Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[CH2:11][O:10]C1(C)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.O>[C:1]([NH:8][C@H:12]([C:13]#[CH:14])[CH2:11][OH:10])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: C#C[C@@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: C#C[C@H](CO)NC(=O)OC(C)(C)C

Procedure:
A solution of (R)-N-Boc-2,2-dimethyl-4-ethynyl-oxazolidine (200 mg, 0.89 mmol) (Example 91A above) in a mixture of MeOH (10 mL) and water (1 mL) was treated with p-toluenesulfonic acid monohydrate (16 mg, 0.09 mmol). After stirring at reflux overnight a thermodynamic mixture of starting material and product was obtained (appr. 1:1). The solvent was concentrated and the product was separated from the starting material via silica gel column chromatography with a 0-60-100% EtOAc in hexanes gradient. The recovered starting material was subjected to the above process for two more times yielding (R)-N-Boc-2-amino-but-3-yn-1-ol. (Yield 150 mg, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[CH:28]([NH2:30])=O.C(O)(=O)C>C(Cl)Cl.O>[CH:13]1([NH:12][C:10](=[O:11])[C:9]2[CH:16]=[CH:17][C:18]([CH3:19])=[C:7]([N:6]3[C:2]4=[N:1][CH:28]=[N:30][C:20]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)=[C:3]4[CH:4]=[N:5]3)[CH:8]=2)[CH2:15][CH2:14]1
Reactant: NC=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc2c(-c3ccccc3)ncnc21
Temperature: 160 °C
Yield: 62 %

Procedure:
The mixture of 3-(5-Amino-4-benzoyl-pyrazol-1-yl)-N-cyclopropyl-4-methyl-benzamide (72 mg, 0.20 mmol), formamide (1.0 mL, excess), and acetic acid (0.2 mL) was heated in the microwave at 160° C. for 20 min. After cooling, the mixture was diluted with CH2Cl2 and water, and the CH2Cl2 layer was separated, dried over Na2SO4, filtered and concentrated. The crude product was purified by preparatory HPLC to provide the title compound (46 mg, 62%) as a white solid. HPLC tR=2.3 min; MS m/z 370.3 [M+H]+.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]([F:25])([F:24])[C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[F:15][C:16]([F:24])([F:25])[C:17]1[CH:18]=[C:19]([NH:20][CH:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2cccc(C(F)(F)F)c2)CC1
Reaction time: 1 h
Yield: 99.9 %

Procedure:
A Solution of 1,1-Dimethylethyl 4-Oxo-1-Piperidinecarboxylate (0.5 g, 2.5 mmol), 3-(trifluoromethyl)aniline (0.402 g, 2.5 mmol) and sodium tri(acetoxy)borohydride (0.80 g, 3.75 mmol) in 1,2-DCE (5 ml) was stirred at room temperature, under argon overnight. Saturated aq. NaHCO3 solution (15 ml) was added and stirring continued for 1 h. The reaction mixture was extracted with DCM and the organic phase concentrated in vacuo. Recrystallisation of the solid residue gave the title compound as a white solid (0.86 g). δH (CDCl3, 250 MHz)) 7.25 (1H, t), 6.92 (1H, d), 6.75 (2H, m), 4.06 (2H, m), 3.45 (1H, m), 2.94 (2H, m), 2.04 (2H, m), 1.46 (9H, s), 1.36 (2H, m).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:21]=[CH:20][C:10]2[C:11]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[N:12][O:13][C:9]=2[C:8]=1[Cl:22])C.[OH-].[Na+].Cl>C(O)C>[Cl:22][C:8]1[C:9]2[O:13][N:12]=[C:11]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)[C:10]=2[CH:20]=[CH:21][C:7]=1[O:6][CH2:5][C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)COc1ccc2c(-c3ccc(C)s3)noc2c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2noc3c(Cl)c(OCC(=O)O)ccc23)s1

