Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])(=[O:5])[CH3:4]>CO>[CH3:16][C:12]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]2[CH:7]=[C:6]([C:3](=[O:5])[CH:4]=[CH:3][C:6]3[CH:7]=[CH:8][C:13]([CH3:12])=[CH:14][CH:15]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C=CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 8 h

Procedure:
10 g of 50% strength sodium hydroxide solution were added dropwise to a solution of 50 (0.22 mole) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and 26.1 g (0.22 mole) of 4-tolylaldehyde in 250 ml of methanol. The mixture was stirred overnight, after which it was poured onto ice/water and left to stand for several hours. The precipitated crystals were filtered off under suction and dried to give 70 g of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-3-(4-tolyl)-prop-2-en-1-one of melting point 153°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]=O.[NH2:11][C:12]1[CH:16]=[CH:15][NH:14][N:13]=1.O=[C:18]([CH2:25][CH2:26][CH3:27])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH:4]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:18]([CH2:25][CH2:26][CH3:27])[NH:11][C:12]2=[N:13][NH:14][CH:15]=[C:16]12
Reactant: CCCC(=O)CC(=O)OCC
Reactant: O=Cc1c(F)cccc1Cl
Reactant: Nc1cc[nH]n1
Product: CCCC1=C(C(=O)OCC)C(c2c(F)cccc2Cl)c2c[nH]nc2N1

Procedure:
The title compound was prepared from 2-chloro-6-fluorobenzaldehyde, 3-aminopyrazole and ethyl 3-ketohexanoate in the same manner as in Example 25.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:16][N:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:18](Cl)=[O:19]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:18](=[O:19])[N:17]([CH3:16])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Product: CN(C(=O)Oc1ccc(OCc2ccccc2)cc1)c1ccccc1

Procedure:
The title compound was prepared from 4-benzyloxy-phenol and N-methyl-N-phenylcarbamoyl chloride. The crude product was recrystallized (ethanol/water) (83%, white crystals). HPLC-MS m/z=334.2 (M+1), Rt: 4.88 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([OH:19])=O)[C:10](=[O:23])[CH:9]=2)[CH:7]=1.[NH2:26][C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]([CH3:37])[CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:24]#[N:25])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH:20]([CH3:22])[CH3:21])[C:17]([NH:26][C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[C:29]([CH3:37])[CH:28]=3)=[O:19])[C:10](=[O:23])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(C(=O)O)C(C)C)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: COC(=O)c1ccc(N)cc1C
Product: COC(=O)c1ccc(NC(=O)C(C(C)C)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1C

Procedure:
120 mg (333 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-methylbutanoic acid (racemate) and 60.4 mg (366 μmol, 1.1 eq.) of methyl 4-amino-2-methylbenzoate were reacted according to General Method 5A. The crude product was purified by flash chromatography (silica gel 50, cyclohexane/ethyl acetate mixtures). Yield: 155 mg (88% of theory)
Reaction SMILES: [CH2:1]1[O:29][C:4]2=[CH:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=4)=[N:11][N:10]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[C:9](=[O:27])[CH2:8][C:7]=3[CH:28]=[C:3]2[O:2]1.O.NN>C(O)C.Cl.[Ni]>[NH2:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[C:6]3[CH:5]=[C:4]4[O:29][CH2:1][O:2][C:3]4=[CH:28][C:7]=3[CH2:8][C:9](=[O:27])[N:10]([CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[N:11]=2)=[CH:14][CH:15]=1
Reactant: CCC(CC)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1=O)OCO3
Agent: [Ni]
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CCC(CC)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1=O)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.4 %

Procedure:
To a solution of 7,8-methylenedioxy-1-(4-nitrophenyl)-3-(3-pentyl)-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (48 mg, 0.123 mmol) in ethanol (10 mL) was added hydrazine hydrate (0.5 mL), 3 drops of conc. HCl, and excess amount of Raney Ni and the mixture obtained was stirred at room temperature for 1.5 h. Then the Raney Ni was removed by decanting. The crude product obtained by removal of the solvent was purified by flash chromatography (1:1 of hex:EtOAc) to give the product (42 mg, 94%), 1H NMR (CDCl3) 7.46 (d, J=8.3, 2H), 6.69 (d, J=8.3, 2H), 6.85 (s, 1H), 6.70 (s, 1H), 6.04, (bs, 1H), 6.01 (bs, 1H), 4.49 (heptet, J=4.9, 1H), 3.92 (bs, 2H), 3.50 (d, J=16.3, 1H), 3.29 (d, J=16.3, 1H), 2.10 (m, 1H), 1.72 (m, 1H), 1.48 (m, 21H), 0.98 (t, J=7.2, 3H), 0.48 (t, J=7.2, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4](F)[CH:3]=1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])=[C:4]([NH:23][CH2:19][CH2:20][CH2:21][CH3:22])[CH:3]=1
Reactant: CCCCN
Reactant: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCCCNc1cc(Br)ccc1C(=O)OCc1ccccc1
Temperature: 75 °C
Yield: 14.1 %

