Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][C:5](Cl)=[O:6].Cl.Cl.[CH3:10][N:11]1[CH:15]=[N:14][C:13]([C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=3)=[N:20][CH:21]=2)=[N:12]1>C(Cl)Cl.O>[Cl:3][CH2:4][C:5]([N:25]1[CH2:24][CH2:23][C:22]([C:19]2[CH:18]=[CH:17][C:16]([C:13]3[N:14]=[CH:15][N:11]([CH3:10])[N:12]=3)=[CH:21][N:20]=2)=[CH:27][CH2:26]1)=[O:6]
Reactant: Cn1cnc(-c2ccc(C3=CCNCC3)nc2)n1
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: Cn1cnc(-c2ccc(C3=CCN(C(=O)CCl)CC3)nc2)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Added 1N NaOH (50 ml, 50 mmol) and Chloroacetyl chloride (3 ml, 37.7 mmol) in CH2Cl2 (50 ml) dropwise to a solution of 5-(1-methyl-1H-1,2,4-triazol-3-yl)-2-(1,2,3,6-tetrahydropyridin-4-yl)pyridine dihydrochloride (5BX) (1 g, 3.60 mmol) in CH2Cl2 (50 ml at 0° C., maintaining pH at >12. Mixture was stirred for 2 hours at 0° C., then reaction was diluted with CH2Cl2 (200 ml) and H2O (100 ml). The organic layer was separated, washed with H2O (50 ml), dried (Na2SO4), filtered and solvent evaporated yielding title product as a white solid (1.1 g, 100%) MS (MH, 318)
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH3:11][C@H:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1(C)C=CC=CC=1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[N:19][C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:11])=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: C[C@H](N)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C=N[C@@H](C)c2ccccc2)cc1
Temperature: 25 °C
Yield: 102.1 %

Procedure:
A mixture of p-anisaldehyde (11.24 g, 82.5 mmol) and (S)-α methyl benzyl amine (10.0 g, 82.5 mmol) in toluene (100 mL) was heated to reflux with removal of water by a Dean-Stark apparatus. After cooling to ambient temperature, the mixture was concentrated to provide 20.15 g (100%) of the desired product. 1H NMR (300 MHz, CDCl3) δ 8.30 (s, 1H), 7.75-7.68 (m, 2H), 7.45-7.15 (m, 5H), 4.50 (q, 1H, J=6.6 Hz), 3.82 (s, 3H), 1.58 (d, 3H, J=6.6 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:13]1[C:18]([N+:19]([O-])=O)=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:10]([CH3:12])[CH3:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[CH2:7][CH2:8][N:9]([C:13]1[C:18]([NH2:19])=[CH:17][N:16]=[C:15]([Cl:22])[N:14]=1)[CH:10]([CH3:12])[CH3:11])([CH3:3])([CH3:4])[CH3:2]
Reactant: [H][H]
Reactant: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Yield: 98.8 %

Procedure:
A mixture of 1.6 g (0.0045 mole) of 3-[(2-chloro-5-nitro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (IV-43) in 50 mL of ethyl acetate and 0.5 g of 5% palladium on carbon catalyst was stirred under an atmosphere of hydrogen until hydrogen uptake was complete. The mixture was filtered through a pad of Celite, washing the filter pad with dichloromethane. Concentration of the filtrate under reduced pressure gave 1.4 g of 3-[(5-amino-2-chloro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (V-43). This material was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[N+:5]([O-:23])=[CH:6][CH:7]=1
Reactant: Cc1ccnc(-c2cc(C)ccn2)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(-c2cc(C)cc[n+]2[O-])c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 71.1 %

Procedure:
4,4′-Dimethyl-2,2′-bipyridyl (4.8 g, 26 mmol) and 3-chloroperbenzoic acid (77%, 8.7 g, 39 mmol) were dissolved in chloroform (25 ml), and the mixture was stirred at room temperature for 24 hrs. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethylacetate-methanol (4:1, v/v) were collected, concentrated and crystallized from dimethyl ether to give the titled compound (3.7 g, 71%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[C:23]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]>>[C:23]([CH:27]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:29][CH2:28]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)C1CCNCC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(C)(C)C1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)CC1

