Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl.C(O)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:28][CH:29]=1)=[NH:13])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCCOc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: N=C(NC(=O)OCc1ccccc1)c1ccc(OCCCCC(=O)O)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 91.9 %

Procedure:
A mixture of ethyl 5-[4-(N-benzyloxycarbonylamidino)phenoxy]valerate (17.4 g) in 10% hydrochloric acid (150 ml) and acetic acid (100 ml) was stirred at 50° C. for 1.5 hours. After cooled to room temperature, the reaction mixture was adjusted to pH≈4.0 with 4N sodium hydroxide solution. The resulting precipitate was collected by filtration to give 5-[4-(N-benzyloxycarbonylamidino)phenoxy]valeric acid (14.87 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]2[NH:12][C:13](=[O:17])[CH:14]([CH3:16])[CH3:15])[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)C(=O)NC1CCCCC1Oc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCC3NC(=O)C(C)C)c2c1N

Procedure:
Prepared as in Example 2a from N-(2-(3-amino-2-cyanophenoxy)cyclohexyl)isobutyramide (Example 39b) and ethyl 3-oxobutanoate as a yellow solid (63%). MS 414 (MH+).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CCO>[CH2:5]([CH:12]1[CH2:17][CH2:16][N:15]([CH2:3][CH2:2][C:1]#[N:4])[CH2:14][CH2:13]1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: C=CC#N
Solvent: CCO
Product: N#CCCN1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 99.9 %

Procedure:
Acrylonitrile (9.37 mL, 142 mmol, 2.50 equiv) was added at 0° C. to a solution of 4-benzylpiperidine (10.0 mL, 56.9 mmol, 1.00 equiv, Aldrich) in EtOH (60 mL) and the resulting solution was stirred for 1.5 hours at room temperature. The solvent was removed to give 12.98 g (99%) of colorless oil, which was characterized spectroscopically and used without purification for the next reaction.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:57])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCC)cc2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 35.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (111 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, the mixture was stirred for 1 hour at −10° C. to −25° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (73.5 mg) (Compound 335) as yellow amorphous, and to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-propylimidazol-2-yl)methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (18.8 mg) (Compound 336) as yellow amorphous.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([CH:30]([OH:34])[CH2:31][CH2:32][CH3:33])[N:25]=[C:24]2[CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCc1nc(C(O)CCC)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCc1nc(C(O)CCC)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
16 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 1.07 g of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-4-(1-hydroxybutyl)-2-propylimidazole-5-carbonitrile [prepared as described in step (b) above] in 16 ml of ethanol, and the resulting mixture was worked up in a similar manner to that described in Example 45(c), to afford 0.82 g of the title compound as an amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:32]=[C:33]([C:37](O)=[O:38])[S:34][C:35]=1[CH3:36]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:37]([C:33]4[S:34][C:35]([CH3:36])=[C:31]([CH3:30])[CH:32]=4)=[O:38])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1cc(C(=O)O)sc1C
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)c(C)s2)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 4,5-dimethylthiophene-2-carboxylic acid (23 mg, 0.15 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[OH:35])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([O:31][CH3:32])=[O:30])=[CH:22][N:23]3[CH:26]([CH3:28])[CH3:27])=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:43]1[CH:48]=[CH:47][CH2:46][CH2:45][CH2:44]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>ClCCl>[C:1]([O:5][C:6]([N:8]([CH2:33][C@@H:34]([C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1)[O:35][CH:44]1[CH2:45][CH2:46][CH2:47][CH2:48][O:43]1)[CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:25]=[C:24]3[C:20]([C:21]([C:29]([O:31][CH3:32])=[O:30])=[CH:22][N:23]3[CH:26]([CH3:27])[CH3:28])=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)c1cn(C(C)C)c2cc(-c3ccc(CCN(C[C@H](O)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cn(C(C)C)c2cc(-c3ccc(CCN(C[C@H](OC4CCCCO4)c4cccc(Cl)c4)C(=O)OC(C)(C)C)cc3)ccc12