Procedure:
A mixture of 15.0 g of ethyl{[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazole-6-yl]oxy}acetate of Example 9b and 10 ml of 50% NaOH in 800 ml of ethanol is refluxed for 30 minutes and then 100 ml of 5% HCl is added, making the solution homogeneous. A product begins to crystallize as the solution cools and additional water is added. The product is filtered off and recrystallized form isopropanol giving {[7-chloro-3-(5-methyl-2-thienyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 235°-238° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23](=[O:30])[NH:24][CH2:25][CH:26]([OH:29])[CH2:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([O:18][C:19](=[O:31])[NH:20][CH2:21][CH2:22][C:23](=[O:30])[NH:24][CH2:25][C:26](=[O:29])[CH2:27][CH3:28])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCC(O)CNC(=O)CCNC(=O)OCc1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)CNC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of oxalyl chloride (2 M in DCM) (13.35 ml, 26.5 mmol) in dry DCM at −78° C. is added dropwise DMSO (2.5 ml, 35.4 mmol). After stirring for 15 minutes, the reaction mixture is treated with a solution of [2-(2-hydroxy-butylcarbamoyl)-ethyl]-carbamic acid benzyl ester (step 1) (6.5 g, 22.1 mol) in dry DCM (40 ml). Triethylamine (13 ml) is added after 1 hour and after stirring at −78° C. for 90 minutes, the reaction mixture is allowed to warm to room temperature. The reaction is diluted with DCM (100 ml) and washed with HCl (1M, 200 ml), saturated sodium bicarbonate solution (200 ml), water (200 ml) and brine (200 ml). The organic portion is dried over MgSO4, filtered and concentrated in vacuo to yield the titled compound as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[C:13]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:14]([C@H:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20]([OH:22])=[O:21])=[C:15]([CH3:18])[CH:16]=2)[CH:11]=[CH:10][C:9]1=[O:35])C1C=CC=CC=1.IC>>[C:24]([O:23][C@@H:19]([C:14]1[C:13]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)=[C:12]2[C:17](=[CH:16][C:15]=1[CH3:18])[N:8]([CH3:1])[C:9](=[O:35])[CH:10]=[CH:11]2)[C:20]([OH:22])=[O:21])([CH3:27])([CH3:25])[CH3:26]
Reactant: Cc1cc2c(ccc(=O)n2Cc2ccccc2)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Solvent: CI
Product: Cc1cc2c(ccc(=O)n2C)c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-Butoxy-2-(5-(4-chlorophenyl)-1,7-dimethyl-2-oxo-1,2-dihydroquinolin-6-yl)acetic acid (67) (2.0 mg) was prepared in a similar manner as compound (S)-2-(1-benzyl-5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)-2-tert-butoxyacetic acid of Example 65 except using iodomethane instead of benzyl bromide. 1H-NMR 400 MHz (CD3OD) δ 7.6-7.5 (m, 4 H), 7.3-7.26 (m, 2 H), 6.49 (d, J=10 Hz, 1 H), 5.06 (s, 1 H), 3.78 (s, 3 H), 2.64 (s, 3 H), 0.97 (s, 9 H); LCMS-ESI+ (m/z): [M+H]+ calcd for C23H25ClNO4: 414.1. Found: 414.2; LCMS-ESI− (m/z): [M−H]− calcd for C23H23ClNO4: 412.1. Found: 412.0.
Reaction SMILES: C([Li])CCC.[S:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.CN(C)[CH:17]=[O:18].Cl>CCCCCC.C(OCC)C>[S:6]1[C:7]([CH:17]=[O:18])=[CH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]1=2
Reactant: c1ccc2sccc2c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: O=Cc1cc2ccccc2s1
Temperature: -20 °C
Reaction time: 2 h