Procedure:
Phenylmethyl 4-bromo-2-fluorobenzoate (Example 192, 315 mg, 1.02 mmol) was combined with n-butylamine (110 μl, 1.12 mmol, 1.1 eq.) and solid cesium carbonate (1.66 g, 5.1 mmol, 5.0 eq.) in anhydrous methyl sulfoxide (4 mL) and heated at 75° C. for 1.5 hours. The reaction was cooled and partitioned between diethyl ether and water. The aqueous layer was separated and extracted with fresh ether. The organic layers were combined, washed with brine (4×), dried (MgSO4), and concentrated in vacuo to a crude oil. The crude was purified by flash chromatography on silica gel eluted with 95:5 hexanes/ether to provide the title compound as a yellow oil (52 mg, 14%): 1H NMR (300 MHz, CDCl3) δ7.76 (d, 1 H), 7.71 (broad s, 1 H), 7.41-7.32 (m, 5 H), 6.80 (s, 1 H), 6.63 (d, 1 H), 5.26 (s, 2 H), 3.16-3.10 (m, 2 H), 1.69-1.60 (m, 2 H), 150-1.38 (m, 2 H), 0.95 (t, 3 H); MS m/z 362.0 and 364.0 (MH+ and MH+2).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26](SC)[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].C1COCC1>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([C:21]3[C:32](=[O:33])[N:31]([CH3:34])[C:24]4[N:25]=[C:26]([NH:37][CH3:36])[N:27]=[CH:28][C:23]=4[CH:22]=3)[CH:15]=2)=[O:12])[N:7]([CH3:35])[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4C)ccc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)nn4C)ccc3C)c(=O)n(C)c2n1
Yield: 28 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (217 mg, 0.441 mmol) and 2.0N methylamine in THF (2.2 mL, 4.41 mmol) were combined and purified by reverse phase chromatography (Biotage C18-25 column, 10-100% acetonitrile/water) and neutralized with 10% sodium carbonate to give 1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(4-methyl-3-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (60 mg, 28% yield). 1H NMR (300 MHz, DMSO-d6): δ 1.15 (s, 9H), 2.06 (s, 3H), 2.90 (s, 3H), 3.53-3.63 (m, 6H), 6.02 (s, 1H), 7.12-7.14 (m, 1H), 7.23-7.26 (m, 1H), 7.34 (s, 1H), 7.66-7.80 (m, 2H), 8.42 (s, 1H), 8.58-8.68 (m, 1H), 8.79 (s, 1H); MS (ESI) m/z: 475.2 (M+H+).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[C@@H:21]4[C@@H:16]([C:17]5[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][C:18]=5[CH2:19][CH2:20]4)[CH2:15][CH2:14][CH2:13]3)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:29][NH:30][CH3:31]>>[CH3:29][N:30]([CH3:31])[C:26]([C:23]1[CH:24]=[CH:25][C:17]2[C@@H:16]3[C@H:21]([CH2:20][CH2:19][C:18]=2[CH:22]=1)[N:12]([C:10]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][CH:2]=[N:3][C:4]=2[CH:9]=1)=[O:11])[CH2:13][CH2:14][CH2:15]3)=[O:28]
Reactant: CNC
Reactant: O=C(O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Product: CN(C)C(=O)c1ccc2c(c1)CC[C@H]1[C@@H]2CCCN1C(=O)c1ccc2[nH]cnc2c1
Yield: 20 %

