Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6](Cl)=[O:7].[N+:18]([C:21]1[CH:37]=[CH:36][C:24]([CH2:25][C@@H:26]2[CH2:31][C@@H:30]([NH:32][C:33](=[O:35])[CH3:34])[CH2:29][CH2:28][NH:27]2)=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])O.[Na+]>C(Cl)Cl>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[C:6]([N:27]1[CH2:28][CH2:29][C@H:30]([NH:32][C:33](=[O:35])[CH3:34])[CH2:31][C@H:26]1[CH2:25][C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:37][CH:36]=1)=[O:7]
Reactant: CC(=O)N[C@H]1CCN[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)N[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.49 g (9.0 mmol) of 3,5-bis-trifluoromethylbenzoyl chloride are added in the course of 1 hour at 0-5° C. to a stirred suspension of 2.50 g (9.0 mmol) of (2R*,4S*)-N-[2-(4-nitro-benzyl)-piperidin-4-yl]-acetamide in 20 ml of methylene chloride and 20 ml of a 10% aqueous sodium hydrogen carbonate solution. The mixture is then stirred for 1 hour at 25° C. The organic phase is dried over sodium sulfate, concentrated to dryness by evaporation and chromatographed on silica gel with methylene chloride/methanol. The title compound is obtained in the form of a yellowish resin. TLC: methylene chloride/methanol/conc. ammonia (90:9:0.5) Rf =0.45. 1H-NMR (200 MHz, D2O): rotameric mixture. δ 8.28-7.08 (m, 7H), 5.41 (br d, NH), 5.36-5.20 (m, 0.5H), 4.87-4.73 (m, 0.5H), 4.51-4.30 (m, 1H), 4.00-3.82 (m, 0.5H), 3.60-2.85 (m, 3.5H), 1.98 (s, 3H), 2.30-1.92 (m, 2H), 1.62-1.22 (m, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[C:13](C(OCC)=O)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)=O.[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:12][CH2:11][CH2:10][C:9]1=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=C1CCCN1Cc1ccccc1)c1ccc(OC)c(OC)c1
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Product: COc1ccc(C=C2CCCN2Cc2ccccc2)cc1OC

Procedure:
Boil 31.5 g of 1-benzyl-2-(α-ethoxycarbonyl-3,4-dimethoxybenzylidene)pyrrolidine under reflux with 75 ml of conc. hydrochloric acid until carbon dioxide ceases to evolve. After cooling, alkalize the thus-prepared reaction mixture with sodium hydroxide solution. Recrystallize the formed precipitate from ethanol to obtain a yield [11.3 g (44% of theory)] of title compound (m.p. 105°).
Reaction SMILES: N1C2C(=CC=CC=2)C(C2CCC(=O)CC2)=C1.O1[C:21]2([CH2:26][CH2:25][CH:24]([C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[C:33]([O:36][CH3:37])[CH:34]=4)[NH:29][CH:28]=3)[CH2:23][CH2:22]2)[O:20]CC1>>[CH3:37][O:36][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][CH:28]=[C:27]2[CH:24]1[CH2:25][CH2:26][C:21](=[O:20])[CH2:22][CH2:23]1
Reactant: COc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Agent: O=C1CCC(c2c[nH]c3ccccc23)CC1
Product: COc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Yield: 84.8 %