Procedure:
To a solution of methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-hydroxyethyl]amino]-ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylate (340 mg) in dichloromethane (5 ml) were added 3,4-dihydro-2H-pyran (0.105 ml) and a catalytic amount of pyridinium p-toluenesulfonate at room temperature under nitrogen, and the mixture was stirred at the same temperature for 12 hours. The resulting mixture was poured into water and the aqueous layer was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate=4/1) to give methyl 6-[4-[2-[(tert-butoxycarbonyl)[(2R)-2-(3-chlorophenyl)-2-(tetrahydro-2H-pyran-2-yloxy)ethyl]amino]ethyl]phenyl]-1-isopropyl-1H-indole-3-carboxylate (310 mg).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:8]=[C:9]([C:24]([OH:26])=O)[C:10](=[CH:14][C:15]=2[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[F:23][C:20]1[CH:21]=[CH:22][C:17]([NH:16][C:15]2[CH:14]=[C:10]3[C:11](=[O:13])[O:12][C:24](=[O:26])[C:9]3=[CH:8][C:7]=2[NH:6][C:5]2[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:18][CH:19]=1
Reactant: O=C(O)c1cc(Nc2ccc(F)cc2)c(Nc2ccc(F)cc2)cc1C(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: O=C1OC(=O)c2cc(Nc3ccc(F)cc3)c(Nc3ccc(F)cc3)cc21

Procedure:
A steady stream of argon is passed through a suspension of 4.49 g (11.68 mmol) of 4,5-bis(4-fluoroanilino)phthalic acid in 75 ml of toluene and 3.32 ml (35.12 mmol, 3 eq) of acetic anhydride is added. The reaction mixture is heated to 60°-65° for 90 minutes with vigorous stirring. The reaction mixture is cooled to 10° for 15 minutes, theyellow orange crystals are filtered off and washed with toluene/hexane to yield the title compound in the form of yellow orange crystals, FAB-MS: 367 [M+ +H].
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][C:12](=[S:22])[NH:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:33])=[O:32])=[CH:27][CH:26]=1>C1COCC1.O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[Cl:3][C:4]1[CH:9]=[C:8]([C:10]2[NH:11][C:12]([S:22][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:33])=[O:32])=[CH:27][CH:26]=3)=[N:13][C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH:7]=[CH:6][N:5]=1
Reactant: CS(=O)c1ccc(CCl)cc1
Reactant: Fc1ccc(-c2[nH]c(=S)[nH]c2-c2ccnc(Cl)c2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)c1ccc(CSc2nc(-c3ccc(F)cc3)c(-c3ccnc(Cl)c3)[nH]2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
NaH (55-65%; 0.1 g; about 2 mmol) was introduced into a solution of 24a (0.31 g; 1.0 mmol) in absolute THF (15 ml). The initial charge was stirred at room temperature for 5 min, and 4-methylsulfinylbenzyl chloride (3, 0.19 g; 1.0 mmol) was added. The reaction mixture was stirred at room temperature for 2 h. The yellow-brown solution was diluted with H2O and neutralized with 10% strength citric acid. The THF was removed and the aqueous solution was extracted with ethyl acetate (2×). The combined organic extract was washed with saturated NaCl solution (2×), dried over Na2SO4 and concentrated. The solids residue was purified by column chromatography (SiO2 60, CH2Cl2/EtOH 9.5+0.5). M.p. 179° C.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]([CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([CH3:24])[CH:18]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][NH:8][CH2:9]2)=[CH:18][C:19]=1[CH3:24]
Reactant: Cc1cc(OCC2CCCCN(Cc3ccccc3)C2)ccc1F
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(OCC2CCCCNC2)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-5 (226 mg, 0.690 mmol) in MeOH (5 ml) was treated with 10 mol % palladium hydroxide on carbon (48.5 mg, 0.069 mmol). The flask was evacuated and backfilled with H2(g) three times and stirred under a H2(g) atmosphere (1 atm) at RT for 30 min. The mixture was filtered though a syringe filter and the filtrate was concentrated to yield 1-6. Data for 1-6: LRMS m/z (M+H): 238.1.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:38]
Reactant: COc1ccc(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c23)c(OCC2CC2)c1
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-cyclopropylmethoxy-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A151) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: C1O[C:4]([C:6]2[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=2)([CH3:5])[O:3]C1>C(O)CO>[SH:12][C:9]1[CH:10]=[CH:11][C:6]([C:4](=[O:3])[CH3:5])=[CH:7][CH:8]=1
Reactant: CC1(c2ccc(S)cc2)OCCO1
Solvent: OCCO
Product: CC(=O)c1ccc(S)cc1

