Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[O:9])[NH:5][CH:6]=[N:7][N:8]=1.C(N(CC)C(C)C)(C)C.[CH:19]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20]1>CN(C)C=O.N1C=CC=CC=1>[O:9]=[C:4]1[C:3]([CH2:2][NH:1][C:23]([CH:19]2[CH2:22][CH2:21][CH2:20]2)=[O:24])=[N:8][N:7]=[CH:6][NH:5]1
Reactant: NCc1nnc[nH]c1=O
Reactant: O=C(Cl)C1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(NCc1nnc[nH]c1=O)C1CCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 6-aminomethyl-4H-[1,2,4]triazin-5-one (500 mg, 3.96 mmol) and N,N-diisopropylethylamine (DIEA) (0.829 mL, 4.76 mmol) in anhydrous N,N-dimethylformamide (DMF) (20 mL) and anhydrous pyridine (2 mL) was dropwise charged with cyclobutanecarbonyl chloride (0.451 mL, 3.96 mmol) at 0° C. then warmed to rt and stirred for an additional 1.5 h. The reaction mixture was quenched with H2O (2 mL) and concentrated in vacuo and was purified by chromatography on silica gel [eluting with 5% MeOH in DCM (200 mL)→10% MeOH in DCM (800 mL)], affording the title compound; 1H NMR (DMSO-d6, 400 MHz) δ 1.7-1.82 (m, 1H), 1.70-1.92 (m, 1H); 1.97-2.07 (m, 2H); 2.07-2.19 (m, 2H); 3.55-3.67 (m, 1H); 4.19 (d, 2H); 7.97 (brt, J=5.6 Hz, 1H); 8.67 (s, 1H); MS (ES+): m/z 209.25 (100) [MH+], HPLC: tR=1.56 min (MicromassZQ, polar—5 min).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:60][CH3:61])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@H:3]([C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[CH:41]([CH3:40])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[CH2:4][C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
A solution containing the product from Example 2C (0.01 g, 0.019 mmol) in THF (0.2 mL) was treated with the product from Example 7B (0.009 g, 0.021 mmol), DEPBT (0.009 g, 0.030 mmol), and N,N-diisopropylethylamine (0.016 mL, 0.092 mmol), stirred at 25° C. for 16 hours and partitioned between a mixture of dichloromethane, ethyl acetate (2:1, respectively) and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was purified by reversed phase chromatography on a C18 column eluting with a gradient starting with 5-100% acetonitrile in water (0.1% TFA). The product was partitioned between a mixture of dichloromethane and ethyl acetate (2:1, respectively) and saturated NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, filtered and concentrated to give the title compound (0.0076 g, 51% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.82 (m, 18 H), 1.31 (m, 3 H), 1.52 (m, 2 H), 1.80 (m, 1 H), 2.45 (s, 3 H), 2.67 (m, 4 H), 3.09 (m, 4 H), 3.50 (s, 1 H), 3.66 (m, 1 H), 3.84 (d, J=9.93 Hz, 1 H), 3.93 (d, J=11.03 Hz, 1 H), 4.14 (m, 1 H), 4.35 (s, 1 H), 4.67 (d, J=7.35 Hz, 1 H), 6.64 (d, J=9.93 Hz, 1 H), 7.21 (m, 12 H), 7.66 (t, J=7.72 Hz, 1 H), 7.86 (m, 4 H), 8.63 (d, J=4.78 Hz, 1 H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][OH:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CN1CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH:10]=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(CO)CC1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)N1CCC(C=O)CC1
Reaction time: 3 h
Yield: 51.5 %

Procedure:
A solution of 1-isopropylpiperidine-4-methanol (0.40 g, 2.5 mmol) and N-methylmorpholine (0.46 g, 3.8 mmol) in methylene chloride (20 mL) was treated with tetrapropylammonium perruthenate (0.089 g, 0.25 mmol). After 3 h, the mixture was concentrated and the residue purified by column chromatography (SiO2: 10% to 20% methanol:methylene chloride) affording 0.20 g (50%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:11][O:12][NH:13][CH3:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([N:13]([O:12][CH3:11])[CH3:14])=[O:8]
Reactant: O=C(O)c1cncc(Br)c1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1cncc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.9 %

