Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CC(O)=O.[Pd]>[CH2:1]([C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH2:17][C:18]([OH:20])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CC(=O)O)c(C(=O)c2ccccc2)c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(CC(=O)O)c(Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 104.9 %

Procedure:
2-Benzoyl-4-methoxyphenylacetic acid (215.5 g, 0.80 mole) was divided into two equal portions, and each was dissolved in glacial AcOH (1.5 L) in a 2.5 L pressure bottle. 5% Pd/C (10 g, 0.0048 mole) was added to each, and each mixture was shaken at ambient temperature under hydrogen on a Parr apparatus. After 2.5 hr, the mixtures were filtered to remove the catalyst, and the filter pads were washed with EtOAc. The combined filtrates were concentrated to give the title compound (215 g, quantitative) as a heavy yellow oil which crystallized on standing: 1H NMR (250 MHz, CDCl3) δ7.05-7.35 (m, 6H), 6.77 (dd, J=8.3, 2.7 Hz, 1H), 6.71 (d, J=2.7 Hz, 1H), 4.00 (s, 2H), 3.76 (s, 3H), 3.54 (s, 2H).
Reaction SMILES: [CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10]Cl)[N:6]=1)[C:2]([CH3:4])=[O:3].C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1COCC1>[CH2:1]([C:5]1[O:9][N:8]=[C:7]([CH2:10][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:6]=1)[C:2]([CH3:4])=[O:3]
Reactant: C1CCNCC1
Reactant: CC(=O)Cc1nc(CCl)no1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Cc1nc(CN2CCCCC2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.8 %

Procedure:
To a solution of 15.0 g of 5-acetonyl-3-chloromethyl-1,2,4-oxadiazole in 50 ml of THF were added dropwise 17.4 g of triethylamine and subsequently 11.0 g of piperidine. The mixture was stirred at room temperature for 24 hours and then heated under reflux for 6 hours. After cooling, the precipitated material was removed by filtration and the filtrate was evaporated in vacuo. The residue was chromatographed on silica gel using chloroform-methanol (20:1, v/v) as eluent to give 10.9 g of 5-acetonyl-3-piperidinomethyl-1,2,4-oxadiazole as a colorless solid, m.p. 66°-67° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:19])[C:7]=1[C:8]1[CH:9]=[C:10]([C:15]([O:17][CH3:18])=[O:16])[S:11][C:12]=1[CH2:13][CH3:14])=[CH2:2]>CO.[Pd]>[CH2:13]([C:12]1[S:11][C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:9][C:8]=1[C:7]1[N:6]([CH3:19])[N:5]=[CH:4][C:3]=1[CH2:1][CH3:2])[CH3:14]
Reactant: C=Cc1cnn(C)c1-c1cc(C(=O)OC)sc1CC
Agent: [Pd]
Solvent: CO
Product: CCc1cnn(C)c1-c1cc(C(=O)OC)sc1CC
Reaction time: 1 h
Yield: 94.1 %

Procedure:
To a solution of methyl 4-(4-ethenyl-1-methyl-1H-pyrazol-5-yl)-5-ethyl-2-thiophenecarboxylate (187 mg, 0.68 mmol) in methanol (2.5 ml) was added Pd—C (7.20 mg, 0.07 mmol). The reaction mixture was hydrogenated at 1 atm (balloon) for 1 h. The solution was then purged with N2, filtered through Celite and concentrated affording methyl 5-ethyl-4-(4-ethyl-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (187 mg, 0.64 mmol, 95% yield) as a clear oil which was used without further purification: LCMS (ES) m/e 279 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[N:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[Si]([C:23]#[N:24])(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15][CH3:16])=[CH:11][CH:10]=2)[C:23]#[N:24])=[CH:17][CH:18]=1
Reactant: COc1ccc(C=Nc2ccc(SC)cc2)cc1
Reactant: C[Si](C)(C)C#N
Product: COc1ccc(C(C#N)Nc2ccc(SC)cc2)cc1

Procedure:
Following a procedure similar to that described in Example 1(ii), but using N-(4-methoxybenzylidene)-4-methylthioaniline [prepared as described in step (i) above] and trimethylsilyl cyanide as starting materials, the title compound was obtained as a pale brown powder (yield 92%).
Reaction SMILES: [CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([O:28]CC)=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1)[CH3:2].N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2C=1>>[CH2:1]([S:3][C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[CH2:24][CH:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22]4[CH:31]=[CH:32][CH:33]=[CH:34][C:21]=4[CH2:20][C:19]=3[CH:35]=2)[CH:5]=1)[CH3:2]
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3cc(SCC)ccn3)cc2Cc2ccccc21
Agent: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Product: CCSc1ccnc(NCCCOc2ccc3c(c2)Cc2ccccc2C(CC(=O)O)C3)c1