Procedure:
4'-Mercaptoacetophenone ethylene acetal (0.656 g; obtained by the reaction of 4'-mercaptoacetophenone and ethylene glycol using an analogous procedure to that described in the third paragraph of the portion of Example 7 which is concerned with the preparation of starting materials) was added to a mixture of 2,4-dibromothiazole (0.82 g), potassium carbonate (0.468 g) and NMP (4 ml). The mixture was stirred and heated to 90° C. for 2.5 hours. The mixture was cooled to ambient temperature and partitioned between diethyl ether and brine. The organic phase was dried (MgSO4) and evaporated. The mixture was purified by column chromatography using a 3:1 mixture of ethyl acetate and petroleum ether as eluent. There was thus obtained 4'-[4-bromothiazole-2-ylthio]acetophenone ethylene acetal (1.1 g, 90%), m.p. 71° C.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=2)[CH2:4]1.C(=O)([O-])[O-].[K+].[K+].O.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1>C(OCC)(=O)C>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:2][CH:3]2[CH2:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=3)[CH2:4]2)(=[O:33])=[O:32])=[CH:27][CH:26]=1
Reactant: COC(=O)Cc1ccc2c(c1)CC(N)C2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1ccc2c(c1)CC(NS(=O)(=O)c1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
A mixture of methyl (2-aminoindan-5-yl)acetate hydrochloride (2.43 g), potassium carbonate (5.52 g), water (60 ml), ethyl acetate (60 ml) and 4-chlorophenylsulfonyl chloride (2.11 g) is stirred at room temperature for one hour. The ethyl acetate layer is separated from the reaction mixture, washed with aqueous saline solution, dried, and distilled under reduced pressure to remove the solvent. The resulting crude product is recrystallized from a mixture of ethyl acetate and n-hexane to give methyl [2-[(4-chlorophenyl)sulfonylamino]indan-5-yl]acetate (3.02 g).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=1)[CH2:3][NH2:4].[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](=O)[CH3:22])=[CH:16][CH:15]=1>>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH3:12])[CH:6]=2)[CH3:22])=[CH:16][CH:15]=1
Reactant: CCc1cccc(C(O)CN)c1
Reactant: CC(=O)Cc1ccc(C)cc1
Product: CCc1cccc(C(O)CNC(C)Cc2ccc(C)cc2)c1

Procedure:
The title compound was prepared as described in Example 3 using 2-hydroxy-2-(3-ethylphenyl)ethanamine and (4-methylphenyl)propanone. The residual oil was chromatographed on Kieselgel 60. Elution with 2% methanolchloroform gave the title compound, isolated as the hydrochloride salt, as a 54:46 mixture of diastereoisomers m.p. 97-104. τ(d6DMSO) 8.85 (3H, d, J=6 Hz), 8.8 (3H, d, J=6 Hz), 7.7 (3H, s), 7.4 (2H, q, =6 Hz), 6.3-7.2 (5H, m), 4.9 (1H, m), 3.8 (1H, broad, disappears with D2O), 2.8 (4H, s), 2.6-2.8 (4H, m), 1.1+0.2 (2H, broad, both disappear with D2O).
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].Cl.[CH3:33][N:34]1[C:38]([CH3:39])=[C:37]([CH2:40][NH2:41])[C:36]([CH3:42])=[N:35]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:41][CH2:40][C:37]1[C:36]([CH3:42])=[N:35][N:34]([CH3:33])[C:38]=1[CH3:39])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: Cc1nn(C)c(C)c1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1nn(C)c(C)c1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 44.3 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), (1,3,5-trimethyl-1H-pyrazol-4-yl)methanamine-HCl (18.33 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were added to DMF (1 mL). This was stirred for 1 h before it was purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)-N-((1,3,5-trimethyl-1H-pyrazol-4-yl)methyl)acetamide (17.2 mg, 0.031 mmol, 44.8% yield): LCMS=553.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.14 (2 H, d, J=8.28 Hz), 7.50-7.69 (8H, m), 5.10 (1 H, s), 4.19 (2 H, d, J=5.27 Hz), 3.65 (3 H, s), 2.17 (3 H, s), 2.12 (3 H, s); HPLC peak RT=2.6 min (Method E).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[Br:12][CH2:13][CH2:14]Br.C(=O)([O-])[O-].[K+].[K+]>>[Br:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1ccc(OCCBr)cc1
Yield: 99 %

