g, 5.50 mmol) in 50 ml of anhydrous DCM were stirred at room temperature for 1 h. The solution was then washed with 0.5 N hydrochloric acid (75 ml) and the aqueous phase was extracted with DCM (25 ml). The combined organic phases were washed with a saturated solution of sodium hydrogencarbonate (50 ml) and brine (50 ml), dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/EA, 80:20, then 75:25) to give 3.01 g of the title compound as a yellow solid melting at 88-90° C.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Br:5][C:6]1[C:10]([Br:11])=[C:9]([Br:12])[NH:8][N:7]=1.C(OC(=O)C)(=O)C>C(O)(=O)C>[N+:1]([N:7]1[C:6]([Br:5])=[C:10]([Br:11])[C:9]([Br:12])=[N:8]1)([O-:4])=[O:2]
Reactant: Brc1n[nH]c(Br)c1Br
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])n1nc(Br)c(Br)c1Br
Temperature: 15 °C
Reaction time: 2 h

Procedure:
HNO3 (d=1.50 g/ml; 18 ml, 0.429 mol) was added dropwise over 10 minutes to a solution of 3,4,5-tribromopyrazole (50 g, 0.164 mol) in glacial acetic acid (750 ml) while maintaining the temperature at 15° C. Acetic anhydride (250 ml) was added and the reaction mixture was stirred at room temperature for 2 hours. Once the reaction was complete, the reaction mixture was poured onto crushed ice (1 kg). After stirring for 1 hour, the crude product was filtered off and then washed with demineralized water (2×60 ml) to give crude 1-nitro-3,4,5-tribromopyrazole. The water (24.6 ml) contained in the wet product was removed by heating a solution of the product in toluene (750 ml) at reflux in Dean-Stark apparatus. The toluene solution was maintained at reflux for a further 30 minutes until a TLC (eluent:toluene) showed that the rearrangement of the 1-nitro-3,4,5-tribromopyrazole (Rf=0.77), the intermediate formed, into 3,4,5-dibromo-4-nitropyrazole 2 (Rf=0.05) was complete. The solution was concentrated to a residual volume of 150 ml and then allowed to cool to 60° C., followed by addition of hexane (275 ml). The solution was cooled to 0-5° C. for 1 hour and the 3,5-dibromo-4-nitropyrazole 2 (29.1 g, 65%) was recovered by filtration and drying under vacuum in the form of a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH3:17].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:16]([N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1)[CH3:17]
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 102.1 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (V-1) (3 g, 15 mmol) in DMF (6 mL) were added bromoethane (3.24 g, 30 mmol) and K2CO3 (4.26 g, 30 mmol). The reaction mixture was stirred at 60° C. overnight, then diluted with EtOAc, washed with water and then brine. The organic layer was separated, then dried over Na2SO4, and concentrated to afford the title compound (3.40 g). MS (m/z): 223 (M+1)+.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH3:12][O:13][N:14]=[CH:15][C:16]1[N:17]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[CH:20][C:19]=2[N:28]=1.[OH-].[NH4+:34].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:12][O:13][N:14]=[CH:15][C:16]1[N:17]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:18]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:34])[C:19]=2[N:28]=1
Reactant: [NH4+]
Reactant: CON=Cc1nc2cnc3ccccc3c2n1CC(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CON=Cc1nc2c(N)nc3ccccc3c2n1CC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
mCPBA (1.75 g of 77% pure material, 7.79 mmol) was added in portions over a period of five minutes to a solution of 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime (1.1 g, 3.9 mmol) in chloroform (40 mL), and the reaction was stirred at room temperature for one hour. Ammonium hydroxide (20 mL) was added, and the resulting mixture was stirred for five minutes before the addition of p-toluenesulfonyl chloride (0.891 g, 4.68 mmol) in portions. The reaction mixture was stirred at room temperature for 1.5 hours. The aqueous layer was then separated and extracted with dichloromethane (3×30 mL). The combined organic fractions were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.2 g of crude product as a brown foamy solid. The crude product was dissolved in dichloromethane (15 mL) and purified by chromatography using a HORIZON HPFC system (FLASH 40M silica cartridge available from Biotage, Inc., eluting with 2% to 7% methanol in ethyl acetate). The resulting product (580 mg) was recrystallized from acetonitrile (10 mL), and the crystals were isolated by filtration, washed with diethyl ether, and dried overnight in a vacuum oven at 65° C. to provide 236 mg of 4-amino-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-carbaldehyde O-methyloxime as a brown solid, mp 181-183° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([OH:10])[CH:3]=1.[CH3:11][NH:12][NH2:13]>>[NH2:9][C:8]1[C:7]2[C:2](=[CH:3][C:4]([OH:10])=[CH:5][CH:6]=2)[N:12]([CH3:11])[N:13]=1
Reactant: N#Cc1ccc(O)cc1F
Reactant: CNN
Product: Cn1nc(N)c2ccc(O)cc21
Temperature: 25 °C

