Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]#[C:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].[C:24](OC(=O)C)(=[O:26])[CH3:25]>CO>[C:24]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]#[C:11][C:12]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:26])[CH3:25]
Reactant: COC(=O)c1ccc(OC)cc1C#Cc1cc(OC)ccc1N
Reactant: CC(=O)OC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(OC)cc1C#Cc1cc(OC)ccc1NC(C)=O

Procedure:
Compound 12 (84 mg, 0.27 mmol) was dissolved in MeOH (4 mL), and then acetic anhydride (28 μL, 0.30 mmol) was added. The reaction mixture was refluxed for 30 min. The reaction solvent was removed by evaporation, and then the residue was dissolved in CH2Cl2 (30 mL), and washed with H2O (3×10 mL). The organic layer was collected, dried over Na2SO4, filtered, concentrated and purified by silica column chromatography (40% EtOAc in hexanes) to afford methyl 2-((2-acetamido-5-methoxyphenyl)ethynyl)-4-methoxybenzoate in 81.8% (78 mg) yield as a yellow solid. 1H-NMR (CDCl3, 400 MHz) δ 9.30 (1H, s, NH), 8.51 (1H, d, J=9.6 Hz, Ar), 8.03 (1H, d, J=8.8 Hz, Ar), 7.14 (1H, s, Ar), 7.01 (1H, s, Ar), 6.93 (1H, d, J=9.6 Hz, Ar), 6.89 (1H, d, J=8.8 Hz, Ar), 3.88 (6H, s, 2×OCH3), 3.79 (3H, s, OCH3), 2.39 (3H, s, CH3); 13C-NMR (CDCl3, 100 MHz) δ 169.8, 166.0, 162.7, 154.9, 135.3, 132.8, 126.2, 122.5, 121.2, 118.2, 116.7, 116.2, 114.9, 112.4, 94.6, 91.0, 55.8, 55.7, 52.3, 24.6; MS (ESI) m/z Calcd for C20H19NO5 (M+): 353.1, Found: 352.0 (M−H+). LiOH.H2O (25 mg, 0.60 mmol) was added to a solution of methyl 2-((2-acetamido-5-methoxyphenyl)ethynyl)-4-methoxybenzoate (41 mg, 0.12 mmol) in THF/MeOH/H2O (ratio=3:1:1, 2 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was neutralized by adding 1M HCl (aq) and partitioned between EtOAc and sat'd NaH2PO4 (aq). The organic layer was collected, dried over Na2SO4, filtered, concentrated and dried under vacuum to afford compound 13 in 99.5% (40 mg) yield as a brown solid. 1H-NMR (DMSO-d6, 400 MHz) δ 9.69 (1H, s, NH), 8.27 (1H, d, J=8.4 Hz, Ar), 8.01 (1H, d, J=8.0 Hz, Ar), 7.19 (1H, s, Ar), 7.08 (1H, s, Ar), 7.06 (1H, d, J=8.0 Hz, Ar), 6.99 (1H, d, J=8.4 Hz, Ar), 3.87 (3H, s, OCH3), 3.77 (3H, s, OCH3), 2.26 (3H, s, CH3); 13C-NMR (DMSO-d6, 100 MHz) δ 169.5, 167.6, 161.4, 154.8, 135.0, 133.1, 124.3, 121.6, 117.5, 116.6, 115.6, 115.2, 113.2, 96.1, 89.8, 56.0, 55.7, 24.5; MS (ESI) m/z Calcd for C19H17NO5 (M+): 339.1, Found: 338.1 (M−H+).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][C:9](O)=[O:10])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH2:9][OH:10])[CH:3]=1
Reactant: O=C(O)Cc1cccnc1
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Product: OCCc1cccnc1
Yield: 34.5 %

Procedure:
A round-bottomed flask equipped with a magnetic stirring bar is charged with 13.9 g (0.08 mol) of (3-pyridinyl)acetic acid, hydrochloride salt (Aldrich Chemical Co.) and 400 ml of tetrahydrofuran (THF) under a nitrogen atmoshphere. To this solution lithium aluminum hydride (6.0 g, 0.16 mol) is added at room temperature for 24 hr. Saturated aqueous sodium sulfate is then added dropwise until the mixture becomes white. The solution is dried over anhydrous sodium sulfate. After filtration and concentration the resulting yellow oil is purified by 324 g of HPLC grade silica gel, eluting with ethyl acetate-hexane-ethanol (10:1:1) and collecting 40 ml fractions. Fractions 21-43 homogeneous on TLC are combined and concentrated in vacuo to give a light yellow oil (3.4 g, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[NH:13]1[CH2:16][CH2:15][CH2:14]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[N:13]1([C:9](=[O:11])[CH2:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:16][CH2:15][CH2:14]1
Reactant: C1CNC1
Reactant: O=C(O)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Br)cc1)N1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 115.9 %

