Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([N:16]2[CH2:15][CH2:14][N:13]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17]2)[CH:3]=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: COc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1[N+](=O)[O-]
Yield: 66.9 %

Procedure:
A mixture of 5-fluoro-2-nitroanisole (3.00 g, 17.5 mmol), tert-butyl piperazine-1-carboxylate (4.57 g, 24.5 mmol) and potassium carbonate (3.63 g, 26.3 mmol), in dimethyl sulfoxide (20 mL) was heated at 90° C. for 1.5 hours under a nitrogen atmosphere. The reaction mixture was cooled and diluted with water (100 mL). The resulting precipitate was filtered and dried to give a bright yellow solid. The solid was suspended in a 5:1 solution of petroleum ether/diethyl ether (50 mL), sonicated for 2 minutes, filtered and dried to give the title compound (I1) (3.95 g, 66%) as a bright yellow solid; 1H NMR (300 MHz, d6-DMSO) δ 1.42 (s, 9H), 3.46 (brs, 8H), 3.90 (s, 3H), 6.52 (s, 1H), 6.57 (d, 1H, J=9.5 Hz) and 7.89 (d, 1H, J=9.3 Hz). LCMS Method B: rt 7.45 min; m/z 338.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:21]([O:23]CC)=[O:22])[CH:13]([C:17]([F:20])([F:19])[F:18])[O:14]3)=[CH:9][C:8]=2[Cl:26])=[C:4]([F:29])[CH:3]=1.[OH-].[Na+].Cl>CO.C1COCC1>[NH2:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:16]=[C:15]3[C:10]([CH:11]=[C:12]([C:21]([OH:23])=[O:22])[CH:13]([C:17]([F:20])([F:18])[F:19])[O:14]3)=[CH:9][C:8]=2[Cl:26])=[C:4]([F:29])[CH:3]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(Oc3ccc(N)cc3F)cc2OC1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.4 %

Procedure:
The ester from Step 2 (0.10 g, 0.23 mmole) was dissolved in 0.5 mL methanol and 0.5 mL THF. Sodium hydroxide (2.5 N) (0.2 mL, 0.46 mmole) was added to above solution and stirred at room temperature for overnight. The reaction mixture was acidified with 0.5 N HCl. The compound was extracted out with EtOAc. The organic layer was washed with water and dried over anhydrous MgSO4. The filtrate was evaporated and dried in vacuo to afford the title compound as a yellow solid (0.07 g, 75%): LCMS m/z 402.85 (M+H). 1H NMR (acetone-d6/400 MHz) 7.89 (s, 1H), 7.73 (s, 1H), 7.67 (dd, 1H, J=10.8, 2.4 Hz), 7.53 (dd, 1H, J=10, 1.6 Hz), 7.47 (m, 1H), 5.81 (q, 1H, J=7.0 Hz).
Reaction SMILES: [O:1]=[CH:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]=[CH:22]/[CH:23]=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1>C(Cl)(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([S:18]([N:21]2[CH:22]=[CH:23][C@H:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:3]([CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:2]2=[O:1])(=[O:19])=[O:20])=[CH:16][CH:17]=1
Reactant: CCOC(=O)/C=C/C=O
Reactant: COc1ccc(S(=O)(=O)N=C/C=C/c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C[C@@H]1C(=O)N(S(=O)(=O)c2ccc(OC)cc2)C=C[C@@H]1c1ccccc1
Yield: 90 %

