Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:9]1[CH:10]=[C:11]([CH:26]=[CH:27][C:28]=1[O:29]CC1C=CC=CC=1)[O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH:17]([C:22](=O)[CH2:23][CH3:24])C(=O)CC)C1C=CC=CC=1.[OH:37][C:38]1C=C(C=[CH:56][C:57]=1O)OCCCCC(C(=O)CC)C(=O)CC>>[OH:29][C:28]1[CH:9]=[CH:10][C:11]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:22][CH2:23][CH:24]([C:11](=[O:12])[CH2:10][CH3:9])[C:38](=[O:37])[CH2:57][CH3:56])=[CH:26][CH:27]=1
Reactant: CCC(=O)C(CCCCOc1ccc(O)c(O)c1)C(=O)CC
Reactant: CCC(=O)C(CCCCOc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)CC
Product: CCC(=O)C(CCCCCCCOc1ccc(O)cc1)C(=O)CC

Procedure:
By a similar hydrogenolysis procedure 4-[4-(3,4-dibenzyloxyphenoxy)butyl]-3,5-heptanedione can be coverted to 4-[4-(3,4-dihydroxyphenoxy)butyl]-3,5-heptanedione [I; Ar is 3,4-(HO)2C6H3, Alk is CH2CH2CH2CH2, R and R' are CH3CH2CO].
Reaction SMILES: [CH2:1]([S:6][C:7]1[S:8][C:9]2[CH:15]=[C:14]([S:16]([N:19]([CH2:25][C:26]3[CH:31]=CC=C[CH:27]=3)[C@H](C)C(O)=O)(=[O:18])=[O:17])[CH:13]=[CH:12][C:10]=2[N:11]=1)CCCC.C(Cl)(=O)[C:33]([Cl:35])=[O:34].CN(C=O)C>ClCCl>[CH3:31][CH:26]([CH3:27])[C@@H:25]([NH:19][S:16]([C:14]1[CH:13]=[CH:12][C:10]2[N:11]=[C:7]([S:6][CH3:1])[S:8][C:9]=2[CH:15]=1)(=[O:17])=[O:18])[C:33]([Cl:35])=[O:34]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCCCCSc1nc2ccc(S(=O)(=O)N(Cc3ccccc3)[C@H](C)C(=O)O)cc2s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CSc1nc2ccc(S(=O)(=O)N[C@@H](C(=O)Cl)C(C)C)cc2s1
Temperature: 0 °C

Procedure:
(2R)-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl) benzylamino]propionic acid (157 mg, 0.328 mmol) prepared in Example 33 was dissolved in dichloromethane (2 mL) and cooled down to 0° C. Oxalylchloride (0.114 mL, 10 equi.) and DMF of catalytic amount were added and the reaction solution was refluxed for 3 hours at RT. After reaction, the solution was distilled under reduced pressure to remove the solvent and dried under reduced pressure to give (2R)-3-methyl-2-[(2-methylthiobenzthiazol-6-sulfonyl)amino]butanoic chloride. The compound was then dissolved in THF (1 mL) to obtain acid chloride THF solution. Hydroxyamine hydrochloride salt (0.23 g, 10 equi.) and NaHCO3 (0.33 g, 12 equi.) were dissolved in THF/H2O (3 mL/3 mL) and cooled down to 0° C. to give a hydroxyamine solution. The above acid chloride THF solution was slowly added to the hydroxyamine solution at 0° C. After 1 hour, the solvent was removed from the reaction solution. Then, the product was extracted with ethylacetate 10 mL), washed with H2O and 0.1N HCl, dried over MgSO4, distilled under reduced pressure and vacuum-dried to prepare the titled compound, (2R)-N-hydroxy-2-[(2-n-pentylthiobenzthiazol-6-sulfonyl)benzylamino]propionamide (163 mg, 100%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1)(=O)C.[OH-].[Na+]>CO>[CH2:13]([O:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][OH:4])[N:7]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OCc1cccc(OCc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: OCc1cccc(OCc2ccccc2)n1
Reaction time: 8 h