Procedure:
The title compound is prepared from cis-4-(1H-benzoimidazole-5-carbonyl)-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline-8-carboxylic acid and dimethylamine (2 mol/L in tetrahydrofuran) following a procedure analogous to that described in Example 1. Yield: 20% of theory; LC (method 1): tR=2.08 min; Mass spectrum (ESI+): m/z=403 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:11][CH2:10]3)[C:8](=O)[NH:7][C:6]=2[CH:14]=1>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:12][C:9]3([CH2:10][CH2:11]3)[CH2:8][NH:7][C:6]=2[CH:14]=1
Reactant: O=C1Nc2cc(Br)ccc2OC12CC2
Solvent: C1CCOC1
Product: Brc1ccc2c(c1)NCC1(CC1)O2
Temperature: 25 °C
Yield: 93.9 %

Procedure:
To a stirred solution of 6-bromospiro[4H-1,4-benzoxazine-2,1′-cyclopropane]-3-one (2.6 g, 10.2 mmol) in THF (20 mL) was added 1 M solution of borane-tetrahydrofuran complex in THF (51.0 mL, 51.2 mmol). After refluxing for 6 h, the reaction mixture was cooled to room temperature and quenched by the addition of methanol. Volatiles were evaporated under reduced pressure, and the resulting residue was taken up in ethyl acetate and washed with saturated aq. sodium bicarbonate solution, water, and brine. The organic layer was dried over sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography to furnish 6-bromospiro[3,4-dihydro-1,4-benzoxazine-2,1′-cyclopropane] (2.3 g).
Reaction SMILES: [CH2:1]([N:5]1[C:9](=[O:10])[C:8]2[CH:11]=[CH:12][C:13]3[C:18]([C:7]=2[S:6]1(=[O:20])=[O:19])=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:2]([CH3:4])=[O:3].[Na].Cl>C(O)C>[C:2]([C:1]1[NH:5][S:6](=[O:20])(=[O:19])[C:7]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:8]=2[C:9]=1[OH:10])(=[O:3])[CH3:4]
Reactant: CC(=O)CN1C(=O)c2ccc3ccccc3c2S1(=O)=O
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reaction time: 2 h
Yield: 5.4 %

Procedure:
28.9 gm (1.0 mol) of 2-acetonyl-3-oxo-naphth[2,1-d]isothiazoline-1,1-dioxide were added to a solution of 4.7 gm (2.04 gm-atom) of sodium in 125 ml of ethanol at 30° C. The resulting mixture was kept at 55° C for 2 hours, while stirring, and was subsequently refluxed for 15 minutes. After cooling, the reaction mixture was acidified with 350 ml of aqueous 9% hydrochloric acid, and the solid product formed thereby was suction-filtered off and washed with ice-cold 50% ethanol. Recrystallization from ethanol yielded 15.6 gm (54% of theory) of 3-acetyl-4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-1,1-dioxide, m.p. 191°-192° C.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([O:15][CH3:16])[C:13]([C:17]#[N:18])=[C:12]([C:19]#[N:20])[CH:11]=2)=[CH:6][CH:5]=1.C([O-])(=O)C.[Na+]>C(O)(=O)C.O>[Br:1][C:11]1[C:12]([C:19]#[N:20])=[C:13]([C:17]#[N:18])[N:14]([O:15][CH3:16])[C:10]=1[C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1
Reactant: COn1c(-c2ccc(Cl)cc2)cc(C#N)c1C#N
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COn1c(C#N)c(C#N)c(Br)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
Bromine (0.341 g, 0.00213 mol) is added to a stirred mixture of 5-(p-chlorophenyl)-1-methoxypyrrole-2,3-dicarbonitrile (0.5 g, 0.00193 mol) and sodium acetate (0.318 g, 0.00388 mol) in acetic acid. The reaction mixture is heated at 95°-100° C. overnight, cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined ethyl acetate extracts are washed sequentially with water, saturated sodium bicarbonate solution, aqueous sodium metabisulfite solution, water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to yield a solid that is crystallized from ethyl acetate/hexanes to give the title compound as a yellow solid (0.406 g, 62%), mp 166.5°-167° C.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]([C:13](=[O:22])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:10](=[O:12])[CH3:11])[C:3](OCC)=[O:4].C([SiH](CC)CC)C>FC(F)(F)C(O)=O.C(OCC)C>[O:4]=[C:3]1[CH:2]([CH3:1])[CH:8]([NH:23][C:24](=[O:26])[CH3:25])[CH:9]([C:13](=[O:22])[NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH:10]([CH3:11])[O:12]1
Reactant: CCOC(=O)C(C)C(NC(C)=O)C(C(C)=O)C(=O)Nc1ccc(Cl)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(=O)NC1C(C)C(=O)OC(C)C1C(=O)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 64 %

