Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:16]=[C:17](/[C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)\[C:18]([OH:20])=[O:19])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[CH3:28]O>>[CH3:28][O:19][C:18](=[O:20])/[C:17](/[C:21]1[CH:22]=[CH:23][C:24]([OH:27])=[CH:25][CH:26]=1)=[CH:16]\[C:10]1[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=[C:8]([O:7][CH3:6])[CH:9]=1
Reactant: COc1cc(/C=C(\C(=O)O)c2ccc(O)cc2)cc(OC)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)/C(=C\c1cc(OC)cc(OC)c1)c1ccc(O)cc1
Yield: 35 %

Procedure:
Concentrated sulfuric acid. (10 drops) was added to a stirred methanol suspension of thoroughly dried 19 (0.60 g, 2.0 mmol) under argon and heated at reflux for 18 h. Methanol was evaporated under reduced pressure, residue was taken up in ethyl acetate (20 mL) and washed with water (20 mL), saturated aqueous Na HCO3 (10 mL) and brine (10 mL). The organic layer was dried on anhydrous magnesium sulfate, filtered and the solvent was evaporated. The crude product obtained was purified by chromatography over silica gel and eluted with hexane-ethyl acetate (7:3) to yield 20 as white solid (0.24 g, 35%): 1HNMR (400 MHz, CDCl3) δ 7.26 (d, J=8.4 Hz, 2H), 6.82 (s, 1H), 6.76 (d, J=8.4 Hz, 2H), 6.45 (d, J=2.0 Hz, 2H), 6.34 (t, J=2.0 Hz, 1H), 4.97 (s, 1H), 3.73 (s, 3H), 3.72 (s, 6H).
Reaction SMILES: [NH2:1][CH:2]([C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C@H:19]3[O:23]C(C)(C)[N:21]([C:26](=[O:30])[CH:27]([F:29])[F:28])[C@H:20]3[CH2:31][F:32])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:1][CH:2]([C:7]1[N:12]=[CH:11][C:10]([C:13]2[CH:14]=[CH:15][C:16]([C@@H:19]([OH:23])[C@H:20]([NH:21][C:26](=[O:30])[CH:27]([F:29])[F:28])[CH2:31][F:32])=[CH:17][CH:18]=2)=[CH:9][CH:8]=1)[C:3]([F:4])([F:5])[F:6]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(C(N)C(F)(F)F)nc3)cc2)[C@H](CF)N1C(=O)C(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 40.6 %

Procedure:
To a stirred solution of 1-((4R,5R)-5-{4-[6-(1-Amino-2,2,2-trifluoro-ethyl)-pyridin-3-yl]-phenyl}-4-fluoromethyl-2,2-dimethyl-oxazolidin-3-yl)-2,2-difluoro-ethanone (35 mg, 0.076 mmol) in CH2Cl2 (1 mL) is added trifluoroacetic acid (1 mL) at 0° C. then stirred to room temperature for 3 hours. The solvent evaporated in vacuo and the crude material is diluted with ammonia solution and extract with ethyl acetate. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by preparative TLC using in 70% ethyl acetate in hexane to afford the title compound (0.013 g): 1H-NMR (400 MHz, DMSO-d6) δ: 2.66 (d, J=7.28 Hz, 2H), 4.30-4.36 (m, 1.5H), 4.40-4.44 (m, 0.5H), 4.54-4.55 (m, 0.5H), 4.61-4.68 (m, 1.5H), 4.89 (t, J=3.8 Hz, 1H), 5.93 (d, J=4.36 Hz, 1H), 6.19 (t, J=53.8 Hz, 1H), 7.45 (d, J=8.32 Hz, 2H), 8.00 (d, 1.16 Hz, 2H), 8.05 (d, J=8.28 Hz, 2H), 8.73 (s, 1H), 8.84 (d, J=8.56 Hz, 1H). LC-MS (m/z): [M+H]=422.0.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>O1CCCC1>[CH3:24][NH:25][C:26]([NH:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][S:16]([CH3:19])(=[O:18])=[O:17])=[CH:11][C:10]=3[O:20][CH3:21])[NH:8][C:4]=2[CH:3]=1)=[O:27]
Reactant: COc1cc(OS(C)(=O)=O)ccc1-c1nc2ccc(N)cc2[nH]1
Reactant: CN=C=O
Solvent: C1CCOC1
Product: CNC(=O)Nc1ccc2nc(-c3ccc(OS(C)(=O)=O)cc3OC)[nH]c2c1
Reaction time: 0.25 h

