Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH2:19][OH:20])=[C:14]([C:15]([F:18])([F:17])[F:16])[C:8]=2[C:7]1=[O:21])[CH3:2].O.CC1C=CC(S(O)(=O)=O)=CC=1.I(C1C=CC=CC=1C(O)=O)(=O)=O>>[CH2:22]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][C:9]2[NH:12][C:13]([CH:19]=[O:20])=[C:14]([C:15]([F:16])([F:18])[F:17])[C:8]=2[C:7]1=[O:21])[CH3:23]
Reactant: CCN(CC)CCN1CCc2[nH]c(CO)c(C(F)(F)F)c2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: O
Product: CCN(CC)CCN1CCc2[nH]c(C=O)c(C(F)(F)F)c2C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 33.8 %

Procedure:
A stirred solution of 5-(2-diethylamino-ethyl)-2-hydroxymethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (1.208 g, 3.63 mmol) and 4-methylbenzenesulfonic acid monohydrate (690 mg, 3.63 mmol) in 8 ml of N,N-dimethyl sulfoxide was added dropwise with 2-iodoxybenzoic acid (1.63 g, 5.8 mmol) in 8 ml of N,N-dimethyl sulfoxide. Upon the completion of the addition, the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was added with ice to quench the reaction and filtered. The filtrate was added with saturated sodium carbonate to adjust pH9˜10, extracted with dichloromethane (50 ml×5). The combined organic phase was washed with saturated sodium carbonate (10 ml), saturated sodium chloride (10 ml), dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by the silica gel column chromatography with dichloromethane:n-hexane:methanol:ammonia (200:20:10:0.5) as eluents to give 5-(2-diethylamino-ethyl)-3-trifluoromethyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde (407 mg, 28%) as a yellow solid.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[NH:11][C:12]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:13][CH:14]=2)[CH2:6][O:5]C(=O)[NH:3]1.CO.O1CCCC1.[OH-].[Na+]>O>[NH2:3][C@:2]([CH3:1])([CH2:8][CH2:9][C:10]1[NH:11][C:12]([C:15](=[O:26])[CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:13][CH:14]=1)[CH2:6][OH:5]
Reactant: C[C@@]1(CCc2ccc(C(=O)CCCCc3ccccc3)[nH]2)COC(=O)N1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@](N)(CO)CCc1ccc(C(=O)CCCCc2ccccc2)[nH]1
Temperature: 25 °C
Yield: 76.1 %

Procedure:
To a solution of (4R)-4-methyl-4-{2-[5-(5-phenylpentanoyl)pyrrol-2-yl]ethyl}-1,3-oxazolidin-2-one (41.0 mg, 0.12 mmol) obtained in Example (42a) in a mixed solvent of methanol (2 ml), tetrahydrofuran (2 ml) and water (2 ml) was added 10N aqueous sodium hydroxide solution (0.12 ml, 1.17 mmol), and the resulting mixture was refluxed for 4 days. After cooling to room temperature, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (20:1) as the eluent to afford the title compound (30.0 mg, yield: 79%).
Reaction SMILES: [O:1](C1C=C(C=CC=1)C=O)C1C=CC=CC=1.[Na:16].[CH3:17][C:18]1([CH3:30])[C@@H:20]([CH:21]([Br:26])[C:22]([Br:25])([Cl:24])[Cl:23])[C@@H:19]1[C:27](Cl)=[O:28]>[Cl-].[Zn+2].[Cl-]>[Na:16].[CH3:17][C:18]1([CH3:30])[C@@H:20]([CH:21]([Br:26])[C:22]([Br:25])([Cl:24])[Cl:23])[C@@H:19]1[C:27]([O-:1])=[O:28]
Reactant: O=Cc1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@@H](C(=O)Cl)[C@@H]1C(Br)C(Cl)(Cl)Br
Agent: [Cl-]
Agent: [Na]
Agent: [Zn+2]
Product: CC1(C)[C@@H](C(=O)[O-])[C@@H]1C(Br)C(Cl)(Cl)Br
Temperature: 20 °C
Reaction time: 17 h

