Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:18])[CH:14]=2)[C:9]21[CH2:22][CH2:21][CH2:20][CH2:19]2
Reactant: O=[O+][O-]
Reactant: CC=CCC1C(=O)c2cc(C)ccc2C12CCCC2
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Reaction time: 1 h
Yield: 99 %

Procedure:
An ozone stream (3 g ozone/hour) was conducted for 60 minutes while stirring through a solution, cooled to -70°, of 12.7 g of (RS)-2'-(2-buten-1-yl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one in 250 ml of anhydrous dichloromethane and 50 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 5.54 ml of dimethyl sulfide, the mixture was stirred at room temperature for 17 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 160 ml of dichoromethane and, after the addition of 15 ml of water and 15 ml of trifluoroacetic acid, stirred at room temperature for 2.5 hours. The mixture was subsequently poured into 150 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 150 ml of dichloro-methane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 12.0 g (99%) of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one were obtained as a light red oil.
Reaction SMILES: [CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[CH:6]=[C:5]([OH:17])[N:4]=1)[CH3:2].Cl.Cl[CH2:20][C:21]1[CH:22]=[N:23][C:24]2[C:29]([CH:30]=1)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=2.[Li+].[OH-]>C1COCC1>[CH2:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6]([CH2:20][C:21]2[CH:22]=[N:23][C:24]3[C:29]([CH:30]=2)=[CH:28][C:27]([O:31][CH3:32])=[CH:26][CH:25]=3)=[C:5]([OH:17])[N:4]=1)[CH3:2]
Reactant: CCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COc1ccc2ncc(CCl)cc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(O)c(Cc2cnc3ccc(OC)cc3c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 1-ethyl-6,7-dimethoxyisoquinolin-3-ol SLA 28136 (288 mg, 1.18 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added 3-(chloromethyl)-6-methoxyquinoline hydrochloride SLA 47088B (275 mg, 1.18 mmol) and a 2 N aq. LiOH solution (1.20 mL, 2.40 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to RT, THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:MeOH=100:0 to 94:6) followed by a new purification by column chromatography (RP 18, eluent CH3CN:H2O=100:0 to 34:66) gave 1-ethyl-6,7-dimethoxy-4-((6-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (3.0 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 1-ethyl-6,7-dimethoxy-4-((6-methoxyquinolin-3-yl)methyl)isoquinolin-3-ol dihydrochloride 85 as a brown solid (46.5 mg, 8% yield).
Reaction SMILES: [Na].Cl.[NH2:3][C:4]1[CH2:8][CH2:7][CH2:6][N:5]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]=[C:17]=[O:18])=[CH:12][CH:11]=1>CC(C)=O>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:3][C:4]2[CH2:8][CH2:7][CH2:6][N:5]=2)=[O:18])=[CH:12][CH:11]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NC1=NCCC1
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: O=C(NC1=NCCC1)Nc1ccc(Br)cc1

Procedure:
Following a procedure similar to that described in Example 2 but using 4.6 g. sodium in 300 ml. dry acetone, 23.2 g. 2-amino-1-pyrroline hydrochloride and 38.9 g. 4-bromophenyl isocyanate in 200 ml. dry acetone, there was obtained after recrystallization from ethyl alcohol 10.8 g. of the hydrochloride of 1-(4-bromophenyl)-3-(1-pyrrolin-2-yl)urea; m.p. 221°-224°C.
Reaction SMILES: [H-].[Na+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][OH:14].Cl[C:16]1[N:21]=[CH:20][C:19]([C:22](OC)=[O:23])=[CH:18][CH:17]=1.O>CN(C)C=O>[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][O:14][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][N:21]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: OCc1ccc2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCc1ccc(OCc2ccc3ccccc3n2)nc1
Reaction time: 1 h
Yield: 50.5 %