Procedure:
A mixture of (4-bromophenyl)acetic acid (1 g, 4.65 mmol), azetidine hydrochloride (481 mg, 5.12 mmol), HATU (1.95 g, 5.12 mmol) and NMM (1.03 g, 10.23 mmol) in DMF (30 mL) was stirred at room temperature for 16 hours. The reaction mixture was diluted with EtOAc and washed with 1N HCl (15 mL×2) and 1M aqueous K2CO3 (15 mL×2). The organic phase was washed with brine, dried over sodium sulfate and concentrated in vacuo to give 1-(azetidin-1-yl)-2-(4-bromophenyl)ethanone (1.37 g) as a solid which was used directly in the next step without purification. 1H NMR (400 MHz, CD3OD) δ 7.47 (d, 2H), 7.197 (d, 2H), 4.26 (t, 2H), 4.01 (t, 2H), δ 3.45 (s, 2H), δ 2.30 (p, 2H).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.C([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)C(O)=O.ClCCl>C(#N)C>[N:22]1([C:2]2[S:3][C:4]3[CH:10]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: COC(=O)c1ccc2nc(Br)sc2c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CC#N
Product: COC(=O)c1ccc2nc(N3CCNCC3)sc2c1
Temperature: 25 °C

Procedure:
Methyl 2-bromobenzo[d]thiazole-6-carboxylate (0.52 g, 1.90 mmol), Boc-piperazine (0.44 g. 2.38 mmol) and potassium carbonate (0.53 g, 3.80 mmol) were suspended in acetonitrile (21 ml) and refluxed overnight. The resulting mixture was then cooled to room temperature, concentrated in vacuo to approximately 2 ml, diluted with water and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated in vacuo to yield a residue which was treated with trifluoroacetic acid/dichloromethane (6 ml, 1:1) for 1.5 hrs. The resulting mixture was concentrated in vacuo, the resulting residue was dissolved in dichloromethane and washed with saturated sodium bicarbonate to yield methyl 2-(piperazin-1-yl)benzo[d]thiazole-6-carboxylate.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][C:8]=1[N:17]=[N:18][NH:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]#[N:31])#[N:6]>CCOCC>[CH3:1][NH:2][C:3]([N:17]([C:8]1[CH:9]=[C:10]([C:13]([F:14])([F:15])[F:16])[CH:11]=[CH:12][C:7]=1[C:5]#[N:6])[N:18]=[N:19][C:20]1[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=1[C:30]#[N:31])=[O:4]
Reactant: CN=C=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Solvent: CCOCC
Product: CNC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N
Reaction time: 12 h

Procedure:
A solution of 0.38 g. (6.7 mmol.) of methyl isocyanate in 20 ml. of ether is added dropwise to 1.6 g. (4.2 mmol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in 125 ml. of ether. The reaction mixture is stirred at 25° for 12 hours, refluxed for 6 hours, then left to stand at 25° for 48 hours. Removal of the solvent under reduced pressure gives 3-(N-methylcarbamoyl)-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene, m.p. 170° (dec.).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[NH2:12].[C:13](OCC)(OCC)(OCC)[CH3:14]>C(O)C>[CH3:13][C:14]1[NH:1][C:2]2[C:11]3[C:6]([CH:5]=[CH:4][C:3]=2[N:12]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1ccc2ccccc2c1N
Solvent: CCO
Product: Cc1nc2ccc3ccccc3c2[nH]1