Procedure:
One gram (3.0 mmol) of 5-amino-2-(2'-methoxy-4'-methanesulfonyloxy-phenyl)-benzimidazole was dissolved in 30 ml of pure tetrahydrofuran, 2.0 ml of methylisocyanate were added, and the mixture was refluxed. After 15 minutes that solvent and any excess methylisocyanate were evaporated off in vacuo, and the residue obtained was chromatographed over 250 gm of aluminium oxide (neutral) (eluant: methylene chloride with 4% ethanol).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]>S(Cl)(Cl)=O>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([O:8][C:5]([CH3:9])([CH3:6])[CH3:4])=[O:7])([O-:3])=[O:2]
Reactant: O=C(O)c1ccccc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)c1ccccc1[N+](=O)[O-]
Yield: 141.3 %

Procedure:
A mixture of 2-nitrobenzoic acid (25.0 g.) and thionyl chloride (50 ml.) was refluxed for an hour and then evaporated. To the residue was added benzene (125 ml.) followed by removal of benzene. To the residue were added benzene (125 ml.), pyridine (23.7 g.) tert-butyl alcohol (22.2 g.) under ice-cooling and then the resulting solution was refluxed under heating for 2 hours. The reaction mixture was poured into ice water. The benzene layer was separated, washed successively with water, 1 N aqueous solution of sodium hydroxide (twice), water 1 M aqueous solution of citric acid (twice), water and an aqueous solution of sodium chloride, dried over magnesium sulfate and then treated with activated charcoal. Thus obtained organic layer was chromatographed on silica gel (150 g.) eluting with a mixture of benzene and n-hexane (1:1) to give a yellowish oil of the title compound (23.6 g.)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2C=N[CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].BrC1[S:19]C=CN=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]2[S:19][CH:14]=[CH:13][N:12]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Brc1nccs1
Reactant: Cc1ccc(-c2cnccn2)c(C(=O)O)c1
Product: Cc1ccc(-c2nccs2)c(C(=O)O)c1

Procedure:
The title compound was prepared following the same general protocol as described for 5-methyl-2-(pyrazin-2-yl)benzoic acid in Example A19, starting from 2-bromothiazole. ESI-MS (m/z): 220 [M+1]+.
Reaction SMILES: [CH2:1]([NH:5][C:6]([NH2:8])=[O:7])[CH:2]([CH3:4])[CH3:3].Cl[CH:10]([C:16]([C:18]([F:21])([F:20])[F:19])=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>>[CH3:3][CH:2]([CH3:4])[CH2:1][NH:5][C:6]1[O:7][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:16]([C:18]([F:19])([F:21])[F:20])[N:8]=1
Reactant: CCOC(=O)C(Cl)C(=O)C(F)(F)F
Reactant: CC(C)CNC(N)=O
Product: CCOC(=O)c1oc(NCC(C)C)nc1C(F)(F)F
Yield: 33.7 %

Procedure:
By the procedure of Example 4, 7.0 g (60 mmol) of isobutyl urea was reacted with 10.9 g (50 mmol) of ethyl 2-chloro-4,4,4-trifluoroacetoacetate at 140°-150° C. for 18 hours. The product was separated and then recrystallized from methylcyclohexane to yield 4.72 g of a yellow powder product (m.p.=43°-44° C.) identified in Table I.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40](O)=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(C1N=C(C2C=C(OC3CC4N(C(=O)CCCCCCC=CC5C(C([NH:88][S:89]([CH:92]6[CH2:94][CH2:93]6)(=[O:91])=[O:90])=O)(NC4=O)C5)C3)C3C(=CC(OC)=CC=3)N=2)SC=1)(C)C>>[CH:1]([C:4]1[N:5]=[C:6]([C:9]2[CH:18]=[C:17]([O:19][CH:20]3[CH2:38][CH:37]4[N:22]([C:23](=[O:43])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[CH:31][CH:32]5[C:34]([C:40]([NH:88][S:89]([CH:92]6[CH2:94][CH2:93]6)(=[O:91])=[O:90])=[O:41])([NH:35][C:36]4=[O:39])[CH2:33]5)[CH2:21]3)[C:16]3[C:11](=[C:12]([CH3:46])[C:13]([O:44][CH3:45])=[CH:14][CH:15]=3)[N:10]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCCCC(=O)N4C3)cc(-c3nc(C(C)C)cs3)nc2c1C

