Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C2ON=C(C3C=CN=CC=3)C=2)CC1.[CH:15]1([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH2:17][CH2:16]1.[H][H]>[Pt]=O.C(O)C>[NH2:19][C:18]([CH:15]1[CH2:17][CH2:16]1)=[CH:22][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: c1cc(-c2cc(C3CC3)no2)ccn1
Reactant: [H][H]
Agent: O=[Pt]
Agent: c1cc(-c2cc(C3CC3)on2)ccn1
Solvent: CCO
Product: NC(=CC(=O)c1ccncc1)C1CC1

Procedure:
A 1.0 g. sample of the mixture of 4-(5-cyclopropyl-3-isoxazolyl)pyridine and 4-(3-cyclopropyl-5-isoxazolyl)pyridine, obtained as described in Examples 2 and 3, is mixed with 0.125 g. of platinum oxide and 75 ml. of ethanol. This mixture is treated with hydrogen on a Parr apparatus at 40 psi for 2 hours at room temperature. The mixture is filtered and the filtrate concentrated to yield a solid. Recrystallization from ethyl acetate-petroleum ether (30°-60° C.) provides 3-amino-3-cyclopropyl-1-(4-pyridyl)-2-propen-1-one as white crystals, melting point 124°-125° C. The ethyl acetate petroleum ether (30°-60° C.) filtrate is concentrated to a solid which is recrystallized from aqueous ethanol to give 4-(5-cyclopropyl-3-isoxazolyl)pyridine as white crystals, melting point 78°-79.5° C., nmr spectrum δ6.85 (DMSO-d6, s, 4-isoxazolyl H).
Reaction SMILES: [CH2:1]([OH:11])[C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1.[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](O)=[O:21].O>CCCCCC>[CH3:12][CH:13]([CH3:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:11][CH2:1][C:2]1[CH:10]=[CH:9][C:6]([O:7][CH3:8])=[C:4]([OH:5])[CH:3]=1)=[O:21]
Reactant: COc1ccc(CO)cc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCCCCC
Solvent: O
Product: COc1ccc(COC(=O)CCCCCCC(C)C)cc1O
Temperature: 50 °C
Yield: 80.5 %

Procedure:
Isovanillyl alcohol (447 mg, 2.90 mmol), 8-methylnonanoic acid (501 mg, 2.90 mmol) and Novozyme 435 (50 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (25 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was developed by PTLC (n-hexane:ethyl acetate=2:1), and silica gel containing the object product was stirred with ethyl acetate (100 ml) for 30 min for extraction. The silica gel was filtered off, and the filtrate was concentrated under reduced pressure to give isovanillyl 8-methylnonanoate (0.72 g, yield 81.0%) as a colorless oil.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][C:20]([N:29]([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)(=[O:3])[CH3:2].[Si]([Cl:36])(C)(C)C>C(OCC)(=O)C>[ClH:36].[C:1]([O:4][CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[CH:17]1[CH2:22][CH2:21][C:20]([N:29]([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)Cl
Agent: CC(=O)OCCCc1c(C2CCC(c3ccccc3)(N(C)C)CC2)[nH]c2ccccc12
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 1 h

Procedure:
3-(2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl)propyl acetate (less polar diastereomer) (190 mg, 0.51 mmol) was dissolved in ethyl acetate (50 ml). Me3SiCl (128 μl, 1.02 mmol) was then added dropwise at RT. The mixture was stirred for 1 h. A white precipitate precipitated out. The precipitate was filtered off with suction, washed with ethyl acetate (2×5 ml) and then dried. Example 186 (120 mg, m.p. 217-220° C., 58%) was a white solid 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.68-2.03-(m, 10H), 2.37-2.47 (m, 1H), 2.54-2.62 (m, 6H), 2.68-2.78 (m, 2H), 2.98-3.11 (m, 1H), 3.12-3.22 (m, 2H), 3.93 (t, J=6.50, 6.50 Hz, 2H), 6.87-7.06 (m, 2H), 7.25 (d, J=7.80 Hz, 1H), 7.42 (d, J=7.80, 1 H) 7.48-7.60 (m, 3H), 7.67-7.82-(m, 2H), 10.00 (s, 1H), 11.34 (s, 1H)
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:10]=[CH:9][C:8](O)=[C:7]([C:12]#[N:13])[C:6]2=[O:14])[CH2:3][CH2:2]1.P(Br)(Br)([Br:17])=O>CN(C=O)C>[Br:17][C:8]1[CH:9]=[CH:10][N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6](=[O:14])[C:7]=1[C:12]#[N:13]
Reactant: N#Cc1c(O)ccn(CC2CC2)c1=O
Reactant: O=P(Br)(Br)Br
Solvent: CN(C)C=O
Product: N#Cc1c(Br)ccn(CC2CC2)c1=O
Temperature: 110 °C
Yield: 63.8 %