Procedure:
Sodium hydride (60%, oily, 1.58 g) was added to a solution of 2-quinolylmethanol (6.29 g) and methyl 6-chloro-3-pyridinecarboxylate (6.78 g) in N,N-dimethylformamide (100 ml) at 0° C., and the mixture was stirred for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. Lithium aluminium hydride (1.50 g) was added to a solution of the residue in tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 10 minutes. Sodium sulfate decahydrate (12.7 g) was added to the reaction mixture, which was stirred at room temperature for 1 hour. The precipitate was removed by filtration, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to obtain 2-(2-quinolylmethoxy)-5-pyridylmethanol (5.31 g, yield 50%) as colorless crystals from the fraction eluted with ethyl acetate. This was recrystallized from ethyl acetate-hexane. Melting point: 124–125° C.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([CH2:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:17]=1[O:24][CH3:25])[N:6]2[CH2:11][CH2:12][CH2:13][CH3:14].[NH4+:26].[OH-]>O1CCOCC1>[CH3:25][O:24][C:17]1[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=1[CH2:15][C:5]1[N:6]([CH2:11][CH2:12][CH2:13][CH3:14])[C:7]2[C:3]([N:4]=1)=[C:2]([NH2:26])[N:10]=[CH:9][N:8]=2
Reactant: CCCCn1c(Cc2cc(OC)ccc2OC)nc2c(Cl)ncnc21
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCn1c(Cc2cc(OC)ccc2OC)nc2c(N)ncnc21

Procedure:
To a solution of 6-chloro-8-(2,5-dimethoxybenzyl)-N9-butyl purine (1 mmol) in dioxane was added 28% NH4OH (50 mmol) and the mixture was then heated at 100 C in a seal tube for 48 h. Solvent was removed by azeotrope distillation with toluene. Purification on a silica gel column (see above) gave pure 8-(2,5-dimethoxybenzyl)-9-butyl adenine, 1.1. Rf=0.35 in 5% MeOH in EtOHAc. 1H NMR (DMSO-d6) δ 8.08 (s, 1H), 7.04 (br s, 2H), 6.94 (d, 1H), 6.80 (dd, 1H), 6.66 (d, 1H), 4.14 (s, 2H), 4.04 (t, 2H), 3.72 (s, 3H), 3.63 (s, 3H), 1.52 (m, 2H), 1.22 (m, 2H), 0.82 (t, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH2:19])[CH2:4][CH3:5])[CH3:2].[CH3:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[CH2:1]([N:3]([CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:19][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([CH3:20])=[CH:22][CH:23]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CCn1c(N)nc2ccc(OC)cc21
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: CCN(CC)CCn1c(NC(=O)c2ccc(C)cc2)nc2ccc(OC)cc21

Procedure:
1-(N,N-Diethylaminoethyl)-2-(4-methylbenzamido)-6-methoxybenzimidazole was prepared by the method of Example 2 using 1-(N,N-diethylaminoethyl)-2-amino-6-methoxybenzimidazole and 4-methylbenzoyl chloride. 1H NMR (DMSO): δ 1.33(t, 6H), 2.51 (s, CH3 ar), 3.40 (m, 4H), 3.58 (m, 2H), 3.98 (s, 3H), 4.87 (m 2H), 6.99-8.28 (4 m, 7 H), 11.61 (broad s, NH).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[C:19](=[S:22])([O-:21])[CH3:20].[K+].O>CC(C)=O.[I-].[K+]>[C:19]([S:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8])(=[O:21])[CH3:20]
Reactant: COC(=O)c1ccc(-c2nc(CCl)c(C)o2)cc1
Reactant: CC([O-])=S
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2nc(CSC(C)=O)c(C)o2)cc1
Yield: 104.9 %