Procedure:
To a solution of 5-bromo-nicotinic acid (2.02 g, 10 mmol) and O,N-dimethyl-hydroxylamine (670 mg, 11 mmol) in DMF (100 mL) was added HOBt (400 mg, 0.3 mmol), EDCI (2.09 g, 11 mmol) and Et3N (1.11 g, 11 mmol). The resulting mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and it was extracted with EtOAc. The organic layer was washed with brine, dried by anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was then purified by flash chromatography to give the title compound (2.08 g, 85%) as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.O([Si:30]([CH3:33])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:31][Si:30]([CH3:33])([CH3:32])[O:13][C:11]([C:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)=[CH2:12]
Reactant: CC(=O)c1ccnc2ncccc12
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C)c1ccnc2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1,8]Naphthyridin-4-yl-ethanone from Preparation 18 (250 mg, 1.45 mmol), 2,6-lutidine (0.254 ml, 2.18 mmol) in DCM (3.6 ml) was treated with trimethylsilyl triflate (0.276 ml, 1.53 mmol) and allowed to stir at RT overnight. Mixture diluted with DCM and washed with satd. NaHCO3. Organics dried over Na2SO4 and concentrated, furnished 350 mg 4-(1-trimethylsilanyloxy-vinyl)-[1,8]-naphthyridine as an oil. MS (ESI+) for m/z 245 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:26]=[CH:25][C:6]([C:7]([NH:9][C:10]2[NH:11][N:12]=[C:13]([CH2:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[CH:18]=3)[CH:14]=2)=[O:8])=[CH:5][CH:4]=1)#[N:2].[OH-:27].[Na+]>C(O)C.O>[CH3:24][O:23][C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][C:13]2[CH:14]=[C:10]([NH:9][C:7]([C:6]3[CH:5]=[CH:4][C:3]([C:1]([NH2:2])=[O:27])=[CH:26][CH:25]=3)=[O:8])[NH:11][N:12]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: [OH-]
Reactant: COc1cccc(CCc2cc(NC(=O)c3ccc(C#N)cc3)[nH]n2)c1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1cccc(CCc2cc(NC(=O)c3ccc(C(N)=O)cc3)[nH]n2)c1
Temperature: 80 °C
Yield: 9.5 %

Procedure:
4-Cyano-N-[5-[2-(3-methoxyphenyl)ethyl]-2H-pyrazol-3-yl]benzamide (Example 23) (0.2 g, 0.58 mmol) and NaOH (69 mg, 1.73 mmol) were added to a solution of ethanol/water (20 ml, 3:1) and heated at 80° C. until complete consumption of starting material was observed. Care was required as the amide further hydrolysed to the carboxylic acid. The reaction was extracted with DCM (3×50 ml), dried and the solvent was removed in vacuo to yield a white solid. This was triturated with DCM to afford a white solid (20 mg, 10%); 1H NMR (400.132 MHz, DMSO) δ 2.90 (s, 4H), 3.75 (s, 3H), 6.42 (s, 1H), 6.82-6.75 (m, 3H), 7.20 (t, 1H), 7.46 (s, 1H), 7.95 (d, 2H), 8.16-8.03 (m, 3H), 10.82 (s, 1H), 12.18 (s, 1H); MH+366.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9](C=O)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C1C=C(Cl)C=C(C(OO)=[O:21])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([OH:21])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc2c(c1)OCCO2
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccc2c(c1)OCCO2
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.7 %