Procedure:
To a solution of intermediate 3 (10.4 g, 54.67 mmol) in DMF (250 ml) was added phosphoric tribromide (31.3 g, 109.3 mmol) and the mixture was heated at 110° C. for 1.5 hours. After cooling in an ice bath the solution was partitioned between water and EtOAc. After three extractions with EtOAc the combined organic fractions were washed with brine, dried over MgSO4 and the solvent evaporated in vacuo. The crude product was purified by column chromatography (silica gel; DCM as eluent). The desired fractions were collected and evaporated in vacuo to yield intermediate 5 (8.83 g, 64%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]([OH:20])=O)=[N:6]1)[CH2:2][CH2:3][CH3:4].C(Cl)(=O)C(Cl)=O.C[N:28](C=O)C>ClCCl>[CH2:1]([N:5]1[C:9]([CH2:10][CH2:11][S:12]([CH2:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:8][C:7]([C:18]([NH2:28])=[O:20])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1nc(C(=O)O)cc1CCS(=O)(=O)CCC
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CCCCn1nc(C(N)=O)cc1CCS(=O)(=O)CCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxylic acid (4.00 g, 13.22 mmol) in dichloromethane (66 mL) was added oxalyl chloride (3.5 mL, 39.7 mmol) and a drop of DMF. The solution bubbled vigorously and was stirred at ambient temperature for 30 minutes. The solution was concentrated under reduced pressure. The residue was dissolved in dichloromethane (66 mL) and the resulting solution was cooled in an ice bath, then concentrated ammonium hydroxide (66 mL) was added dropwise. After the addition was complete, the ice bath was removed and the mixture was stirred at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to afford a slurry that was extracted with chloroform (2×100 mL). The organic layers were combined and concentrated under reduced pressure to afford 4.0 g of 1-butyl-5-[2-(propylsulfonyl)ethyl]-1H-pyrazole-3-carboxamide as a white solid.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:26]=[CH:25][C:18]([CH2:19][CH2:20][NH:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[CH:29]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][C:33]=1[N:39]1[C:43](=[O:44])[CH2:42][S:41]/[C:40]/1=[N:45]\[C:46](=O)[O:47]C1C=CC([N+]([O-])=O)=CC=1)([CH3:31])[CH3:30]>>[CH2:22]([N:21]([CH2:20][CH2:19][C:18]1[CH:25]=[CH:26][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:27])[F:28])=[CH:9][CH:8]=3)[N:11]=2)=[CH:16][CH:17]=1)[C:46](/[N:45]=[C:40]1\[S:41][CH2:42][C:43](=[O:44])[N:39]\1[C:33]1[CH:34]=[C:35]([CH3:38])[CH:36]=[CH:37][C:32]=1[CH:29]([CH3:30])[CH3:31])=[O:47])[CH:23]=[CH2:24]
Reactant: Cc1ccc(C(C)C)c(N2C(=O)CS/C2=N\C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: C=CCNCCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Product: C=CCN(CCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)C(=O)/N=C1\SCC(=O)N1c1cc(C)ccc1C(C)C