Procedure:
A solution of methyl 4-[4-(chloromethyl)-5-methyl-1,3-oxazol-2-yl]benzoate (5 g, 18.82 mmol, 1.00 equiv), potassium ethanethioate (2.68 g, 23.47 mmol, 1.25 equiv) and potassium iodide (120 mg, 0.72 mmol, 0.04 equiv) in acetone (40 mL) was stirred at 35° C. for 30 min. Water (50 mL) was added to quench the reaction. The resulting solution was extracted with 3×100 mL of ethyl acetate. The combined organic layers was washed with 2×200 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 6.03 g of crude methyl 4-[4-[(acetylsulfanyl)methyl]-5-methyl-1,3-oxazol-2-yl]benzoate as a white solid.
Reaction SMILES: C=O.[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([C:11]1[CH:20]=[CH:19][C:18]2[NH:17][C:16](=[O:21])[C:15]3[NH:22][CH:23]=[CH:24][C:14]=3[C:13]=2[CH:12]=1)#[CH:10].[CH2:25]([C:27]([O-:29])=[O:28])[CH3:26].C(O)(=O)C>O1CCOCC1.[Cu](I)I>[N:3]1([CH2:25][C:10]#[C:9][C:11]2[CH:20]=[CH:19][C:18]3[NH:17][C:16](=[O:21])[C:15]4[NH:22][CH:23]=[CH:24][C:14]=4[C:13]=3[CH:12]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[CH2:25]([C:27]([O-:29])=[O:28])[CH3:26]
Reactant: C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Reactant: C1COCCN1
Agent: I[Cu]I
Agent: C=O
Agent: CCC(=O)[O-]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: O=c1[nH]c2ccc(C#CCN3CCOCC3)cc2c2cc[nH]c12
Temperature: 85 °C
Yield: 12.4 %

Procedure:
15 mg (0.17 mmol) of para-formaldehyde, 15 mg (0.17 mmol) of morpholine and 3 mg (0.02 mmol) of copper iodide are added to a suspension of 47 mg (0.17 mmol) of 8-ethynyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 5 ml of anhydrous dioxan, then a drop of acetic acid is added and the mixture is heated at 85° C. for 48 hours. The raw reaction product is then filtered, the filtrate is evaporated and the residue is purified by preparative LCMS to give 4 mg (6%) of 8-(3-morpholin-4-yl-prop-1-ynyl)-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][N:7]([CH2:26][CH2:27][C:28](=[NH:31])[NH:29][OH:30])[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([CH3:23])[CH:17]=2)=[O:9])=[CH:4][CH:3]=1.Cl[C:35](Cl)([O:37]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:26][CH2:27][C:28]2[N:31]=[C:35]([OH:37])[O:30][N:29]=2)[C:8]([C:10]2([CH3:25])[CH2:13][CH2:12][N:11]2[C:14](=[O:24])[CH2:15][C:16]2[CH:17]=[C:18]([CH3:23])[CH:19]=[C:20]([CH3:22])[CH:21]=2)=[O:9])=[CH:32][CH:33]=1
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCC(=N)NO)Cc2ccc(Cl)cc2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)N(CCc2noc(O)n2)Cc2ccc(Cl)cc2)c1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-[2-(N-hydroxycarbamimidoyl)-ethyl]-amide (1 eq.) in dioxane was added triphosgene (1.7 eq.) under nitrogen. The reaction was stirred at 20° C. for 15 h. The crude was concentrated under reduced pressure then partitioned between water and EtOAc. The layers were separated, the organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc/DCM/MeOH: 50/50/0/0 to 50/50/90/10) to afford 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid (4-chloro-benzyl)-[2-(5-hydroxy-[1,2,4]oxadiazol-3-yl)-ethyl]-amide.
Reaction SMILES: [SH:1][C:2]1[N:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[OH-].[Na+].Br[CH2:13][N+:14]([O-:16])=[O:15]>CN(C=O)C.O>[N+:14]([C:13]1[S:1][C:2]2=[N:9][CH:8]=[CH:7][CH:6]=[C:3]2[C:4]=1[NH2:5])([O-:16])=[O:15]
Reactant: N#Cc1cccnc1S
Reactant: O=[N+]([O-])CBr
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c([N+](=O)[O-])sc2ncccc12
Reaction time: 0.33 h
Yield: 76.2 %

