Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8](S(C3C=CC=CC=3)(=O)=O)[C:9]([CH3:11])=[CH:10][C:3]=12.[Cl:21][C:22]1[CH:23]=[N:24][N:25]([CH2:52][CH3:53])[C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[C:37]([Sn](C)(C)C)[CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][N:34]2S(C1C=CC=CC=1)(=O)=O)=[O:28].C1(S)C=CC=CC=1>CN(C=O)C>[Cl:21][C:22]1[CH:23]=[N:24][N:25]([CH2:52][CH3:53])[C:26]=1[C:27]([NH:29][C:30]1[CH:38]=[C:37]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][C:9]([CH3:11])=[CH:10][C:3]=23)[CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2)=[O:28]
Reactant: CCn1ncc(Cl)c1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Reactant: Cc1cc2c(Br)ccnc2n1S(=O)(=O)c1ccccc1
Agent: Sc1ccccc1
Solvent: CN(C)C=O
Product: CCn1ncc(Cl)c1C(=O)Nc1cc(-c2ccnc3[nH]c(C)cc23)cc2[nH]ncc12
Temperature: 135 °C
Reaction time: 8 h

Procedure:
4-Bromo-2-methyl-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (63 mg) in DMF (0.4 ml) was added to 4-chloro-1-ethyl-N-[1-(phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-yl]-1H-pyrazole-5-carboxamide (100 mg) in DMF (0.4 ml). Solvias catalyst (4 mg) was added and the sealed vessel was heated in the Anton Paar microwave at 135° C. for 20 min. PS-thiophenol resin was added and the reaction was stirred overnight before being filtered onto a C18SPE cartridge, pre-washed with 0.1% TFA, with acetonitrile. The cartridge was washed with 0.1% TFA in acetonitrile and the collected solvent was removed under a stream of nitrogen. The residue was dissolved in DMSO (1 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo. The residue was dissolved in isopropanol (0.3 ml), 2M sodium hydroxide (aq) (0.3 ml) was added and the reaction was left at room temperature overnight, then heated to 60° C. for 1 h. The solvent was removed under a stream of nitrogen and the residue was dissolved in DMSO (0.5 ml) and purified by MDAP (method C). The solvent was evaporated in vacuo to give title compound, 6 mg.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[N:7]([CH2:15][CH2:16][F:17])[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1I)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O>>[C:1]([O:5][C:6](=[O:18])[N:7]([C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[Cl:19])[CH2:15][CH2:16][F:17])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCF)c1cnccc1I
Reactant: OB(O)c1ccccc1Cl
Product: CC(C)(C)OC(=O)N(CCF)c1cnccc1-c1ccccc1Cl