Procedure:
A mixture of 8 g of 3-phenoxy-benzaldehyde and 15.5 g of 1R, trans 2,2-dimethyl-3-(1',2'-dibromo-2',2'-dichloroethyl)-cyclopropane-1-carboxylic acid chloride was warmed to obtain a homogeneous liquid and the mixture was cooled to 20° C. 0.150 g of anhydrous zinc chloride were added thereto and the mixture was stirred at 20° C. for 17 hours to obtain raw RS α-chloro-3-phenoxy-benzyl 1R, trans 2,2-dimethyl-3-(1',2'-dibromo-2',2'-dichloroethyl)-cyclopropane-1-carboxylate whose IR spectrum showed an absorption at 1750 cm-1 (carbonyl) andwhose RMN Spectrum showed the absence of an aldehydic proton.
Reaction SMILES: CC[C:3](C1C=CC=CC=1)=[S:4].Br[CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14].C[S-].[Na+]>C(O)C>[CH3:3][S:4][CH2:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)=[O:14]
Reactant: CCC(=S)c1ccccc1
Reactant: O=C(CBr)c1ccc2ccccc2c1
Agent: C[S-]
Agent: [Na+]
Solvent: CCO
Product: CSCC(=O)c1ccc2ccccc2c1

Procedure:
The procedure is as in Example 4 for the preparation of α-methylthioacetophenone, starting with 2-(2-bromoacetyl)naphthalene (12.5 g) and sodium methanethiolate (3.5 g) in ethanol (100 cc). 2-[2-(Methylthio)acetyl]naphthalene (8 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][C:3](=[O:6])[CH2:2]1.C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:27][C:28]1[CH:29]=[CH:30][C:31]([CH:35]2[CH2:37][CH2:36]2)=[C:32]([Pb+3])[CH:33]=1.Cl>C(Cl)(Cl)Cl.ClCCl>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([CH:35]2[CH2:37][CH2:36]2)=[C:30]([CH:2]2[C:3](=[O:6])[CH2:4][CH2:5][C:1]2=[O:7])[CH:29]=1
Reactant: O=C1CCC(=O)C1
Reactant: Brc1ccc(C2CC2)c([Pb+3])c1
Agent: CC(=O)[O-]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: O=C1CCC(=O)C1c1cc(Br)ccc1C1CC1
Temperature: 80 °C

Procedure:
To a solution of cyclopentane-1,3-dione (0.57 g, 0.0058 mol) and N,N-dimethylaminopyridine (3.64 g, 0.030 mol) in chloroform (33 ml) is added toluene (9 ml) then 5-bromo-2-cyclopropylphenyl lead triacetate (3.77 g, 0.0065 mol). This solution is heated at 80° C. for 20 hours then cooled to room temperature and dilluted with dichloromethane and 2M aqueous hydrochloric acid. The resulting biphasic suspension is filtered through diatomaceous earth and the two phases are separated. The organic layer is further washed with 2M aqueous hydrochloric acid and the aqueous phase is extracted again with dichloromethane. All organic fractions are combined, washed with brine, dried over magnesium sulfate then concentrated in vacuo. The crude product is finally purified by flash column chromatography on silica gel (isohexane/ethyl acetate eluant) to afford 2-(5-bromo-2-cyclopropylphenyl)cyclopentane-1,3-dione as a pale yellow solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][N:16]([CH3:18])[CH3:17])[CH:13]=2)[NH:8][C:7]=1[C:19]([F:22])([F:21])[F:20])C.[NH3:24]>CO>[CH3:17][N:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:19]([F:22])([F:21])[F:20])=[C:6]2[CH2:5][C:4]([NH2:24])=[O:3])[CH3:18]
Reactant: CCOC(=O)Cc1c(C(F)(F)F)[nH]c2ccc(CN(C)C)cc12
Reactant: N
Solvent: CO
Product: CN(C)Cc1ccc2[nH]c(C(F)(F)F)c(CC(N)=O)c2c1
Temperature: 80 °C
Reaction time: 144 h
Yield: 100 %