Procedure:
A solution of 6-fluoro-4-hydroxy benzonitrile (Aldrich, 10.1 g, 73.9 mmol) in methyl hydrazine (Aldrich, 20.0 mL, 379 mmol) was stirred at 80° C. for 16 h. After cooling to RT, the volatile portion was removed in vacuo. The residue was triturated with DCM and MeOH. The title compound was obtained by filtration as an off-white solid. The filtrate was concentrated in vacuo and purified by silica gel chromatography (DCM/MeOH: 100/0 to 95/5) to give an additional amount of the title compound as a white solid.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3].[OH:14]/[N:15]=[C:16](\[NH2:18])/[CH3:17].C(N(CC)CC)C>ClCCl>[NH2:18]/[C:16](=[N:15]\[O:14][C:2]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][N:13]=1)[C:7]([O:9][CH3:10])=[O:8])=[O:3])/[CH3:17]
Reactant: C/C(N)=N/O
Reactant: COC(=O)c1ccnc(C(=O)Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccnc(C(=O)O/N=C(/C)N)c1

Procedure:
To a solution of methyl 2-(chlorocarbonyl)isonicotinate in dichloromethane (500 mL) was added (Z)-N′-hydroxyacetimidamide and triethylamine, keeping the temperature at 25-30° C. for 1 day. The reaction was concentrated in vacuo to afford (Z)-methyl 2-((1-aminoethylideneaminooxy)carbonyl)isonicotinate as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH2:23])([CH3:4])([CH3:3])[CH3:2].C([O:29][C:30](=O)[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[O:41][N:40]=2)[CH:34]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:21])([F:22])[F:20])=[CH:10][C:9]=1[NH:23][C:30](=[O:29])[CH2:31][C:32](=[O:52])[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:43]=[C:42]([CH2:44][O:45][CH:46]3[CH2:51][CH2:50][CH2:49][CH2:48][O:47]3)[O:41][N:40]=2)[CH:34]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Product: CC(C)(C)OC(=O)Nc1cc(N2CCCC2)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1

Procedure:
The title compound was prepared from (2-amino-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J12) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionic acid tert.-butyl ester (Example K15) according to the general procedure M. Obtained as a yellow foam (522 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:14]([CH3:13])[C@H:15]2[CH2:34][N:19]3[C:20]4[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]3[CH2:17][CH2:16]2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)Cc1ccc(F)c(Cl)c1
Product: CN(C(=O)Cc1ccc(F)c(Cl)c1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from (3-chloro-4-fluorophenyl)acetic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 429.
Reaction SMILES: I[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14]=1[C:3]1[O:4][C:5]2[C:10]([C:11](=[O:12])[CH:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: O=c1c(I)coc2ccccc12
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2nc3ccccc3[nH]2)oc2ccccc12
Temperature: 0 °C
Yield: 87.3 %

Procedure:
To an eggplant type flask (25 ml), 3-iodochromone (136 mg) prepared in Example 1, benzimidazole (236 mg), potassium carbonate (1382 mg), and dimethylformamide (15 ml) were added and the mixture was reacted at 80° C. for 2 hours with stirring. The reaction mixture was added to ice water and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purifiedby the silica gel column chromatography, and the purified compound was recrystallized from benzene/hexane to give the titled compound (114.5 mg; yield=87.0 %) as white needle crystals. Melting point: 232° C. 1H-NMR(CDCl3, δ ppm): 6.59 (s, H3), 8.28 (dd, H5), 7.48-7.64 (m, H6), 7.78 (t, H7), 7.48-7.64 (m, H8), 8.48 (s, H2'), 7.86-7.94 (m, H4'), 7.45-7.50 (m, H5'), 7.45-7.50 (m, H6'), 7.86-7.94 (m, H7').
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[CH3:20][NH:21][CH2:22][CH2:23][CH3:24]>CS(C)=O>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:21]([CH3:20])[CH2:22][CH2:23][CH3:24])[C:11]([Cl:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Reactant: CCCNC
Solvent: CS(C)=O
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1Cl