Procedure:
A mixture of 2-acetoxymethyl-6-benzyloxypyridine (1.65 g, 6.4 mmol) and aqueous sodium hydroxide (0.58 mL, 40%) in methanol (10 mL) was stirred at room temp. overnight. The resulting solution was concentrated under vacuum, and the residue was partitioned between water and dichloromethane. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluting with 0-5% ethyl acetate in chloroform gradient. Collection and concentration of appropriate fractions provided 2-benzyloxy-6-hydroxymethylpyridine as colorless oil.
Reaction SMILES: [OH:1][C@H:2]1[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]1=[O:4].O[C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=1>>[CH2:8]([O:22][C:20]([C:19]1[CH:23]=[CH:24][C:16]([O:1][C@@H:2]2[CH2:8][CH2:7][C@@H:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[O:5][C:3]2=[O:4])=[CH:17][CH:18]=1)=[O:21])[CH2:7][CH2:6][CH2:9][CH3:10]
Reactant: CCCCCC[C@@H]1CC[C@H](O)C(=O)O1
Reactant: O=C(O)c1ccc(O)cc1
Product: CCCCCC[C@@H]1CC[C@@H](Oc2ccc(C(=O)OCCCCC)cc2)C(=O)O1

Procedure:
A crude product was obtained in the same manner as described in Example 22 except that (2S,5R)-2-hydroxy-5-hexyl-δ-valerolactone was used in an amount of 125 mg and 125 mg of p-hydroxybenzoic acid was used instead of 120 mg of 4-octyloxy-3-cyanobenzoic acid. The crude product was purified by the silica gel column chromatography to obtain 20 mg of (2R,5R)-2-(4'-pentyloxycarbonylphenoxy)-5-hexyl-δ-valerolactone.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[C:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36]OS(C3C=CC(C)=CC=3)(=O)=O)[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH:24]1([C:30]2[O:31][C:32]([CH3:48])=[C:33]([CH2:35][CH2:36][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)([CH3:14])[C:4]([OH:3])=[O:23])=[CH:12][CH:11]=3)[N:34]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)cc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccccc3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)cc2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(4-fluorophenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-phenyl-5-methyl-oxazol-4-yl)-ethyl ester using the procedure of Example 63. 1H NMR (400 MHz, CDCl3) δ 7.17 (d, 2H, J=8.60 Hz), 6.95-6.85 (m, 4H), 6.79 (d, 2H, J=8.60 Hz), 4.12 (t, 2H, J=6.26 Hz), 3.20 (d, 1H, J=14.08 Hz), 3.11 (d, 1H, J=14.08 Hz), 2.95 (t, 2H, J=6.26 Hz), 2.85 (tt, 1H, J=11.73 Hz, J=3.52 Hz), 2.30 (s, 3H), 2.02-1.99 (m, 2H), 1.83-1.78 (m, 2H), 1.72-1.69 (m, 1H), 1.58-1.49 (m, 2H), 1.36 (s, 3H), 1.33-1.22 (m, 3H); HRMS (ES+) m/z exact mass calcd for C28H33NO5F 482.2343, found 482.2347.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[O:36][N:35]=2)[CH:29]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27](=[O:47])[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:38]=[C:37]([CH2:39][O:40][CH:41]3[CH2:46][CH2:45][CH2:44][CH2:43][O:42]3)[O:36][N:35]=2)[CH:29]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2cc(COC3CCCCO3)on2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cc(COC4CCCCO4)on3)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-3-yl]-phenyl}-propionic acid tert.-butyl ester (Example K15) according to the general procedure M. Obtained as a yellow foam (232 mg).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C(=O)([O-])[O-].[K+].[K+].C1(C(C2C=CC=CC=2)[N:18]2[CH2:21][CH:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH2:19]2)C=CC=CC=1>C(Cl)Cl>[F:32][C:29]([F:30])([F:31])[C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][CH:20]1[CH2:21][N:18]([C:1]([Cl:4])=[O:2])[CH2:19]1
Reactant: O=C(Cl)Cl
Reactant: FC(F)(F)c1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(Cl)N1CC(Oc2cccc(C(F)(F)F)c2)C1
Reaction time: 18 h
Yield: 62 %