Procedure:
A solution of (5-dimethylaminomethyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (200 mg, 0.609 mmol) in a mixture of methanol (5 mL) and liquid ammonia (30 mL) is stirred for 6 days in an autoclave at 80° C. After careful evaporation of the ammonia, the remaining solvent is evaporated in vacuo to afford the title compound as a red solid (182 mg, 0.609 mmol, 100%). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=12.18 (bs, 1H), 7.75 (s, 1H), 7.49 (d, J=8.6 Hz, 1H), 7.42 (bs, 1H), 7.35 (d, J=8.6 Hz, 1H), 6.95 (bs, 1H), 3.67 (s, 2H), 3.16 (s, 2H), 2.62 (s, 6H). MS (ES+): 248 (M(C14H17NO3)+H)+. MS (ES+): 300
Reaction SMILES: [Si]([O:8][CH:9]([C:22]1[O:23][C:24]([C:27]2[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][N:28]=2)=[CH:25][N:26]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C(C)(C)C)(C)C>CCOC(C)=O>[C:16]1([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([C:22]2[O:23][C:24]([C:27]3[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][N:28]=3)=[CH:25][N:26]=2)=[O:8])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(CCCCCCc3ccccc3)O[Si](C)(C)C(C)(C)C)o2)nc1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)nc1
Yield: 56.3 %

Procedure:
The title compound was prepared from methyl 6-(2-(1-(tert-butyldimethylsilyloxy)-7-phenylheptyl)oxazol-5-yl)nicotinate (44 mg, 0.086 mmol) following General Procedure C. Flash chromatography (10-20% EtOAc) yielded the title compound as a white solid (19 mg, 56%): 1H NMR (CDCl3, 500 MHz) δ 9.32 (d, 1H, J=2.0 Hz), 8.48 (dd, 1H, J=8.5, 2.0 Hz), 8.06 (s, 1H), 8.00 (d, 1H, J=8.5 Hz), 7.36-7.33 (m, 2H), 7.26-7.24 (m, 3H), 4.07 (s, 3H), 3.19 (t, 2H, J=7.0 Hz), 2.69 (t, 2H, J=7.5 Hz), 1.89-1.84 (m, 2H), 1.75-1.69 (m, 2H), 1.54-1.47 (m, 4H); 13C NMR (CDCl3, 125 MHz) δ 188.9, 165.5, 158.2, 152.8, 151.7, 149.8, 143.1, 138.7, 129.1, 128.8, 128.7, 126.3, 126.0, 120.1, 53.0, 39.6, 36.3, 31.7, 29.4, 29.4, 24.3; MALDI-FTMS m/z 393.1811 (M+H+, C23H25N2O4, requires 393.1809).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])[C:21]([Cl:38])=[CH:20][N:19]=1>>[Cl:38][C:21]1[C:22]([NH:24][C:25]2[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:26]=2[C:27]([NH:29][CH2:30][C:31]#[CH:32])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: C#CCNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: C#CCNC(=O)c1cccc(F)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-fluoro-N-prop-2-ynyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-prop-2-ynyl-benzamide in an analogous manner to Example 308c. Product isolated as a yellow foam (126 mg, 60%). LCMS (m/e) 523 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.33 (bs, 1H), 8.08 (s, 1H), 7.42-7.37 (m, 1H), 7.36-7.28 (m, 2H), 7.14 (s, 1H), 7.09 (d, 1H, J=7.9 Hz), 6.90 (d, 1H, J=8.1 Hz), 6.82 (s, 1H), 6.31-6.24 (m, 1H), 4.15-4.10 (m, 2H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.90-2.83 (m, 2H), 2.81-2.73 (m, 4H), 2.73-2.65 (m, 4H), 2.23-2.20 (m, 1H).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:11])[O:6]CC(C)C>Cl>[NH2:1][CH2:2][C@@H:3]([OH:13])[CH2:4][P:5]([CH3:12])(=[O:6])[OH:11]
Reactant: CC(C)COP(C)(=O)C[C@H](O)CN
Agent: Cl
Product: CP(=O)(O)C[C@H](O)CN
Temperature: 25 °C