Procedure:
This compound was prepared in the manner described above for intermediate 3a by replacing 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-1H-indole with 3-(1,4-dioxa-spiro[4,5]dec-8-yl)-5-methoxy-1H-indole (5.85 g) to afford 4.2 g (85%) of the title compound as a white solid: mp 103-106° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[O:12][CH3:13].F[P-](F)(F)(F)(F)F.[N:21]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2N=N1.ClCCl>C(N(CC)CC)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:21][C@H:25]2[CH2:24][CH2:29][C@@H:28](/[CH:7]=[CH:2]/[CH2:3][CH2:4][CH3:5])[CH2:27][CH2:26]2)=[O:11])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COc1cc(CC(=O)O)ccc1O
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC/C=C/[C@H]1CC[C@@H](NC(=O)Cc2ccc(O)c(OC)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a mixture of the above product (2) (2.17 g), 4-hydroxy-3-methoxyphenyacetic acid (1.16 g), benzotriazol-1-yloxy-tris(pyrrolidino)phosphonium hexafluorophosphate (3.33 g) and dichloromethane (50 ml) under ice-cooling was added triethylamine (2.68 ml). The reaction mixture was stirred at room temperature for 1 hour, and then washed with saturated aqueous ammonium chloride and then brine. The organic layer was dried over sodium sulfate, and then the solvent was removed in vacuo. The residue was purified by a silica gel chromatography (eluent: gradient from 100% hexane/0% ethyl acetate to 0% hexane/100% ethyl acetate) and the recrystallized from hexane-ethyl acetate to give 770 mg of the desired compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](O)=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:51][O:52][C:53](=[O:64])[CH2:54][CH:55]([NH2:63])[C:56]1[CH:57]=[N:58][CH:59]=[C:60]([Br:62])[CH:61]=1.C(N(C(C)C)C(C)C)C>CN(C)C=O.O>[Br:62][C:60]1[CH:61]=[C:56]([CH:55]([NH:63][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:9][CH2:10]3)[CH2:19]2)=[O:25])[CH2:54][C:53]([O:52][CH3:51])=[O:64])[CH:57]=[N:58][CH:59]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)N2CCC[C@@H](C(=O)O)C2)CC1
Reactant: COC(=O)CC(N)c1cncc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CC(NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(Br)c1
Temperature: 0 °C
Reaction time: 24 h
Yield: 103.9 %

Procedure:
3.324 g (9.02 mmol) (3R)-1-{3-[1-(tert-butoxycarbonyl)piperidin-4-yl]propanoyl}piperidine-3-carboxylic acid (Bioorg. Med. Chem. 13 (2005) 4343-4352, Compound 10) were suspended in 52 ml N,N-dimethylformamide and cooled to 0° C. 3.694 g (9.71 mmol) HATU, a solution of 1.798 g (6.94 mmol) 3-amino-3-(5-bromo-pyridin-3-yl)-propionic acid methyl ester in 78 ml N,N-dimethylformamide and 3.56 ml (20.82 mmol) N-ethyl-diisopropylamine were added. The mixture was stirred at 0° C. for 5 minutes and at room temperature for 24 hours. 160 ml water were added and the mixture extracted with 280 ml dichloromethane. The organic phase was washed with water, dried over sodium sulfate and concentrated in vacuum. Chromatography over 55 g basic silica gel (dichloromethane/ethanol 100/0-97/3-94/6) gave 4395 mg (104%) tert-butyl 4-{3-[(3R)-3-{[1-(5-bromopyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=2[C:11]#[N:12])=[C:4]([N+:18]([O-])=O)[CH:3]=1.[Sn](Cl)[Cl:22]>C(O)C.Cl>[ClH:22].[F:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:10]=3[C:11]([NH2:12])=[N:18][C:4]=2[CH:3]=1
Reactant: Cl[Sn]Cl
Reactant: Cc1ccc(Nc2ccc(F)cc2[N+](=O)[O-])c(C#N)c1
Agent: Cl
Solvent: CCO
Product: Cc1ccc2c(c1)C(N)=Nc1cc(F)ccc1N2
Reaction time: 16 h
Yield: 72.7 %

Procedure:
Heat a solution of 2-(4-fluoro-2-nitro-phenylamino)-5-methyl-benzonitrile (1.747 g, 6.44 mmol) in ethanol (35 ml) to 60° C. and add a solution of tin (II) chloride (6.06 g, 31.96 mmol) in 5.0 N hydrochloric acid (35 ml). Reflux the resulting mixture to reflux for 40 hours. Cool the reaction to room temperature and place in a freezer for 16 hours. The product precipitates from the solution and is collected by filtration to obtain 1.3 g of the title compound (4.68 mmol, 73% yield) as a yellow-green amorphous solid: Mass Spectrum (m/e): 241 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[N:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[C:65]([C:69]1[CH:70]=[C:71]2[C:76](=[C:77]([F:79])[CH:78]=1)[C:75](=[O:80])[N:74]([C:81]1[CH:91]=[CH:90][CH:89]=[C:88](B3OC(C)(C)C(C)(C)O3)[C:82]=1[CH2:83][O:84]C(=O)C)[N:73]=[CH:72]2)([CH3:68])([CH3:67])[CH3:66].[OH-].[Na+]>C(O)CCC.O.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:65]([C:69]1[CH:70]=[C:71]2[C:76](=[C:77]([F:79])[CH:78]=1)[C:75](=[O:80])[N:74]([C:81]1[CH:91]=[CH:90][CH:89]=[C:88]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[N:15][C:14]([O:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=3)[C:82]=1[CH2:83][OH:84])[N:73]=[CH:72]2)([CH3:68])([CH3:66])[CH3:67]
Reactant: CN(C)CCOc1cnc(Nc2cc(Cl)nn(C)c2=O)cn1
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCCCO
Product: CN(C)CCOc1cnc(Nc2cc(-c3cccc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)nn(C)c2=O)cn1
Temperature: 110 °C
Yield: 48.1 %