Procedure:
Ethyl 2-methyl-3-acetylamino-4-(4'-chlorophenylcarbamoyl)-5-oxohexanoate (Example 25) (12 g) was dissolved in trifluoroacetic acid (50 ml), treated with triethylsilane (7.5 ml) and stirred at room temperature for 40 hours. The reaction mixture was diluted with diethyl ether and filtered. The solid was warmed with ethyl acetate then cooled and filtered to give 2-oxo-3,6-dimethyl-4-acetylamino-5-(4'-chlorophenylcarbamoyl)-3,4,5,6-tetrahydro-2H-pyran (ttt isomer) (6.8 g) m.p. 280° C. decomp.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=NC(I)=C[N:3]=1.[F:9][C:10]1[CH:11]=[C:12]([C:16]#[CH:17])[CH:13]=[CH:14][CH:15]=1.[CH2:18]([N:20](CC)CC)[CH3:19]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[Cl:1][C:2]1[N:3]=[N:20][C:18]([C:17]#[C:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([F:9])[CH:11]=2)=[CH:19][CH:7]=1
Reactant: CCN(CC)CC
Reactant: Clc1cnc(I)cn1
Reactant: C#Cc1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1cccc(C#Cc2ccc(Cl)nn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.4 %

Procedure:
To a well stirred solution of 2-chloro-5-iodopyrazine (600 mg, 2.5 mmol), 3-fluorophenyl-acetylene (315 mg, 303 μl, 2.62 mmol, 1.05 equiv.) in 7 ml of THF were added under argon atmosphere bis(triphenylphosphine)-palladium(II)dichloride (175 mg, 0.250 mmol, 0.02 equiv.), copper(I) iodide (23.8 mg, 0.125 mmol, 0.01 equiv.) and triethylamine (556 mg, 761 ul, 5.49 mmol, 2.2 equiv.). The mixture was stirred for 2 hours at room temperature. The crude mixture was filtered, adsorbed on silicagel and purified by flash chromatography over a 50 g silicagel column using a heptane to 25% ethyl acetate in heptane gradient. The title compound (450 mg, 78% yield) was obtained as a crystalline light-yellow solid, MS: m/e=233.1, 235.0 (M+H+).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([CH3:43])([NH:29][C:30]([O:32][CH:33]2[CH:40]3[CH2:41][CH:36]4[CH2:37][CH:38]([CH2:42][CH:34]2[CH2:35]4)[CH2:39]3)=[O:31])[C:12]([NH:14][CH2:15][CH:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:17]=[CH:18][C:19]([O:21][CH3:22])=[O:20])=[O:13])=[CH:2]1>[Pd].C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([CH3:43])([NH:29][C:30]([O:32][CH:33]2[CH:40]3[CH2:39][CH:38]4[CH2:37][CH:36]([CH2:35][CH:34]2[CH2:42]4)[CH2:41]3)=[O:31])[C:12]([NH:14][CH2:15][CH:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[O:13])=[CH:2]1
Reactant: COC(=O)C=CC(CNC(=O)C(C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCC(CNC(=O)C(C)(Cc1c[nH]c2ccccc12)NC(=O)OC1C2CC3CC(C2)CC1C3)c1ccccc1
Yield: 95 %

Procedure:
The ester from Step 3 (0.228 g, 0.39 mmol) wa hydrogenated over 10% palladium on charcoal in absolute ethanol (50 mL) under an atmosphere of hydrogen at 45 psi and 30° C. for 7 hours. The catalyst was filtered and the solvent removed in vacuo, giving the product (0.217 g, 95%) as a white solid, mp 69°-76° C.; IR (film) 1714 and 1660 cm-1 ; NMR (CDCl3) 1.48-1.93 (19H, m), 2.11.varies.2.17 (2H, m), 2.50-2.68 (1H, m), 3.14-3.65 (7H, m), 4.74 (1H, s), 5.11 (1H, bs), 6.00-6.13 (1H, m), 6.90-6.99 (3H, m), 7.08-7.22 (5H, m), 7.35 (1H, d, J 8.0 Hz), 7.54-7.58 (1H, m), 8.28 (1H, bs); Anal. (C35H43N3O5.0.5H2O) C, H. N.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH2:21][C:22]#[CH:23])[CH2:16][CH2:15]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([N:20]([C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:21][C:22]#[CH:23])[CH2:18][CH2:19]2)=[C:10]([CH2:24][NH:25][CH3:26])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCN[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: C#CCN(C(=O)c1ccc(Cl)cc1)[C@H]1CC[C@H](c2ccc(C(=O)OC(C)(C)C)cc2CNC)CC1

