Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:13])([CH3:12])[C:7](=[O:14])[C:6]([C:15](OCC)=[O:16])=[C:5]2[OH:20].Cl.[CH3:22][O:23][C:24](=[O:28])[C@@H:25]([CH3:27])[NH2:26].C(N(C(C)C)C(C)C)C>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([CH3:12])([CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:26][C@@H:25]([C:24]([O:23][CH3:22])=[O:28])[CH3:27])=[O:16])=[C:5]2[OH:20]
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Reactant: COC(=O)[C@@H](C)N
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)[C@@H](C)NC(=O)C1=C(O)c2cc(Cl)ccc2C(C)(C)C1=O
Temperature: 80 °C
Yield: 65.4 %

Procedure:
To ethyl 6-chloro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalene-3-carboxylate (100 mg, 339 μmol, see Example 2) and D-alanine methyl ester hydrochloride (71 mg, 509 mmol) was added 1,4-dioxane (339 μL) and N-ethyl-N-isopropylpropan-2-amine (177 μL, 1018 μmol). The reaction was then heated at 80° C. for 16 hours. The resulting reaction mixture was evaporated to give the title compound (78 mg) as an amorphous solid after purification via preparatory LC. MS m/e=352 (M+1)+.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([C:17]([F:20])([F:19])[F:18])[CH:9]=2)[CH2:6][CH2:5][NH:4][C:3]1=[O:21]>CO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([N:7]2[CH2:6][CH2:5][NH:4][C:3](=[O:21])[CH:2]2[CH3:1])=[CH:9][C:10]=1[C:17]([F:20])([F:19])[F:18]
Reactant: CC1C(=O)NCCN1c1ccc([N+](=O)[O-])c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: CC1C(=O)NCCN1c1ccc(N)c(C(F)(F)F)c1
Yield: 92 %

Procedure:
A solution of 3-methyl-4-(4-nitro-3-trifluoromethyl-phenyl)-piperazin-2-one (118 mg, 0.39 mmol) in MeOH (2 mL) was stirred at RT under a hydrogen atmosphere (1 bar) in the presence of palladium (10% on activated charcoal, 20 mg), then after 45 min insoluble material was removed by filtration through diatomaceous earth. The filtrate was evaporated to afford the title compound (98 mg, 92%). Light yellow viscous oil, MS: 274.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[CH:7][C:8]3[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=3[C:10]=2[N:11]=1.[N+:17]([O-])([OH:19])=[O:18]>>[OH:1][C:2]1[C:3]([OH:16])=[N:4][C:5]2[CH:6]=[C:7]([N+:17]([O-:19])=[O:18])[C:8]3[CH2:15][CH2:14][CH2:13][CH2:12][C:9]=3[C:10]=2[N:11]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1nc2ccc3c(c2nc1O)CCCC3
Product: O=[N+]([O-])c1cc2nc(O)c(O)nc2c2c1CCCC2
Temperature: -10 °C