Procedure:
The title compound was prepared from 18-[2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (29) following the procedure reported for synthesis of N-[[18-[2-[4-(isopropyl)thiazol-2-yl]-7-methoxyquinolin-4-yloxy]-2,15-dioxo-3,16-diazatricyclo[14.3.0.04,6]nonadec-7-en-4-yl]carbonyl](cyclopropyl)sulfonamide 11: m/z=750 (M+H)+. 1H NMR (CDCl3): 0.90-1.00 (m, 1H), 1.1-1.2 (m, 4H), 1.4 (d, J=6.9 Hz, 6H), 1.4-1.6 (m, 4H), 2.15-2.25 (m, 1H), 2.3-2.4 (m, 1H), 2.45-2.55 (m, 2H), 2.65 (s, 3H), 2.6-2.7 (m, 2H), 2.85-2.95 (m, 1H), 3.15-3.5 (m, 7H), 3.95 (d, J=10.8 Hz, 1H), 3.95 (s, 3H), 4.1 (dd, J=11.5 Hz, J=3.8 Hz, 1H), 4.6 (t, J=8 Hz, 1H), 5.0 (t, J=9 Hz, 1H), 5.5 (t, J=3.14 Hz, 1H), 5.7-5.8 (dd, J=18.2 and J=8.2 Hz, 1H), 6.85 (s, 1H), 7.02 (s, 1H), 7.2 (d, J=9.5 Hz, 1H), 7.5 (s, 1H), 7.85 (d, J=9.5 Hz, 1H), 10.5 (br s, 1H).
Reaction SMILES: P([O:4][CH2:5][C@H:6]1[O:10][C@@H:9]([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[C@H:8]([O:19][CH2:20][CH2:21][C:22]#[N:23])[C@@H:7]1[OH:24])(N)O>C(#N)C>[C:22]([CH2:21][CH2:20][O:19][C@@H:8]1[C@H:7]([OH:24])[C@@H:6]([CH2:5][OH:4])[O:10][C@H:9]1[N:11]1[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]1=[O:13])#[N:23]
Reactant: N#CCCO[C@@H]1[C@H](O)[C@@H](COP(N)O)O[C@H]1n1ccc(=O)[nH]c1=O
Solvent: CC#N
Product: N#CCCO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=O

Procedure:
RNA synthesis program (condensation time: 10 min.) was carried out using four kinds of anhydrous acetonitrile solution of 2′-O-cyanoethyluridine phosphoramidite unit (compounds 7, 14, 18 and 26, 0.1M) by means of a DNA/RNA automatic synthesizer (Applied Bio System) provided with a long aminoalkyl chain CPG (1 μl) in which 2′-O-cyanoethyluridine was introduced via a succinyl linker by a conventional way (16 μl mol/g), which was filled into a socket for solid-phase synthesis. After the synthesis had been completed, excision of the resulting oligonucleotide from the solid phase and removal of a protecting group of the nucleic acid base moiety were carried out by treatment with ammonia water-ammonium acetate (10% wt/wt: 1 ml) for 90 min. After diluted appropriately with ammonium acetate buffer, the oligonucleotides were purified with a reverse phase column cartridge or an anion exchange HPLC. The oligonucleotides obtained by a desalting operation with the reverse phase column cartridge were lyophilized to give a titled compound with a yield of 6%. Analysis profile obtained in the anion exchange HPLC is shown in FIG. 1C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18].O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:15][CH2:16][O:17][CH3:18])[C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ncc(Cl)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(Cl)cnc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 60 %

Procedure:
5-Chloro-2-nitro-pyridine-3-ol (1.15 mmol) is dissolved in DMF (2 ml) and NaH (1.4 eq., 60% suspension in liquid paraffin) is added and the suspension is stirred 45 min at room temperature. 1-Bromo-2-methoxy-ethane (1 eq.) is added and the reaction suspension is heated to 100° C. for 24 hours. The reaction solution is pored into water and extracted with dichloromethane. The combined organic layers are washed with brine, dried over MgSO4 and the solvent is removed in vacuo. 5-Chloro-3-(2-methoxy-1-ethoxy)-2-nitro-pyridine is obtained after column chromatography as beige solid in a yield of 60%; mp. 71.5-72.5°; HPLC (method C): 1.63 min; LC-MS (method A): 1.36 min, 232.95 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:5][CH:4]=1.[Br:18]Br>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:18])=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:16][CH:17]=1
Reactant: COc1ccc(CSc2ccnc(N)c2)cc1
Reactant: BrBr
Solvent: CC(=O)O
Product: COc1ccc(CSc2cc(N)ncc2Br)cc1
Yield: 54.2 %