Procedure:
The title compound was prepared according to the general procedure from ethyl trans-4-oxo-2-butenoate and trans-N-(4-methoxybenzenesulfonyl)-3-phenyprop-2-ene-1-imine using 10 mol % 9 as the catalyst in 90% yield as a white solid. [α]D20 (c 1.19, CHCl3)=+105.2; mp=111-113° C.; 1H NMR (400 MHz, CDCl3) δ 8.04 (dd, 2H, J=7.0, 2.1 Hz), 7.16-7.12 (m, 2H), 7.06-6.99 (m, 4H), 6.58 (dd, 2H, J=8.0, 1.1 Hz), 5.60 (dd, 1H, J=8.0, 6.5 Hz), 4.18-4.08 (m, 2H), 3.92 (s, 3H), 3.65 (t, 1H, J=6.9 Hz), 3.55-3.53 (m, 1H), 2.57 (dd, 1H, J=17.3, 6.1 Hz), 1.94 (dd, 1H, J=17.3, 7.5 Hz), 1.21 (t, 3H, J=7.0 Hz); 13C NMR (100 MHz, CDCl3) δ 171.7, 169.0, 164.3, 136.8, 131.4, 129.2, 128.9, 127.9, 127.9, 124.6, 114.3, 113.6, 61.0, 56.0, 44.1, 42.0, 31.6, 14.3; IR (thin film) ν 3086, 2982, 1720, 1594, 1496, 1454, 1406, 1367, 1264, 1132, 1091, 1026 cm−1; HRMS (ESI) calcd for C22H23NO6S [M+Na]+ 452.1138, found 452.1160; >99% ee (3R,4R)-isomer as determined by HPLC (AS-H, 9:1 hexanes/i-PrOH), tr (3S,4S)=53.9 min, tr (3R,4R)=39.2 min. For the (3R,4R) enantiomer (Table 2, entry 2), [α]D20 (c 0.98, CHCl3)=−112.7.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:23])[CH3:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH2:18]([O:20][C:21](=[O:31])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH:23][C:12](=[O:14])[C:11]1[CH:10]=[CH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=2)=[CH:16][CH:15]=1)[CH3:19]
Reactant: O=C(O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(-c2ccc(O)cc2)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 4-(4-hydroxyphenyl)benzoic acid (3.0 g) and L-phenylalanine ethyl ester hydrochloride (3.38 g) in DMF (30 ml) were added WSC.HCl (2.7 g), HOBT (1.89 g) and triethylamine (2 ml), and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 10% aqueous citric acid solution, water, a saturated aqueous sodium hydrogen-carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][C:26]3([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH2:29]3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH2:37]([S:39]([NH2:42])(=[O:41])=[O:40])[CH3:38]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:42][S:39]([CH2:37][CH3:38])(=[O:41])=[O:40])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:24][CH2:25][C:26]3([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH2:29]3)[CH2:27][CH2:28]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc12
Yield: 62 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-methylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.75 g, 0.16 mmol) obtained in step 2 and ethanesulfonamide (0.082 g, 0.78 mmol), the title compound (0.057 g, 66%) was obtained.
Reaction SMILES: [N:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=[C:17]([NH2:24])[C:16]=2[N:15]=[C:14]1[CH3:25]>>[NH2:24][C:17]1[C:16]2[N:15]=[C:14]([CH3:25])[N:13]([CH2:12][CH2:11][NH:10][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[C:21]=2[C:20]([CH3:22])=[C:19]([CH3:23])[N:18]=1
Reactant: Cc1nc(N)c2nc(C)n(CCN)c2c1C
Reactant: O=C(Cl)N1CCOCC1
Product: Cc1nc(N)c2nc(C)n(CCNC(=O)N3CCOCC3)c2c1C

Procedure:
Using the method of Examples 118-133, 4-morpholinecarbonyl chloride was reacted with 1-(2-aminoethyl)-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The observed accurate mass was 333.2025.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][N:4]=1.[C-:13]#[N:14].[K+]>C(O)C.O>[C:13]([CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[NH:5][N:4]=1)#[N:14]
Reactant: ClCc1n[nH]c2ccc(Cl)cc12
Reactant: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1n[nH]c2ccc(Cl)cc12
Temperature: 5 °C
Yield: 69.9 %

Procedure:
A solution of 3-chloromethyl-5-chloro-1H-indazole (4.5 g) in ethanol (50 ml) is dropwise added to a solution of potassium cyanide (17 g) in water (10 ml) while stirring at 5° C, and the resulting mixture is stirred at room temperature for 2 hours and at 50° C for 2 hours. The reaction mixture is cooled and the precipitated potassium chloride is removed by filtration. The filtrate is concentrated under reduced pressure, admixed with water and extracted with ether. The ether layer is washed with water, dried over anhydrous magnesium sulfate and concentrated to give 3-cyanomethyl-5-chloro-1H-indazole (3.0 g) as resinous material.
Reaction SMILES: S[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[C:4]([OH:14])[N:3]=1>[Ni].N>[OH:14][C:4]1[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[CH:2][N:3]=1
Reactant: Oc1cc(-c2ccccc2)nc(S)n1
Agent: [Ni]
Agent: N
Product: Oc1cc(-c2ccccc2)ncn1
Yield: 55.2 %