Procedure:
The title compound was prepared as described in Example 95 using N-(4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenethyl)prop-2-en-1-amine (CB26) and (Z)-4-nitrophenyl (3-(2-isopropyl-5-methylphenyl)-4-oxothiazolidin-2-ylidene)carbamate (CA50), purified by flash column chromatography using 0-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes, as eluent and isolated as a brown oil (0.040 g, 43%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:18]=[C:19]([C:23](O)=[O:24])[O:20][C:21]=3[CH3:22])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](=[O:43])(=[O:42])[NH2:41])=[CH:36][CH:35]=1)(C)(C)C.C(=O)(OC(C)(C)C)N.[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].ClCCl>>[F:53][C:54]([F:59])([F:58])[C:55]([OH:57])=[O:56].[NH2:32][CH2:33][C:34]1[CH:35]=[CH:36][C:37]([S:40]([NH:41][C:23]([C:19]2[O:20][C:21]([CH3:22])=[C:17]([CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=4)=[CH:10][CH:11]=3)[CH:18]=2)=[O:24])(=[O:42])=[O:43])=[CH:38][CH:39]=1
Reactant: COc1ccc(-c2ccc(OCc3cc(C(=O)O)oc3C)cc2)cc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)(C)OC(N)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(-c2ccc(OCc3cc(C(=O)NS(=O)(=O)c4ccc(CN)cc4)oc3C)cc2)cc1

Procedure:
4-(4′-Methoxy-biphenyl-4-yloxymethyl)-5-methyl-furan-2-carboxylic acid (4) (50 mg) was reacted with (4-sulphamoyl-benzyl)-carbamic acid tert-butyl ester (85 mg) in an analogous manner to that described in Example 2A. The intermediate tert-butyl carbamate was hydrolysed with 1% trifluoroacetic acid/dichloromethane over 24 hours, then concentrated in vacuo to give compound 12 as a white solid (10 mg). LC/MS System C: Rt=4.67 mins, m/z (ES−)=493 (M−1 for C27H26N2O6S).
Reaction SMILES: C([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])=[CH2:26])[CH:20]=1)C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH3:26])[CH:20]=2)[C:9]=1[OH:8])([CH3:16])([CH3:17])[CH3:18]
Reactant: C=C(c1cccc(-c2cccc(C(C)(C)C)c2OCc2ccccc2)c1)c1ccccc1OC
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccccc1C(C)c1cccc(-c2cccc(C(C)(C)C)c2O)c1
Reaction time: 4 h
Yield: 96 %

Procedure:
A solution of 38 (0.7 g, 1.56 mmol) in methanol (40 mL) and ethyl acetate (60 mL) was treated with 20% palladium on activated carbon (50% wet, 0.100 g) and was hydrogenated at 40 psi in a Parr shaker for 4 hr. The catalyst was filtered out and washed with ethyl acetate. The filtrate was stripped and the crude product was purified by chromatography on silica (40 g) hexane (3 L) to afford pure E2 (0.54 g, 96%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH:21]1([NH:24][C:25]([C:27]2[C:28]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:29]=3[S:30][C:31]=2[CH3:32])=[O:26])[CH2:23][CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:21]1([NH:24][C:25]([C:27]2[C:28]3[CH:36]=[CH:35][C:34]([O:37][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]([N:13]6[CH2:17][CH2:16][CH2:15][C@H:14]6[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=45)=[CH:33][C:29]=3[S:30][C:31]=2[CH3:32])=[O:26])[CH2:23][CH2:22]1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NC1CC1
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NC5CC5)c(C)sc4c3)c2s1
Yield: 70 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (124 mg, 0.40 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide 8c (119 mg, 0.48 mmole) and Cs2CO3 (391 mg, 1.2 mmole) in a manner as previously described for example 1 to give a yellow solid (146 mg, 70%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H. d, J=5.27 Hz), 8.46 (1H, d, J=4.33 Hz), 8.03 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.80 (1H, d, J=8.67 Hz), 7.32 (1H, dd, J=2.17, 8.76 Hz), 6.75 (1H, d, J=5.27 Hz), 4.30 (1H, m), 3.84 (2H, m), 3.53 (1H, m) 3.42 (1H, m), 3.27 (3H, s), 2.89 (1H, m), 2.57 (3H, s), 2.09-1.81 (4H, m) 0.72 (2H, m), 0.59 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=C)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[O-:22]I(=O)(=O)=O.[Na+].O>C(O)(C)(C)C.O1CCOCC1.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:22])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: C=Cc1ccc2nccc(Cl)c2c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: C1COCCO1
Solvent: O
Product: O=Cc1ccc2nccc(Cl)c2c1
Yield: 82.7 %