Procedure:
To a solution of 31.25 ml of a 1.6M solution of n-butyl lithium in hexane and 100 ml of dry diethyl ether at -20° C. was added a solution of 6.7 g of 1-benzothiophene in 100 ml of dry diethyl ether. The mixture was stirred at -20° C. for 2 hours. A solution of 3.8 ml of dimethylformamide and 10 ml of dry diethyl ether was added and the reaction was allowed to warm to 0° C. The reaction was stirred an additional 1 hour at 0° C., at which time 75 ml of 1N hydrochloric acid were added. After stirring for 15 minutes, the layers were separated and the aqueous layer was extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and evaporated to dryness. The resulting oil was stored at about 0° C. for 3 days, at which time a solid formed. The solid weighed 8.5 g and was identified as the desired subtitled intermediate based upon the mass spectral and proton NMR data.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][NH:9][CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1.[CH3:24][N:25]=[C:26]=[O:27]>>[Cl:1][C:2]1[C:3]([Cl:23])=[CH:4][C:5]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)=[N:10][N:9]([C:26](=[O:27])[NH:25][CH3:24])[CH:8]([CH3:21])[CH2:7][C:6]=2[CH:22]=1
Reactant: CC1Cc2cc(Cl)c(Cl)cc2C(c2ccc([N+](=O)[O-])cc2)=NN1
Reactant: CN=C=O
Product: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc(Cl)c(Cl)cc2CC1C
Yield: 97 %

Procedure:
0.33 g (0.94 mmoles) of 7,8-dichloro-4-methyl-1-(4-nitrophenyl)-4,5-dihydro-3H-2,3-benzodiazepine obtained in Example 9, Step C are reacted with methyl isocyanate according to Example 3. The crude product is purified by suspending it in hot ethanol. Thus, 0.37 g (97%) of the title compound are obtained. M.p.: 221°-223° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1.C(N(CC)CC)C.CN(C1C=CC=CN=1)C.C1(C)C=CC(S([Cl:42])(=O)=O)=CC=1>ClCCl.O1CCCC1>[Cl:42][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:5]([N+:14]([O-:16])=[O:15])[CH:4]=1
Reactant: CC(=O)NCc1ccc(CO)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCc1ccc(CCl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 157.4 %

Procedure:
To a solution of N-(4-hydroxymethyl-2-nitrophenylmethyl)acetamide (9.1 g), triethylamine (6.2 ml) and dimethylaminopyridine (0.99 g) in dichloromethane (150 ml)-tetrahydrofuran (50 ml) was added p-toluenesulfonyl chloride (8.5 g) under ice-cooling. This mixture was stirred at room temperature for 3 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow oil (15.5 g). The obtained yellow oil was purified by silica gel column chromatography (developing solvent; chloroform:methanol=20:1) to give the title compound (12 g) as a pale-brown solid (7.8 g).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:4]=[C:5]([C:8]([OH:10])=O)[S:6][CH:7]=1.[NH2:13][C:14]1[C:19]([Cl:20])=[C:18]([O:21][CH3:22])[CH:17]=[CH:16][C:15]=1[C:23](=[O:25])[CH3:24].C(C1C=CC(OC)=CC=1NC(C1SC=C(C(C)C)N=1)=O)(=O)C>>[C:23]([C:15]1[C:14]([NH:13][C:8]([C:5]2[S:6][CH:7]=[C:3]([C:2]([F:1])([F:12])[F:11])[N:4]=2)=[O:10])=[C:19]([Cl:20])[C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:25])[CH3:24]
Reactant: O=C(O)c1nc(C(F)(F)F)cs1
Reactant: COc1ccc(C(C)=O)c(N)c1Cl
Agent: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(C)C)cs2)c1
Product: COc1ccc(C(C)=O)c(NC(=O)c2nc(C(F)(F)F)cs2)c1Cl
Yield: 65 %