Procedure:
To a solution of 7.38 g of 1,2-diaminonaphthalene in 175 ml of ethanol was added 8.56 ml of triethyl orthoacetate and the reaction mixture heated to reflux for 3.5 hours. The solvent was removed in vacuo and the residue partitioned between chloroform and water. The organic phase was separated, dried over magnesium sulfate and concentrated to a dark oil, 9.0 g.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH2:10][N:11]([CH3:13])[CH3:12])=[O:9])=[N:4][N:3]=1.[CH3:14]C(OC(OC(OC(C)(C)C)=O)=O)(C)C>C1COCC1.O>[CH3:14][CH2:1][C:2]1[S:6][C:5]([NH:7][C:8]([CH2:10][N:11]([CH3:12])[CH3:13])=[O:9])=[N:4][N:3]=1
Reactant: Cc1nnc(NC(=O)CN(C)C)s1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: O
Product: CCc1nnc(NC(=O)CN(C)C)s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of AK-1 (2.00 g, 13.1 mmol) in THF (25 mL) is added Boc2O (3.45 mL, 15.0 mmol) and TEA (3.64 mL, 26.1 mmol). The reaction mixture is stirred at rt for 18 h and then diluted with H2O and extracted with EtOAc. The organic layers are concentrated to yield AK-2.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]([CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH2:13][NH:14][C:15]([C:17]1[S:27][C:26]2[N:28]3[C:19](=[CH:20][N:21]=[C:22]3[CH:23]=[CH:24][CH:25]=2)[CH:18]=1)=[O:16].C(N(CC)CC)C>ClCCl.O>[O:11]=[C:12]([CH2:29][N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)[CH2:13][NH:14][C:15]([C:17]1[S:27][C:26]2[N:28]3[C:19](=[CH:20][N:21]=[C:22]3[CH:23]=[CH:24][CH:25]=2)[CH:18]=1)=[O:16]
Reactant: O=C(NCC(O)CN1CCC(c2ccccc2)CC1)C1=Cc2cnc3cccc(n23)S1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: O=C(CNC(=O)C1=Cc2cnc3cccc(n23)S1)CN1CCC(c2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.39 g (3.05 mM) of oxalyl chloride in 20 ml of dichloromethane was added 0.43 ml (6.11 mM) of dimethyl sulfoxide dropwise at −78° C. The mixture was stirred for 5 minutes, at the end of which time a solution of 0.885 g (2.037 mM) of N-[2-hydroxy-3-(4-phenylpiperidino)propan-1-yl]-5-thia-1,8b-diazaacenaphthylene-4-carboxamide in 20 ml of dichloromethane was added and the mixture was stirred at −78° C. for 15 minutes. To this mixture was added 1.70 ml (12.2 mM) of triethylamine and the temperature was increased to room temperature. This reaction mixture was poured in water and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1 to 4/1) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[N:8][CH:9]=[CH:10][C:5]=2[S:4][C:3]=1[CH:11]=[O:12].[CH:13]1([Mg]Br)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+].C[N+]1([O-])CCOCC1>O1CCCC1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH:13]1([C:11]([C:3]2[S:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Br[Mg]C1CCCCC1
Reactant: Cc1c(C=O)sc2ccncc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: Cc1c(C(=O)C2CCCCC2)sc2ccncc12
Reaction time: 1 h
Yield: 31 %

Procedure:
To a solution (40 mL) of 3-methylthieno[3,2-c]pyridine-2-carbaldehyde (1.87 g) synthesized above in tetrahydrofuran was added a 1.0M solution (21.2 mL) of cyclohexylmagnesium bromide in tetrahydrofuran at 0° C., and the mixture was stirred for 1 hr. A 1.0M solution (10.0 mL) of cyclohexylmagnesium bromide in tetrahydrofuran was additionally added, and the mixture was further stirred at 0° C. for 1 hr. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-90% ethyl acetate/hexane) to give a pale-yellow solid. To a mixture of the obtained solid, 4-methylmorpholine N-oxide (1.24 mg) and acetonitrile (30 mL) was added tetrapropylammonium perruthenate (164 mg), and the mixture was stirred at room temperature for 4 hr, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10-50% ethyl acetate/hexane) to give the title object compound (864 mg, 31%) as a white solid.
Reaction SMILES: C(OC1C=C(C=C([N+]([O-])=O)C=1C1C=CC=CC=1)C(O)=O)C1C=CC=CC=1.[CH2:27]([S:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([N+:46]([O-])=O)[C:39]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]([OH:36])=[O:35])[CH:28]=[CH2:29]>>[CH2:27]([S:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([NH2:46])[C:39]=1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]([OH:36])=[O:35])[CH:28]=[CH2:29]
Reactant: C=CCSc1cc(C(=O)O)cc([N+](=O)[O-])c1-c1ccccc1
Agent: O=C(O)c1cc(OCc2ccccc2)c(-c2ccccc2)c([N+](=O)[O-])c1
Product: C=CCSc1cc(C(=O)O)cc(N)c1-c1ccccc1