Procedure:
4-(4-methoxybenzylthio)pyridine-2-amine (2.4 g, 9.7 mmol) was dissolved in acetic acid (30 mL). Bromine (1M in AcOH, 9.8 ml, 9.8 mmol) was added dropwise at ambient temperature and the reaction stirred for 30-minutes. The solution was concentrated and the residue was neutralized with saturated NaHCO3 solution. The solution was extracted with EtOAc and the organic layer was dried and concentrated. The residue was purified by flash chromatography (70% EtOAc/hexanes) to obtain the desired product (1.71 g, 54% yield) as a yellow solid.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>CC(CC(C)C)=O>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[O:25][CH2:24][CH2:23][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: ClCCOC1CCCCO1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: C1=C(c2c[nH]c3ccccc23)CCN(CCOC2CCCCO2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6.93 g of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole [described in French Pat. No. 2,362,628] dissolved at 100° C. in 70 ml of isobutyl methyl ketone admixed with 11.13 g of sodium carbonate and 14 ml of 2-(2-chloroethoxy)-tetrahydro-2H-pyran was refluxed with stirring under an inert atmosphere for 51/2 hours and was then cooled and poured into ice water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, with aqueous sodium chloride solution, dried and evaporated to dryness. The 9.9 g of crystalline residue was chromatographed over silica gel and eluted with an 85-10-5 chloroform-acetonetriethylamine mixture to obtain 7.85 g of 3-[1-(2-{2-tetrahydropyranyloxy}-ethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole in the form of crystals melting at 135° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]([CH:11]1[CH2:13][CH2:12]1)[NH2:10].CCN(C(C)C)C(C)C.CN([CH:26]=[O:27])C>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[C:26](=[O:27])[NH:10][CH:9]2[CH:11]1[CH2:13][CH2:12]1
Reactant: CN(C)C=O
Reactant: NC(c1cc(Cl)ccc1Br)C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1NC(C2CC2)c2cc(Cl)ccc21
Temperature: 130 °C
Yield: 68.7 %

Procedure:
A mixture of (2-bromo-5-chlorophenyl)(cyclopropyl)methanamine (2 g, 7.7 mmol), Pd(dppf)Cl2 (0.2 g), DIPEA (3 g, 23.1 mmol) in 20 mL of DMF was heated in an autoclave at 130° C. under 2 MPa of CO (g) for 16 hours. After the reaction, the mixture was diluted with AcOEt (150 mL) and washed with brine (30 mL×3). The organic layer was dried over anhy. Na2SO4, filtered, and concentrated in vacuo to give a crude product which was purified by chromatography to give title compound (1.1 g, yield 68.7%) as a yellow solid. MS: 207.9 (M+H+, 1C1).
Reaction SMILES: [C:1]([N:5]=[N:6][C:7]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[NH3:16].C(=O)=O.O>CO>[C:1]([N:5]=[N:6][C:7]1([NH:13][C:14]([NH2:16])=[S:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N
Reactant: CC(C)(C)N=NC1(N=C=S)CCCCC1
Agent: O=C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)N=NC1(NC(N)=S)CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 7.4 grams (0.032 moles) of 1-t-butylazo-1-isothiocyanatocyclohexane in 80 ml of methanol in a 250 ml reaction flask equipped with magnetic stirrer, thermometer, dry-ice condenser and gas addition tube was added NH3 gas until an NH3 reflux was obtained in the condenser. The reaction mixture was stirred for 3 hours at room temperature while maintaining a gentle NH3 reflux in the dry ice condenser. The reaction mixture was then poured into 200 ml of water and the product extracted with methylene chloride. The methylene chloride extract was washed with 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the methylene chloride evaporated under reduced pressure. The residue was slurried in pentane and the slurry filtered. The white solid filter cake was air dried and weighed 4.5 grams (57% crude yield). The product melted at 155°-157° C. with decomposition. The infrared spectrum of the product contained a strong band at 1525 cm-1 and 3 NH bands at 3180, 3250 and 3400 cm-1.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:27][CH2:26][CH:25]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH2:24]2)=[CH:19][CH:18]=1)=O.OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1>CC(N(C)C)=O.C(Cl)Cl>[CH3:14][O:13][C:7]1[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:6][C:15]([C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:27][CH2:26][CH:25]([N:28]([CH3:32])[C:29](=[O:31])[CH3:30])[CH2:24]3)=[CH:21][CH:22]=1)=[N:1]2
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(=O)N(C)C1CCN(c2ccc(C=O)cc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N(C)C(C)=O)C4)cc3)nc2c1
Temperature: 150 °C
Yield: 87.2 %