Procedure:
According to the procedure of Example 6 (c), except substituting ethyl (±)-10,11-dihydro-3-[3-[4-(ethylthio)pyridin-2-y lamino]-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate for the ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was prepared as a yellow: 1H NMR (400 MHz, DMSO-d6) δ7.77-7.76 (d, 1 H), 7.17-7.15 (d, 1 H), 7.13-7.12 (d, 2 H), 7.08-7.07 (m, 1 H), 6.96-6.94(d, 1 H), 6.81-6.80 (s, 1 H), 6.68-6.67 (d, 1 H), 6.52 (s, 1 H), 6.35-6.33 (d, 2 H), 6.30 (s, 1 H), 4.20-4.16 (d, 1 H), 3.99-3.96 (t, 2 H),3.89-3.85 (d, 1 H), 3.65-3.63 (m, 1 H), 3.36-3.32 (m, 2 H), 3.22-3.15 (m, 1 H), 2.96-2.90 (m, 2 H); 2.85-2.78 (m, 1 H), 2.62-2.56(m, 2 H), 1.94-1.90(m, 2 H), 1.26-1.22 (t, 3 H), MS (ES) m/e463.4(M+H)+.
Reaction SMILES: [O:1]=[C:2]([NH:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[S:23][CH:24]=1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([NH:19][C:20]1[N:21]=[C:22]([C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[S:23][CH:24]=1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)Nc1csc(-c2ccncc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: N[C@@H](Cc1ccccc1)C(=O)Nc1csc(-c2ccncc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a rt solution of 4.B (163 mg, 384 μmol) in dioxane (2.5 mL) was added 6.0 N HCl (1 mL). After stirring at rt for 30 min, the reaction mixture was poured into saturated aqueous NaHCO3 (5 m L), diluted with water (5 mL) and extracted by 30% iPrOH/CHCl3 (3×10 mL). The combined solution was washed with brine and dried over MgSO4. After removal of organic solvent under reduced pressure, purification of the residue by flash chromatography on silica gel using 0-20% MeOH/CH2Cl2 for elution provided 4.C as a colorless solid (105 mg, 85%)
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH2:10])=[C:4]([NH2:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[CH:11]([N:14]=[C:15]=S)([CH3:13])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>N1C=CC=CC=1>[Cl:1][C:2]1[C:3]2[N:10]=[C:15]([NH:14][CH:11]([CH3:13])[CH3:12])[NH:9][C:4]=2[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)N=C=S
Reactant: Nc1cc(Cl)cc(Cl)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Product: CC(C)Nc1nc2c(Cl)cc(Cl)cc2[nH]1
Yield: 59.9 %

Procedure:
3,5-Dichloro-1,2-phenylenediamine (1.30 g, 7.32 mmol), isopropyl isothiocyanate (0.81 g, 8.00 mmol), 1-cyclohexyl-1-3-(2-morpholinoethyl)carbodiimide metho-p-toluenesulfonate (4.19 g, 9.89 mmol) and pyridine (25 mL) were used according to general procedure I. The product was recrystallized from 1,4-dioxane to afford 1.07 g (60%) of a white solid. Anal. calcd for C10H11Cl12N3-(0.25 C4H8O2): C, 49.64; H, 4.92; N, 15.79. Found: C, 49.54; H, 4.94; N, 15.79.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[S-:11][C:12]#[N:13].[Na+].BrBr.O>C(O)(=O)C>[N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#[N:13])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: N#C[S-]
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: BrBr
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CSc1ccc(N)c([N+](=O)[O-])c1
Temperature: 15 °C
Yield: 91.8 %