Procedure:
A solution of 35.6 g (0.36 mole) of phosgene in 200 ml of methylene chloride at 5° C. was stirred with 50 g (0.36 mole) of potassium carbonate for 1 hr. To the mixture was added dropwise 115 g (0.3 mole) of 1-diphenylmethyl-3-[3-(trifluoromethyl)phenoxy]azetidine in 400 ml of methylene chloride. After stirring for 18 hr, the reaction mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and concentrated on a rotary evaporator to a viscous oil residue, 133.2 g. Trituration of the residue with hexane gave a solid which was recrystallized from cold hexane to yield 52 g (62%) of white crystals, m.p. 72.5°-74° C.
Reaction SMILES: [N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O-:29])=[O:28])=[CH:22][CH:21]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>C(O)C>[N:1]1([CH:6]2[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[C:12]3[CH:11]=[C:10]([C:18]#[C:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][CH:25]=4)[CH:9]=[CH:8][C:7]2=3)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(CC(=O)[O-])cc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)CCC(n2ccnc2)c2ccc(C#Cc3ccc(CC(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
[4-(5-imidazol-1-yl-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl-ethynyl)-phenyl]-acetate (Compound 136, 50.0 mg, 0.13 mmol) in ethanol (4 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 40.0 mg (83%) of the title compound as a pale-orange solid.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][C:11]#[N:12])[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[CH3:29][N:27]([CH3:28])[CH:26]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:1])([F:13])[F:14])[CH:5]=1)[C:11]#[N:12]
Reactant: N#CCc1cccc(OC(F)(F)F)c1
Reactant: COC(OC)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C=C(C#N)c1cccc(OC(F)(F)F)c1
Yield: 72 %

Procedure:
A mixture of 3-trifluoromethoxyphenylacetonitrile (2.5 grams, 12.43 mmol), DIPEA (0.321 grams, 2.48 mmol), and dimethyl formamide dimethyl acetal (20 mL) were heated at reflux for 4 h. On cooling, the reaction was partitioned between EtOAc and saturated aqueous NH4Cl solution. The aqueous phase was extracted with ethyl acetate and the combined organic phase washed with brine and concentrated in vacuo. The crude product was purified by chromatography (ethyl acetate/hexane, 0-10%) on silica gel (24 grams) to give pure product (2.3 grams, 8.98 mmol, 72% yield.).
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1>N1C=CC=CC=1>[C:1]1([CH2:7][C:8]([O:18][C:15]2[CH:16]=[CH:17][C:12]([Br:11])=[CH:13][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc(Br)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cc1ccccc1)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Phenylacetyl chloride (9.4 g) was added dropwise to 4-bromophenol (10 g) in pyridine, and the reaction mixture was stirred at room temperature for 1 hour then evaporated to dryness under reduced pressure. The residue was taken up in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and evaporated under reduced pressure to give 4-bromophenyl phenylacetate.
Reaction SMILES: [C:1]1(=[N:11]O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-:14].[Na+]>O>[NH:11]1[C:6](=[O:14])[CH2:7][CH2:8][CH2:9][C:10]2[CH:5]=[CH:4][CH:3]=[CH:2][C:1]1=2
Reactant: O=C([O-])O
Reactant: ON=C1CCCc2ccccc21
Agent: [Na+]
Solvent: O
Product: O=C1CCCc2ccccc2N1

Procedure:
A mixture of 1.0 g (6.2 mmole) of 1-tetralone oxime and 10 g polyphosphoric acid was heated at 105° for 1 hr. The warm mixture was poured into 100 mL water with stirring. The pH was carefully adjusted to 6-7 by addition of solid sodium bicarbonate and the mixture was extracted with 60 mL ethyl ether. The organic phase was washed with 10 mL saturated sodium chloride, dried (MgSO4) and concentrated under reduced pressure. The residue was recrystallized from ether/hexane to give 1,3,4,5-Tetrahydro-benzo[b]azepin-2-one, 0.682 g, m.p. 141-142°.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1)=[O:4].[CH2:14]([CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)C>[CH2:14]([CH:21]1[CH2:26][CH2:25][N:24]([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=2)=[O:4])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(NC(=O)CCl)cc1
Reactant: c1ccc(CC2CCNCC2)cc1
Solvent: CCOCC
Product: N#Cc1ccc(NC(=O)CN2CCC(Cc3ccccc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-cyano-phenyl)-acetamide [J. Org. Chem., 23, 141. (1958)] and 4-benzyl-piperidine according to the method described in Example 142b. Melting Point: 120-124° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15].[CH2:17]([Sn](CCCC)(CCCC)C#C)[CH2:18]CC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:17]#[CH:18])[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH2:15]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1N
Reactant: C#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C#Cc1cc(C(=O)OC)c(N)cc1C(F)(F)F
Temperature: 120 °C
Yield: 69 %

