Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]([S:8][C:9](=O)[CH3:10])([CH3:7])[CH3:6])[CH3:2].[F:13][C:14]([F:29])([F:28])CCOS(C1C=CC(C)=CC=1)(=O)=O.C[O-].[Na+]>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]([CH3:7])([S:8][CH2:9][CH2:10][C:14]([F:29])([F:28])[F:13])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)SC(C)=O
Reactant: Cc1ccc(S(=O)(=O)OCCC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C)(C)SCCC(F)(F)F
Temperature: 25 °C
Yield: 82.6 %

Procedure:
A solution of 2-acetylsulfanyl-2-methyl-propionic acid ethyl ester (1.7 g, 8.72 mmol), toluene-4-sulfonic acid 3,3,3-trifluoro-propyl ester (2.3 g, 8.72 mmol) and sodium methoxide (1.9 g, 34.9 mmol) in ethanol (13 mL) are heated to 130° C. in a sealed tube for 4 h. The reaction is cooled to room temperature and concentrated under reduced pressure. The residue is diluted with DCM and washed with saturated aqueous NaHCO3 solution and brine. The organic layer is dried (Na2SO4), filtered and the filtrate concentrated under reduced pressure to afford 1.76 g of title compound as a brown solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.28 (3H, t, J=7 Hz), 1.51 (3H, s), 2.26-2.42 (2H, m), 2.76-2.85 (2H, m), 4.18 (2H, q, J=6.96 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]([CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:12](O)=[O:13])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].C(C1NC=CN=1)(C1NC=CN=1)=O.C(=O)=O.[BH4-].[Na+].Cl>C1COCC1.O.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:10][C@H:11]([CH2:12][OH:13])[CH2:15][C:16]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:17])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CC(C)(C)OC(=O)C[C@H](Nc1ccc(C#N)c(Cl)c1)C(=O)O
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)C[C@@H](CO)Nc1ccc(C#N)c(Cl)c1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
To a solution of (2S)-2-[(3-chloro-4-cyanophenyl)amino]-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoic acid (115.0 g, 0.35 mol) in THF (300 mL) at −65° C. in a dry-ice/acetone bath was added portionwise carbonyl diimidazole (68.9 g, 0.43 mol) at such a rate as to maintain or decrease temperature. After the addition was complete, the reaction was stirred for an additional 1 h. This solution was transferred to a jacketed addition funnel containing dry ice in the jacket to maintain a solution temperature of −70° C., then added to a mixture of NaBH4 (16.1 g, 0.43 mol), ice (600 mL), and THF (100 mL); the addition of the solution to the NaBH4 mixture was carried out at such a rate that the temperature did not exceed 0° C. over the course of the addition. The resultant reaction mixture was stirred for an additional 1 h at 0° C. The reaction mixture was allowed to warm to ambient temperature, whereupon EtOAc (400 mL) and H2O (400 mL) were added. The mixture was then acidified with 2 N HCl (approximately 800 mL) to pH 2.5. The organic layer was separated, and the aqueous phase was extracted twice with EtOAc (400 mL). The combined organics were washed with H2O (400 mL), aqueous NaHCO3 (400 mL), and brine (400 mL), dried over MgSO4, then filtered, before the solvents were removed in vacuo. The resultant solid was dissolved in CH2Cl2 (200 mL), then hexane (400 mL) was added to the solution to precipitate the product. The resultant slurry was filtered, and the collected solids were placed under vacuum in an oven at ambient temperature to yield the desired product, 109.8 g (99.8%). LC-MS (ES) m/e 311.5 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@H:7]([NH2:11])[C:8]([NH2:10])=[O:9])=[CH:3][CH:2]=1.[CH2:12]1[CH2:18][S:15](=[O:17])(=[O:16])[O:14][CH2:13]1>O1CCCC1.O1CCOCC1>[NH2:10][C:8](=[O:9])[C@@H:7]([NH:11][CH2:13][CH2:12][CH2:18][S:15]([OH:17])(=[O:16])=[O:14])[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: NC(=O)[C@@H](N)c1ccccc1
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: NC(=O)[C@@H](NCCCS(=O)(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
To a solution of L-Phenylglycine amide (670 mg, 5.9 mmol) in tetrahydrofuran (10 mL) and 1,4-dioxane (4 mL) was added 1,3-propanesultone (674 mg, 5.6 mmol). The solution stirred at reflux for 2 hours. The reaction was cooled to room temperature. The solid was collected by filtration and washed with acetone (2×20 mL). The solid was dissolved in 50% water/EtOH mL). Dowex Marathon C ion exchange resin (strongly acidic) was added to the solution. The suspension was stirred for 15 minutes before the resin was removed by filtration. The filtrate was evaporated under reduced pressure. The solid was suspended in acetone (50 mL), filtered and dried in the vacuum oven (50° C.), affording the title compound (743 mg, 50%). 1H NMR (D2O, 500 MHz) δ ppm 7.38 (m, 5H), 4.92, (s, 1H), 3.01 (m, 1H), 2.91 (m, 1H), 2.78 (t, 2H, J=7.3 Hz), 2.0 (m, 2H). 13C (D2O, 125 MHz) δ ppm 170.15, 130.95, 130.24, 129.94, 128.74, 63.40, 47.99, 44.92, 21.27. [α]D=−124° (c=0.0041 in water), ES-MS 271 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][CH2:10][C:11]([F:14])([F:13])[F:12].C1C(=O)N([Br:22])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([O:9][CH2:10][C:11]([F:13])([F:12])[F:14])[CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(F)c(OCC(F)(F)F)c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)cc1OCC(F)(F)F