Procedure:
from trans-4-(4-tert.butoxycarbonyl-methylaminomethylphenyl)-N-propargylcyclohexylamine and 4-chlorobenzoylchloride. Colourless oil. Rf value: 0.46 (silica gel, petroleum ether/ethyl acetate=2:1, v:v).
Reaction SMILES: C([O:3][C:4]([C@H:6]1[C@H:8]([C:9](=[O:31])[NH:10][CH:11]([CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)[C:12]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[O:7]1)=[O:5])C.[Li+].[OH-]>C1COCC1.CO.O>[F:24][C:22]1[CH:21]=[CH:20][C:18]2[N:19]=[C:15]([NH:14][C:12](=[O:13])[C@@H:11]([NH:10][C:9]([C@@H:8]3[O:7][C@H:6]3[C:4]([OH:5])=[O:3])=[O:31])[CH2:25][C:26]3[N:27]=[CH:28][NH:29][CH:30]=3)[S:16][C:17]=2[CH:23]=1
Reactant: CCOC(=O)[C@@H]1O[C@H]1C(=O)NC(Cc1c[nH]cn1)C(=O)Nc1nc2ccc(F)cc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(Nc1nc2ccc(F)cc2s1)[C@H](Cc1c[nH]cn1)NC(=O)[C@@H]1O[C@H]1C(=O)O
Yield: 42.2 %

Procedure:
Synthesized following general saponification procedure using the following quantities: the corresponding peptidomimetic epoxide ethyl ester 18f (125 mg, 0.26 mmol); LiOH (6.2 mg, 0.26 mmol); THF/MeOH/H2O (1.5 mL: 1.0 mL: 0.5 mL); yielded 31b as a white solid (46 mg, 39.1%). 1H NMR (400 MHz, MeOD-d4): δ 11.88 (bs, 1H), 8.89-8.83 (dd, 1H, J=7.4 Hz, J=7.4 Hz); 7.91-7.89 (d, 1H, J=2.5 Hz); 7.78-7.72 (q, 1H); 7.56 (s, 1H); 7.30 (td, 1H, J=2.6 Hz); 6.85 (s, 1H); 4.81-4.76 (m, 1H): 3.76-3.74 (dd, 1H, J=1.68 Hz); 3.45-3.43 (dd, 1H, J=1.65 Hz); 3.11-3.00 (m, 2H). 13C NMR (DMSO-d6, 100 MHz): 171.13, 167.48, 165.83, 160.32, 158.21, 145.64, 135.40, 133.23, 122.17, 114.83, 108.74, 53.86, 53.40, 51.86. ESI-HRMS (m/z): [M+H+] calcd. for C17H14FN5O5S: 420.0773, observed: 420.0769.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)(O)[O-].[Na+].CN(C)C=O>O>[CH2:18]([N:9]1[CH2:8][CH2:7][CH:6]([C:4](=[O:5])[C:3]2[CH:12]=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:2]=2[OH:1])[CH2:11][CH2:10]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc(C(=O)C2CCNCC2)c(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)C2CCN(Cc3ccccc3)CC2)c(O)c1
Reaction time: 15 h
Yield: 57.4 %

Procedure:
A mixture of 14.50 g of 4-(2-hydroxy-4-methoxybenzoyl)piperidine, 6.40 ml of benzyl bromide, 10.20 g of sodium bicarbonate and 74.0 ml of dimethylformamide was stirred at 60° for 15 hrs. The reaction mixture was poured into 250 ml of water and a precipitate formed. The precipitate was collected, washed with water and recrystallized from ethanol to yield 10.0 g (57.4%) of product, mp, 123°-125°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[Cl:12][Si](C)(C)[CH3:14]>CO>[ClH:12].[NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:14])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: Nc1cccc(CC(=O)O)c1
Solvent: CO
Product: COC(=O)Cc1cccc(N)c1
Product: Cl
Temperature: 20 °C
Reaction time: 1 h