Procedure:
To a solution of 2-mercaptonicotinonitrile (1 g, 7.4 mmol) in DMF (20 mL) was added a solution of NaOH (0.88 g, 22 mmol) in water (5 mL) at 0° C. The mixture was stirred for 20 min, then bromonitromethane (2 g, 14.7 mmol) was added dropwise. The resulting mixture was stirred for 1 h at 0° C., diluted with water (100 mL), and filtered. The filter cake was washed with water (20 mL×3) to give a yellow solid (1.1 g, yield 78%), which was used in the next step without further purification. ESI MS: m/z 196 [M+H]+.
Reaction SMILES: O.[NH2:2][NH2:3].[CH2:4]([O:6][CH:7]1[CH2:12][CH2:11][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH2:22][C:23]([C:25]3[C:26]([C:33]([O:35]C)=O)=[C:27]([CH3:32])[N:28]([CH3:31])[C:29]=3[CH3:30])=O)[CH:18]=[CH:19][C:20]=2[F:21])=[O:14])[CH2:9][CH2:8]1)[CH3:5]>C(O)(=O)C>[CH2:4]([O:6][CH:7]1[CH2:8][CH2:9][N:10]([C:13]([C:15]2[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=2[F:21])[CH2:22][C:23]2[C:25]3[C:26](=[C:27]([CH3:32])[N:28]([CH3:31])[C:29]=3[CH3:30])[C:33](=[O:35])[NH:2][N:3]=2)=[O:14])[CH2:11][CH2:12]1)[CH3:5]
Reactant: NN
Reactant: CCOC1CCN(C(=O)c2cc(CC(=O)c3c(C(=O)OC)c(C)n(C)c3C)ccc2F)CC1
Solvent: O
Solvent: CC(=O)O
Product: CCOC1CCN(C(=O)c2cc(Cc3n[nH]c(=O)c4c(C)n(C)c(C)c34)ccc2F)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 32.7 %

Procedure:
Hydrazine hydrate (0.028 mL, 0.38 mmol) was added to methyl 4-(2-(3-(4-ethoxypiperidine-1-carbonyl)-4-fluorophenyl)acetyl)-1,2,5-trimethyl-1H-pyrrole-3-carboxylate (55) (0.158 g, 0.34 mmol) in acetic acid (4 mL). The resulting solution was stirred at room temperature for 2 days. The resulting mixture was evaporated to dryness and the residue was azeotroped with toluene to afford the crude product, which was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the desired compound (0.049 g, 32.3% yield); 1H NMR (400.132 MHz, DMSO) δ 1.11 (3H, t), 1.29 (1H, m), 1.41 (1H, m), 1.72 (1H, m), 1.86 (1H, m), 2.29 (3H, s), 2.60 (3H, s), 3.05 (1H, m), 3.28 (3H, s), 3.46 (2H, m), 3.53 (3H, s), 3.96 (1H, m), 4.12 (2H, s), 7.16-7.28 (3H, m), 11.17 (1H, s); m/z (LC-MS, ESI+), RT=1.78 min (M+H=441.11).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[S:16][C:17]([CH2:20]Cl)=[CH:18][N:19]=2)([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][S:23]([C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1)(=[O:25])=[O:24].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([F:14])([C:15]2[S:16][C:17]([CH2:20][O:32][C:29]3[CH:28]=[CH:27][C:26]([S:23]([CH3:22])(=[O:25])=[O:24])=[CH:31][CH:30]=3)=[CH:18][N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(CCl)s2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(F)(c2ncc(COc3ccc(S(C)(=O)=O)cc3)s2)CC1