Procedure:
Methyl 4-hydroxybenzoate (5.0 g, 32.86 mmol) was combined with 1,2-dibromoethane (35 mL) and potassium carbonate (6.8 g, 49.23 mmol, 1.5 eq.) then heated at reflux for 18 h. The reaction mixture was concentrated under reduced pressure then the residue partitioned between ethyl ether (500 mL) and water (200 mL). The ether was extracted with 2 N sodium hydroxide (5×50 mL). The solvent was removed under reduced pressure to give the desired product as a white solid (8.47 g, 99%).
Reaction SMILES: O[CH:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:3]1=[O:21].[H-].[Na+].[C:24](Cl)(=[O:27])[CH:25]=[CH2:26]>C(Cl)Cl>[C:24]([CH:2]1[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[Cl:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:3]1=[O:21])(=[O:27])[CH:25]=[CH2:26]
Reactant: COc1ccc(N2C(=O)C(O)C2c2ccccc2Cl)cc1
Reactant: C=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)C1C(=O)N(c2ccc(OC)cc2)C1c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.4 %

Procedure:
To a solution of C3-hydroxy β-lactam 24 (5.80 g, 19.1 mmol) in 30 ml of freshly distilled CH2Cl2 was added NaH (60% suspension in mineral oil, 0.83 g, 21.0 mmol), and the mixture was stirred for 15 min at room temperature. Acryloyl chloride (2.59 g, 28.64 mmol) was then added dropwise and the resultant mixture was stirred until TLC indicated the disappearance of starting material. The reaction was quenched with a 5% solution of NH4Cl and extracted (3×20 ml) with CH2Cl2. The combined organic layers were dried over anhydrous MgSO4 and purified with column chromatography on silica gel (1:4, EtOAc:hexanes) to give 4.92 g (72%) of 25 as a white solid, mp 99-100° C. 1H NMR (250 MHz) δ 7.33 (d, J=7.9 Hz, 1H), 7.23-7.10 (m, 5H), 6.75 (d, J=8.9 Hz, 2H), 6.17 (d, J=5.0 Hz, 1H), 5.98 (dd, J=16.9, 1.00 Hz, 1H), 5.74 (dd, J=16.9, 10.4 Hz, 1H), 5.69 (d, J=5.0 Hz, 1H), 5.59 (d, J=10.4, 1.0 Hz, 1H), 3.66 (s, 3H). 13C NMR (63 MHz) δ 163.6, 161.2, 156.6, 133.7, 132.3, 130.3, 130.1, 129.8, 128.5, 126.8, 126.5, 118.6, 114.4, 75.3, 61.3, 58.2, 55.3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][CH:13]=[CH:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:16][C:17]([F:30])([F:29])[C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[NH2:21]>>[F:16][C:17]([F:29])([F:30])[C:18]1[CH:19]=[C:20]([NH:21][C:4](=[O:6])[C:3]2[CH:7]=[C:8]([N:11]3[CH:15]=[CH:14][CH:13]=[CH:12]3)[CH:9]=[CH:10][C:2]=2[OH:1])[CH:22]=[C:23]([C:25]([F:26])([F:28])[F:27])[CH:24]=1
Reactant: O=C(O)c1cc(-n2cccc2)ccc1O
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(-n2cccc2)ccc1O
Yield: 57.8 %

Procedure:
Using 2-hydroxy-5-(pyrrol-1-yl)benzoic acid and 3,5-bis(trifluoromethyl)-aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: C([Li])CCC.[CH2:6]([NH:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[O:22][CH3:23])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C.Cl>O1CCCC1>[CH2:6]([NH:13][C:14]([C:15]1[CH:20]=[CH:19][C:18]([B:25]([OH:30])[OH:26])=[CH:17][C:16]=1[O:22][CH3:23])=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1cc(Br)ccc1C(=O)NCc1ccccc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)ccc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
n-Butyl lithium(1.6 M in hexane solution, 8.0 ml, 12.88 mmol) was added slowly to a solution of N1-benzyl-4-bromo-2-methoxybenzamide (1.65 g, 5.15 mmol) in tetrahydrofuran (40 mL) at −78° C. After 30 minutes, triisopropyl borate (1.8 mL, 7.73 mmol) was added rapidly. The reaction mixture was allowed to warm up to room temperature after 13 minutes and stirred for 16 hours. Hydrochloric acid (2.5N, 36 mL) was added and the mixture was stirred overnight. Organic solvent was removed and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash column chromatography using dichloromethane/methanol (95:5) as mobile phase to give 4-[(benzylamino)carbonyl]-3-methoxyphenylboronic acid (0.675 g, 46%). 1H NMR (DMSO-d6) δ 3.90 (s, 3H), 4.51 (d, J=6.18 Hz, 2H), 7.24 (m, 1H), 7.34 (m, 4H), 7.43 (d, J=7.55 Hz, 1H), 7.59 (s, 1H), 7.69 (d, J=7.55 Hz, 1H), 8.23 (s, 2H), 8.69 (m, 1H).