Procedure:
The title compound was prepared in analogy to example 72, from (2-fluoro-ethyl)-(4-iodo-pyridin-3-yl)-carbamic acid tert-butyl ester and 2-chlorophenylboronic acid (CAS RN 1679-18-1). Yellow oil (86%). MS (ESI): m/z=351.13 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>O>[CH2:26]([O:9][C:6]1[CH:5]=[C:4]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:3]([O:2][CH3:1])=[N:8][CH:7]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ncc(O)cc1CC(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ncc(OCc2ccccc2)cc1CC(C)(C)C
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 6-methoxy-5-neopentylpyridin-3-ol (2.00 g), potassium carbonate (4.25 g) and DMF (20 mL) was added benzyl bromide (2.40 mL) at room temperature, and the mixture was stirred at 50° C. for 30 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give a crude product of the title compound as a colorless oil. This compound was used for the next step without further purification.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]([C:9]3[C:16]([NH:17][C:18]4C=CC(S([O-])(=O)=O)=C(N)C=4)=[CH:15][C:14]([S:29]([O-:32])(=[O:31])=[O:30])=[C:13]([NH2:33])[C:10]=3[C:11](=[O:12])[C:4]2=[CH:3][CH:2]=1)=[O:8].[Na+:34].[Na+].[O-][Mn](=O)(=O)=O.[K+]>CC(O)=O.O>[CH3:18][NH:17][C:16]1[C:9]2[C:7]([C:5]3[C:4]([C:11](=[O:12])[C:10]=2[C:13]([NH2:33])=[C:14]([S:29]([O-:32])(=[O:31])=[O:30])[CH:15]=1)=[CH:3][CH:2]=[CH:1][CH:6]=3)=[O:8].[Na+:34]
Reactant: Nc1cc(Nc2cc(S(=O)(=O)[O-])c(N)c3c2C(=O)c2ccccc2C3=O)ccc1S(=O)(=O)[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1cc(S(=O)(=O)[O-])c(N)c2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of AQ-1 (51.5 g, 343 mmol) in AcOH (500 mL) is added a solution of KMnO4 (59.7 g, 36.6 mmol) in H2O (500.0 mL) dropwise at 5° C. The reaction mixture is then stirred at rt for 1 h. The mixture is extracted with EtOAc, washed with aq. NaHCO3, dried (Na2SO4) and concentrated. The resultant residue is purified by recrystallization to yield AQ-2.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].[C:6]([N:13]1[CH2:19][CH2:18][CH2:17][C@H:14]1[CH:15]=[O:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[C:6]([N:13]1[CH2:19][CH2:18][CH2:17][C@H:14]1[C:15](=[O:16])[CH:1]([CH3:3])[CH3:2])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Reactant: CC(C)[Mg]Cl
Product: CC(C)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
30.1 ml (60.2 mmol) 2 M isopropylmagnesium chloride (diethyl ether) and 4.0 g (20.1 mmol) BOC-L-prolinal were allowed to react at −80° C. for 30 min according to procedure F. Yield of the crude product 4.31 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.84 g (7.6 mmol, 38%). The product was oxidized to the corresponding ketone according to procedure G. Yield of crude product 1.59 g. The product was purified with a silica column using 16% ethyl acetate in petroleum ether as eluent. Yield 1.15 g (4.8 mmol, 63%).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C(N(C(C)C)CC)(C)C.[CH2:20]([O:22][CH2:23]OCl)[CH3:21]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:20]([O:22][CH2:23][O:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH3:21]
Reactant: Cc1cccc(C=O)c1O
Reactant: CCOCOCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOCOc1c(C)cccc1C=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 52 %

Procedure:
To a stirred solution of 2-hydroxyl-3-methylbenzaldehyde (1.46 g, 10.7 mol), diisopropyl ethylamine (3.3 mL, 20.0 mmol) and 4-(dimethylamino)pyridine (122 mg, 1.0 mmol) in dichloromethane (35 mL) was added ethoxymethoxyl chloride (1.85 mL, 20.0 mmol) at RT. The mixture was stirred at RT for 17 h. The reaction was quenched with water (30 mL). The product was extracted with CH2Cl2 (3×40 mL). The combined organic extracts were washed with water (50 mL), and brine (50 mL), dried over anhydride Na2SO4. The residue was purified by flash column chromatography (hexanes/ethyl acetate=5:1, v/v) to provide the title compound (2.02 g, 97%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:32])[CH3:31])=[C:9]2[N:8]=1)[CH2:4][CH3:5].N[C@H](CO)[C@@H](C)[OH:36]>>[OH:1][CH2:2][C@@H:3]([NH:6][C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:19][CH:20]=2)[N:10]2[N:27]=[CH:28][C:29]([CH:30]([CH3:31])[CH3:32])=[C:9]2[N:8]=1)[C@H:4]([OH:36])[CH3:5]
Reactant: C[C@@H](O)[C@H](N)CO
Reactant: CC[C@H](CO)Nc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Product: CC(C)c1cnn2c(NCc3ccc(-c4ccccn4)cc3)nc(N[C@H](CO)[C@@H](C)O)nc12
Yield: 43 %