Procedure:
To 2-mercapto-6-hydroxy-4-phenylpyrimidine (10 g) in ‘880’ ammonia solution (100 ml) was carefully added Raney nickel (32.5 g, 50% slurry) portionwise. Immediate effervescence took place. The mixture was heated to reflux for 4 hours, filtered and concentrated under reduced pressure. The initial residue was azeotroped with toluene (×2) to remove final traces of water. The pale blue residue was dissolved in hot ethanol and filtered and then the filtrate was treated with charcoal. The resulting green solution was evaporated under reduced pressure to afford crude 4-hydroxy-6-phenylpyrimidine (4.65 g) as a green solid (m.p.>300° C.) which was used in the next stage without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.[Br:16]Br.[OH-].[Na+]>O1CCOCC1>[Br:16][CH:9]([O:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=1)[C:10](=[O:15])[C:11]([CH3:12])([CH3:14])[CH3:13]
Reactant: BrBr
Reactant: CC(C)(C)C(=O)COc1cccc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)C(Br)Oc1cccc(Cl)n1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
A stirred solution of 227.68 g (1.0 mole) of 1-(6-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone, prepared above, in 1000 ml dioxane was heated to 65° C. The heat source was removed and 175.8 g (1.1 mole) bromine added dropwise. After the addition of the bromine, the solution was stirred for 10 minutes and then poured into 3 liters ice water containing 25 g sodium bisulfite. The mixture was made slightly basic with 50% NaOH and twice extracted with 500-ml portions of pentane. The pentane extracts were washed with 1000 ml of 5% NaOH and dried, giving 259 g (84% yield) of 1-bromo-1-(6-chloro-2-pyridinyloxy)-3,3-dimethyl-2-butanone. Crystallization from pentane gave a white solid melting at 50°-52° C.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[CH:12][CH:11]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3].Cl[CH2:26][CH2:27]N1CCCC1>>[NH2:1][C:2]([NH:4][C:5]1[CH:9]=[C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][N:19]3[CH2:21][CH2:27][CH2:26][CH2:20]3)=[CH:14][CH:15]=2)[S:7][C:6]=1[C:22]([NH2:24])=[O:23])=[O:3]
Reactant: ClCCN1CCCC1
Reactant: CN(C)CCOc1ccc(-c2cc(NC(N)=O)c(C(N)=O)s2)cc1
Product: NC(=O)Nc1cc(-c2ccc(OCCN3CCCC3)cc2)sc1C(N)=O

Procedure:
Prepared by the method of Example 9(b) using the product of Example 10 (a) and N-(2-chloroethyl)pyrrolidine.
Reaction SMILES: C(OC(=O)[N:7]([CH2:12][C@H:13]([N:31]([C:33]([O:35]C(C)(C)C)=O)[CH3:32])[CH2:14][O:15][C:16](=[O:30])[NH:17][C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)[CH:19]=1)[CH2:8][CH:9]([F:11])[F:10])(C)(C)C.C(O)(C(F)(F)F)=O.[Cl:48][C:49]1[C:68]([F:69])=[CH:67][CH:66]=[CH:65][C:50]=1[CH2:51][NH:52]C(=O)OC1C=CC([N+]([O-])=O)=CC=1>C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]([C:20]2[CH:19]=[C:18]([NH:17][C:16](=[O:30])[O:15][CH2:14][C@@H:13]([N:31]([CH3:32])[C:33]([NH:52][CH2:51][C:50]3[CH:65]=[CH:66][CH:67]=[C:68]([F:69])[C:49]=3[Cl:48])=[O:35])[CH2:12][NH:7][CH2:8][CH:9]([F:10])[F:11])[O:22][N:21]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CN(C(=O)OC(C)(C)C)[C@H](COC(=O)Nc1cc(-c2cccc(F)c2)no1)CN(CC(F)F)C(=O)OC(C)(C)C
Reactant: O=C(NCc1cccc(F)c1Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CNCC(F)F)COC(=O)Nc1cc(-c2cccc(F)c2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39 %

Procedure:
To a solution of {(S)-2-(tert-Butoxycarbonyl-methyl-amino)-3-[3-(3-fluoro-phenyl)-isoxazol-5-ylcarbamoyloxy]-propyl}-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (291 mg, 0.62 mmol) in DCM (5 mL) was added TFA (1.0 mL). The mixture was stirred at RT for 1 h, concentrated, and dissolved in THF (10 mL). To the resulting solution were added 4-nitrophenyl 2-chloro-3-fluorobenzylcarbamate (220 mg, 0.68 mmol) and TEA (0.3 mL, 1.24 mmol) at 0° C. The resulting mixture was stirred at 0° C. for 1 h. The solvent was removed and the resulting residue was purified on RP-HPLC using a mixture of acetonitrile and water to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(2,2-difluoroethylamino)propyl 3-(3-fluorophenyl)isoxazol-5-ylcarbamate (135 mg, 39% for two steps) as white solid. LRMS (M+H+) m/z 559.2.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1.[CH3:11]I>O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][CH3:11])=[N:8][CH:9]=1
Reactant: Nc1ccc(F)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CNc1ccc(F)cn1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 22.9 %