Procedure:
A solution of 1.6 g of isobutyl P-[3-amino-2(R)-hydroxy-propyl]-P-methyl-phosphinate in 20 ml of 36% aqueous hydrochloric acid is heated to reflux for a period of 12 hours. The reaction mixture is then allowed to cool to room temperature, concentrated under reduced pressure, and co-evaporated four times with 25 ml of water. The crude material is dissolved in water, washed with ether and the aqueous layer is treated with activated charcoal. The solution is filtered hot, the filtrate is concentrated under reduced pressure, the residue dissolved in 20 ml of ethanol and treated with 1 ml of propylene oxide. The mixture is stirred until the precipitated solid is free of halogen. The solid is then recrystallised from methanol/acetone to give P-[3-amino-2(R)-hydroxy-propyl]-P-methyl-phosphinic acid, m.p. 222°-225°, 31P-NMR spectrum: δ=+38.8 ppm (D2O), [α]D25 =+5.9(c=0.918% in H2O).
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[CH3:15][CH:16]([CH3:22])[C:17](=O)[CH2:18][CH:19]=O>>[CH2:8]([S:7][C:5]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:6]=[C:2]2[N:1]=[C:17]([CH:16]([CH3:22])[CH3:15])[CH:18]=[CH:19][N:3]2[NH:4]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)C(=O)CC=O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Product: CC(C)C1=NC2=NC(SCc3ccccc3)(SCc3ccccc3)NN2C=C1
Yield: 96 %

Procedure:
This material was prepared in 96% yield from 3-amino-5-benzylthio-1,2,4-triazole and 4-methyl-3-oxopentanal following the general procedure described in Example 7. The desired product was isolated as a solid, m.p. 65°-66° C. IR and 1H NMR were in agreement with the assigned structure.
Reaction SMILES: Br[C:2]1[N:6]2[C:7]([CH3:17])=[N:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]2=[N:4][C:3]=1[O:18][CH2:19][C:20]1[N:21]([CH2:25][CH3:26])[N:22]=[CH:23][N:24]=1.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:25]([N:21]1[C:20]([CH2:19][O:18][C:3]2[N:4]=[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[N:9][N:8]=[C:7]([CH3:17])[N:6]3[C:2]=2[C:28]2[S:27][CH:31]=[CH:30][CH:29]=2)=[N:24][CH:23]=[N:22]1)[CH3:26]
Reactant: OB(O)c1cccs1
Reactant: CCn1ncnc1COc1nc2c(-c3ccccc3)nnc(C)n2c1Br
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCn1ncnc1COc1nc2c(-c3ccccc3)nnc(C)n2c1-c1cccs1
Temperature: 90 °C
Yield: 14.7 %

Procedure:
A mixture of 3-bromo-2-(2-ethyl-2H-[1,2,4]triazol-3-ylmethoxy)-5-methyl-8-phenylimidazo[1,2-d][1,2,4]triazine (70 mg, 0.169 mmol), 2-thiopheneboronic acid (32 mg, 0.254 mmol) and cesium carbonate (110 mg, 0.338 mmol) in anhydrous 1,4-dioxane (5 ml) was degassed using three freeze-pump-thaw cycles. Tris(dibenzylideneacetone)dipalladium(0) (15.5 mg, 0.017 mmol) and a 0.1M solution of tri-tert-butylphosphine in 1,4-dioxane (0.406 ml, 0.406 mmol) was added, and the mixture was further degassed with two more freeze-pump-thaw cycles before heating at 90° C. under nitrogen for 17 h. The mixture was filtered through glass fibre paper, washed with ethyl acetate. The filtrate was washed with saturated NaCl solution, separated, dried over MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography (SiO2; 2% MeOH in CH2Cl2), and the product recrystallised from CH2Cl2 to afford the title compound (10.4 mg) as a white solid. δH (400 MHz; CDCl3) 1.28 (3H, t, J 7.2), 2.58 (3H, d), 4.19 (2H, q, J 7.2), 5.68 (2H, s), 7.18 (2H, m), 7.57 (4H, m), 7.89 (1H, s), 8.61 (2H, m); m/z (ES+) 414/416 (M++H).
Reaction SMILES: C([O:8][NH:9][C:10]([C@H:12]([C@@H:24]([CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)[C:25]([N:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[CH2:13][N:14]1[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH3:22])[C:15]1=[O:23])=[O:11])C1C=CC=CC=1>C(O)C.[Pd]>[CH:34]1([CH2:33][C@H:24]([C@@H:12]([C:10](=[O:11])[NH:9][OH:8])[CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:21])([CH3:20])[N:16]([CH3:22])[C:15]2=[O:23])[C:25]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[O:26])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CN1C(=O)N(C[C@H](C(=O)NOCc2ccccc2)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: [Pd]
Solvent: CCO
Product: CN1C(=O)N(C[C@H](C(=O)NO)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Yield: 85.5 %