Procedure:
The title compound was prepared from (4,5-dichloro-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example B2) (3.0 g, 9.77 mmol) and N-methyl-propyl-amine (2.50 g, 34.2 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a pale brown solid (3.58 g).
Reaction SMILES: O.[C:2]([NH:5][O-:6])(=[O:4])[CH3:3].[K+].[Cl:8][C:9]1[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH2:15][CH2:16]Br)=[CH:11][CH:10]=1.[K+].[Br-]>COCCO>[C:2]([NH:5][O:6][CH2:16][CH2:15][CH2:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([Cl:8])=[CH:19][CH:18]=1)(=[O:4])[CH3:3]
Reactant: Clc1ccc(OCCCBr)cc1
Reactant: CC(=O)N[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: COCCO
Product: CC(=O)NOCCCOc1ccc(Cl)cc1
Temperature: 50 °C
Yield: 105.8 %

Procedure:
To a solution of 0.91 kg (8.0 moles) of potassium acetohydroxamate hydrate in 4.96 kg of 2-methoxyethanol solution was added 1650 g (6.62 moles) of 3-(4-chlorophenoxy)propyl bromide. An additional 200 mL of 2-methoxyethanol was added and the reaction mixture was heated 2 hours at 50° C. After cooling to room temperature the KBr was removed by filtration and washed with 100 mL of 2-methoxyethanol. The filtrate and washings were concentrated on a rotovap, diluted with 1.0 L of EtOAc, and washed with a 600 mL and a 400 mL portion of water before concentration at high vacuum to yield 1707 g of crude 3-(4chlorophenoxy)propyl acetohydroxamate which was used without further purification. This crude material was dissolved in 5.0 L of methanol and 640 g of conc. HCl was added. After 15 hr the starting material was consumed, as determined by TLC utilizing the diazonium spray. The mixture was concentrated at oil pump vacuum to give 1537 g of crude product which was used without further purification. A sample recrystallized from EtOAc melted 115-116° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH2:15])[CH:6]=1)[CH3:3].[N+](N[C:20]1[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]2[CH:33]=[CH:32][N:31]([CH3:34])[C:30](=[O:35])[CH:29]=2)=[CH:22][N:21]=1)([O-])=O.N1C=CC=CC=1>C(O)C>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11][S:12][CH2:13][CH2:14][NH:15][C:20]2[NH:25][C:24](=[O:26])[C:23]([CH2:27][C:28]3[CH:33]=[CH:32][N:31]([CH3:34])[C:30](=[O:35])[CH:29]=3)=[CH:22][N:21]=2)[CH:6]=1)[CH3:1]
Reactant: Cn1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cc1=O
Reactant: CN(C)Cc1ccnc(CSCCN)c1
Solvent: c1ccncc1
Solvent: CCO
Product: CN(C)Cc1ccnc(CSCCNc2ncc(Cc3ccn(C)c(=O)c3)c(=O)[nH]2)c1
Yield: 56.5 %

Procedure:
2-[4-(Dimethylaminomethyl)pyrid-2-ylmethylthio]ethylamine (0.63 g) and 2-nitroamino-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (0.69 g) were refluxed in ethanol (12 ml) for 72 hours. As the reaction was not complete, the ethanol was replaced by pyridine (12 ml) and the solution refluxed for a further 6 hours. The reaction mixture was evaporated under reduced pressure to afford a residue which was washed with diethyl ether and recrystallised from isopropanol/ether to give 2-[2-[4-(dimethylaminomethyl)pyrid-2-ylmethylthio]ethylamino]-5-(1-methyl-2-oxopyridin-4-ylmethyl)pyrimidin-4-one (0.62 g), m.p. 137°-139° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[NH:8][C:7]=12.[CH2:13](I)[CH:14]=[CH2:15]>>[CH2:15]([N:8]1[C:7]2=[C:2]([Cl:1])[N:3]=[CH:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]1[CH3:12])[CH:14]=[CH2:13]
Reactant: Cc1[nH]c2c(Cl)nccc2c1C
Reactant: C=CCI
Product: C=CCn1c(C)c(C)c2ccnc(Cl)c21
Yield: 75 %