Procedure:
A stirred mixture of o-nitroaniline (82.5 g.), dry sodium thiocyanate (180 g.) and acetic acid (1 liter) was treated at 11°-12° C. with a solution of bromine (96.5 g.) in acetic acid (100 ml.). The stirring was continued for a further hour at 11°-12° C. and the mixture was then allowed to warm to 15° C. and poured into water (3.5 liters). The yellow solid was filtered off, washed with water, and dissolved in acetone (1 liter). The solution was filtered and the filtrate was evaporated to give 2-nitro-4-thiocyanato-aniline (107 g.), m.p. 110°-112° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:33]([NH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=3)[CH:15]=[CH:16][C:17]=1[CH3:18])[N:5]=2)(=[O:35])[CH3:34]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Oc1ccc2nc(N)sc2n1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 28 h
Yield: 71.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (200 mg, 0.450 mmol) produced in Example C12(iv) in pyridine (5 mL) were added acetyl chloride (128 μL, 1.80 mmol) and N,N-dimethylpyridine-4-amine (8.8 mg, 0.0720 mmol), and the mixture was stirred at room temperature for 28 hr. The title compound (157 mg, 72%) was obtained as white crystals by operation in the same manner as in Example C81. The present compound was recrystallized from ethyl acetate and tetrahydrofuran.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]1[CH2:16][CH2:15][CH2:14][C:13](=[O:22])[C:12]2=1.S(OC)(OC)(=O)=O.O>CC(C)=O>[CH3:7][O:8][C:9]1[CH:10]=[C:11]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:1])[C:17]1[CH2:16][CH2:15][CH2:14][C:13](=[O:22])[C:12]2=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2[nH]c3c(c2c1)C(=O)CCC3
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc2c(c1)c1c(n2C)CCCC1=O
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
Anhydrous potassium carbonate (2.24 g) was added to a solution of the product of Stage (i) (3 g) in acetone (30 ml) at room temperature and stirred for 30 min. Dimethyl sulphate (1.6 ml) was added and the mixture was heated to reflux for 4 h. The resulting solution was poured into water (150 ml) and the resulting precipitate filtered off to give the title compound as a solid (2.5 g), m.p. 150°-151°.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([S:20]([C:23]1[CH:28]=[C:27]([Cl:29])[C:26]([O:30][C:31]2[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[C:34]([F:41])=[CH:33][C:32]=2[C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[CH:25][C:24]=1[F:48])(=[O:22])=[O:21])[C:15]1[N:16]=[CH:17][S:18][CH:19]=1)(C)(C)C>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:29][C:27]1[C:26]([O:30][C:31]2[CH:36]=[C:35]([C:37]([F:38])([F:40])[F:39])[C:34]([F:41])=[CH:33][C:32]=2[C:42]2[CH:47]=[CH:46][N:45]=[N:44][CH:43]=2)=[CH:25][C:24]([F:48])=[C:23]([S:20]([NH:14][C:15]2[N:16]=[CH:17][S:18][CH:19]=2)(=[O:22])=[O:21])[CH:28]=1
Reactant: CC(C)(C)OC(=O)N(c1cscn1)S(=O)(=O)c1cc(Cl)c(Oc2cc(C(F)(F)F)c(F)cc2-c2ccnnc2)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1cscn1)c1cc(Cl)c(Oc2cc(C(F)(F)F)c(F)cc2-c2ccnnc2)cc1F
Reaction time: 2 h

Procedure:
Trifluoroacetic acid (9 mL) was added to a solution of tert-butyl({5-chloro-2-fluoro-4-[4-fluoro-2-pyridazin-4-yl-5-(trifluoromethyl)phenoxy]phenyl}sulfonyl)1,3-thiazol-4-ylcarbamate (2.0 g, 3.1 mmol) in dichloromethane (20 mL). After 2 hours, the reaction mixture was concentrated in vacuo to afford the title compound as an amber foam (2.37 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[Br:11]Br.C(OC(=O)C)C>C(O)(=O)C.Br>[BrH:11].[Br:11][CH2:9][C:8]([C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1ccncc1F
Agent: Br
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1ccncc1F
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
Into a stirred solution of 3-fluoropyridine (14 g, 144.2 mmol) in anhydrous THF (150 mL), cooled to −78° C. and under argon, 79.2 mL (158.6 mmol) of a 2N solution of lithiumdiisopropylamide (LDA) in n-heptane, THF, ethylbenzene, were slowly dropped in about 1 h. After stirring for 2.5 h a cooled solution (ca. 0° C.) of acetaldehyde (8.9 mL, 158.5 mmol) in 25 mL of anhydrous THF was slowly dropped and the reaction mixture was stirred at −78° C. for 1.5 h. The solution was warmed to −30° C. and a solution of ammonium chloride (150 g) in 700 mL of water was added. The mixture was extracted with ethylacetate (3×400 mL) and the organic layers were washed with brine (4×200 mL) and dried over sodium sulfate. After concentration, the oil was crystallized with n-hexane (40 mL) and 15.6 g (76% yield) of 1-(3-fluoropyridin-4-yl)ethanol were obtained. A mixture of 1-(3-fluoropyridin-4-yl)ethanol (10 g, 70.3 mmol) and commercial activated MnO2 (8 g, 92.1 mmol) in toluene (100 mL) were refluxed until disappearance of starting material. After cooling, the mixture was filtered on a bed of celite, the cake washed with toluene and the organic phases concentrated to give 3-fluoro-4-acetyl pyridine (6.9 g, 70%) that was used directly in the next step. To a stirred solution of 3-fluoro-4-acetylpyridine (5.3 g, 38.1 mmol) in glacial acetic acid (14 mL) and 48% hydrobromic acid (5.3 mL), bromine (2 mL, 38 mmol) in glacial acetic acid (5.3 mL) was added slowly and dropwise. After addition, the solution was stirred at 60° C. for 2.5 hour. This solution was cooled down and ethylacetate (70 mL) was added. After 30 minutes of stirring, the mixture was filtered and the solid was washed thoroughly with ethylacetate and dried. The title compound was obtained in 82% yield (9.4 g).
Reaction SMILES: C([Li])CCC.[C:6]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])#[CH:7].[CH2:20]([Sn:24](Cl)([CH2:29][CH2:30][CH2:31][CH3:32])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:21][CH2:22][CH3:23]>C1COCC1>[CH2:29]([Sn:24]([CH2:20][CH2:21][CH2:22][CH3:23])([CH2:25][CH2:26][CH2:27][CH3:28])[C:7]#[C:6][CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:30][CH2:31][CH3:32]
Reactant: C#CC1CCCN1C(=O)OC(C)(C)C
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](C#CC1CCCN1C(=O)OC(C)(C)C)(CCCC)CCCC
Temperature: -30 °C
Yield: 61.2 %