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 117.8 mg, 4.91 mmol) in tetrahydrofuran (25 ml) was added a solution of 5-fluoropyridin-2-amine (500 mg, 4.46 mmol) in tetrahydrofuran (25 ml) at room temperature and the reaction mixture was stirred at 40° C. for 30 min. Then to the reaction mixture was added methyl iodide (696.9 mg, 4.91 mmol) at −40° C. and the resulting mixture was stand at room temperature overnight with stirring. The reaction was quenched by the addition of water and whole mixture was extracted with ethyl acetate. The organic extracts were dried over sodium sulfate and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to afford 129 mg (23%) of the title compound:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(N(CC)C(C)C)(C)C.[NH2:32][C:33]1[S:34][C:35]([C:38]([NH2:40])=[O:39])=[CH:36][N:37]=1>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4](/[C:12](=[N:16]\[O:17][CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)/[C:13]([NH:32][C:33]2[S:34][C:35]([C:38]([NH2:40])=[O:39])=[CH:36][N:37]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: NC(=O)c1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(/C(=N\OC2CCCC2)C(=O)Nc2ncc(C(N)=O)s2)cc1Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 12.1 %

Procedure:
(E)-(3-Chloro-4-methanesulfonyl-phenyl)-cyclopentyloxyimino-acetic acid (prepared as in Example 1, 96 mg, 0.28 mmol), N,N-diisopropylethylamine (145 μL, 0.83 mmol) and 2-amino-thiazole-5-carboxylic acid amide (prepared as in Example 12, 48 mg, 0.34 mmol) were combined in acetonitrile (1.4 mL) and cooled to 0° C. O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (106 mg, 0.28 mmol) was added and the cooling bath was removed. After stirring 16 h, the reaction mixture was treated with saturated aqueous sodium bicarbonate solution (30 mL) and extracted with 10% methanol/chloroform (3×35 mL). The combined organic phases were dried over magnesium sulfate and evaporated in vacuo. The residue was purified by flash column chromatography (Merck silica gel 60, 40-63 μm; 2% methanol/chloroform) to afford (E)-2-[2-(3-chloro-4-methanesulfonyl-phenyl)-2-cyclopentyloxyimino-acetylamino]-thiazole-5-carboxylic acid amide (16 mg, 12%) as a white solid after lyophilization from aqueous dioxane: LC-MS (ESI) m/e calcd for C18H19ClN4O5S2 [M+] 470.05, found 471 [M+H+]: H1-NMR (400 MHz, CD3OD) δ ppm 1.66 (m, 4 H, 2×CH2), 1.92 (m, 4 H, 2×CH2), 3.34 (s, 3 H, SO2CH3), 5.04 (m, 1 H, OCH), 7.66 (dd, Jo=8.2, Jm=1.6 Hz, 1 H, Ar), 7.78 (d, Jm=1.6 Hz, 1 H, Ar), 8.05 (s, 1H, Ar), 8.17 (d, Jo=8.2 Hz, 1 H, Ar).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([Si](C)(C)C)=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2].[I:28]Cl>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([I:28])=[CH:19][C:18]=1[F:27])=[O:5])[CH3:2]
Reactant: ClI
Reactant: CCOC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1C
Solvent: ClCCl
Product: CCOC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1C
Reaction time: 1 h
Yield: 52 %