Procedure:
A mixture of 2.68 g (12.8 mmol) of 1-fluoro-4-methyl-2-(2,2,2-trifluoro-ethoxy)-benzene, 2.3 g (12.9 mmol) of NBS and 140 mg of dibenzoylperoxide in 60 ml of CCl4 was refluxed for 6 hours. Solvent was removed and the crude residue was used without any further purification for the next step.
Reaction SMILES: ClC1C=C[CH:5]=[C:4]([C:8]([O:10]O)=[O:9])[CH:3]=1>ClCCl>[CH3:5][C:4]1([CH3:3])[C:8](=[O:9])[O:10][CH2:4][C:8](=[O:9])[O:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)OC(=O)COC1=O
Temperature: -18 °C

Procedure:
A solution of 5 g of cyclic keto-ester (39 mmol) and 8.1 g of metachloroperbenzoic acid (1.2 eq.) in 40 ml of dichloromethane is heated under reflux for 24 hours. The complete conversion of the ring with 5 members is monitored by NMR 1H on a sample. The reaction medium is then cooled down to −18° C. overnight then filtered on frit in order to eliminate the metachlorobenzoic acid formed. The filtrate is concentrated under vacuum. The residue is recrystallized from ethyl acetate at −18° C. 3.9 g of analytically pure, 3,3-dimethyl-2,5-dioxane-1,4-dione are thus obtained (70% of isolated product yield). The product is characterized by NMR 1H [4.97 (s, 2H), 1.70 (s, 6H)] and 13C [167.7 and 163.9 (C═O), 79.8 (Cq), 65.8 (CH2), 25.8 (CH3)], RX (cf. FIG. 1), mp (84-85° C.) and elementary analysis. Calculated C: 50.00, H: 5.56. Found C: 49.98, H: 5.33.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:22])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1>CO>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][C:5]([OH:22])=[O:4])=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)CCc1ccc(OCc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCc1ccc(OCc2ccccc2)cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
An aqueous solution of NaOH (1 M, 270 mL) was added to a mixture of the 3-(4-benzyloxyphenyl)propionic acid methyl ester from Step 2 above in MeOH (600 mL) and the reaction was stirred overnight. The crystalline ppt was collected by filtration, air dried and then partitioned between EtOAc/Et2O/1 M HCl (500 mL, 250 mL, 150 mL). The organic phases were dried over MgSO4 and evaporated to give the product as a white solid (16.2 g, 70%, 3 Steps). 1H NMR (CDCl3) δ 2.61-2.68 (m, 2H), 2.86-2.93 (m, 2H), 5.03 (s, 2H), 6.88-6.93 (m, 2H), 7.10-7.15 (m, 2H), 7.28-7.45 (m, 5H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:13])[C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][CH:7]=[CH:6][N:5]=1.[H][H]>CO.[Pd]>[NH2:10][C:9]1[C:4]([C:3]([NH:2][CH3:1])=[O:13])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: CNC(=O)c1ncccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)c1ncccc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To N-methyl-3-nitropicolinamide (3.0 g, 16.6 mmol) in methanol (150 mL) was added Pd/C (10% Pd in carbon, 0.45 g, 15 wt %) under argon. Hydrogen balloon was used as the hydrogen source. The reaction was stirred at room temperature overnight. The mixture was filtered through celite and the celite pad was washed several times. The solvent was removed to obtain the desired product (quantitative yield).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][CH:18]1[C:22]2[C:23]([OH:27])=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19]1>CN(C)C=O>[CH3:17][CH:18]1[C:22]2[C:23]([O:27][C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)=[CH:24][CH:25]=[CH:26][C:21]=2[CH2:20][O:19]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC1OCc2cccc(O)c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1OCc2cccc(Oc3ccc([N+](=O)[O-])cn3)c21
Temperature: 110 °C
Yield: 92.6 %