Procedure:
7,8,9,10-Tetrahydro-2,3-dihydroxybenzo (f) quinoxaline (0.43 g, 2 mmol) was dissolved in 5 ml of nitric acid (d 1.48) by portionwise addition, with vigorous stirring on a salt/ice - bath at -10° C. After stirring at this temperature for 2 min, the mixture was poured onto 50 ml of ice/water. The precipitate was filtered off, washed with water, a small amount of ethanol, and ether affording 0.48 g (92%) of the mononitro compound; m.p. >300° C.; IR (KBr): 1720cm-1, (C=0); 1H-NMR (DMSO-d6): 1.5-1.9 (m, 4H, 2×CH2), 2.5 - 3.0 (m, 4H, 2×CH2), 7.50 (s, 1H, H-5), 11.2 (broad s, 1H, 0H), 11.9 (broad s, 1H, 0H).
Reaction SMILES: NC(=O)[C@@H](NC(C1(NC(=O)OC(C)(C)C)CCOCC1)=O)CC1C=CC(C2C=CC(F)=CC=2)=CC=1.[NH2:36][C:37](=O)[C@@H:38]([NH:58][C:59]([C:61]1([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1)=[O:60])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl>[C:37]([C@@H:38]([NH:58][C:59]([C:61]1([NH:67][C:68](=[O:74])[O:69][C:70]([CH3:71])([CH3:73])[CH3:72])[CH2:66][CH2:65][O:64][CH2:63][CH2:62]1)=[O:60])[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][C:49]([S:52]([CH:55]([CH3:57])[CH3:56])(=[O:54])=[O:53])=[CH:48][CH:47]=2)=[CH:42][CH:41]=1)#[N:36]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)cc1
Agent: CC(C)(C)OC(=O)NC1(C(=O)N[C@@H](Cc2ccc(-c3ccc(F)cc3)cc2)C(N)=O)CCOCC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Product: CC(C)S(=O)(=O)c1ccc(-c2ccc(C[C@@H](C#N)NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The mixture of (S)-tert-butyl 4-(1-amino-3-(4′-fluorobiphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate and (S)-tert-butyl 4-(1-amino-3-(4′-(isopropylsulfonyl)biphenyl-4-yl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 4, step (i), 620 mg) in dichloromethane (15 mL) was treated with Burgess' reagent (462 mg) and the mixture was stirred at room temperature for 2 days. The reaction was absorbed onto silica and was purified by chromatography on silica eluting with 25% ethyl acetate in isohexane and then 50% ethyl acetate in isohexane to afford after evaporation of the relevant fractions (S)-tert-butyl 4-(1-cyano-2-(4′-fluorobiphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (218 mg) and (S)-tert-butyl 4-(1-cyano-2-(4′-(isopropylsulfonyl)biphenyl-4-yl)ethylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (300 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.O1CCCC1.C([Li])CCC.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[CH2:31][CH2:30][C:29](=O)[CH:28]=2)=[CH:23][CH:22]=1>CCCCCC.C(OCC)C.O>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH:32]2[C:27]([C:24]3[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=3)=[CH:28][C:29]([C:2]3[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=3)=[CH:30][CH2:31]2)=[CH:38][CH:37]=1
Reactant: Fc1ccc(Br)cc1
Reactant: COc1ccc(C2=CC(=O)CCC2c2ccc(OC)cc2)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C2=CC(c3ccc(F)cc3)=CCC2c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A solution of 6.11 ml. of 4-bromofluorobenzene in 200 ml. of tetrahydrofuran was cooled to -60° C. by means of an external cooling bath. Under a nitrogen atmosphere, 33.75 ml. of a 1.6M solution of n-butyllithium in hexane were added at such a rate as to maintain the temperature between -65° to -55° C. After the addition was complete, the reaction was stirred for about 20 minutes. A solution of 15.11 g. of 3,4-bis(4-methoxyphenyl)-2-cyclohexen-1-one in 200 ml. of tetrahydrofuran was added over a period of about one hour. The reaction was then allowed to warm to 0° C. during the next three hours. Sixty milliliters of water were then added in a dropwise fashion. The solution was added to three liters of diethyl ether and the organic solution was washed several times with water. The organic solution was dried over sodium sulfate and evaporated in vacuo to dryness. The residue was dissolved in 400 ml. of toluene and treated with 2.5 g. of p-toluenesulfonic acid. The solution was allowed to reflux overnight. The solvent was then removed by evaporation and the residue was purified by chromatography to afford 13.98 g. of the title diene intermediate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:15][C:16]2[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[C:6]([CH:14]=1)[C:7](N(CC)CC)=[O:8].[Li+].CC([N-]C(C)C)C>C1COCC1.CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C>[Br:1][C:2]1[CH:14]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:15][C:16]1[CH:17]=[N:18][C:19]([Cl:22])=[CH:20][C:21]=1[C:7]2=[O:8]
Reactant: CCN(CC)C(=O)c1cc(Br)ccc1Oc1ccc(Cl)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: O=c1c2cc(Br)ccc2oc2cnc(Cl)cc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.2 %

Procedure:
A solution of 5-bromo-2-(6-chloropyridin-3-yloxy)-N,N-diethylbenzamide (457.5 g, 1.23 mol) in THF (3 L) was cooled to −74 to −78° C. and treated with a solution of LDA (2M in heptane/THF/ethyl benzene, 2.25 L, 4.5 mol. After the addition was complete, the solution was stirred for 30 min at −78° C. The cold bath was removed and then the reaction was quenched with saturated aqueous NH4Cl (1 L), maintaining the temperature below 10° C. The mixture was added to an addition funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3×2.5 L). The combined organic layers were dried over sodium sulfate, filtered and passed through a pad of silica gel. The filtrate was evaporated, and the residue was triturated with DCM to give 35 g of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one. The mother liquor was evaporated and the solid thus obtained was purified by recrystallization using dichloromethane/hexanes to give 90 g of 7-bromo-3-chloro-5H-chromeno[2,3-c]pyridin-5-one.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].[OH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1.C1CCN(C(Cl)=[N+]2CCCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CCOC(C)=O.C(Cl)Cl>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[CH:15][C:16]([NH:17][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][C:22]([OH:21])=[CH:23][CH:24]=3)=[CH:18][CH:19]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:1]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cc2)CC1
Agent: ClC(N1CCCCC1)=[N+]1CCCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(NC(=O)c3ccc(O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.8 %