Procedure:
To a solution of 2,3-dihydro-benzo[1,4]dioxin-6-carboxaldehyde (30.0 g, 183 mmol) in 500 ml CH2Cl2 was added mCPBA (37.85 g, 219 mmol). The suspension was heated to 50° C. After 16 h saturated NaHCO3 was added and the mixture was extracted with CH2Cl2. The combined organics were concentrated in vacuo and taken up in MeOH and 200 ml 4M NaOH was added. After 2 h the mixture was acidified with 4M HCl and extracted with ethyl acetate. The combined organics were washed with saturated NaHCO3, washed with brine, concentrated in vacuo, and taken up in CH2Cl2. The solution was filtered to remove the precipitate. The resulting solution was stirred with saturated NaHCO3 for 1 h, separated, dried over MgSO4, filtered and concentrated in vacuo to give 2,3-dihydro-benzo[1,4]dioxin-6-ol (26.92 g, 94%).
Reaction SMILES: F[C:2]1C([B-](C2C(F)=C(F)C(F)=C(F)C=2F)(C2C(F)=C(F)C(F)=C(F)C=2F)C2C(F)=C(F)C(F)=C(F)C=2F)=C(F)C(F)=C(F)C=1F.[Li+].CCOCC.[C:52]([C:56]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([CH3:65])([CH3:64])C)N=1)([CH3:55])(C)C>C1(C)C=CC=CC=1.C([Pd]Cl)C=C>[CH2:61]([C:60]12[CH2:64][CH:62]([CH2:58][CH2:59]1)[CH:65]=[CH:2]2)[CH2:56][CH2:52][CH3:55]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)n1
Reactant: Fc1c(F)c(F)c([B-](c2c(F)c(F)c(F)c(F)c2F)(c2c(F)c(F)c(F)c(F)c2F)c2c(F)c(F)c(F)c(F)c2F)c(F)c1F
Agent: C=CC[Pd]Cl
Agent: [Li+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCC12C=CC(CC1)C2

Procedure:
A 50 weight percent solution of butylnorbornene (5.0 g, 0.033 mol) was prepared in toluene. Lithium tetrakis(pentafluorophenyl)borate.2.5 Et2O (0.0012 g, 0.0014 mmol) was combined with (allyl)palladiumchloride dimer (100 μl of a 1.4 mmol solution in toluene) and 2,6-di-t-butylpyridine (100 μl of a 2.9 mmol solution in toluene) in toluene and added to the monomer mixture. A polymeric puck formed within 5-10 min at room temperature.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:21])[C:9]2[C:18]3[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:20]=1.[OH-].[Na+].Cl.[C:25](OC(=O)C)(=[O:27])[CH3:26]>O>[C:25]([NH:3][CH2:4][CH2:5][CH2:6][C:7]1[N:8]([CH3:21])[C:9]2[C:18]3[CH:17]=[C:16]([CH3:19])[CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:20]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc2ncc3nc(CCCN)n(C)c3c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)NCCCc1nc2cnc3ccc(C)cc3c2n1C

Procedure:
A sample of 2-(3-aminopropyl)-1,8-dimethyl-1H-imidazo[4,5-c]quinoline dihydrochloride (from Example 147) was dissolved in water. Excess sodium hydroxide was added to neutralize the hydrochloric acid and then excess acetic anhydride was added. The precipitate was separated by filtration, washed with water, and recrystallized from water to provide 2-(3-acetamidopropyl)-1,8-dimethyl-1H-imidazo[4,5-c]quinoline, m.p. 213°-215° C. Analysis: Calculated for C17H20N4O: %C, 68.9; %H, 6.8; %N, 18.9; Found: %C, 68.8; %H, 6.8; %N, 19.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:26]([OH:28])=O)=[CH:11][C:12]3[N:16]([CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[CH:15]=[N:14][C:13]=3[C:24]=2[F:25])=[C:4]([Cl:29])[CH:3]=1.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH:47]([O:49][CH2:50][CH2:51][O:52][NH2:53])=[CH2:48].CCN=C=NCCCN(C)C>CN(C)C=O.C(OCC)(=O)C.O>[CH:47]([O:49][CH2:50][CH2:51][O:52][NH:53][C:26]([C:10]1[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=2[Cl:29])=[C:24]([F:25])[C:13]2[N:14]=[CH:15][N:16]([CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12]=2[CH:11]=1)=[O:28])=[CH2:48]
Reactant: C=COCCON
Reactant: O=C(O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: C=COCCONC(=O)c1cc2c(ncn2CC2CCCCO2)c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 29.9 %