Procedure:
In a 15 mL microwave reaction vial was added 6-chloro-4-[5-(2-dimethylamino-ethoxy)-pyrazin-2-ylamino]-2-methyl 2H-pyridazin-3-one (89 mg, 274 μmol, Eq: 1.00) in 7 mL n-butanol and 1.4 mL water. To the solution was added potassium phosphate tribasic (128 mg, 603 μmol), X-PHOS (19.6 mg, 41.1 μmol, Eq: 0.15) and acetic acid 2-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl ester (279 mg, 395 μmol, Eq: 1.44) with stirring and bubbling of argon. To this mixture was added bis(dibenzylideneacetone)palladium (11.8 mg, 20.6 μmol, Eq: 0.075) and the reaction was heated at 110° C. for 3 hrs. The reaction was cooled to room temperature and treated with a solution of NaOH (220 mg) in water (1.5 mL). The resultant mixture was stirred at room temperature for 20 h. The reaction mixture was diluted with DCM (50 mL) and water (50 mL). The organic phase was separated, washed with water (30 mL) and concentrated. The residue was purified on silica gel with 0-10% (10% NH4OH in MeOH) in (1/1) EtOAc/Hex. The pure fractions were concentrated and dissolved in DCM. Heptane was added to precipitate the product. The liquid was decanted off to afford 81 mg (46%) of the title compound as an off white solid. mp: 185-190° C.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C@:5]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17])([OH:9])[C@H:6](O)[CH3:7].C1(C)C=CC(S([N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)(=O)=O)=CC=1.N1C=CN=N1>CN(C=O)C.O>[F:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[C@@:5]1([CH2:4][N:27]2[CH:31]=[N:30][CH:29]=[N:28]2)[C@H:6]([CH3:7])[O:9]1
Reactant: Cc1ccc(S(=O)(=O)n2cncn2)cc1
Reactant: C[C@@H](O)[C@@](O)(CCl)c1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Agent: c1c[nH]nn1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
First, 0.21 g (5.10 mmol) of sodium hydride (60% content) was suspended in 3 mL of DMF, and the resulting suspension was cooled in ice. A solution of 0.53 g (2.19 mmol) of (2R,3R)-1-chloro-2-(2,4-difluorophenyl)butane-2,3-diol in 5 mL of DMF was added thereto, and stirring was performed for 1 hour. A solution of 0.64 g (2.85 mmol) of 1-(p-toluenesulfonyl)-1,2,4-triazole and 0.06 g (0.88 mmol) of triazole in 3 mL of DMF was added, and the reaction solution was stirred at 60° C. for 3 hours. Then, the resulting solution was cooled to room temperature, and 10 mL of water was added to stop the reaction. The resulting product was extracted with ethyl acetate (20 mL×2), and concentration was performed under reduced pressure. A quantitative analysis was performed by HPLC. Thereby, the title compound was obtained in a yield of 43% (HPLC conditions, column: CAPCELL PAK C18 TYPE MG manufactured by Shiseido Co. Ltd., mobile phase: acetonitrile/20 mM (potassium) phosphate buffer solution (pH=2.5)=2/8, flow rate: 1.0 mL/min, column temperature: 30° C., detector: UV 210 nm, retention time: 37 minutes). 1H-NMR (400 MHz, CDCl3) δ: 1.64 (d, 3H, J=5.6 Hz), 3.19 (q, 1H, J=5.6 Hz), 4.42 (d, 1H, J=14.6 Hz), 4.87 (d, 1H, J=14.6 Hz), 6.69-6.80 (m, 2H), 6.98-7.03 (m, 1H), 7.81 (s, 1H), 7.98 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].[NH2:12][C@H:13]([CH2:18]O)[C:14]([CH3:17])([CH3:16])[CH3:15]>ClC1C=CC=CC=1>[C:14]([C@H:13]1[CH2:18][O:9][C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=2)=[N:12]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[C@H](N)CO
Reactant: N#Cc1ccc(C(=O)O)cc1
Solvent: Clc1ccccc1
Product: CC(C)(C)[C@H]1COC(c2ccc(C#N)cc2)=N1
Yield: 78 %