Procedure:
Compound 64d was synthesized from 4-(trifluoromethyl)-1,3-thiazole-2-carboxylic acid and 1-(2-amino-3-chloro-4-methoxyphenyl)-ethanone as a beige solid in 65% yield, following the procedure as described for compound 42a.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]3[C:19]([C:22]([O-])=[O:23])=[CH:20][N:21]=[C:15]3[CH:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[Li+].ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[CH:38]1([C:41]2[C:49]3[C:48]([NH2:50])=[CH:47][CH:46]=[CH:45][C:44]=3[N:43]([CH2:51][C:52]3[CH:56]=[CH:55][N:54]([CH:57]([CH3:59])[CH3:58])[N:53]=3)[N:42]=2)[CH2:40][CH2:39]1.[OH-].[Na+]>CN1C(=O)CCC1>[CH:38]1([C:41]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][C:48]=3[NH:50][C:22]([C:19]3[N:16]4[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)=[CH:14][C:15]4=[N:21][CH:20]=3)=[O:23])[N:43]([CH2:51][C:52]3[CH:56]=[CH:55][N:54]([CH:57]([CH3:59])[CH3:58])[N:53]=3)[N:42]=2)[CH2:39][CH2:40]1
Reactant: CC(C)N1CCN(CCOc2ccn3c(C(=O)[O-])cnc3c2)CC1
Reactant: CC(C)n1ccc(Cn2nc(C3CC3)c3c(N)cccc32)n1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [Li+]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)N1CCN(CCOc2ccn3c(C(=O)Nc4cccc5c4c(C4CC4)nn5Cc4ccn(C(C)C)n4)cnc3c2)CC1
Temperature: 88 °C
Reaction time: 1 h
Yield: 61.1 %

Procedure:
To a solution of lithium 7-(2-(4-isopropylpiperazin-1-yl)ethoxy)imidazo[1,2-a]pyridine-3-carboxylate (123 mg, 0.364 mmol; prepared according to Example 62, Step B) in NMP (10 mL) at 0° C. was added 2,4,6-trichlorobenzoyl chloride (57.9 μL, 0.363 mmol). The cold bath was removed once the addition was complete. The mixture was stirred for one hour. 3-Cyclopropyl-1-((1-isopropyl-1H-pyrazol-3-yl)methyl)-1H-indazol-4-amine (80 mg, 0.271 mmol; prepared according to Example 63, step E) was added and the reaction mixture was heated at 88° C. for 11 hours. The reaction mixture was cooled to ambient temperature, and NMP was removed under reduced pressure to give an oily residue. To this was added 10% NaOH aqueous solution (10 mL) and the resulting clear solution was stirred at 80° C. for 30 minutes. The solution was cooled to ambient temperature and extracted with DCM. The combined organic extracts were dried (Na2SO4) and concentrated under reduced pressure to give a residue, which was triturated with Et2O (50 mL). The resulting solids were isolated by filtration, washed with ether and dried under vacuum to give the product (101 mg). MS (ES+APCI) m/z=610 (M+H).
Reaction SMILES: C[N:2](/[CH:4]=[N:5]/[C:6]([C:8]1[S:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=1)=O)C.O.[NH2:17]N>CC(O)=O>[N+:13]([C:10]1[S:9][C:8]([C:6]2[N:5]=[CH:4][NH:2][N:17]=2)=[CH:12][CH:11]=1)([O-:15])=[O:14]
Reactant: NN
Reactant: CN(C)/C=N/C(=O)c1ccc([N+](=O)[O-])s1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2nc[nH]n2)s1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
N-[(1E)-(Dimethylamino)methylene]-5-nitrothiophene-2-carboxamide (7.00 g, 30.8 mmol) was combined with AcOH (70 mL) and hydrazine hydrate (65% wt, 2.76 mL, 37.0 mmol) and stirred at 90° C. for 1.5 h. The yellow solution was cooled to room temperature and concentrated. The resulting slurry was diluted with CH2Cl2 and saturated NaHCO3 and stirred. The yellow precipitate was isolated by filtration and dried to provide the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=O)=[CH:4][CH:3]=1.COCCO[AlH2-]OCCOC.[Na+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:8]2[CH2:13][CH:12]3[C:10]([C:14]4[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=4)([CH2:11]3)[CH2:9]2)=[CH:21][CH:22]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC2CC2(c2ccc(Cl)cc2)C1
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: c1ccccc1
Product: Clc1ccc(CN2CC3CC3(c3ccc(Cl)cc3)C2)cc1