Procedure:
6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3-(tetrahydro-pyran-2-ylmethyl)-3H-benzoimidazole-5-carboxylic acid 11r (0.11 g, 0.23 mmol) is dissolved in N,N-dimethylformamide (2 mL). HOBT (0.037 g, 0.27 mmol) and triethylamine (0.094 mL, 0.68 mmol) are added. Then O-(2-vinyloxy-ethyl)-hydroxylamine (0.028 g, 0.27 mmol) and EDCI (0.056 g, 0.29 mmol) are added and the reaction mixture is stirred at room temperature under N2 until HPLC shows the reaction is complete (2-3 days). The reaction mixture is poured into a separatory funnel, diluted with ethyl acetate and water and the layers separated. The ethyl acetate layer is washed successively with aqueous saturated NH4Cl (2×), brine (1×), aqueous saturated sodium bicarbonate (2×), water (1×), and brine (1×), dried (Na2SO4) and concentrated under reduced pressure. The resulting solid is purified by FCC (eluting with 15:1 methylene chloride:methanol) to yield 0.039 g (79%) of the pure desired product as an off-white solid. MS ESI (+) m/z 567, 569 (M+, Br pattern) detected.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:50]>CN(C=O)C>[Br:50][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([C:14]2[NH:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:9][C:8]=1[CH3:29]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCO)c(C)c3)nc2c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCCCBr)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-[4-(4-hydroxy-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (675 mg, 1.69 mmol) in DMF (10 mL) were added PPh3 (489 mg, 1.86 mmol) and CBr4 (619 mg, 1.86 mmol). The reaction mixture was stirred at room temperature for 16 hours. Solvent was removed under reduced pressure. The residue was triturated with ether and ethyl acetate. The solid was dried and then purified by the Simpliflash system using 5% methanol in CH2Cl2 as the eluent to give 2-[4-(4-bromo-butoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one as a white solid. Yield: 494 mg (63%).
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.ClCCl.Cl[C:18]([O:20][CH2:21][CH3:22])=[O:19].Cl>C(N(CC)CC)C>[CH2:21]([O:20][C:18]([N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2)=[O:19])[CH3:22]
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)n1c2ccccc2c2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.6 %

Procedure:
An argon filled RB flask containing carbazole (0.500 g, 2.99 mmol) at 0° C. was treated with dichloromethane (12.5 mL) and triethylamine (2.5 mL), followed by slow addition of ethyl chloroformate (0.59 mL, 5.98 mmol). The mixture was stirred at ambient temperature for 16 h, poured into 25 mL of 2N HCl, and extracted with chloroform. The organic portion was washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4) and concentrated. The crude product was treated with methanol (4 mL) and filtered. The filtrate was concentrated to give carbazole-9-carboxylic acid ethyl ester (169 mg). Carbazole-9-carboxylic acid ethyl ester (95 mg, 0.39 mmol) was converted to hydroxamic acid by procedure A. Purification by HPLC gave the title compound (19 mg). 1H NMR (400 MHz, CD3CN): δ 9.43 (br, 1H), 8.08 (d, 2H, J=7.7 Hz), 7.50 (d, 2H, J=8.1 Hz), 7.43 (t, 2H, J=7.1 Hz), 7.22 (t, 2H, J=7.1 Hz). 13C NMR APT (100 MHz, CD3OD): δ 125.8 (down), 120.3 (down), 119.4 (down), 110.6 (down). ESI-MS (m/z): [M+Na]+ 249.6. Analytical HPLC: Purity=99%, tR=8.51 min, Method A.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1B(O)O.[NH2:20][C:21]1[N:26]=[C:25](Cl)[C:24]([CH:28]=[O:29])=[C:23]([Cl:30])[N:22]=1.ClCCl>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:20][C:21]1[N:22]=[C:23]([Cl:30])[C:24]([CH:28]=[O:29])=[C:25]([C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[CH3:9])[N:26]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1ccc(-c2nc(N)nc(Cl)c2C=O)c(C)c1
Temperature: 100 °C