Procedure:
Under an argon atmosphere, a mixture of 4-cyanobenzoic acid (7.2 mmol), L-tert-leucinol (6.0 mmol), Zn4(OCOCF3)6O (0.3 mmol) and chlorobenzene (10 mL) was heated under reflux for 18 hours. From the resulting solution, the solvent was removed using an evaporator, and the residues were purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (V/V)) to give (S)-4-tert-butyl-2-(4-cyanophenyl)-1,3-oxazoline in 78% yield.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[N:8][C:6]=2[N:7]=1.[I:17]I.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[C:5]2[S:10][C:9]([I:17])=[N:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2scnc2n1
Reactant: II
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1nc(N2CCOCC2)c2sc(I)nc2n1
Temperature: -50 °C
Reaction time: 8 h

Procedure:
4-(5-Chlorothiazolo[4,5-d]pyrimidin-7-yl)morpholine 16 was dissolved in tetrahydrofuran and iodine (3 eq) was added. The solution was cooled to −50° C. and potassium bis(trimethylsilyl)amide (1.2 eq of 0.5M solution in toluene) was added over a period of 10 minutes. The solution was warmed to room temperature and stirred overnight. Water was added to quench the reaction and the tetrahydrofuran was removed in vacuo. The residue was brought up in methylene chloride, washed with saturated sodium bicarbonate solution and dried with magnesium sulfate. The solution was concentrated a purified by silica gel chromatography to yield 4-(5-chloro-2-iodothiazolo[4,5-d]pyrimidin-7-yl)morpholine 27.
Reaction SMILES: C(O[C:4](=[O:15])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)C.CC[O-].[Na+].[Na].C(OCC)(=O)[C:22]([O:24]CC)=[O:23].S(=O)(=O)(O)O>C1(C)C=CC=CC=1.C(O)C>[O:15]=[C:4]([CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CCOC(=O)CCCCc1ccccc1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(O)C(=O)CCCCc1ccccc1
Temperature: 0 °C

Procedure:
47.9 g of 5-phenylvaleric acid ethyl ester are added to a sodium ethylate suspension, prepared from 6.4 g of sodium and 100 ml of ethanol with subsequent evaporation of excess ethanol and addition of 100 ml of toluene. 44.1 g of diethyl oxalate are added dropwise, whilst stirring, and the mixture is heated under reflux for 2.5 hours. After cooling, the solution is stirred with 500 ml of ice-water and the mixture is acidified to pH 2 with 2 N sulphuric acid. Extraction several times with methylene chloride gives, after drying, filtration through a short silica gel column and concentration, 62.1 g of 3-ethoxycarbonyl-2-oxo-6-phenylhexanoic acid ethyl ester, which is reacted according to (a), without further purification.
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[C:12](=[O:19])[NH:11]3)[CH:4]=[CH:3]1.S(=O)(=O)(O)O.[N+:25]([O-])([O-:27])=[O:26].[K+].[OH-].[Na+]>>[N+:25]([C:17]1[CH:16]=[C:15]2[C:10](=[CH:9][C:8]=1[N:5]1[CH:6]=[CH:7][C:2](=[O:1])[CH:3]=[CH:4]1)[NH:11][C:12](=[O:19])[C:13](=[O:18])[NH:14]2)([O-:27])=[O:26]
Reactant: O=c1ccn(-c2ccc3[nH]c(=O)c(=O)[nH]c3c2)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [Na+]
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1
Temperature: 60 °C
Yield: 71 %