Procedure:
For the debenzylation, a suspension of 5.5 g of 1-[2(R)-[1(R)-(benzyloxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine from Example 8 or 9 in 40 ml of ethanol and 1.7 g of Pd/C (5%) was hydrogenated at 22°/1 bar for 4 h. The suspension was filtered, the filtrate was concentrated completely and the residue was crystallized from water, there being obtained 3.9 g (85%) of pure 1-[3-cyclopentyl-2(R)-[1(R)-(hydroxycarbamoyl)-2-(3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]propionyl]piperidine (X), MS (El): 436 (40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH2:21])[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33]>>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[C:19]2[O:18][CH:17]([CH2:20][NH:21][C:32](=[O:33])[O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:16][C:15]=2[CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(-c2cccc3c2OC(CN)C3)c(OC)c1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc3c2OC(CNC(=O)OCc2ccccc2)C3)c(OC)c1
Yield: 85.4 %

Procedure:
Treatment of (±)-1-[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (1.42 g, 4.41 mmol) with diisopropylethylamine (0.855 g, 6.62 mmol) followed by benzyl chloroformate (0.828 g, 4.85 mmol) generally according to the procedure described for Intermediate 12 provided 1.58 g (85%) of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a colorless oil. Anal. calcd. for C25H25NO5: C, 71.58; H, 6.01; N, 3.34. Found: C, 71.24; H, 5.92; N, 3.09. Chiral HPLC separation of (±)-benzyl {[7-(2,4-dimethoxyphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralcel OD, ethanol) provided two fractions. Fraction 1 (Rt=5.107 min, Chiralcel OD, ethanol); Fraction 2 (Rt=6.134 min, Chiralcel OD, ethanol).
Reaction SMILES: CC1C=CC(C(O)=O)=CC=1.C(ON1C(=O)C2=CC=CC=C2C1=O)(=O)C.O=O.[C:28](O)(=[O:38])[C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=1>[Ti].O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.O.O.O.O.C([O-])(=O)C.[Mn+2].C([O-])(=O)C.C(O)(=O)C>[C:33]([C:32]1[CH:36]=[CH:37][C:29]([CH:28]=[O:38])=[CH:30][CH:31]=1)([OH:35])=[O:34]
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Agent: [Co+2]
Agent: [Mn+2]
Agent: [Ti]
Solvent: CC(=O)O
Solvent: O
Product: O=Cc1ccc(C(=O)O)cc1
Yield: 70.6 %

Procedure:
In a 500-ml titanium autoclave, 15.36 g (0.113 mol) of p-toluic acid, 0.232 g (1.13 mmol) of N-acetoxyphthalimide, 0.79 mmol of cobalt(II) acetate tetrahydrate, 0.79 mmol of manganese(II) acetate tetrahydrate and 107 g of acetic acid were placed, the resulting mixture was stirred at 150° C. in an atmosphere of a mixture of oxygen and nitrogen gases (1:1) [4 MPa (gauge pressure)] for 1 hour and thereby yielded terephthalic acid in a yield of 70.6% with a conversion from p-toluic acid of 74.3%. A small amount of 4-carboxybenzaldehyde was by-produced.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH:36]([CH3:38])[CH3:37]>CN(C)C=O>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH:36]([CH3:38])[CH3:37])[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)n1c(C(=O)N2CCC(F)(F)CC2)cc2cc(C(=O)N3CCN(C4CCCC4)CC3)ccc21
Yield: 27 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), sodium hydride and 2-bromopropane in N,N-dimethylformamide give the desired product as a colorless foam (27%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[CH2:7]OS(C1C=CC(C)=CC=1)(=O)=O.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>>[CH:19]1([NH:22][CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH2:21][CH2:20]1
Reactant: NC1CC1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCCCO2)cc1
Product: C1CCC(CNC2CC2)OC1
Temperature: 110 °C