Procedure:
3-Aminophenylacetic acid (1 wt) was suspended in methanol (5 vol) under nitrogen at 20° C. Chlorotrimethylsilane (1.26 vol) was added over 60 minutes at 20° C. The reaction mixture was stirred at 20° C. for one hour, then concentrated under reduced pressure to 3 vol. Methyl-t-butyl ether (4 vol) was added and the resulting suspension was stirred at room temperature for 18 hours. The solid was collected by filtration, washing with methyl-t-butyl ether (4×1 vol). The material was dried in oven at 40° C. for 5 hours to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[CH2:11][CH:10]([CH2:12][CH2:13][F:14])[CH2:9]2)[CH:3]=1.[CH:15]([Si:18]([C:25]#[CH:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])([CH3:17])[CH3:16].C(N(CC)CC)C>[Cu](I)I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:14][CH2:13][CH2:12][CH:10]1[CH2:11][CH:8]([C:4]2[CH:3]=[C:2]([C:26]#[C:25][Si:18]([CH:15]([CH3:17])[CH3:16])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:7]=[CH:6][CH:5]=2)[CH2:9]1
Reactant: FCCC1CC(c2cccc(Br)c2)C1
Reactant: C#C[Si](C(C)C)(C(C)C)C(C)C
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC(C)[Si](C#Cc1cccc(C2CC(CCF)C2)c1)(C(C)C)C(C)C
Yield: 80.4 %

Procedure:
In a CEM snap top microwave vial were combined 1-Bromo-3-[3-(2-fluoro-ethyl)-cyclobutyl]-benzene (0.250 gm 9.72 mmol), triisopropylsilylacetylene (0.22 gm, 1.21 mmol), copper iodide (7 mg, 0.178 mmol), tetrakis(triphenylphosphine)palladium (22 mg, 0.088 mmol) and triethylamine (0.600 g, 5.93 mmol). The vial was quickly agitated then irradiated in a CEM Explorer™ microwave instrument for 30 minutes at 80° C. Purification by column chromatography (hexanes) afforded an oil 349 mg. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.06 (s, 21H) 1.62-1.81 (m, 2H) 1.82-1.97 (m, 1H) 2.00-2.45 (m, 4H) NMR (400 MHz, DMSO-d6) δ ppm 3.31-3.62 (m, 1H) 4.30-4.51 (m, 2H) 7.17-7.41 (m, 4H); MS (EI) m/z 256 [M+·].
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][C:22](=[O:35])[NH:23][C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:25]=2[O:33][CH3:34])[C:11]1=[O:36])(C)(C)C.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39].CCOC(C)=O>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[NH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][C:22]([NH:23][C:24]2[CH:29]=[C:28]([Cl:30])[C:27]([O:31][CH3:32])=[CH:26][C:25]=2[O:33][CH3:34])=[O:35])[C:11]1=[O:36]
Reactant: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCNC(=O)OC(C)(C)C)c(=O)c3ccccc32)cc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OC)c(NC(=O)Cn2c(=O)n(CCN)c(=O)c3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(2-{1-[(5-Chloro-2,4-dimethoxy-phenylcarbamoyl)-methyl]-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl}-ethyl)-carbamic acid tert-butyl ester (100 mg, 1.88 mmol) is taken up in DCM (2 ml) and treated with TFA (2 ml). The reaction is stirred at RT for 2 hours and then treated with EtOAc (20 ml). After 5 minutes, the white solid present is filtered, washed with EtOAc, ether and dried under vacuum to give the title compound as a white solid; [M+H]+ 433,
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]1=[O:10].[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([C:8]1[CH:7]=[CH:6][C:5]2[NH:1][C:2](=[O:10])[NH:3][C:4]=2[CH:9]=1)=[O:17]
Reactant: O=C(Cl)CCCCCl
Reactant: O=c1[nH]c2ccccc2[nH]1
Product: O=C(CCCCCl)c1ccc2[nH]c(=O)[nH]c2c1
Yield: 57.9 %

Procedure:
Using 1,3-dihydro-2H-benzimidazol-2-one (4.00 g) and 5-chlorovaleryl chloride (9.24 g) according to the same method as that of Reference Example 1, the title compound (4.36 g) was obtained as colorless crystals.