Procedure:
First, 510 mg of 6-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione was added to 5 ml of conc. sulfuric acid with ice-cooling and dissolved therein. Then, 253 mg of potassium nitrate was added to the resultant solution. The mixture was heated at 60° C. for 3 hours with stirring. Then, 20 ml of ice water was added to the mixture and the pH of the solution was adjusted to 5 with a solution of 4N sodium hydroxide. The precipitated yellow crystals were filtered. The crystals thus obtained were washed with water and dried to give 426 mg of 6-nitro-7-(4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1.[C:19]([N:29]1[CH2:34][CH2:33][C:32](=[O:35])[CH2:31][CH2:30]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O1CCCC1>[C:19]([N:29]1[CH2:30][CH2:31][C:32]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)([OH:35])[CH2:33][CH2:34]1)([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CCC(O)(c2cccnc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.8 %

Procedure:
To a cooled solution (-78° C.) of n-butyllithium (2.0M in hexane, 12.9 mL, 28.3 mmol, 1.2 eq) in tetrahydrofuran (200 mL) under nitrogen was added 3-bromopyridine (2.27 mL, 23.6 mmol, 1.1 eq). The solution became a dark green color as the pyridine was added. The reaction was stirred at this temperature for 1 h, at which time 1-carbobenzyloxy-4-piperidone (described in example 87c) (5.00 g, 21.4 mmol) was added as a tetrahydrofuran solution (20 mL). The cooling bath was removed and the reaction warmed to room temperature, stirring at that temperature for 18 h. The reaction was quenched by the addition of water (125 mL) and the aqueous phase extracted with ethyl acetate (3×75 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and reduced to an oil. The reaction product was purified by flash chromatography over silica gel (300 mL, eluent: ethyl acetate) to yield 5.00 g (75%) of the title compound as an oil. TLC analysis (Rf 0.10, ethyl acetate). MS (CI, CH4) m/z 313 (M+1,100), 341 (M+29,15), 295 (15)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][C:18]([O:20][CH3:21])=[O:19]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][CH:8]=1)[O:9][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COc1cccc(O)c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a mixture of 3-methoxyphenol (20 g, 161.3 mmol) and Cs2CO3 (52.4 g, 161.3 mmol) in DMF (200 mL), methyl bromoacetate (24.5 g, 161.3 mmol) was added. The reaction mixture was stirred at room temperature under argon overnight. The inorganic precipitate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was partitioned between water (200 mL) and CH2Cl2 (200 mL×3). The combined organic solution was dried over Na2SO4 and evaporated to give (28 g, 90%) product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:41])[CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: CCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCC(=O)N1CCN(c2ccc(-c3nc4cc(OC)cc(OC)c4c(=O)[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.4 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.120 g, 0.32 mmol) in CH2Cl2 (10 mL) was added Et3N (0.06 mL, 0.48 mmol) and hexanoyl chloride (0.03 mL, 0.28 mmol). The resulting solution was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo. The material was purified by flash chromatography, eluting with 2% to 10% of MeOH/CH2Cl2, to afford the title compound (0.050 g, 38%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.03 (d, J=8.8 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.75-4.05 (m, 6H), 3.47-3.73 (m, 4H), 3.17-3.43 (m, 4H), 2.20-2.40 (m, 2H), 1.41-1.62 (m, 2H), 1.15-1.38 (m, 4H), 0.76-0.98 (m, 3H); APCI MS m/z 465 [M+H]+.
Reaction SMILES: [N:1]1[N:2]([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[N:3]=[CH:4][CH:5]=1>C(O)=O>[N:3]1[N:2]([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[N:1]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2nccn2)cs1
Solvent: O=CO
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1nccn1)c1csc(N)n1)C(=O)O
Yield: 14.7 %

Procedure:
(2R,3S)-2-((2H-1,2,3-triazol-2-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (70 mg, 0.11 mmol) was stirred with formic acid (2.0 mL) at rt for 4 h then concentrated in vacuo. The crude residue was purified by reverse phase prep HPLC (XBridge, 30×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 1 mL/min), affording the title compound (8.1 mg, 15%) as a white solid. LCMS: m/z=500.9 (M−1); 1H NMR (400 MHz, D2O): δ 7.60 (s, 2H), 6.94 (s, 1H), 5.39 (d, J=5.2 Hz, 1H),), 4.83-4.78 (m, 2H), 4.78-4.68 (m, 1H assumed; obscured by solvent residual peak), 1.26 (s, 3H), 1.25 (s, 3H).