Procedure:
To a solution of 2-amino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (1.5 g, 4.35 mmol) in dioxane (80 mL) were added tributyl(ethynyl)tin (1.4 mL, 4.78 mmol) and (Ph3P)4Pd (251.2 mg, 0.217 mmol) and the mixture was heated to 120° C. for 1.5 h. After cooling to r.t., the solvent was removed in vacuo and the residue was purified by two successive flash chromatographies (150 g silica gel, hexanes→DCM:hexanes (3:7 to 1:1) and then (50 g silica gel, hexanes→EtOAc:hexanes (1:9)) to provide the title compound (730 mg, 69%) as a beige-orange solid. API-ES: m/z 244 [M+H]+, rt 5.14 min.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].C[O:7][C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1.Cl>O.O1CCCC1>[CH3:16][N:15]([CH3:17])[C:12]1[CH:13]=[CH:14][C:9]([C:8]([NH:2][OH:3])=[O:7])=[CH:10][CH:11]=1
Reactant: NO
Reactant: COC(=O)c1ccc(N(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)c1ccc(C(=O)NO)cc1
Reaction time: 8 h
Yield: 44.2 %

Procedure:
7.4 g of hydroxylamine hydrochloride was dissolved in 200 ml of water to which was added dropwise 106 ml of 1 N aqueous solution of sodium hydroxide while cooling. The resulting mixture was added with stirring to 300 ml of a tetrahydrofuran solution containing 9.0 g of 4-dimethylaminobenzoic acid methyl ester dissolved at room temperature. After stirring for 8 hours, 5 ml of 1 N aqueous solution of sodium hydroxide was added thereto and the mixture was further stirred for 3 days. After adjusting the pH of the resulting mixture between 4 and 5 by adding a diluted aqueous hydrochloric acid solution, the mixture was extracted with ethyl acetate and the extract was dried with sodium sulfate and concentrated. The resulting crystals were recrystallized from acetonitrile to obtain 4 g of the desired compound having a melting point of 162° to 163° C. The structure of the compound was confirmed using mass spectrum and NMR spectrum, etc.
Reaction SMILES: [CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([OH:9])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[CH3:20][N:21]([CH3:28])[CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>>[CH:1]1([C@@:6]([OH:16])([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:7]([N:25]2[CH2:26][CH2:27][CH:22]([N:21]([CH3:28])[CH3:20])[CH2:23][CH2:24]2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(O)[C@](O)(c1ccccc1)C1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C1CCN(C(=O)[C@](O)(c2ccccc2)C2CCCC2)CC1
Reaction time: 12 h
Yield: 60 %

Procedure:
To a stirred solution of (R)-cyclopentylhydroxyphenyl acetic acid (5.00 g, 22.7 mmol) in DCM (200 mL, 3 mol) was added dimethylpiperidin-4-yl amine (2.91 g, 22.7 mmol). DIPEA (11.9 mL, 68.1 mmol) and HOBt (5.21 g, 34 mmol) were added, followed by EDCI (5.22 g, 27.2 mmol). The mixture was stirred for 12 hours, then washed with water (300 mL), a saturated aqueous NaCl solution (300 mL), dried over MgSO4 and then filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography (10% MeOH/DCM w/1% NH3 (aq)) to afford 4.5 g of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[CH:25]=[N:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH:13]2[CH:9]1[CH2:10][N:11]([C:16]1[CH:25]=[N:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=1)[CH2:12]2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1cnc2ccccc2n1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2CN(c3cnc4ccccc4n3)CC21
Temperature: 80 °C
Yield: 84 %

Procedure:
Intermediate 2 (0.51 mmol), 2-chloro-quinoxaline (0.51 mmol) and K2CO3 (1.53 mmol) were taken up in DMF (0.2 M). The mixture heated to 80° C. and allowed to heat at 80° C. overnight. The mixture was cooled to room temperature, diluted with water, and extracted with diethyl ether (3×100 mL). The organics were combined, dried over MgSO4, filtered, and concentrated. The resulting crude product was purified by flash column chromatography (FCC) (50-100% EtOAc/hex) to provide 3-quinoxalin-2-yl-3,6-diaza-bicyclo[3.2.0]heptane-6-carboxylic acid tert-butyl ester (84%). MS (ESI) mass calcd. for C18H22N4O2, 326.39; m/z found, 327.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.48 (s, 1H), 7.93-7.87 (m, 1H), 7.76-7.69 (m, 1H), 7.62-7.55 (m, 1H), 7.45-7.36 (m, 1H), 4.90 (br s, 1H), 4.41 (br s, 1H), 4.27-4.09 (m, 2H), 3.68-3.61 (m, 1H), 3.49-3.41 (m, 1H), 3.34-3.20 (m, 2H), 1.45 (br s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:20][C:21]4[N:26]([CH2:27][C:28]5[NH:32][CH:31]=[N:30][CH:29]=5)[C:25](=[O:33])[CH2:24][O:23][C:22]=4[N:34]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH:32]1[C:28]([CH2:27][N:26]2[C:25](=[O:33])[CH2:24][O:23][C:22]3[N:34]=[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)[C:19]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:20][C:21]2=3)=[CH:29][N:30]=[CH:31]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3cnc[nH]3)C(=O)CO4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(Cc3cnc[nH]3)C(=O)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 75.5 %