Procedure:
A 16.60 g. portion of 3-(p-chlorobenzoyl)-1-(p-chlorophenyl)-3-azabicyclo[3.1.0]hexane is dissolved in 160 ml. of benzene and 55.5 g. of Vitride® is added dropwise. The mixture is refluxed for 2 hours, cooled and quenched slowly with 10 N sodium hydroxide. Water is added, the organic layer is separated and washed 3 times with water and then dried over magnesium sulfate. Removal of the solvent yields an off-white solid, m.p. 88°-92° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]1(=O)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1>C(O)C.[C].[Pd]>[OH:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: O=C1CCC(=O)CC1
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Yield: 57.8 %

Procedure:
1.97 g of dibenzylamine, 1.68 g of 1,4-cyclohexanedione and 40 mg of 10% palladium-carbon were heated with stirring in 40 ml of ethanol at 50° C. to 60° C. and reacted for 8 hours under air bubbling. During the reaction, ethanol was added as needed. After the completion of the reaction, the catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The resultant was purified by silica gel column chromatography (n-hexane:ethyl acetate=30:1) and further separated by silica gel column chromatography (n-hexane:ethyl acetate=10:1), and 1.67 g of N-(4-hydroxyphenyl)dibenzylamine was obtained (yield 57%).
Reaction SMILES: C(C1(COC2C(C3CC3)=CC(C(OC(C)(C)C)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]3([F:57])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([O:42]C(C)(C)C)=[O:41])[CH2:34][CH2:33]1>>[CH:32]1([C:35]2[C:36]([O:49][CH2:50][C:51]3([F:57])[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]3)=[CH:37][C:38]([F:48])=[C:39]([CH:47]=2)[C:40]([OH:42])=[O:41])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F
Agent: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C#N)C3CC4CC(C3)CC2C4)cc1F
Product: O=C(O)c1cc(C2CC2)c(OCC2(F)CCCCC2)cc1F

Procedure:
Following the procedure as described in Example 332 Step 6 and making non-critical variations to replace tert-butyl 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoate with tert-butyl 5-cyclopropyl-2-fluoro-4-((1-fluorocyclohexyl)-methoxy)benzoate, the title compound was obtained as a colorless solid (0.48 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.52 (d, J=8.4 Hz, 1H), 6.57 (d, J=12.5 Hz, 1H), 3.98 (d, J=17.9 Hz, 2H), 2.10-1.89 (m, 2H), 1.76-1.51 (m, 6H), 1.39-1.21 (m, 1H), 0.95-0.86 (m, 2H), 0.69-0.59 (m, 2H).
Reaction SMILES: [NH:1]([C:32]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:33])[C@H:2]([C:7]([NH:9][C@@H:10]([C:22]([O:24]CC1C=CC=CC=1)=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].C(O)(=O)C.CN(C=O)C.[H][H]>CO.[Pd]>[NH:1]([C:32]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:33])[C@H:2]([C:7]([NH:9][C@@H:10]([C:22]([OH:24])=[O:23])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH3:21])[CH:13]=1)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)Cc1ccccc1)C(=O)N[C@H](Cc1cn(C)c2ccccc12)C(=O)O
Yield: 95.4 %

Procedure:
To a solution of N-phenylacetyl-L-Leu-D-Trp(CH3)-OBzl (5.9 g) in a mixture of methanol (60 ml), acetic acid (60 ml) and DMF (100 ml) was added 10% palladium on activated carbon (0.6 g). The mixture was stirred for 5 hours at 3 atmospheric pressure of hydrogen at room temperature. The solution was filtered and the filtrate was concentrated in vacuo. The residue was triturated with ether-ethyl acetate to give N-phenylacetyl-L-Leu-D-Trp(CH3)-OH (4.69 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[C:7](=O)[C:6]=2[CH:19]=1.C>O1CCOCC1.C(O)C.S(=O)(=O)(O)O.C(Cl)Cl.[Pd]>[OH:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[CH2:7][C:6]=2[CH:19]=1
Reactant: Cc1cccc(-c2coc3cc(O)c(O)cc3c2=O)c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1cccc(C2COc3cc(O)c(O)cc3C2)c1