Procedure:
Following Example 216, to a well stirred solution of 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid and 4-tert-butylpiperidine to give 252. MS: (ESI+)=427.1
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]1[CH2:13][CH:12]([OH:14])[C:11](=O)[C:10]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23].CO.Cl>O1CCCC1>[OH:14][CH:12]1[CH2:13][C:9](=[O:8])[C:10]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:11]1
Reactant: COC(=O)CCCCCCC1=C(OC)CC(O)C1=O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)CCCCCCC1=CC(O)CC1=O
Reaction time: 2 h

Procedure:
222 Parts of redistilled tetrahydrofuran is cooled to 0° and then treated with 15.6 parts by volume of 1M lithium aluminum hydride in tetrahydrofuran. The temperature of that mixture is lowered to -70° and 6.92 parts of methyl 2-methoxy-4-hydroxy-5-oxocyclopent-1-eneheptanoate dissolved in 53 parts of tetrahydrofuran is added. The addition takes place over a 2 minute period and the temperature of the reaction mixture is not allowed to rise above -60°. After the addition is complete, the temperature is lowered to -70° and the reaction mixture is stirred for 41/2 hours. Then 4 parts of methanol and 8.9 parts of tetrahydrofuran is added and the temperature of the reaction mixture is allowed to rise to -20° at which time 60 parts by volume of a 1 N hydrochloric acid solution is slowly added. The resulting mixture is allowed to stand for 16 hours at a temperature of about 4°. Then the solvent is removed under reduced pressure and the residue which remains is diluted with ethyl acetate. The aqueous and organic layers which form are separated and the organic layer is washed with water, potassium bicarbonate and water and dried over anhydrous sodium sulfate. After the solvent is removed under reduced pressure, the remaining material is chromatographed on silicic acid with ethyl acetate-benzene (1:4) as eluant to afford methyl 3-hydroxy-5-oxocylopent-1-eneheptanoate.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([C:14](O)=[O:15])[CH:11]=[C:10]([CH3:17])[N:9]=1>C(OCC)C>[Cl:7][C:8]1[CH:13]=[C:12]([CH2:14][OH:15])[CH:11]=[C:10]([CH3:17])[N:9]=1
Reactant: Cc1cc(C(=O)O)cc(Cl)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Cc1cc(CO)cc(Cl)n1
Reaction time: 8 h

Procedure:
To a slurry of lithium aluminum hydride (0.45 g, 11.9 mmol) in anhydrous diethyl ether (40 mL) at 0° C., a solution of 2-chloro-6-methylpyridine-4-carboxylic acid (2.0 g, 11.7 mmol) in diethyl ether (30 mL) was added. The resulting mixture was stirred at room temp. overnight, and quenched with successive addition of water (0.45 mL), 15% aqueous NaOH (0.45 mL), and water (1.35 mL). The resultant slurry was stirred at room temp. for 30 min., and filtered through a small plug of Celite. The filtrate was washed brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum to provide 2-chloro-4-hydroxymethyl-6-methylpyridine.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[CH3:37][C:38]1[S:42][C:41]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:40]([C:49](=O)[CH3:50])[CH:39]=1.[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:49]([C:40]2[CH:39]=[C:38]([CH3:37])[S:42][C:41]=2[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:50]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(=O)c1cc(C)sc1-c1ccccc1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c(-c2ccccc2)s1
Yield: 6 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(5-methyl-2-phenyl-thiophen-3-yl)-ethanone (56 mg, 0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (8 mg, 6% yield). MS: 544.27 (M+H+) HPLC Procedure A, retention time=17.05 min.
Reaction SMILES: O[CH2:2][C@@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>C(Cl)(Cl)Cl>[Cl:38][CH2:2][C@@H:3]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH2:5][N:4]1[C:12]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13]
Reactant: ClC(Cl)(Cl)Cl
Reactant: C=CCOC(=O)N1CC=C(C(=O)OC)[C@H]1CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: C=CCOC(=O)N1CC=C(C(=O)OC)[C@H]1CCl
Yield: 24 %