Procedure:
Aqueous potassium phosphate was added to a suspension of 2,4-dimethylbenzene boronic acid and 2-amino-4,6-dichloro-5-pyrimidinecarbaldehyde (3 eq) in 1,4-dioxan, under a nitrogen atmosphere. Dichloro bis(triphenylphosphine)palladium (II) (cat.) was added and the mixture heated, ˜100° C., for ˜90 mins. The resulting mixture was allowed to cool and dichloromethane added, the mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude solid was purified by column chromatography on silica eluting with mixtures of diethyl ether and hexane.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[NH:11][CH2:12][CH2:13][CH:14]1[CH2:16][CH2:15]1)=[O:5])[CH3:2].[CH3:17][S:18]([NH:21][C:22]1[CH:37]=[CH:36][C:25]2[NH:26][C:27]([CH2:32][C:33](O)=[O:34])=[N:28][S:29](=[O:31])(=[O:30])[C:24]=2[CH:23]=1)(=[O:20])=[O:19].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH2:9][CH2:8][C@@H:7]1[N:11]([CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16]1)[C:33](=[O:34])[CH2:32][C:27]1[NH:26][C:25]2[CH:36]=[CH:37][C:22]([NH:21][S:18]([CH3:17])(=[O:20])=[O:19])=[CH:23][C:24]=2[S:29](=[O:30])(=[O:31])[N:28]=1)=[O:5])[CH3:2]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(CCC1CC1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of cis-2-(2-cyclopropylethylamino)-cyclopentanecarboxylic acid ethyl ester (42.7 mg, 0.189 mmol) in N,N-dimethylformamide (3.0 mL) was added (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 94.8 mg, 0.284 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (73.9 mg, 0.378 mmol), and 4-dimethylaminopyridine (5.8 mg, 0.047 mmol). After stirring at 25° C. for 14 h, the mixture was diluted with ethyl acetate and acidified with 1.0 M aqueous hydrochloric acid solution. The layers were separated and the organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, cis-2-{(2-cyclopropylethyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)acetyl]amino}-cyclopentanecarboxylic acid ethyl ester, as a yellowish oil. The crude product was used in the next step without further purification. LC-MS (ESI) calcd for C23H32N4O7S2 540.17, found 541.4 [M+H+].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)=[CH:5][CH:4]=1>CO.[Pd]>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2=CCNCC2)cc1
Agent: [Pd]
Solvent: CO
Product: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reaction time: 4 h
Yield: 93 %

Procedure:
A mixture of 0.54 g (1.22 mmol) of 4-(4-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 0.1 g of 10% Pd/C in 20 mL of MeOH was stirred under a hydrogen atmosphere at 45 psi for 4 h. The reaction mixture was filtered through a thin pad of celite eluting with CH2Cl2. The solution was concentrated to give 0.26 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[N:13][C:12]([C:15]([NH:17][NH2:18])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[N:19]([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>Cl.O>[CH3:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[N:13][C:12]([C:15]([N:17]=[N+:18]=[N-:19])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1Oc1ccc(C(=O)NN)nn1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Cc1ncccc1Oc1ccc(C(=O)N=[N+]=[N-])nn1
Yield: 50.9 %

Procedure:
A solution of 6-(2-methylpyridin-3-yloxy)-pyridazine-3-carboxylic acid hydrazide (D12) (0.62 g, 2.53 mmol) in conc. hydrochloric acid (9 ml) and water (7.5 ml) cooled to 0° C. in an ice-bath was treated with a solution of sodium nitrite (0.18 g, 2.53 mmol) in water (1.5 ml) dropwise keeping the temperature below 5° C. After 10 minutes saturated potassium carbonate was added until basic. The precipitate was filtered off, washed with water and air dried to give a cream solid (0.33 g, 51%).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=O)[C:10]([O:12]CC)=[O:11])[N:8]=1)=[O:2].[OH-].[K+].Cl.[NH2:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>O1CCCC1.N1C=CC=CC=1>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[N:20][O:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: CC(C)(C)OC(=O)CON
Reactant: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1nc(NC=O)sc1Cl
Reaction time: 0.17 h
Yield: 42.3 %

Procedure:
Ethyl (2-formamido-5-chlorothiazol-4-yl)glyoxylate (14.5 g) was added to a solution of 1 N aqueous potassium hydroxide (110 ml) at ambient temperature, and the mixture was stirred for 10 minutes to prepare the solution of potassium (υ-formamido-5-chlorothiazol-4-yl)glyoxylate. After this solution was adjusted to pH 2 with 10% hydrochloric acid under ice-cooling, thereto were added pyridine (20 ml) and a solution of tert-butyl 2-aminooxyacetate (10.3 g) in tetrahydrofuran (50 ml), followed by stirring at ambient temperature for 5 hours. After the reaction mixture was washed with ethyl acetate, the remaining aqueous solution was adjusted to pH 1.5 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave 2-(2-formamido-5-chlorothiazol-4-yl)-2-tert-butoxycarbonylmethoxyiminoacetic acid (syn isomer) (8.5 g), mp 166° to 167° C. (dec.).