Procedure:
A mixture of 4-(5-Chloromethyl-thiazol-2-yl)-4-fluoro-piperidine-1-carboxylic acid tert-butyl ester (1.42 g, 4.24 mmol), 4-methanesulfonyl-phenol (731 mg, 1.0 eq.) and K2CO3 (878 mg, 1.5 eq.) in acetone (30 mL) was heated to reflux overnight. After cooling, the solid was filtered off through a pad of celite. The filtrate was concentrated in vacuo. The crude product was purified on silica gel (EtOAc:hexanes=1:1) to afford the desired product as a white solid. 1H NMR (CDCl3): δ 7.86 (2H, d, J=9.2 Hz), 7.35 (1H, s), 7.10 (2 H, d, J=9.2 Hz), 5.22 (2H, s), 4.08 (2H, br), 3.19 (2H, br), 3.02 (3H, s), 2.05˜2.32 (4H, m), 1.46 (9H, s).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3][C:2]1=[O:11].C(=O)([O-])[O-].[K+].[K+].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CC(C)=O>[C:18]1([S:24]([N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[NH:1][C:2](=[O:11])[CH2:3]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CNc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CN(S(=O)(=O)c2ccccc2)c2ccccc2N1
Yield: 52 %

Procedure:
A suspension of 10 g. (0.068 mole) of 3,4-dihydro-2(1H)-quinoxalinone (3,4-dihydro-2-hydroxyquinoxaline) [prepared in 50% yield according to the procedure described by W. H. Perkin et al. in the Journal of the Chemical Society, Vol. 123, p.2399(1923)] and 9.6 g. (0.069 mole) of potassium carbonate in 250 ml. of acetone was stirred under a nitrogen atmosphere at 40° C., while 11.5 g. (0.07 mole) of benzenesulfonyl chloride was added during the course of a 30-minute period. The reaction mixture was next heated at reflux temperature for 14 hours and then poured onto 500 ml. of ice. The resulting brown solid was recrystallized from ethyl acetate to yield 10.2 g (52%) of pure 4-benzenesulfonyl-3,4-dihydro-2(1H)-quinoxalinone, m.p. 183°-185° C. The pure product was further characterized by means of nuclear magnetic resonance data and elemental analysis.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O>>[CH3:20][O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]2[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: COCc1ccccc1B(O)O
Product: COCc1ccccc1-c1ccc(OCc2nc(C(=O)O)cs2)cc1

Procedure:
2-(2′-Methoxymethyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using general procedure 2 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 2-methoxymethylphenylboronic acid (available from Apollo Scientific Ltd., Stockport, UK). Mass spectrum MH+=356.
Reaction SMILES: I[C:2]1[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=1[CH3:11].Br[C:13]1[CH:14]=[C:15]([NH2:20])[C:16]([Cl:19])=[N:17][CH:18]=1>>[NH2:20][C:15]1[CH:14]=[C:13]([C:2]2[S:6][C:5]([NH:7][C:8](=[O:10])[CH3:9])=[N:4][C:3]=2[CH3:11])[CH:18]=[N:17][C:16]=1[Cl:19]
Reactant: Nc1cc(Br)cnc1Cl
Reactant: CC(=O)Nc1nc(C)c(I)s1
Product: CC(=O)Nc1nc(C)c(-c2cnc(Cl)c(N)c2)s1
Yield: 25 %

Procedure:
Using an analogous method to that described in Example 7, N-(5-iodo-4-methyl-1,3-thiazol-2-yl)acetamide was reacted with 5-bromo-2-chloropyridin-3-amine to give the title compound (Method A HPLC: retention time 5.5 minutes) in 25% yield; 1H NMR Spectrum: (acetone-d6) 12.17 (1H, br s); 7.68 (1H, d); 7.20 (1H, d); 5.70 (2H, br s); 2.34 (3H, s); 2.14 (3H, s); Mass Spectrum: M+H+ 283 and 285.
Reaction SMILES: CCCCC.C([Li])CCC.[Br-].[CH2:12]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=O)=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:60])([CH3:59])[CH3:58])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[CH2:38]([O:45][C:46]1[CH:47]=[CH:48][C:49]2[O:53][C:52]([CH:54]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:51][C:50]=2[C:56]=1[C:57]([CH3:58])([CH3:60])[CH3:59])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: CCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1c(OCc2ccccc2)ccc2oc(C=O)cc12
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCCC=Cc1cc2c(C(C)(C)C)c(OCc3ccccc3)ccc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91.2 %