Procedure:
To a solution of 1-allyl 3-methyl(2S)-2-(hydroxymethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (1.29 g, 4.28 mmol) in carbontetrachloride (16 ml) was added at room temperature triphenylphosphine (1.35 g) and the mixture was refluxed under heating for 6 hours. The insoluble materials were dissolved in chloroform and the solvent was removed in vacuo. The residue was purified with silica gel (150 g) column chromatography (hexane/ethyl acetate 4/1→2/1) to give 1-allyl 3-methyl (2S)-2-(chloromethyl)-2,5-dihydro-1H-pyrrole-1,3-dicarboxylate (268 mg, 24%).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([O:35]CC)=O)[C:15]1=[O:38].[NH2:39][CH2:40][CH2:41][N:42]1[CH2:46][CH2:45][NH:44][C:43]1=[O:47].OS([O-])(=O)=O.[Na+]>CCO>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][N:14]1[C:23]2[C:18](=[N:19][CH:20]=[C:21]([CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH:22]=2)[C:17]([OH:32])=[C:16]([C:33]([NH:39][CH2:40][CH2:41][N:42]2[CH2:46][CH2:45][NH:44][C:43]2=[O:47])=[O:35])[C:15]1=[O:38]
Reactant: NCCN1CCNC1=O
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: CCO
Product: O=C(NCCN1CCNC1=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2C(=O)c3ccccc3C2=O)c1=O
Temperature: 25 °C

Procedure:
A solution of ethyl 1-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (0.025 g, 0.049 mmol) in EtOH (1 mL) under nitrogen was treated with 1-(2-aminoethyl)-2-imidazolidinone (0.0078 g, 0.03 mmol, 50% W/W in IPA) for 30 min.@150° C. The reaction was further microwaved for 30 min.@150° C. after the addition of an additional 0.6 equivalents (0.015 mL) of the amine, cooled to ambient temperature, and treated with 1N NaHSO4. The resulting suspension was filtered and the filtrate was concentrated in vacuo. The filtrate residue was purified by reversed phase HPLC. Pure fractions were combined and concentrated to afford the title compound as a pale yellow glass: 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.82 (s, 1 H), 3.38-3.51 (m, 4 H), 3.52-3.65 (m, 4 H), 4.00 (t, J=6.67 Hz, 2 H), 4.04-4.10 (m, 2 H), 4.26 (s, 1 H), 4.46 (t, J=6.74 Hz, 2 H), 6.91-7.04 (m, 2 H), 7.10-7.21 (m, 2 H), 7.70-7.78 (m, 3 H), 7.79-7.85 (m, 2 H), 8.51 (d, J=1.26 Hz, 1 H), 10.24 (t, J=6.04 Hz, 1 H); ES+ MS: 599 (M+H+).
Reaction SMILES: [N:1]([C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O:11]CC1C=CC([N+]([O-])=O)=CC=1)=[O:10])=[N+]=[N-].C(=O)(O)[O-].[Na+:29]>O1CCOCC1.O.C(O)C.[Pd]>[NH2:1][C:4]1[CH2:5][C@@H:6]2[CH2:23][C:22](=[O:24])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+:29]
Reactant: [N-]=[N+]=NC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)C[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: NC1=C(C(=O)[O-])N2C(=O)C[C@H]2C1

Procedure:
A solution of p-nitrobenzyl 2-azido-carbapen-2-em-3-carboxylate (3.3 mg, 10 micromol) in dioxane (300 microliter), deionized water (180 microliter), absolute ethanol (25 μl), and aqueous sodium bicarbonate solution (20 microliter of 0.5M) was shaken with 10% palladium on charcoal (3.3 mg) under hydrogen (50 psig) at ambient temperature for 40 min. The mixture was centrifuged and the pellet was washed with deionized water (3×0.3 ml). The combined supernates were extracted with ethyl acetate (3×0.4 ml) and lyophilized to provide sodium 2-amino-carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH2:57][C:58]4[N:59]=[CH:60][N:61](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:62]=4)([CH2:32][C:33]4[N:34]=[CH:35][N:36](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:37]=4)[C:14](=[O:31])[N:15]3[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([S:25]([N:28]([CH3:30])[CH3:29])(=[O:27])=[O:26])=[CH:21][CH:20]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)#[N:2]>C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:17]=[C:16]3[C:12]([C:13]([CH2:32][C:33]4[N:34]=[CH:35][NH:36][CH:37]=4)([CH2:57][C:58]4[N:59]=[CH:60][NH:61][CH:62]=4)[C:14](=[O:31])[N:15]3[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([S:25]([N:28]([CH3:29])[CH3:30])(=[O:26])=[O:27])=[CH:23][CH:24]=3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)(Cc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)c3ccc(-c4ccc(C#N)cc4)cc32)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CN(C)S(=O)(=O)c1ccc(CN2C(=O)C(Cc3c[nH]cn3)(Cc3c[nH]cn3)c3ccc(-c4ccc(C#N)cc4)cc32)cc1
Reaction time: 1 h
Yield: 5.5 %