Procedure:
According to the same conditions resulting in the preparation of the compound 2, the compound 12 is prepared from IIa.2 by oxidation reaction of the sulfur atom and then introduction of L-threoninol. Yield=43%. Oil. 1H NMR (300 MHz, CDCl3): δ 8.69 (d, 1H, J=4.7 Hz, Harom), 7.97 (d, 2H, J=8.3 Hz, Harom), 7.78-7.69 (m, 2H, Harom), 7.63 (8, 1H, Harom), 7.45 (d, 2H, J=8.3 Hz, Harom), 7.26-7.21 (m, 1H, Harom), 6.75 (bs, 1H, NH), 5.63 (d, 1H, J=5.8 Hz, NH), 4.77 (d, 2H, J=6.0 Hz, CH2), 4.22-4.15 (m, 1H, CH), 3.97-3.84 (m, 3H, CH+CH2), 3.01 (hept, 1H, J=7.0 Hz, CH), 1.29 (d, 3H, J=6.2 Hz, CH3), 1.28 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 448 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:7]=1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:4]1[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: CN1CCC(N(C)c2cc(N)cc(F)c2)CC1
Product: CN1CCC(N(C)c2cc(F)cc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Combine 5-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 29, 0.036 g, 0.15 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.044 g, 0.23 mmol) and 1,4-doxane (2 mL), stir and heat at reflux. After 3 hr, cool to ambient temperature. Load on a SCX column (10 g), wash with methanol, elute with 2M ammonia-methanol. Concentrate eluent to obtain 0.059 g (100%) the title compound as a free base. Dissolve this material in dichloromethane (5 mL) and treat with 1M hydrochloric acid in ether (0.15 mL, 0.15 mmol). Concentrate to give the title compound as a brown powder: high resolution mass spectrum: Obs. m/z 394.1495; Calc. m/z 394.1497; 1H NMR (CDCl3)of free base: 7.8 (bs, 1H), 7.7 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH3:22])[C:5]2[N:9](COCC[Si](C)(C)C)[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:21]([O:23][CH2:24][C:25]2([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[O:32])[CH2:29][CH2:30]2)[CH3:22])[C:5]2[NH:9][C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1
Reactant: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1n(COCC[Si](C)(C)C)c(=O)n2C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: CCOCC
Product: CC(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2c1[nH]c(=O)n2C
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
tert-Butyl 4-((1-(6-chloro-1-methyl-2-oxo-3-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-benzo[d]imidazol-4-yl)ethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (53 mg, 0.082 mmol) was dissolved in tetrabutylammonium fluoride (1M in tetrahydrofuran, 1 mL, 1 mmol) and immersed in an oil bath which was pre-heated to 60° C. After 1.5 h, the temperature was increased to 65° C. and stirred at that temperature for 5 h. The reaction was sealed and heated at 70° C. overnight. The crude reaction mixture was diluted with diethyl ether and poured into water. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate and concentrated. Column chromatography (25%→75% ethyl acetate/n-hexane) gave 26 mg (61%) as a colorless film. 1H-NMR (CDCl3, 500 MHz) δ 7.66 (bs, 1H), 7.25 (dd, J=8.6, 5.5 Hz, 2H), 7.05 (dd, J=8.9, 8.6 Hz, 2H), 6.80 (d, J=1.5 Hz, 1H), 6.66 (d, J=1.8 Hz, 1H), 4.29 (q, J=6.7 Hz, 1H), 3.73 (m, 2H), 3.32 (d, J=9.2 Hz, 1H), 3.31 (s, 3H), 3.27 (d, J=9.2 Hz, 1H), 2.87-3.12 (m, 2H), 2.20 (m, 1H), 2.06 (m, 1H), 1.81 (m, 1H), 1.74 (bs, 1H), 1.43 (s, 9H), 1.32 (d, J=6.4 Hz, 3H). Mass spec.: 540.10 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([O-])(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[K+].O=P(Cl)(Cl)[Cl:19]>>[Cl:1][C:2]1[C:10]2[S:9][C:8]([S:11]([Cl:19])(=[O:13])=[O:12])=[C:7]([CH3:15])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1c(S(=O)(=O)[O-])sc2c(Cl)cccc12
Agent: [K+]
Product: Cc1c(S(=O)(=O)Cl)sc2c(Cl)cccc12
Temperature: 60 °C
Yield: 61 %

Procedure:
A mixture of potassium 7-chloro-3-methylbenzothiophene-2-sulfonate (100 mg, 0.34 mmol) in POCl3 (5 mL) was heated at 60° C. over night. The POCl3 was evaporated and the crude product was purified on a small amount of silica using CH2Cl2 as eluent to give 58 mg of the title compound (61%).
Reaction SMILES: Br[C@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1.C([O-])([O-])=O.[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH2:39])(=[O:38])=[O:37]>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[S:36]([NH:39][C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1)(=[O:38])=[O:37]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@@H](Br)CN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@H](NS(=O)(=O)c3ccccc3Cl)CN12
Temperature: 80 °C
Yield: 26.7 %