Procedure:
A mixture of 4-chloro-6-ethenylquinoline (5.1 g, 26.88 mmol), 2,6-lutidine (5.76 g, 53.75 mmol), sodium (meta) periodate (22.99 g, 107.51 mmol), and osmium tetroxide (5.48 g of a 2.5% solution in tert-butanol, 0.538 mmol) in 1,4-dioxane:H2O (350 mL of 3:1 mixture) was stirred for 3.5 h at room temperature and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (CH2Cl2) to give the title compound (4.26 g, 83% for 2 steps) as a pale yellow solid. MS (ES)+ m/e 192 [M+H]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][CH:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:22]([Cl:37])[CH:21]=2)(=[O:19])=[O:18])[CH2:13][CH2:12]1.[C:38](Cl)(=[O:41])[CH:39]=[CH2:40]>C1COCC1.C(Cl)Cl>[Cl:37][C:22]1[CH:21]=[C:20]([S:17]([N:14]2[CH2:13][CH2:12][CH:11]([NH:10][C:38](=[O:41])[CH:39]=[CH2:40])[CH2:16][CH2:15]2)(=[O:18])=[O:19])[CH:25]=[CH:24][C:23]=1[NH:26][C:27](=[O:36])[CH2:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)NC1CCN(S(=O)(=O)c2ccc(NC(=O)CCc3ccccc3)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 4.2 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.56 mmol) was added in one portion to a stirred solution of N-[4-(4-Amino-piperidine-1-sulfonyl)-2-chloro-phenyl]-3-phenyl-propionamide (0.05 g, 0.1 mmol) in THF (5 ml), followed by the drop wise addition of acryloyl chloride (0.01 ml, 0.12 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. After this time the mixture was diluted with DCM (20 ml) and washed sequentially with HCl (1M solution, 10 ml), NaOH (1M solution, 10 ml) and brine (10 ml). The organic layer was separated, dried (MgSO4), filtered, concentrated and the resulting residue was purified by flash column chromatography (elution: 2% Methanol, 98% DCM) to give the title compound (0.002 g, 4% yield) as a white solid.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:7][CH:6]1[C:8]1[CH:13]=[C:12]([F:14])[C:11]([O:15][CH2:16][C:17]2[C:18]([S:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[N:19][CH:20]=[CH:21][CH:22]=2)=[C:10]([F:28])[CH:9]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH:25]1([CH2:24][S:23][C:18]2[C:17]([CH2:16][O:15][C:11]3[C:12]([F:14])=[CH:13][C:8]([CH:6]4[CH2:7][CH:5]4[C:3]([OH:4])=[O:2])=[CH:9][C:10]=3[F:28])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:27][CH2:26]1
Reactant: COC(=O)C1CC1c1cc(F)c(OCc2cccnc2SCC2CC2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CC1c1cc(F)c(OCc2cccnc2SCC2CC2)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
After 2-[4-(2-cyclopropylmethylsulfanyl-pyridin-3-ylmethoxy)-3,5-difluoro-phenyl]-cyclopropane carboxylic acid methyl ester (13 mg, 0.031 mmol) obtained in Step A was dissolved in THF/MeOH (1 mL/1 mL), 10N sodium hydroxide solution (30 mg, 0.31 mmol) was added thereto, and the mixture was stirred at room temperature for 12 hours. After the termination of the reaction, the reactant was concentrated under reduced pressure, and the residue was diluted with water. The aqueous layer was added with 1N HCl to adjust the pH to 2˜3, and then extracted with EtOAc. The organic layer was dried with MgSO4, concentrated under reduced pressure, and purified by column chromatography (eluent, MeOH/DCM=5/95) to obtain the title compound (12 mg, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:22][C:23](O)=[O:24])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:26])[CH:10]=1.[Si]([O:32][NH2:33])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:27])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([O:21][CH2:22][C:23]([NH:33][OH:32])=[O:24])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[O:12][C:11](=[O:26])[CH:10]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(=O)O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCC(=O)NO