Procedure:
To a 100 mL round bottomed flask with a stirring bar and an argon inlet was added 4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)aniline (0.868 g, 3.13 mmol), 4-hydroxybenzoic acid (0.525 g, 3.80 mmol), chloro-N,N,N',N',-bis(pentamethylene)formamidinium hexafluorophosphate (1.35 g, 3.74 mmol), and CH2Cl2 (45 mL). This mixture was cooled in an ice bath and diisopropylethylamine (0.96 mL, 5.52 mmol) was added. The ice bath was allowed to expire and the mixture was stirred at ambient temperature 18 h. The mixture was diluted with EtOAc and washed with 10% aqueous citric acid, water and brine. Drying (MgSO4), filtration and removal of the solvent in vacuo gave an oil. This material was chromatographed on 100 g of silica gel using 70% EtOAc-hexane as eluant to give 0.57 g of N-(4-(4-(1,1-dimethylethoxycarbonyl)piperazin-1-yl)phenyl)-4-hydroxybenzamide as a grey solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[CH3:17]>CCOC(C)=O.[Pd]>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[CH3:17])[NH2:8]
Reactant: Cc1ccncc1-c1ccc([N+](=O)[O-])cc1Cl
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccncc1-c1ccc(N)cc1Cl
Reaction time: 18 h
Yield: 88.7 %

Procedure:
To a solution of Intermediate 27A (0.136 g, 0.547 mmol) in EtOAc (2.73 mL) was added Pd/C (0.058 g, 0.055 mmol). The mixture was placed under an atmosphere of H2 for 18 hours. The reaction mixture was filtered through CELITE® and the filter cake was washed with CH2Cl2. The solvent was evaporated and the crude material re-dissolved in a minimal amount of CH2Cl2 and chromatographed. Purification of the crude material by silica gel chromatography using an ISCO machine (40 g column, 1-20% MeOH in CH2Cl2 over 25 min) gave the title compound (0.106 g, 0.485 mmol, 89% yield) as an orange residue. HPLC Ret timej:1.06 min. MS (ES): m/z=219.1 [M+H]+. Intermediate 27 was used in the synthesis of Example 178.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([F:10])=[C:7]([OH:9])[CH:8]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:10][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][C:7]=1[O:9][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Fc1ccc(C(F)(F)F)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-(trifluoromethyl)-2-fluorophenol (2.0 g), benzyl bromide (1.45 ml) and potassium carbonate (1.65 g) in dry DMF (20 ml) was stirred at RT overnight. The mixture was quenched with water and the solid filtered and dried, yield 2.20 g.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.Cl>C(Cl)Cl.O1CCOCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:21][N:22]4[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]4)=[C:19]([OH:35])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2c1ccc(O)c2CN1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.3 %