Procedure:
n-Butyllithium (1.6M in hexanes, 12.3 mL) was added over 2 minutes to a stirred solution of tert-butyl 2-ethynylpyrrolidine-1-carboxylate (3.65 g) in anhydrous THF (80 mL) at −78° C. under nitrogen and then the mixture was allowed to warm to −30° C. over one hour. Tributyltin chloride (6.41 g) was then added dropwise at −30° C. and the mixture was allowed to warm to −10° C. and quenched by addition of saturated sodium bicarbonate solution. The layers were separated and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-5% to give tert-butyl 2-tributylstannanylethynylpyrrolidine-1-carboxylate (5.54 g) as a colourless oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[N:54]=[C:55]([C@@H:57]([NH2:59])[CH3:58])[NH:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.C(Cl)Cl.C(O)C>[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@@H:57]([NH:59][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: C[C@H](N)c1nc2ccc(Cl)cc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 76 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (S)-1-(5-chlorobenzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 76%; Rf value: 0.50 (silica gel; methylene chloride/ethanol=9:1); C22H23ClN4O2 (410.91); mass spectrum: (M−H)−=409/411 (chlorine isotope).
Reaction SMILES: [CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH:2]=[CH2:3].[C:20](N(C(C)(C)C(NC(C)(C)C)=O)O)(C)(C)C.C(Cl)C(=C)C>>[CH2:1]([O:4][N:5]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:6]([CH3:15])([CH3:14])[C:7]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C:2](=[CH2:20])[CH3:3]
Reactant: C=CCON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Reactant: CC(C)(C)NC(=O)C(C)(C)N(O)C(C)(C)C
Agent: C=C(C)CCl
Product: C=C(C)CON(C(C)(C)C)C(C)(C)C(=O)NC(C)(C)C
Yield: 84 %

Procedure:
The compound is prepared in analogy to compound (204) from tert-butyl-(dimethyl-tert-butylaminocarbonyl-methyl)-hydroxylamine and methallylchloride in 84% yield as colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([OH:28])[CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([Li])CCC.[O:34]=[C:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:37][CH2:36]1>O1CCCC1>[Si:11]([O:10][CH2:9][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:35]1([OH:34])[CH2:36][CH2:37][N:38]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:39][CH2:40]1)[OH:28])([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)[Si](OCC(O)c1ccccc1Br)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)N1CCC(O)(c2ccccc2C(O)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 25.9 %