Procedure:
A mixture of toluene-4-sulfonic acid tetrahydro-pyran-2-ylmethyl ester (500 mg, 1.85 mmol) and cyclopropylamine (2 mL, 15 mmol) is heated overnight at 110° C. in a sealed tube. The crude mixture is concentrated and taken up in CH2Cl2. Water is added, the layers are separated and the aqueous one back extracted twice with CH2Cl2. The combined organic extracts are washed with brine, dried over Na2SO4, filtered and concentrated. TLC, Rf (CH2Cl2/MeOH 95:5)=0.3, MS (LC-MS): 156.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:17]1[CH:25]=[C:24]2[C:20]([C:21]3[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]=3[N:23]2[CH3:26])=[CH:19][CH:18]=1>>[CH3:26][N:23]1[C:24]2[C:20](=[CH:19][CH:18]=[C:17]([N:12]3[CH:13]=[CH:14][C:9]([CH2:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:10][C:11]3=[O:15])[CH:25]=2)[C:21]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][C:22]1=2
Reactant: O=c1cc(CCc2ccccc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)C2
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)C2
Yield: 60.5 %

Procedure:
4-Phenethylpyridin-2(1H)-one (817 mg, 4.10 mmol) and tert-butyl 7-bromo-9-methyl-3,4-dihydro-1H-pyrido[3,4-b]indole-2(9H)-carboxylate (1.5 g, 4.1 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (1.2 g, 60%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=8.1 Hz, 1H), 7.34-7.29 (m, 4H), 7.26-7.20 (m, 3H), 7.03 (dd, J=8.2, 1.5 Hz, 1H), 6.50 (s, 1H), 6.09 (dd, J=6.9, 1.6 Hz, 1H), 4.63 (br s, 2H), 3.74 (br s, 2H), 3.63 (s, 3H), 2.98-2.91 (m, 2H), 2.84-2.79 (m, 4H), 1.51 (s, 9H).
Reaction SMILES: BrC1C=CC(CCC(C2C=CC=CC=2)=O)=C(F)C=1.[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:29]/[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:22]([F:41])[CH:21]=1>>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27]/[C:28](/[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)=[CH:29]\[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:22]([F:41])[CH:21]=1
Reactant: CCOC(=O)/C=C(/CCc1ccc(Br)cc1F)c1ccccc1
Agent: O=C(CCc1ccc(Br)cc1F)c1ccccc1
Product: CCOC(=O)/C=C(\CCc1ccc(Br)cc1F)c1ccccc1

Procedure:
By a procedure similar to that of example 1.85.3, starting from 3-(4-bromo-2-fluorophenyl)-1-phenylpropan-1-one, (Z)-ethyl 5-(4-bromo-2-fluorophenyl)-3-phenylpent-2-enoate and (E)-ethyl 5-(4-bromo-2-fluorophenyl)-3-phenylpent-2-enoate were obtained as colourless oils.
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]2[NH:13][C:12](=[O:14])[C:11](=[C:15]([CH3:17])[CH3:16])[CH2:10][C@@H:9]2[OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH:1]1([CH2:7][CH:8]2[NH:13][C:12](=[O:14])[CH:11]([CH:15]([CH3:16])[CH3:17])[CH2:10][CH:9]2[OH:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)=C1C[C@H](O)[C@H](CC2CCCCC2)NC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)C1CC(O)C(CC2CCCCC2)NC1=O

Procedure:
A solution of the product of Example 5 (24.7 g, 98.4 retool) in 500 mL of ethyl acetate was treated with 2.5 g of dry palladium on carbon and hydrogenated at 4 atmospheres of hydrogen for 4 hours at ambient temperature. The reaction mixture was filtered and concentrated to a white foamy solid which was taken on without further purification. m.p. 97°-99° C. [α]D =-95.1° (c=1.075, CHCl3). IR (KBr) 3605, 3400, 2925, 1642 cm-1. 1H NMR (300 MHz, CDCl3) δ6.3 (bs, 1H), 4.11 (m, J=4.5, 1H), 3.47 (m, 1H), 2.72 (bs, 1H), 2.5 (m, 1H), 2.3 (m, 1H), 1.9 (m, 1H), 1.8-1.5 (m, 8H), 1.43-1.12 (m, 6H), 0.97 (d, 3H), 0.87 (m, 3H). 13C NMR (75.5 Hz, CDCl3) ppm 174.2, 67.1, 52.6, 44.3, 37.7, 34.5, 33.8, 32.4, 27.6, 26.4, 26.3, 26.2, 26.0, 20.2, 17.4.