Procedure:
6,7-Dihydroxy-3-(3-methylphenyl)-4H-1-benzopyran-4-one (1.2 g), dissolved in a mixture of dioxan/ethanol 4:6 (40 ml), is hydrogenated for 24 h at room temperature over palladium 5% on active charcoal (0.48 g) in the presence of a few drops of concentrated sulphuric acid. After filtration of the catalyst, the filtrate is evaporated to dryness under vacuum. An oil is obtained which is dissolved in methylene chloride. The solution is washed with water and dried over magnesium sulphate to give an oil which on crystallization yields 3,4-dihydro-6,7-dihydroxy-3-(3-methylphenyl)-2H-1-benzopyran, m.p. 146°-148°.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]([C:14]1[N:19]=[C:18]([C:20](=O)[CH3:21])[CH:17]=[CH:16][CH:15]=1)[CH3:13])([CH3:3])[CH3:2].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:20](=[N:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:23]([CH3:25])[CH3:24])[CH3:21])[N:19]=1)[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1
Reactant: CC(C)c1ccccc1N
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1

Procedure:
4.0 g (0.0135 mol) of 1-{6-[1-(2-isopropyl-6-methyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 15, 2.76 g (0.0204 mol) of 2-Isopropyl-phenylamine 9 (4.0 g, 0.0135 mol), 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under a flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 10 ml of ethanol. The yield of (2-Isopropyl-6-methyl-phenyl)-(1-{6-[1-(2-isopropyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-amine 16 was 4.83 g (87%) as a yellow solid. 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)): δ 166.9 (C═N), 166.2 (C═N).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11]
Reactant: Cc1cc(C(C)O)ccc1Br
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)c1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.6 %

Procedure:
1-(4-bromo-3-methylphenyl)ethanol (2.14 g, 9.9 mmol) and pyridinium chlorochromate (2.62 g, 12 mmol) were added to a solution of dichloromethane (30 mL) under nitrogen atmosphere. And the reaction was stirred at room temperature for 12 hours. The mixture was partitioned between dichloromethane (3*20 mL) and brine (20 mL). The organic layer was concentrated to dryness and the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=30:1) to give 1-(4-bromo-3-methylphenyl)ethanone (2.08 g, 99%) as a colorless oil. LRMS (M+H+) m/z: calcd 211.98. found 211. 1H NMR (300 MHz, CDCl3): δ 7.81 (s, 1H), 7.62-7.61 (m, 2H), 2.58 (s, 3H), 2.46 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].[CH2:16]([C@@H:23]1[CH2:29][C@@H:28]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:27](=[O:37])[O:26][C:24]1=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C@H:4]([CH2:6][S:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:27](=[O:37])[C@H:28]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[CH2:29][C@@H:23]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[C:24]([OH:26])=[O:25]
Reactant: COC(=O)[C@@H](N)CSCc1ccccc1
Reactant: O=C1OC(=O)[C@H](Cc2ccccc2)C[C@H]1Cc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CSCc1ccccc1)NC(=O)[C@H](Cc1ccccc1)C[C@@H](Cc1ccccc1)C(=O)O

Procedure:
A solution of 4.5 g of S-benzyl-(L)-cysteine methyl ester and 2.8 g of (S,S)-2,4-dibenzylglutaric anhydride in 25 ml of pyridine and 25 ml of methylene chloride is stirred at room temperature overnight. The mixture is concentrated, the residue is dissolved in ether and the solution is washed with lN hydrochloric acid, saturated sodium chloride, dried over magnesium sulfate, concentrated, to yield N-[(S,S)-2,4-dibenzyl-4-carboxybutyryl]-S-benzyl-(L)-cysteine methyl ester (oil).