Procedure:
A solution of 2-amino-4,6-dimethoxybenzamide (0.797 g, 4.07 mmol) and N-(1-(4-formylphenyl)pyrrolidin-3-yl)-N-methylacetamide (1.0 g, 4.07 mmol) in DMA (75 mL) was treated with NaHSO3 (0.466 g, 4.5 mmol) and p-TsOH (0.078 g, 0.41 mmol). The mixture was heated at 150° C. for 15 hours, cooled to room temperature, diluted with CH2Cl2 (200 mL), and washed with saturated NaHCO3 (100 mL) and water (200 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 1:1 CH2Cl2/92:7:1 CHCl3/MeOH/concentrated NH4OH to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH, to afford the title compound (1.5 g, 88%) as a light brown solid. 1H NMR (300 MHz, DMSO-d6): δ 11.68 (s, 1H), 8.10 (d, J=8.8 Hz, 2H), 6.55-6.67 (m, 3H), 6.44 (d, J=2.2 Hz, 1H), 4.67-5.22 (m, 1H), 3.88 (s, 3H), 3.83 (s, 3H), 3.43-3.60 (m, 2H), 3.22-3.26 (m, 2H), 2.76-2.89 (m, 3H), 1.91-2.27 (m, 5H). ESI MS m/z 423 [M+H]+.
Reaction SMILES: COP([CH2:7][C:8](=[O:16])[C:9]([F:15])([F:14])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[H-].[Li+].[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26]([CH:38]=O)[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20].O>COC(C)(C)C>[C:19]([O:22][C@@H:23]1[C@H:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C@@H:26](/[CH:38]=[CH:7]/[C:8](=[O:16])[C:9]([F:14])([F:15])[CH2:10][CH2:11][CH2:12][CH3:13])[C@H:25]([O:40][CH:41]2[CH2:46][CH2:45][CH2:44][CH2:43][O:42]2)[CH2:24]1)(=[O:21])[CH3:20]
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Agent: [H-]
Agent: [Li+]
Solvent: COC(C)(C)C
Solvent: O
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 6 h
Yield: 21.3 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.051 g, 4.070 mmol) in anhydrous t-butyl methyl ether (16 ml), lithium hydride (30.3 mg, 3.81 mmol) was added and the mixture was stirred for approximately 6 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydro pyranyloxy)cyclopentyl]heptanate (2) (0.903 g, 2.27 mmol) in anhydrous t-butyl methyl ether (3 ml) was added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, water was added to the solution and the mixture was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 36 g/15 g/18 g; ethyl acetate:hexane=1:4) three times, to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.257 g; 0.484 mmol; yield: 21.3%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[O:6][CH2:7][C@H:8]1[O:27][C@H:11]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10][C@@H:9]1[OH:28])([CH3:4])[CH3:3].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][S:42]([O:28][C@@H:9]1[C@@H:8]([CH2:7][O:6][Si:5]([C:2]([CH3:1])([CH3:3])[CH3:4])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:27][C@H:11]([CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[CH2:10]1)(=[O:44])=[O:43]
Reactant: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1O)(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](OC[C@H]1O[C@H](CNC(=O)OCc2ccc([N+](=O)[O-])cc2)C[C@@H]1OS(C)(=O)=O)(c1ccccc1)c1ccccc1

Procedure:
The title compound is prepared by the procedure of Example 277 using 3.39 g of product from Example 284, 0.57 ml of methanesulfonyl chloride, 1.03 ml of triethylamine, and 30 ml of methylene chloride to give, after chromatography, 3.0 g of the desired product.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH:4]=[C:3]1OC.[NH3:16]>CO>[NH2:16][C:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[CH:4]=1
Reactant: COc1cc(=O)c2ccccc2[nH]c1=O
Reactant: N
Solvent: CO
Product: Nc1cc(=O)c2ccccc2[nH]c1=O
Temperature: -78 °C

Procedure:
2,5-Dihydro-2,5-dioxo-3-methoxy-1H-benz[b]azepine (0.4 g) was treated with 80 mL of liquid anhydrous ammonia chilled to -78° C. The mixture was sealed in a pressure vessel and warmed to 23° C. for 18 hours. The excess ammonia was evaporated to give a solid. The solid was dissolved in hot methanol (120 mL); the solution was filtered and evaporated to 60 mL; and crystallization was initiated by cooling the solution in an ice bath. The solid was filtered, washed (cold methanol) and dried under vacuum (25° C., 15 Pa) to give the title compound (0.28 g); mp 295.2°-296.5° C. (dec); NMR: 11.38 (s,1, NH), 8.09 (dd,1, J=8.2, 1.6), 7.54 (m,1), 7.44 (dd,1, J=8.2, 1.6), 7.21 (m,1), 6.23 (s,1). Analysis for C10H8N2O2 : Calculated: C, 63.82; H, 4.28; N, 14.89; Found: C, 63.80; H, 4.41; N, 14.87.