Procedure:
To a stirred solution of 1-(2-bromophenyl)-2-{[tert-butyl (diphenyl)silyl]oxy}ethanol (step 2, 5.63 g, 12.4 mmol) in tetrahydrofuran (36 mL) was added dropwise a 1.59 M solution of butyllithium in tetrahydrofuran (15.9 mL, 25.3 mmol) at −78° C. for 5 min and the mixture was stirred for 5 h at the same temperature. To the mixture was added dropwise a solution of ethyl 4-oxopiperidine-1-carboxylate (2.33 g, 13.6 mmol) in tetrahydrofuran (10 mL) at −78° C. and the mixture was stirred for 2 h at the same temperature. This resulting mixture was slowly warmed up to room temperature and stirred for 16 h at the same temperature. The reaction mixture was quenched by the addition of saturated ammonium chloride aqueous solution, and concentrated to give a yellow residue. The crude material was partitioned between ethyl acetate and water, and then the organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by column chromatography on silica gel (150 g) eluting with hexane/ethyl acetate (2/1) to afford 1.76 g (26%) of the title compound as a colorless solid:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN(C)[CH:16]=[O:17].[BH4-].[Na+]>O1CCCC1.C(O)C>[Br:13][C:9]1[N:8]=[C:7]([CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)C=O
Reactant: Brc1cccc(Br)n1
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: OCc1cccc(Br)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.9 %

Procedure:
Add n-butyl lithium (16.2 mL, 2.5 M in hexanes, 40.5 mmol) dropwise to a solution of 2,6-dibromopyridine (8.00 g, 33.8 mmol) in tetrahydrofuran (100 mL) at −78° C. Stir 30 minutes then add dimethylformamide (12.3 g, 169 mmol) via syringe. Allow solution to warm to ambient temperature then pour it into a solution of sodium borohydride (17.85 g, 338 mmol) in ethanol (50 mL) at −10° C. After 10 minutes, remove the cooling bath. After 1 hour at ambient temperature, add water and 1N hydrochloric acid (gas evolution), then add saturated sodium bicarbonate solution until the mixture is neutralized. Extract the aqueous phase with ethyl acetate, dry over sodium sulfate, filter and concentrate under reduced pressure. Dissolve the residue in diethyl ether and add an excess of hydrogen chloride (2N in diethyl ether). Decant the organic phase and add saturated sodium bicarbonate solution to the residue. Extract with ethyl acetate (3×), dry over sodium sulfate, filter and concentrate under reduced pressure to afford the title compound as a brown oil (2.73 g, 14.5 mmol): MS (m/z): 189 (M+1).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:15])=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:16]1([CH2:22][C:23](Cl)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:1]([C:5]1[C:6]([NH:15][C:23](=[O:24])[CH2:22][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[N:7][N:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CC1CCCCC1
Reactant: Cc1cnc2c(C(C)(C)C)c(N)nn2c1
Product: Cc1cnc2c(C(C)(C)C)c(NC(=O)CC3CCCCC3)nn2c1

Procedure:
The product from Example 178A and cyclohexylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.91-1.03 (m, 2H), 1.11-1.30 (m, 3H), 1.43 (s, 9H), 1.59-1.80 (m, 6H), 2.16-2.18 (m, 2H), 2.29 (d, J=1.0 Hz, 1H), 8.38 (d, J=2.0 Hz, 1H), 8.75 (s, 1H), 9.58 (br s, 1H); MS (DCI) m/z 329 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=C(C#N)[CH:5]=[CH:4][C:3]=1[OH:11].[C:12]([OH:15])(=[O:14])[CH3:13]>O.OS(O)(=O)=O>[F:8][C:7]1[C:2]([F:1])=[C:3]([OH:11])[CH:4]=[CH:5][C:13]=1[C:12]([OH:15])=[O:14]
Reactant: N#Cc1ccc(O)c(F)c1F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(O)c(F)c1F
Yield: 71 %

Procedure:
A mixture of 2,3-difluoro-4-cyanophenol (1 g, 6.45 mmol) in water (8 mL), H2SO4 (8 mL), and acetic acid (8 mL) was refluxed for 48 hours. The solvents were removed by rotary evaporation to give a slurry which was poured onto ice. The product precipitated out of solution and filtered. The solid was washed with water and dried to give 2,3-difluoro-4-hydroxybenzoic acid (800 mg, 71%).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4](N)=[C:5]([C:7]([CH2:9][C@H:10]([NH2:14])[C:11]([OH:13])=[O:12])=[O:8])[CH:6]=1.C(=O)C1C=CC=CC=1>>[NH2:14][CH:10]([CH2:9][CH:7]([OH:8])[C:5]1[CH:6]=[CH:1][CH:2]=[CH:3][CH:4]=1)[C:11]([OH:13])=[O:12]
Reactant: Nc1ccccc1C(=O)C[C@H](N)C(=O)O
Solvent: O=Cc1ccccc1
Product: NC(CC(O)c1ccccc1)C(=O)O

Procedure:
The aldol reaction of L-kynurenine and benzaldehyde catalyzed by kynureninase was found to proceed to give predominantly (80%) the (αS, γR) diastereomer of α-amino-γ-hydroxybenzenebutanoic acid.