Procedure:
A solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-methyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (37.0 g, 96.0 mmol) in CH2Cl2 (500 mL) was cooled to 0-5° C. and treated dropwise with iodine monochloride solution (211 mL, 1M in CH2Cl2). The mixture was allowed to warm and stirring continued for 1 hour. The solution was washed with aqueous sodium thiosulfate solution, dried (MgSO4) and evaporated in vacuo. The resultant residue was triturated with ethyl acetate to give the title compound (21.8 g, 52%) as a yellow solid. LCMS (method B): RT=2.48 min, M+H+=440.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([NH:18][C:19]([C:21]2[C:22](=[O:34])[N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:24]([CH3:27])[C:25]=2[CH3:26])=[O:20])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7](C(N)=O)[CH:6]=1.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC#[N:52]>CCOC(C)=O.O>[NH2:52][C:7]1[CH:6]=[C:5]([O:4][C:3]2[CH:14]=[CH:15][C:16]([NH:18][C:19]([C:21]3[C:22](=[O:34])[N:23]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:24]([CH3:27])[C:25]=3[CH3:26])=[O:20])=[CH:17][C:2]=2[Cl:1])[CH:10]=[CH:9][N:8]=1
Reactant: CC#N
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(C(N)=O)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Solvent: Ic1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)c(Cl)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a suspension of 4-(2-chloro-4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamido)phenoxy)picolinamide (540 mg, 1.13 mmol) in EtOAc (6 mL), CH3CN (6 mL) and H2O (3 mL) was added iodobenzene diacetate (438 mg, 1.36 mmol) at 0° C. The mixture was stirred at 0° C. for 30 minutes, then warmed up to rt and stirred for 4.5 hours. The mixture was concentrated in vacuo and the residue was purified by a silica gel column chromatography (EtOAc/PE (v/v)=6/1) to give the title compound as a beige solid (265 mg, 52.2%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH2:8])[CH3:3].[CH3:10][C:11]1([CH3:17])[CH2:15][CH2:14][CH2:13][C:12]1=O.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:2]([O:4][C:5](=[O:9])[CH2:6][CH2:7][NH:8][CH:12]1[CH2:13][CH2:14][CH2:15][C:11]1([CH3:17])[CH3:10])[CH3:3]
Reactant: CCOC(=O)CCN
Reactant: CC1(C)CCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CCNC1CCCC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
To a solution of 13.8 g (0.090 mole) of 3-amino-propanoic acid ethyl ester HCl salt and 10.0 g (0.090 mole) of 2,2-dimethyl-cyclopentanone in 500 mL of dichloromethane was added 16.4 g (0.198 mole) of sodium acetate and 28.6 g (0.135 mole) of sodium triacetoxyborohydride. The mixture was stirred at ambient temperature overnight and then quenched by the addition of 100 mL of 10% sodium bicarbonate solution. The aqueous layer was extracted twice with 300 mL of dichloromethane, and the combined dichloromethane layers dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated under reduced pressure, and distilled at 0.0015 mm Hg (bp 75 degrees), to give 15.4 g of (rac)-3-(2,2-dimethyl-cyclopentylamino)-propanoic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:16][CH3:17])=[CH:9][CH:10]=3)[C@:5]3([CH2:21][O:20][C:19]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])=[N:18]3)[C:4]=2[CH:3]=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36](O)=[O:37])=[N:34][CH:35]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>C(Cl)Cl.CN(C=O)C.O>[Cl:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([NH:1][C:2]2[CH:3]=[C:4]3[C:13]([O:12][C:11]4[CH:10]=[CH:9][C:8]([O:16][CH3:17])=[CH:7][C:6]=4[C@@:5]43[CH2:21][O:20][C:19]([NH:22][C:23](=[O:28])[C:24]([F:26])([F:25])[F:27])=[N:18]4)=[CH:14][CH:15]=2)=[O:37])=[N:34][CH:35]=1
Reactant: COc1ccc2c(c1)[C@]1(COC(NC(=O)C(F)(F)F)=N1)c1cc(N)ccc1O2
Reactant: O=C(O)c1ccc(Cl)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: COc1ccc2c(c1)[C@]1(COC(NC(=O)C(F)(F)F)=N1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1O2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A 25 mL RBF containing a solution of (S)—N-(2′-amino-7′-methoxy-5H-spiro[oxazole-4,9′-xanthene]-2-yl)-2,2,2-trifluoroacetamide (0.058 g, 0.147 mmol), 5-chloropyridine-2-carboxylic acid (0.030 g, 0.190 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.045 g, 0.235 mmol) in DCM (4 mL) and DMF (0.25 mL) was treated with 1-hydroxy-1H-benzotriazole (0.014 g, 0.104 mmol) and stirred for 1.5 hrs at RT. The reaction was diluted with DCM (50 mL) and water (15 mL). The DCM layer was separated, dried over anhydrous sodium sulfate, and concentrated to dryness to yield (S)-5-chloro-N-(2′-methoxy-2-(2,2,2-trifluoroacetamido)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)picolinamide as a brownish solid. MS (ESI pos. ion) m/z: 533 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH:8][CH3:9].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>>[CH3:9][N:8]1[C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[NH:1][C:11]1=[O:13]
Reactant: CNc1ccncc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: Cn1c(=O)[nH]c2cnccc21
Reaction time: 1 h

Procedure:
To a stirred suspension of 3-amino-4-methylaminopyridine [U.S. Pat. No. 5,371,086 (1993)](190 mg, 1.54 mmol) in CH3 CN (10 mL) was added triphosgene (458 mg, 1.54 mmol) portionwise. After 1 h, the mixture was concentrated in vacuo and the residue was converted to the free base by ion exchange chromatography on a SCX cartridge, eluting with 2 M NH3 in MeOH to give the title compound. MS: m/z=150 (M+1).