Procedure:
The title compound was prepared from 2-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy)acetic acid (Example 49) following the procedure outlined in Example 84 (except TMSONH2 in place of NH2OH•HCl). 1H NMR (400 MHz, DMSO-d6): δ 10.64 (s, 1H), 9.54 (s, 1H), 8.82 (s, 2H), 7.97 (d, 1H), 7.23 (d, 1H), 4.65 (s, 1H), 4.43 (s, 2H), 3.93 (s, 3H); MS (ESI): 425.8.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[OH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:36]4[CH2:35][CH2:34][N:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[OH:26])[CH2:38][CH2:37]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Reactant: Oc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(CN2CCN(c3ccccc3O)CC2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 32 %

Procedure:
Compound 12 was prepared using the method described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-hydroxyphenyl)piperazine (0.51 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 12 (0.39 g, 32%); C27H34ClN3O2, LRMS (m/z)=469 (MH+).
Reaction SMILES: [C:1]([N:5]([C:9]1[CH:10]=[N:11][O:12][C:13]=1[CH3:14])[CH:6]([CH3:8])[CH3:7])(=[O:4])[CH2:2][CH3:3]>[Pd].CCO>[C:13](/[C:9](/[N:5]([CH:6]([CH3:7])[CH3:8])[C:1](=[O:4])[CH2:2][CH3:3])=[CH:10]\[NH2:11])(=[O:12])[CH3:14]
Reactant: CCC(=O)N(c1cnoc1C)C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCC(=O)N(/C(=C/N)C(C)=O)C(C)C
Yield: 105.3 %

Procedure:
4-[N-(Propionyl)-N-(isopropyl)amino]-5-methylisoxazole (Method 6; 330 g, 1.0 eq.) was stirred under hydrogen (1.0 eq), with 10% palladium on carbon (0.1 eq.) in EtOH (10 vol.eq.) at 25° C. overnight. The catalyst was removed by filtration and the EtOH was removed in vacuo to leave an off white solid (351 g, 98%). This was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[S:4][C:3]=1/[CH:8]=[CH:9]/[C:10](N(C)C)=O.[N+]([O-])(O)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH2:29])=[NH:28])=[CH:22][C:21]=1[CH2:30][OH:31]>CC#N>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]2[N:29]=[C:8]([C:3]3[S:4][C:5]([CH3:7])=[N:6][C:2]=3[CH3:1])[CH:9]=[CH:10][N:28]=2)=[CH:22][C:21]=1[CH2:30][OH:31]
Reactant: N=C(N)Nc1ccc(Cl)c(CO)c1
Reactant: Cc1nc(C)c(/C=C/C(=O)N(C)C)s1
Solvent: O=[N+]([O-])O
Solvent: CC#N
Product: Cc1nc(C)c(-c2ccnc(Nc3ccc(Cl)c(CO)c3)n2)s1