Procedure:
4-[6-(4-Cyano-phenyl)-2-oxo-3,3-bis-(1-trityl-1H-imidazol-4-ylmethyl)-2,3-dihydro-indol-1-ylmethyl]-N,N-dimethyl-benzenesulfonamide (0.3 g, 0.4 mmol) was dissolved in a solution of 4.0 ml of TFA and 500 μL of triethylsilane under an atmosphere of dry N2 and stirred for 1 hour. The heterogeneous mixture was concentrated under vacuum and partitioned between aqueous 0.1 N HCl and ethyl ether (Et2O). The water layer was washed with Et2O and then basified to pH˜9 with sodium hydroxide (NaOH). The water layer was then washed 3 times with DCM. The DCM layers were combined and dried over Na2SO4, filtered and concentrated under vacuum to give 13 mg of the titled compound as a purple solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH2:16][CH2:15][CH:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[CH2:13][CH2:12]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:32]=2)[CH2:28][CH2:27]1>>[CH:26]1([NH:29][C:30](=[O:47])[C:31]2[CH:36]=[CH:35][C:34]([CH3:37])=[C:33]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]5([CH2:12][CH2:13][CH:14]([O:17][CH2:18][CH2:19][N:20]6[CH2:21][CH2:22][O:23][CH2:24][CH2:25]6)[CH2:15][CH2:16]5)[C:7](=[O:11])[NH:8]4)=[CH:4][CH:3]=3)[CH:32]=2)[CH2:27][CH2:28]1
Reactant: O=C1Nc2cc(Br)ccc2C12CCC(OCCN1CCOCC1)CC2
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(c1)NC(=O)C21CCC(OCCN2CCOCC2)CC1

Procedure:
Obtained as a white solid (81%) as a single isomer (exact isomeric form not determined) from 6′-bromo-4-(2-morpholinoethoxy)spiro[cyclohexane-1,3′-indolin]-2′-one (preparation 27) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (preparation 40) following the experimental procedure as described in preparation 38 followed by purification by flash chromatography (98:2 to 20:1 dichloromethane/methanol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)/[CH2:6][CH2:7][CH:8]=O)[CH3:2].[NH2:26][C@@H:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]1[OH:36].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.C(O)(=O)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])/[C:5](=[CH:10]/[C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]2)=[C:13]([O:23][CH3:24])[CH:12]=1)/[CH2:6][CH2:7][CH2:8][NH:26][C@@H:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][C@@H:28]1[OH:36])[CH3:2]
Reactant: N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=C/c1ccc(-n2cnc(C)c2)c(OC)c1)CCCN[C@@H]1c2ccccc2C[C@@H]1O
Yield: 78.5 %

Procedure:
To a methylene chloride (2.0 mL) solution of (E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]-5-oxovaleric acid ethyl ester (110 mg), (1R,2S)-amino-2-indanol (63.2 mg), acetic acid (0.1 mL) and sodium triacetoxy borohydride (81.7 mg) were added one by one. After agitating reaction solution at room temperature overnight, a saturated sodium bicarbonate water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated saline solution, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: ethyl acetate=1:1->heptane-ethyl acetate), and 120 mg of the title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18](C(=O)CCC(OC)=O)[C:19](=[N:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([O:28]C)=[O:27])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.[OH-].[Na+].Cl>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:23](=[O:30])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: COC(=O)CCC(=O)N=c1scc(CN2CCC(c3c[nH]c4ccccc34)CC2)n1C(=O)CCC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCC(=O)Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Temperature: 50 °C
Yield: 52.4 %