Procedure:
By replacing in Example 2, step D, 3-benzyloxy-5-nitro-4-phenylbenzoic acid with 3-allylthio-5-nitro-4-phenylbenzoic acid, and following the procedure described, 3-allylthio-5-amino-4-phenylbenzoic acid is obtained with a melting point of 149.5°-150.5° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:34]=1[F:43].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:43][C:34]1[CH:35]=[C:36]([C:39]([F:40])([F:41])[F:42])[CH:37]=[CH:38][C:33]=1[C:2]1[CH:7]=[N:6][NH:5][C:4](=[O:8])[CH:3]=1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Reactant: O=c1cc(Cl)cn[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1cc(-c2ccc(C(F)(F)F)cc2F)cn[nH]1
Temperature: 90 °C
Yield: 21.1 %

Procedure:
A mixture of 5-chloropyridazin-3(2H)-one (1.91 g, 14.6 mmol), bis(pinacolato)diboron (3.89 g, 15.3 mmol), potassium acetate (2.14 g, 21.8 mmol), dioxane (100 ml) and [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium (0.4 g) was degassed (N2), then heated at 90° C. for 16 hours under nitrogen. More catalyst (0.45 g) was added and the mixture heated 7 hours more. After cooling to room temperature 4-bromo-3-fluorobenzotrifluoride (4.5 g, 18.5 mmol) was added along with 2M aqueous sodium carbonate solution (35 ml) and a further portion of catalyst (450 mg). The mixture was heated to 115° C. for 24 h, then cooled to room temperature, diluted with ethyl acetate (250 ml) and filtered. The layers were separated, the aqueous phase extracted with ethyl acetate (100 ml) and the combined organic layers evaporated. The residue was purified by flash column chromatography eluting with 5% methanol in dichloromethane to give the title compound (795 mg, 21%).
Reaction SMILES: [I-].[K+].[CH3:3][N:4]([CH3:25])[C:5]([CH:7]1[CH2:16][N:15]([CH3:17])[C:14]2[N:13]=[C:12]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:11]3=[CH:10][C:9]=2[C:8]1=[O:24])=[O:6].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.C(O)C>[CH3:3][N:4]([CH3:25])[C:5]([C:7]1[C:8](=[O:24])[C:9]2[CH:10]=[C:11]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:12]3=[N:13][C:14]=2[N:15]([CH3:17])[CH:16]=1)=[O:6]
Reactant: CN(C)C(=O)C1CN(C)c2nc3cc(F)c(F)cc3cc2C1=O
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [I-]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cn(C)c2nc3cc(F)c(F)cc3cc2c1=O
Temperature: 77 °C
Yield: 78.5 %

Procedure:
A solution of 1.35 g of potassium iodide in 10 cm3 of water is added with stirring at approximately 20° C. to a suspension of 25 g of N,N-dimethyl-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine-3-carboxamide in 1,000 cm3 of ethanol. The suspension is heated to 77° C., and 25 cm3 of 33% by weight hydrogen peroxide are introduced in the course of 20 minutes at this temperature. The reaction mixture is kept refluxing for a further 1 hour 30 minutes and is then cooled to approximately 20° C. 30 cm3 of 1N sodium thiosulphate solution are introduced in the course of 5 minutes at this temperature. The precipitate obtained is drained at approximately 20° C. and washed with twice 60 cm3 off water. The wet product obtained is dried under reduced pressure (20 kPa) at approximately 50° C. 19.5 g of N,N-dimethyl-7,8-difluoro-1-methyl-4-oxo-1,4-dihydrobenzo[b][1,8]naphthyridine-3-carboxamide are isolated in the form of a light yellow solid, melting point 324° C.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:22][CH:23]1[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]1>CN(C)C=O>[F:8][C:7]1[C:2]([Br:1])=[CH:3][C:4]([NH:22][CH:23]2[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(Br)c(F)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Bromo-2,5-difluoronitrobenzene (0.60 g, 2.5 mmole) was dissolved in dry dimethylformamide (10 ml) and diisopropylethylamine (0.39 g, 3.0 mmole), and 1,1-dimethylethyl 4-amino-1-piperidinecarboxylate (0.53 g, 2.6 mmole) were added at room temperature and subsequently stirred for 1 hour. The mixture was then stirred at 80° C. for 2.5 h, then cooled to room temperature. The mixture was concentrated to dryness under vacuum and the residue partitioned between ethyl acetate and dilute aqueous potassium carbonate solution. The organic layer was dried over MgSO4, filtered and evaporated, and the residue was purified by silica gel chromatography eluting with 10 to 50% diethyl ether in 40-60 pet ether to afford the title compound as an orange/red solid, 0.91 g, 87%. LC/MS—97% m/e-416/418 (M−H).
Reaction SMILES: O[CH2:2][C@@H:3]([CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([NH:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:15]([C@@H:3]1[CH2:2][N:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]1=[O:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC[C@H](CO)C(=O)NOCc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC[C@@H]1CN(OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.8 %