Procedure:
By condensation of 3-dimethylamino-1-(2,4-dimethyl-thiazol-5-yl)-propenone and N-(4-chloro-3-hydroxymethyl-phenyl)-guanidine nitrate. Yellow solid. Mp 245-246° C. Anal. RP-HPLC: tR=14.6 min (10-70% MeCN, purity>95%). 1H-NMR (DMSO-D6) δ: 2.62 (s, 3H, CH3), 2.63 (s, 3H, CH3), 4.53 (d, 2H, J=5.5 Hz, CH2), 5.34 (m, 1H, OH), 7.08 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.29 (m, 1H, Ph-H), 7.73 (m, 1H, Ph-H), 7.94 (s, 1H, Ph-H), 8.51 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 9.78 (s, 1H, NH). MS (ESI+) m/z 347.11 [M+H]+ (C16H15ClN4OS requires 346.84).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@@H:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[C@H:10]([OH:36])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.CO.O1CCOCC1>[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[C:17]4[CH:34]=[CH:35][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH:10]5[OH:36])=[CH:15][C:16]=4[O:25][CH2:24][CH2:23][N:22]3[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@@H]3CCN(C(=O)OC(C)(C)C)C[C@H]3O)cc1OCC2
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3O)cc1OCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of trans-racemic-3-hydroxy-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (180 mg, 0.36 mmol) in DCM (1 mL) and methanol (0.6 mL) was added 4M HCl in dioxane (1.6 mL) slowly and the reaction mixture stirred at RT for 2.5 hr before being concentrated in vacuo. The resultant residue was triturated in diethyl ether to give 4-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)piperidin-3-ol which was resolved to give the (3R,4R) enantiomer 303 as a white solid (172 mg, quantitative). LCMS: RT=2.41 min, [M+H]+ 395. 1H NMR 400 MHz (DMSO-d6) δ: 9.30 (1H, br, s), 9.10 (1H, br, s), 8.36 (1H, d, J=8.28 Hz), 8.10 (1H, br, s), 8.06 (1H, s), 7.04 (1H, d, J=8.38 Hz), 6.91 (1H, s), 5.87 (1H, m), 4.53 (4H, d, J=8.12 Hz), 3.90 (1H, br, m), 3.25 (2H, m), 2.78 (1H, m), 2.52 (2H, m), 1.80 (2H, m), 1.50 (1H, d, J=6.58 Hz)
Reaction SMILES: [F:1][CH:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4].P([O-])([O-])([O-])=O.F[C@@H](CCCCCC)C(OCC)=O.[OH-].[Na+]>O>[F:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCCCCCC(F)C(=O)OCC
Agent: CCCCCC[C@H](F)C(=O)OCC
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCC[C@@H](F)C(=O)OCC
Yield: 100 %

Procedure:
--Quantities: partially resolved ethyl 2-fluorooctanoate 68 (44 g, 0.23 mol), 0.063M phosphate buffer (pH 7.0) (400 ml), deionised water (400 ml), Pseudomonas lipase (Amano PS) (40 mg). The experimental procedure was as described for compound 66. The hydrolysis was continued until the rate of reaction was almost zero, as indicated by a constant pH with zero addition of alkali (reaction time 5 h, 38 ml of 1M sodium hydroxide solution added i.e. 16% hydrolysis). The mixture was extracted with ether (3 times) and the combined organic solutions were washed with brine, dried (K2CO3) and evaporated. The liquid was distilled to give ethyl (R)-(+)-2-fluoroacetate 69 (30.7 g, 0.23 mol), b.p. 63° C. at 0.6 mm Hg; [α]D26 =+8.5° (c 5.9 in CHCl3).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[S:25][CH:26]=[CH:27][N:28]=1.C(Cl)CCl.[Cl-].[Na+]>CN(C=O)C>[S:25]1[CH:26]=[CH:27][N:28]=[C:24]1[NH:23][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:14][CH2:15][NH:16][CH2:17][N:18]=[N:19][N+:20]([O-:22])=[O:21]
Reactant: Nc1nccs1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCCNCN=N[N+](=O)[O-])C(=O)Nc1nccs1
Reaction time: 4 h
Yield: 36.4 %

Procedure:
To a stirred solution of (2S)-2-tert-butoxycarbonylamino-5-(nitroimino-amino)methylaminopentanoic acid (5.00 g, 15.6 mmol) and 2-aminothiazole (1.72 g, 17.2 mmol) in DMF (16 mL) is added EDC (3.30 g, 17.2 mmol). The solution is allowed to stir for 4 h then added to half-saturated aqueous sodium chloride solution and extracted with EtOAc. The combined organic extracts are washed with 1 N sodium bisulfate, 5% aqueous sodium bicarbonate, saturated aqueous sodium chloride, and dried over magnesium sulfate. Concentration in vacuo provides (2S)-2-tert-butoxycarbonylamino-5-(nitroimino-amino)methylaminopentanoic acid 1,3-thiazol-2-ylamide as a solid (2.28 g, 36%).