Procedure:
To a solution of (6R,7aR)-6-Bromo-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (50 mg, 0.130 mmol) in DMF (3 mL) in a sealed tube, was added K2CO3 (27.3 mg, 0.197 mmol) and 2-Chloro-benzenesulfonamide (50.5 mg, 0.263 mmol) and heated to 80° C. for 12 h. All volatiles were removed under reduced pressure and the residue was extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified through biotage column chromatography (elution with 40% ethyl acetate in hexane) to afford 17 mg (26.5%) of the title compound as a white solid. LC-MS: 489 [M+1]+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:16])[C:11](=[CH:14][CH:15]=1)[CH:12]=[O:13].Br[CH2:18][C:19]([CH:21]([CH3:23])[CH3:22])=[CH2:20]>CN(C)C=O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[C:10]([O:16][CH2:20][C:19](=[CH2:18])[CH:21]([CH3:23])[CH3:22])[CH:9]=1
Reactant: C=C(CBr)C(C)C
Reactant: O=Cc1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(COc1cc(Cl)ccc1C=O)C(C)C
Temperature: 70 °C
Yield: 91.6 %

Procedure:
To a solution of 8.8 g (0.064 mol) of potassium carbonate in 100 mL of dimethylformamide was added 10.0 g (0.064 mol) of 4-chlorosalicylaldehyde and 12.5 g (0.077 mol) of 2-(bromomethyl)-3-methyl-1-butene. The reaction mixture was heated at 70° C. for 2 hours, cooled to room temperature and poured into 600 mL ice/water. The crude mixture was extracted with ethyl acetate (3×100 mL). The ethyl acetate was washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford 14.0 g of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1.[C:16]1([CH:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]([N:24]2[CH2:25][CH2:26][CH:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:23]2)=[O:9])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:4][N:3]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1noc(-c2ccccc2)c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2)c1C(=O)N1CCC(c2ccccc2)C1
Temperature: 25 °C

Procedure:
3-Methyl-5-phenyl-4-isoxazolecarboxylic acid (40 mg, 0.197 mmol), 3-phenyl-pyrrolidine (31.6 mg, 0.215 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (86.2 mg, 0.268 mmol) and diisopropylethylamine (25.4 mg, 0.197 mmol) were mixed in dimethylformamide (1.5 mL) and stirred at room temperature. Solvent was evaporated in vacuo, and the residue was taken up in methanol (1 mL), filtered and purified by preparative chromatography. The combined fractions were partitioned between NaHCO3 (sat) and ethylacetate. The organic layer was washed with water and concentrated in vacuo to afford the title compound. HRMS (ESI, pos. ion) m/z calcd for C21H20N2O2: 332.1525, found 332.1535.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:12])[CH2:10][CH3:11])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(Cl)([Cl:16])(=O)=O>C(O)(=O)C>[Cl:16][CH:10]([CH3:11])[C:9](=[O:12])/[C:3](=[N:2]/[OH:1])/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)/C(=N\O)C(=O)CC
Solvent: CC(=O)O
Product: CCOC(=O)/C(=N\O)C(=O)C(C)Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of ethyl 2-(Z)-hydroxyimino-3-oxopentanoate (10 g) in 10 ml of acetic acid was cooled to 0° C. and treated dropwise with sulfuryl chloride (5.3 ml). The mixture was stirred for 3 hours at room temperature and quenched by ice-water. The mixture was extracted with ethyl acetate, and the extracts were washed with brine and dried with magnesium sulfate. The solvent was removed under reduced pressure to afford ethyl 4-chloro-2-(Z)-hydroxyimino-3-oxopentanoate (11.97 g).
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].[Cl:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=1.Cl>CS(C)=O.O>[ClH:15].[S:17]1[C:18]2[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=2[N:20]=[C:16]1[NH:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Clc1nc2ccccc2s1
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)[C@H](Cc1ccccc1)Nc1nc2ccccc2s1
Temperature: 95 °C

Procedure:
11.8 g phenylalanine (71.4 mmol) was added in portions to a suspension of 5.7 g powdered NaOH (143 mmol) in 50 mL DMSO, and stirred under nitrogen. 2-Chlorobenzothiazole (11 g, 65 mmol) was added over fifteen minutes at room temperature. The reaction was heated on an oil bath at about 95° C. for 4 hours. The reaction mixture was then cooled, poured into 200 mL ice and water, and the pH of the resulting mixture was adjusted to about 1-2 by addition of 10N HCl.
Reaction SMILES: [Si]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([O:12]CC)=O)(C(C)(C)C)(C)C.[NH2:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1>>[OH:8][CH:9]([CH2:15][CH2:16][CH2:17][CH3:18])[C:10]([NH:19][C:20]1[S:21][CH:22]=[C:23]([CH3:25])[N:24]=1)=[O:12]
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)OCC
Reactant: Cc1csc(N)n1
Product: CCCCC(O)C(=O)Nc1nc(C)cs1