Procedure:
To a solution of (2R)-2-(hydroxymethyl)-N-[(phenylmethyl)oxy]hexanamide (6) (52 g, 0.21 mol) and Ph3P (60 g, 0.23 mol) in THF (1500 mL) at 0° C. was added DIAD (41.8 g, 0.21 mol). The mixture was warmed up to rt and stirred overnight. TLC indicated completion of the reaction. THF was removed under vacuum. The residue was titurated with ethyl acetate/petroleum ether (1:10) and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography to provide the title compound (52.8 g, 110%). LCMS: (M+H)+: 234.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([N:10]3[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19])[CH2:12][CH2:11]3)=[N:7][C:6]=2[CH:28]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1>CN(C=O)C.C(OCC)(=O)C>[CH:37]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]3[O:9][C:8]([N:10]4[CH2:15][CH2:14][CH:13]([O:16][CH2:17][C@@H:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:19])[CH2:12][CH2:11]4)=[N:7][C:6]=3[CH:28]=2)[CH2:39][CH2:38]1
Reactant: C[C@@H](COC1CCN(c2nc3cc(O)ccc3o2)CC1)NC(=O)OC(C)(C)C
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](COC1CCN(c2nc3cc(OCC4CC4)ccc3o2)CC1)NC(=O)OC(C)(C)C
Temperature: 60 °C

Procedure:
To a solution of tert-butyl [(1S)-2-{[1-(5-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]oxy}-1-methylethyl]carbamate (345 mg) in DMF (5 mL) were added potassium carbonate (366 mg) and (bromomethyl)cyclopropane (0.171 mL), and the mixture was stirred with heating at 60° C. for 1.5 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (375 mg).
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1>>[Cl:29][C:19]1[C:20]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:21]=2[S:22][C:18]=1[C:16]([N:15]([CH2:30][C:31]1[CH:32]=[C:33]([C:44]2[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=2)[CH:34]=[CH:35][C:36]=1[O:37][CH3:38])[CH:12]1[CH2:11][CH2:10][CH:9]([N:8]([CH3:42])[C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:7])[CH3:6])[CH2:14][CH2:13]1)=[O:17]
Reactant: O=Cc1ccc(Br)cc1
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Product: COc1ccc(-c2ccc(C=O)cc2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (600 mg, 0.96 mmol) is coupled to 4-bromobenzaldehyde (213 mg, 1.15 mmol) using Method A to give the title compound.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10](=[O:36])[CH2:11][NH:12][C:13]([C:15]1[CH:35]=[CH:34][C:18]2[N:19]([CH3:33])[C:20]([NH:22][C:23]3[S:24][C:25]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:26]=4[N:27]=3)=[N:21][C:17]=2[CH:16]=1)=[O:14])=[O:4].[OH-].[Li+]>>[Cl:32][C:30]1[CH:29]=[CH:28][C:26]2[N:27]=[C:23]([NH:22][C:20]3[N:19]([CH3:33])[C:18]4[CH:34]=[CH:35][C:15]([C:13]([NH:12][CH2:11][C:10]([N:6]5[CH2:7][CH2:8][CH2:9][C@H:5]5[C:3]([OH:4])=[O:2])=[O:36])=[O:14])=[CH:16][C:17]=4[N:21]=3)[S:24][C:25]=2[CH:31]=1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(Cl)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCC(=O)N3CCC[C@H]3C(=O)O)ccc21
Yield: 61.6 %

Procedure:
(S)-1-(2-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylic acid (54 mg) was prepared by following General Procedure E starting from (S)-1-(2-{[2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-acetyl)-pyrrolidine-2-carboxylic acid methyl ester (90 mg) and lithium hydroxide (29 mg).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][CH:9]=[CH2:10])(=[O:5])[C:2]([CH3:4])=[CH2:3].C1C=C(Cl)C=C(C(OO)=[O:19])C=1>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][CH:9]1[O:19][CH2:10]1)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCOC(=O)C(=C)C
Solvent: ClCCl
Product: C=C(C)C(=O)OCCC1CO1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 3-butenyl methacrylate (5.1 g) was added slowly to the stirred solution of m-CPBA (10.2) in methylene dichloride (70 ml). The resulting solution was stirred at room temperature for 5 hours and then was washed repeatedly with a dilute aqueous solution of potassium carbonate. The solution obtained was then dried with anhydrous magnesium sulfate and evaporated. Pure 3,4-epoxybutyl methacrylate was isolated by column chromatography on silica gel. Yield 3.9 g.