Procedure:
A pentane solution (2.6 ml, 4.2 mmol) of 1.6M n-butyllithium was added dropwise to a solution of n-heptyltriphenylphosphonium bromide (1.84 g, 4.2 mmol) in tetrahydrofuran (10 ml) under a nitrogen atmosphere. After stirring the mixture at room temperature for 30 min, a solution of 5-benzyloxy-4-tert-butyl-2-formylbenzofuran (1.0 g, 3.2 mmol) in tetrahydrofuran (10 ml) was added dropwise. Subsequently, the mixture was stirred at room temperature for 30 min, poured into ice water and subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and water, then dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica Gel chromatography (chloroform) to afford 5-benzyloxy-4-tert-butyl-2-(1-octenyl)benzofuran [1.14 g (yield, 91%)].
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:15])=[CH:5][CH:6]=[C:7]2[C:12]=1[N:11]=[C:10]([O:13][CH3:14])[CH:9]=[CH:8]2.C([O-])(O)=[O:17].[Na+]>CC(C)=O.O>[F:15][C:4]1[C:3]([CH2:2][OH:17])=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C([O-])O
Reactant: COc1ccc2ccc(F)c(CBr)c2n1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2ccc(F)c(CO)c2n1
Yield: 97.7 %

Procedure:
A suspension of 8-bromomethyl-7-fluoro-2-methoxy-quinoline (32.03 g, 118.59 mmol) in acetone (460 mL) and water (585 mL) was treated with NaHCO3 (16.32 g, 194.28 mmol). The mixture was heated at reflux for 6 h. The volatiles were removed under reduced pressure and the aq. phase was extracted with EA (2×250 mL). The combined org. layers were washed with brine, dried over MgSO4 and concentrated to afford the title alcohol as a yellow oil (24 g, 97% yield).
Reaction SMILES: [Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O-:12])=[O:11].[Na+].[C:14]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CN(C)P(N(C)C)(N(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH2:8][CH:7]2[N:4]([C:5](=[O:9])[CH2:6]2)[C:3]=1[C:10]([O:12][CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:19][CH:20]=1)=[O:11]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: O=C([O-])C1=C(Cl)CC2CC(=O)N12
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(COC(=O)C2=C(Cl)CC3CC(=O)N23)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of sodium 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (20 mg), p-(t-butyl)benzyl bromide (34 mg), and anhydrous hexamethylphosphoramide (0.4 ml) is stirred under a nitrogen atmosphere at room temperature for 2.5 hrs. The mixture is diluted with toluene (5 ml), washed with water (5×2 ml) and brine, dried with MgSO4, filtered, and concentrated in vacuo. Chromatography of the residue on a silica gel plate yields p-(t-butyl)benzyl 3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@H:8]1[C@H:12]2[O:13][CH2:14][C@@H:15]([OH:16])[C@H:11]2[O:10][CH2:9]1.[N+:17]([O:20][C@H:21]([CH2:28][O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])([O-:19])=[O:18].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[N+:17]([O:20][C@H:21]([CH2:28][O:29][N+:30]([O-:32])=[O:31])[CH2:22][CH2:23][CH2:24][C:25]([O:16][C@@H:15]1[CH2:14][O:13][C@@H:12]2[C@H:8]([O:7][CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[CH2:9][O:10][C@H:11]12)=[O:26])([O-:19])=[O:18]
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Reactant: O=C(O)CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CCC[C@@H](CO[N+](=O)[O-])O[N+](=O)[O-])O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-(tetrahydro-2H-pyran-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol (2.96 g, 12.9 mmol) in DCM (40.8 mL) a solution of the crude (S)-5,6-di(nitrooxy)hexanoic acid (3.06 g, 12.85 mmol) (Step D) in DCM (9.15 mL) was added followed by EDAC (3.69 g, 19.28 mmol) and 4-dimethylaminopyridine (175 mg, 1.28 mmol). The reaction mixture was stirred at rt for 16.5 hrs. The solvent was removed under reduced pressure. The crude residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 10 to 60%), affording the title product as pale yellow oil.