Procedure:
In accordance with the same procedures as in Step 2 of Example 198, except for using 7-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine prepared in Step 1 of Example 198 and allyl iodide, the titled compound was obtained as a white solid. (Yield: 75%)
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[C:13]([O:17][C:18]([NH:20][CH:21]([CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH2:33])[C:22](O)=[O:23])=[O:19])([CH3:16])([CH3:15])[CH3:14].C(OCC)(=O)C>CN(C)C=O>[C:13]([O:17][C:18]([NH:20][C@@H:21]1[C:22](=[O:23])[NH:33][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[NH:26][CH2:25]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1N)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CNc2ccccc2NC1=O
Reaction time: 18 h
Yield: 71.2 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (8.54 g, 44.5 mmol) was added to a cooled (0° C.) solution of 2-tert-butoxycarbonylamino-3-(2-aminophenylamino)propionic acid (11.95 g, 40.5 mmol) in 100 ml of dimethylformamide and stirred for 18 hours. The reaction was poured into 700 ml of ethyl acetate and washed four times with 100 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered, and evaporated to give a brown solid that was purified by flash chromatography eluting with 3:7 ethyl acetate/hexane to give 8 g (71%) of the title compound: 1H NMR (CDCl3) δ 7.78 (1H, s), 7.02-6.95 (1H, m), 6.88-6.82 (1H, m), 6.82-6.78 (1H, m), 6.75-6.70 (1H, m), 5.8-5.7 (1H, d), 4.55-4.45 (1H, m), 3.95 (1H, s), 3.9-3.82 (1H, m), 3.48-3.40 (1H,m), 1.45 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:9][C:4]1[CH:3]=[C:2]([NH2:1])[CH:7]=[CH:6][C:5]=1[O:8][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: OCc1ccccn1
Reactant: Nc1ccc(O)c(Cl)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Nc1ccc(OCc2ccccn2)c(Cl)c1
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To a mixture of 4-amino-2-chloro-phenol (1.0 g, 6.96 mmol), 2-hydroxymethylpyridine (1.52 g, 13.92 mmol), Ph3P (3.65 g, 13.92 mmol) in THF (30 ml) was added DIAD (2.74 ml, 13.92 mmol). The reaction mixture was stirred overnight and then concentrated in vacuo, and dissolved in EtOAc (100 ml). The resulting solution was extracted with 1N HCl (60 ml); the aqueous layer was washed with EtOAc (2×60 ml), then basified with solid NaHCO3. The mixture was extracted with EtOAc (2×100 ml) and the combined EtOAc extracts were washed with brine (1×40 ml), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel flash column to give 1C (0.54 g, 33%) (50%–80% EtOAc-Hexanes). Analytical HPLC retention time=0.61 min. (YMC S5 ODS column 4.6×50 mm, 10–90% aqueous methanol over 4 minutes containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220 nm) and a LC/MS M++1=235.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25](Cl)[N:24]=2)[CH:18]=1)[S:12]([CH3:15])(=[O:14])=[O:13])(C)(C)C.[NH2:31][CH2:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>>[NH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][C:17]1[CH:18]=[C:19]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:31][CH2:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([S:40]([NH2:43])(=[O:41])=[O:42])=[CH:38][CH:39]=3)[N:24]=2)[CH:20]=[CH:21][CH:22]=1)[S:12]([CH3:15])(=[O:13])=[O:14]
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Reactant: CC(C)(C)OC(=O)NCCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)S(C)(=O)=O
Product: CS(=O)(=O)N(CCCN)Cc1cccc(-c2ccnc(NCCc3ccc(S(N)(=O)=O)cc3)n2)c1

Procedure:
Intermediate 4 was coupled with 4-(2-Amino-ethyl)-benzenesulfonamide following procedure F and the resulting product deprotected following procedure G. LC-MS showed the product had the expected M+H+ of 519. 1H NMR (Varian 300 MHz, CDCl3—CD3OD, shifts relative to the solvent peak at 7.24 ppm) δ 8.0 (m, 2H) 7.8 (m, 1H) 7.6 (m, 4H) 7.4 (m, 1H) 7.2 (m, 2H) 4.3 (s, 2H) 3.8 (m, 2H) 3.4 (m, 2H) 2.9 (m, 2H) 2.8 (s, 3H) 2.6 (m, 2H) 1.6 (m, 2H).
Reaction SMILES: [Si](CO[C:20]1([CH2:23][O:24][C:25]2[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[CH:27][C:26]=2[C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][CH2:38][C:39]3=[O:44])[CH2:22][CH2:21]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:66]1CCC[CH2:67]1>>[OH:66][CH2:67][C:20]1([CH2:23][O:24][C:25]2[C:30]([O:31][CH3:32])=[C:29]([O:33][CH3:34])[CH:28]=[CH:27][C:26]=2[C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH2:37][CH2:38][C:39]3=[O:44])[CH2:22][CH2:21]1
Reactant: C1CCOC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(OC[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)CC2)c1OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COc1ccc(-c2cccc3c2CCC3=O)c(OCC2(CO)CC2)c1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirring solution of 4-(2-((1-((tert-butyldiphenylsilyl)methoxy)cyclopropyl)methoxy)-3,4-dimethoxyphenyl)-2,3-dihydro-1H-inden-1-one (5 g, 6.25 mmol) in tetrahydrofuran, was added tetrabutylammonium fluoride trihydrate (33 mL, 33 mmol) and the resultant reaction mixture was stirred at RT for 16 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×). The combined ethyl acetate layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure. Purification was done by column chromatography (silica gel, 0-40% ethyl acetate in pet ether) to afford the title compound as a yellow solid.