Procedure:
The title compound was prepared in a manner similar to that described for Intermediate A3, starting from ethyl 2-{[tert-butyl(dimethyl)silyl]oxy}hexanoate and 2-amino-4-methylthiazole, 1H NMR (300 MHz, CDCl3) δ 10.30 (br s, 1H), 6.54 (s, 1H), 5.12 (br s, 1H), 4.41 (m, 1H), 2.35 (s, 3H), 2.00 (m, 1H), 1.76 (m, 1H), 1.48 (m, 2H), 1.39 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[C@H:14]1([NH2:21])[CH2:19][CH2:18][C@H:17]([NH2:20])[CH2:16][CH2:15]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:20][C@H:17]2[CH2:18][CH2:19][C@H:14]([NH2:21])[CH2:15][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.21 g, 0.98 mmol) (Example 1, step 2), trans-cyclohexane-1,4-diamine (from Aldrich, 0.13 g, 1.2 mmol) and N,N-diisopropylethylamine (0.34 mL, 2.0 mmol) in isopropyl alcohol (3.3 mL) was heated at 90° C. for 2 h. The solvent in the resulting mixture was removed to give the desired product, which was used directly in the next step. LCMS calculated for C13H17N4O2S (M+H)+: m/z=293.1. Found: 293.0.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Br.Br.[NH2:47][CH:48]1[C:54]2=[N:55][C:56]([C:60]3[CH:65]=[CH:64][N:63]=[CH:62][N:61]=3)=[CH:57][C:58](=[O:59])[N:53]2[CH2:52][CH2:51][NH:50][CH2:49]1>CN(C)C=O>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:47][CH:48]2[C:54]3=[N:55][C:56]([C:60]4[CH:65]=[CH:64][N:63]=[CH:62][N:61]=4)=[CH:57][C:58](=[O:59])[N:53]3[CH2:52][CH2:51][NH:50][CH2:49]2)=[O:8])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Agent: Br
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a solution of 0.040 g (0.199 mmol) of 4amino-5-chloro-2-methoxy-benzoic acid dissolved in 5 mL of anhydrous dimethylformamide was added 0.06 mL (0.43 mmol) of triethylamine, 0.077 g (0.20 mmol) of O-(benzotriazol-1-yl)-N,N,N′N,′-tetramethyluroniumhexafluorophosphate (HBTU). The resulting mixture was stirred at room temperature for 5 min and added slowly at −10° C. to a solution of 0.090 g (0.21 mmol) of (+/−)-9-amino-2-pyrimidin-4-yl-6,7,8,9-tetrahydro-5H-1,4a,7-triaza-benzocyclohepten-4-one dihydrobromide (2:1) dissolved in a mixture of 5 mL of anhydrous dimethylformamide and 0.09 mL (0.64 mmol) of triethylamine. The resulting mixture slowly increases to room temperature and was stirred for 16 hours. After evaporation, the reaction mixture was diluted in dichloromethane and a saturated aqueous solution of sodium carbonate. The organic phase was washed saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 97/3/0.3 to afford 0.022 g (23%) of the pure product as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][C:20]=3[OH:28])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:48]([NH:55][CH2:56][CH2:57]O)([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:48]([NH:55][CH2:56][CH2:57][O:28][C:20]1[CH:21]=[C:22]([CH:25]([CH3:26])[CH3:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[C:11]([C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:10])=[CH:16][CH:15]=[CH:14][N:13]=1)([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49]
Reactant: CC(C)c1ccc(CNc2ncccc2C(=O)Nc2ccc(Cl)cc2)c(O)c1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1ccc(CNc2ncccc2C(=O)Nc2ccc(Cl)cc2)c(OCCNC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 33.7 %

Procedure:
To a solution of N-(4-chlorophenyl)-2-[2-hydroxy-4-isopropylbenzylamino]pyridine-3-carboxamide (0.050 g, 0.13 mmol), triphenylphosphine (0.033 g, 0.13 mmol) and N-Boc-ethanolamine (0.018 mg, 0.11 mmol) in 0.3 mL tetrahydrofuran at −10° C. was added a solution of diethyl azodicarboxylate (0.02 mL, 0.13 mmol) in 0.3 mL tetrahydrofuran. The reaction was stirred at room temperature for 3 days. The solvent was removed in vacuo; and the crude material was purified by chromatography over silica, using an eluent gradient of 20-30% ethyl acetate in hexanes, to afford the named product (0.02 g, 30%).