Procedure:
To 4-[4-(3-indolyl)piperidinomethyl]-2-(3-methoxycarbonylpropionylimino)-3-(3-methoxycarbonylpropionyl)thiazoline (700 mg) were added ethanol (25 ml) and 1N aqueous solution of sodium hydroxide (3.2 ml) and the mixture was warmed at 50° C. for 6.5 hours. To the reaction mixture was added 1N hydrochloric acid (3.2 ml) and the solvent was evaporated. After the residue was recrystallized from a mixture of ethanol and water, the crystal was collected by filtration and washed with water to give 4-[4-(3-indolyl)piperidinomethyl]-2-(3-carboxypropionylamino)thiazole (280 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:33][CH2:32][C@:7]2([O:11][CH2:10][CH:9]([C:12]3[C:20]4[N:19]=[CH:18][N:17](C(OC(C)(C)C)=O)[C:16]=4[CH:15]=[C:14]([C:28]([F:31])([F:30])[F:29])[CH:13]=3)[CH2:8]2)[C@@H:6]1[C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:4]>C(Cl)Cl.[Br-].[Zn+2].[Br-]>[CH3:1][O:2][C:3]([C@H:5]1[CH2:33][CH2:32][C@:7]2([O:11][CH2:10][CH:9]([C:12]3[C:20]4[N:19]=[CH:18][NH:17][C:16]=4[CH:15]=[C:14]([C:28]([F:31])([F:29])[F:30])[CH:13]=3)[CH2:8]2)[C@@H:6]1[C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)=[O:4]
Reactant: COC(=O)[C@H]1CC[C@@]2(CC(c3cc(C(F)(F)F)cc4c3ncn4C(=O)OC(C)(C)C)CO2)[C@@H]1c1ccc(F)cc1
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@@]2(CC(c3cc(C(F)(F)F)cc4[nH]cnc34)CO2)[C@@H]1c1ccc(F)cc1
Yield: 75.7 %

Procedure:
A solution of (5R, 6S, 7S)-6-(4-fluorophenyl)-3-[1-(tert-butyloxycarbonyl)-6-trifluoromethyl-benzimidazol-4-yl)-1-oxaspiro[4.4]nonane-7-carboxylic acid methyl ester (13.5 mg, 0.024 mmol) in methylene chloride (1 mL) was treated with anhydrous zinc bromide (11 mg, 0.049 mmol) for 6 hours at room temperature. The reaction was quenched with saturated NaHCO3 solution, diluted with methylene chloride, the organic layer separated and washed with saturated brine solution, dried (Na2SO4), and evaporated to obtain 8.4 mg of the title compound. 400 MHz 1H NMR (CD3OD): δ 1.92-2.11 (m, 3H), 2.24-2.37 (m, 2H), 2.48 (dd, 1H), 3.13 (m, 1H), 3.41 (m, 1H), 3.56 (s, 3H), 4.17 (t, 1H), 6.75 (br s, 1H), 7.06 (t, 2H), 7.42 (m, 2H), 7.68 (br s, 1H), 8.28 (br s, 1H); Mass spec (NH3 /CI): δ 414 (M+1).
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[N:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:4]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[N:9][CH:10]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1cncc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cncc(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of 5-(2-(trimethylsilyl)ethynyl)pyridin-3-amine (0.279 g, 1.466 mmol) in MeOH (2.0 mL) was added K2CO3 (0.304 g, 2.20 mmol). The reaction was stirred at RT overnight. Solvent was removed under reduced pressure and the residue was extracted with EtOAc (2×). The combined organic layers were washed with H2O (1×) and brine (1×), dried (MgSO4) and concentrated to afford 5-ethynylpyridin-3-amine (0.168 g, 97%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][OH:33])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:19][CH:18]=2)[C:13]1=[O:31])[CH3:11].[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(OCC)(=O)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:34])([CH2:32][O:33][S:36]([CH3:35])(=[O:38])=[O:37])[C@H:10]([N:12]1[CH:16]=[CH:15][N:14]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]([F:30])([F:29])[CH:26]([F:28])[F:27])=[CH:21][CH:22]=2)[C:13]1=[O:31])[CH3:11]
Reactant: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(CO)c1ccc(F)cc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(OCC(F)(F)C(F)F)cc2)c1=O)[C@](O)(COS(C)(=O)=O)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-[(1R,2S)-2-(2,4-Difluorophenyl)-2,3-dihydroxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone (1.2 g) was dissolved in 25 ml of ethyl acetate, to which 0.29 ml of methanesulfonyl chloride and 0.53 ml of triethylamine were added dropwise with ice cooling. After stirring at 0° C. for 30 minutes, the reaction solution was washed with water (15 ml×2) and 15 ml of an aqueous solution of sodium chloride successively. The organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was purified by silica gel chromatography (silica gel: 50 g, eluent; hexane:ethyl acetate=1:1). The desired fraction was concentrated and the residue was recrystallized from a mixture of 5 ml of diisopropyl ether and 10 ml of hexane to give 1.26 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-3-methanesulfonyloxy-1-methylpropyl]-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2(1H,3H)-imidazolone as colorless powdery crystals.