Procedure:
tert-butyl(1-(4-(1-((1H-imidazol-5-yl)methyl)-2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.022 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed by freeze drying overnight to give the desired compound (7.5 mg). 1H-NMR (500 MHz, MeOD) δ 8.81 (1H, s), 7.62 (2H, br), 7.39-7.41 (m, 4H), 7.28-7.30 (3H, m), 7.16-7.18 (2H, m), 5.39 (2H, s), 5.07 (2H, s), 2.7-2.8 (2H, m), 2.55-2.65 (2H, m), 2.2-2.3 (1H, m), 1.9-2.05 (1H, m), LCMS (Method A) RT=2.83 min, M+H+=453.1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH3:25][CH:26]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:35])[C:29]=2[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:30]3[CH:31]=[CH:32][CH:33]=[C:34]4[C:29]=3[CH2:28][CH2:27][CH:26]4[CH3:25])[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC1CCc2c(O)cccc21
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC1CCc2c(Oc3nc(C(=O)NC(C)c4cc(F)c(NS(C)(=O)=O)c(F)c4)co3)cccc21
Yield: 62.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 1-methyl-indan-4-ol (39 mg, 0.26 mmol) to give the title compound (40 mg, 63%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].Cl[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1>O1CCCC1>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: Clc1nc2ccccc2s1
Reactant: CCOC(=O)CC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)c1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
Into a solution of 1,3-diethyl propanedioate (280 g, 1.75 mol, 3.00 equiv) in tetrahydrofuran (1000 mL) in a 2000-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was added sodium hydride (46.15 g, 1.92 mol, 2.00 equiv) in portions. After stirring for 30 min at room temperature, 2-chloro-1,3-benzothiazole (100.0 g, 589.51 mmol, 1.00 equiv) was added. The reaction mixture was stirred for 20 h at 70° C. in an oil bath, cooled to room temperature, quenched with sat. ammonium chloride (200 mL) and extracted with ethyl acetate (3×500 mL). The combined organic layers were dried over anhydrous sodium sulfate. After filtration and concentration under vacuum, the residue was triturated with 1×500 mL of dichloromethane. The solid was collected by filtration to give 166 g of 1,3-diethyl 2-(1,3-benzothiazol-2-yl)propanedioate as a white solid. MS m/z [M+H]+ (ESI): 294.
Reaction SMILES: C([O:8][C:9](=[O:23])[C@H:10]([O:15][C:16]([C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)=[O:17])[CH2:11][CH:12]([CH3:14])[CH3:13])C1C=CC=CC=1.[H][H]>[Pd]>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:16]([O:15][C@H:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:9]([OH:23])=[O:8])=[O:17]
Reactant: [H][H]
Reactant: CC(C)C[C@@H](OC(=O)c1ccco1)C(=O)OCc1ccccc1
Agent: [Pd]
Product: CC(C)C[C@@H](OC(=O)c1ccco1)C(=O)O

Procedure:
A total of 55.5 g. of benzyl-(R)-2-(2-furoyloxy)-isocaproate were hydrogenated in 400 ml. of alcohol after the addition of 5 g. of palladium-on-charcoal (5%) until the theoretical amount of hydrogen had been taken up. The catalyst was filtered off by suction and the filtrate evaporated under reduced pressure at 40°. The oil thus obtained was dissolved in 250 ml. of 8% sodium bicarbonate solution and the resulting solution washed twice with 80 ml. portions of ether. The pH of the bicarbonate solution was adjusted to pH 2 with concentrated hydrochloric acid and extracted three times with 100 ml. portions of ethyl acetate. The ethyl acetate solutions were washed twice with 50 ml. portions of water, dried with magnesium sulphate and evaporated under reduced pressure at 45°. The residual oil was dried for 2 hours at 0.4 Torr and 40° to give (R)-2-(2-furoyloxy)-isocaproic acid; [α]D25 =+7.0 (c = 4.0 in alcohol).