Procedure:
A solution of tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.025 g, 0.053 mmol) in methylene chloride (2.0 mL) was added with a 4 M solution of hydrogen chloride in 1,4-dioxane (2.0 mL), and then the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and then the residue was added with triethylamine and thereby made basic. Then, the mixture was azeotroped with toluene, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxy-7-(piperazin-1-ylmethyl)benzofuran-3(2H)-one (0.012 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]([N:22]3[CH:26]=[N:25][CH:24]=[N:23]3)[CH:19]([CH3:21])[CH3:20])=[CH:14][C:13]=2[N+:27]([O-])=O)=[O:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[K].Cl>CC(O)(C)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[NH:11][C:12]3[C:13]([N:27]=2)=[CH:14][C:15]([CH:18]([N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(c1ccc(NC(=O)Cc2ccc(Cl)cc2)c([N+](=O)[O-])c1)n1cncn1
Agent: Cl
Agent: [K]
Solvent: CC(C)(C)O
Solvent: c1ccncc1
Product: CC(C)C(c1ccc2[nH]c(=O)c(-c3ccc(Cl)cc3)nc2c1)n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a stirred mixture of 11 parts of 4-chloro-N-[4-[2-methyl-1-(1H-1,2,4-triazol-1-yl)propyl]-2-nitrophenyl]benzeneacetamide and 49 parts of pyridine were added 3.6 parts of 2-methyl-2-propanol, potassium salt under a nirogen atmosphere. After stirring for 1 hour at room temperature, the reaction mixture was poured into ice-water. The whole was neutralized with HCl 3N and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 98:2). The eluent of the desired fraction was evaporated, yielding 6.6 parts (61.8%) of 3-(4-chlorophenyl)-6-[2-methyl1-(1H-1,2,4-triazol-1-yl)propyl]-2(1H)-quinoxalinone, N4 -oxide (comp. 221).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([OH:18])=O)[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:8]2)=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[CH3:35][NH:36][OH:37]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:11]3=[CH:12][N:13]=[C:14]([C:16]([N:36]([OH:37])[CH3:35])=[O:18])[CH:15]=[C:10]3[C:9]([CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:8]2)=[CH:25][CH:26]=1
Reactant: CNO
Reactant: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)O)cc12
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOCc1cn(Cc2ccc(F)cc2)c2cnc(C(=O)N(C)O)cc12
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a solution of 1-(4-fluorobenzyl)-3-[(2-methoxyethoxy)methyl]-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid (200 mg 0.5581 mmol) in anhydrous DMF (10 mL) was added CDMT (118 mg 0.6695 mmol 1.2 eq.) and NMM (N-methyl morpholine) (0.074 mL 0.67 mmol 1.2 eq.). The mixture, under nitrogen, was stirred for 1.5 hours, during which it slowly darkened to a deep orange. N-Methylhydroxylamine hydrochloride (233 mg 2.79 mmol 5.0 eq) was added and stirring continued for 10 hours. The reaction was judged to be complete by HPLC-MS analysis and the volatiles were removed in vacuo (ca. 2 torr) to give a golden yellow oil. This oil was dissolved in EtOAc (30 mL) and washed with water (3×20 mL) and brine (20 mL). The organic phase was separated, dried (Na2SO4), and concentrated in vacuo to afford the crude product. Which was purified by chromatography on a column of silica gel (40 mm OD, 100 g, 230-400 mesh, packed with CH2Cl2, eluted with CH2Cl2—MeOH—NH3 97:2:1 v/v, 2.0 L, 25 mL fractions) using the flash technique. Fractions were combined to afford 0.080 g (37%) of 1-(4-fluorobenzyl)-N-hydroxy-3-[(2-methoxyethoxy)methyl]-N-methyl-1H-pyrrolo[2,3-c]pyridine-5-carboxamide. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, ESI, +mode): RT -2.062 min, m/e=388.1 (M+H+, base). 1H-NMR (300 MHz, CDCl3): o=3.38 (s, 3H), 3.47 (s, 3H), 3.57 (m, 2H), 3.68 (m, 2H), 4.78 (s, 2H), 5.37 (s, 2H), 7.04 (m, 2H), 7.13 (m, 2H), 7.42 (s, 1H), 8.46 (s, 1H), 8.64 (s, 1H). Found: C, 61.79; H, 5.83; N, 10.7%. C20H22FN3O4; 0.08H2O, requires C, 61.78; H, 5.74; N, 10.81%.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[NH:5][C:4]([NH2:8])=[N:3][CH:2]=1.[Br:9]Br>C(O)(=O)C>[NH2:8][C:4]1[N:5]=[C:6]([OH:7])[C:1]([Br:9])=[CH:2][N:3]=1
Reactant: Nc1nccc(=O)[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1ncc(Br)c(O)n1
Reaction time: 1 h
Yield: 140 %

Procedure:
To a solution of isocytosine(1.04 g, 9.36 mmol) in acetic acid(25 ml) are added dropwise bromine(0.51 ml, 9.83 mmol) at room temperature. After the addition is completed, the reaction mixture is stirred for 1 hour at this temperature, successively concentrated under reduced pressure to give the residue, which is washed with ethyl ether, dried to afford white powders(2.49 g, 98%).
Reaction SMILES: [NH2:1][C:2]([CH3:46])([CH3:45])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:8]=1)=[O:6].[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:54]([NH:56][C:57](=[O:103])NCCCNC(C1N=C2C(N=CN2[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)=C(NCC(C2C=CC=CC=2)C2C=CC=CC=2)N=1)=O)[CH3:55]>>[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50].[CH2:54]([NH:56][C:57](=[O:103])[NH:1][C:2]([CH3:46])([CH3:45])[CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@@H:16]2[CH2:20][C@H:19]([N:21]3[CH:25]=[C:24]([CH2:26][OH:27])[CH:23]=[N:22]3)[C@@H:18]([OH:28])[C@H:17]2[OH:29])=[C:9]([NH:30][CH2:31][CH:32]([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:8]=1)=[O:6])[CH3:55]
Reactant: CCNC(=O)NCCCNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Reactant: CC(C)(N)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1
Solvent: O=C(O)C(F)(F)F
Product: CCNC(=O)NC(C)(C)CNC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3C[C@H](n4cc(CO)cn4)[C@@H](O)[C@H]3O)c2n1

Procedure:
This compound is prepared from 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid (2-amino-2-methyl-propyl)-amide (Example 84, first step a) using a procedure analogous to that of 9-[(1R,2S,3R,4S)-2,3-dihydroxy-4-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentyl]-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid [3-(3-ethyl-ureido)-propyl]-amide trifluoroacetate (Example 87).
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7](=[O:37])[CH:8]([N:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[N:17]([S:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:16]2=[O:36])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.C(OC([N:45]1[CH2:50][CH2:49][C:48](=O)[CH2:47][CH2:46]1)=O)(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>C1COCC1>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]2[N:17]([S:25]([C:28]3[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)(=[O:27])=[O:26])[C:16](=[O:36])[N:15]([CH:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:7](=[O:37])[N:4]3[CH2:5][CH2:6][CH:2]([NH:1][CH:48]4[CH2:49][CH2:50][NH:45][CH2:46][CH2:47]4)[CH2:3]3)[C:19]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(N)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)n2c(=O)n(C(C(=O)N3CCC(NC4CCNCC4)C3)c3ccccc3)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 88.0 mg (0.16 mmol) of 3-[2-(3-aminopyrrolidin-1-yl)-2-oxo-1-phenylethyl]-5-chloro-1-(4-methoxybenzenesulfonyl)-1,3-dihydrobenzimidazol-2-one (example 166) in 5 ml of THF was mixed with 34.0 mg (0.17 mmol) of 1-tertbutoxycarbonyl-4-piperidone and 162 mg of MP-triacetoxyborohydride resin (Argonaut, 2.55 mmol/g, 0.41 mmol) and shaken at room temperature overnight. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated in vacuo, and the residue was dissolved in 3 ml of dichloromethane, mixed with 3 ml of trifluoroacetic acid and stirred at room temperature for 2 h. The solvent and excess trifluoroacetic acid were removed in vacuo, and the residue was taken up again in toluene and concentrated in vacuo. The residue was dissolved in dichloromethane, mixed with 3 eq. of MP-carbonate (Argonaut, 1.69 mmol/g) and stirred at room temperature for 2 h. The solid phase reagent was filtered off and washed with dichloromethane. The filtrate was concentrated under reduced pressure and dried in vacuo. The residue was purified by preparative RP-HPLC (mobile phase: gradient from 10% to 80% acetonitrile in water, 0.1% trifluoroacetic acid as modulator). Yield: 73.0 mg (72%) of colorless solid
Reaction SMILES: [F:1][C:2]1[C:3](F)=[C:4]2[O:9][CH2:8][CH:7]([CH3:10])[N:6]3[CH:11]=[C:12]([C:17]([OH:19])=[O:18])[C:13](=[O:16])[C:14]([CH:15]=1)=[C:5]23.Br.[N+:22]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][NH:28][CH2:29]2)([O-:24])=[O:23].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[N+:22]([C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[CH2:27][N:28]([C:3]1[C:2]([F:1])=[CH:15][C:14]3[C:13](=[O:16])[C:12]([C:17]([OH:19])=[O:18])=[CH:11][N:6]4[CH:7]([CH3:10])[CH2:8][O:9][C:4]=1[C:5]=34)[CH2:29]2)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1cccc2c1CNC2
Reactant: CC1COc2c(F)c(F)cc3c(=O)c(C(=O)O)cn1c23
Agent: Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC1COc2c(N3Cc4cccc([N+](=O)[O-])c4C3)c(F)cc3c(=O)c(C(=O)O)cn1c23
Yield: 46.8 %

Procedure:
185 mg of 9,10-difluoro-2,3-dihydro-3-methyl-7-oxo-7H-pyrido[1,2,3-de][1,4]-benzoxazine-6-carboxylic acid, 176 mg of 4-nitroisoindoline hydrobromide, 164 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 131 mg of the target compound.