Procedure:
In a microwave vial 3-methyl-1,3-dihydro-2-benzofuran-4-ol (Intermediate 98, 24 mg) was dissolved in N,N-dimethylformamide (1.5 ml) to give a pale yellow solution. 2-chloro-5-nitropyridine (24.07 mg, 0.152 mmol) and potassium carbonate (62.9 mg, 0.455 mmol) were added. The reaction vessel was sealed and heated in a microwave Biotage Initiator at 110° C. for 1 hour. After cooling, the reaction mixture was quenched with 5 ml of water and diluted with 25 ml of Et2O. The organic phase was washed with water (3×10 mL) and the phases were separated. The organic phase was passed through a phase separator cartridge and evaporated under vacuum to give the title compound (38.3 mg).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.[F:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+]>C1(C)C=CC=CC=1.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.O>[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]3[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=23)=[CH:17][CH:16]=1
Reactant: Cc1cc2c(c(Cl)n1)C(=O)OCC2
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc2c(c(-c3ccc(F)cc3)n1)C(=O)OCC2
Temperature: 0 °C
Yield: 41.5 %

Procedure:
8-chloro-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.265 mmol), 4-fluorophenyl boronic acid (265 mg, 1.898 mmol), Pd(PPh3)4 (146 mg, 0.127 mmol) and anhydrous potassium carbonate (350 mg, 2.530 mmol) were suspended in 10 mL of anhydrous toluene and then refluxed for about 15 hours under the nitrogen atmosphere. The mixture was added with 20 mL of a saturated solution of ammonium chloride and 10 mL of distilled water while stirring at 0° C. and then extracted twice with 60 mL of methylene chloride. The resulting organic layer was dried using anhydrous sodium sulfate, filtered and concentrated. A silica gel column chromatography (5% EtOAc/MC) was performed on the resulting residue and 135 mg (42%) of 8-(4-fluorophenyl)-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on was obtained in pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:13](Br)=[CH:12][N:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:10]2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[C:13]([CH:25]2[CH2:27][CH2:26]2)=[CH:12][N:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:17]=[C:10]2[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc2nc(-c3ccccc3)cn2cc1Br
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc2nc(-c3ccccc3)cn2cc1C1CC1
Temperature: 100 °C
Yield: 87.3 %

Procedure:
(6-Bromo-2-phenyl-imidazo[1,2-a]pyridin-7-yl)-carbamic acid tert-butyl ester (Example 67, Step 1-3, 600 mg, 1.54 mmol), cyclopropylboronic acid (265 mg, 3.12 mmol), potassium phosphate (1.64 g), tricyclohexylphosphine (95 mg), and palladium(II) acetate (38 mg) were placed in a round-bottom flask, and the flask was filled with an atmosphere of Argon. Toluene (15 ml) and water (1 ml) were added and the mixture was heated to 100° C. overnight. Upon cooling, the reaction mixture was taken up in ethyl acetate and washed. The organic layers were dried (Na2SO4) and evaporated. The title compound (470 mg, 87%) was isolated from the residue by column chromatography (silica gel, heptane:ethyl acetate=100:0-60:40). MS (m/e)=350.4 [M+H+].
Reaction SMILES: CO[C:3](=[O:31])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][C:18]=1CC1C=CC=CC=1)[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[Cl-].[Li+].[BH4-].[Na+].[Cl-].[Na+]>C(O)C.O1CCCC1>[CH2:9]([O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@@H:4]([CH2:3][OH:31])[NH:5][C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7])=[CH:22][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(N[C@H](CO)Cc1ccc(OCc2ccccc2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 199.8 %

Procedure:
27.25 g of 0-benzyl-N-benzyloxycarbonyltyrosine methyl ester was dissolved in a mixed solvent of 185 ml of ethanol and 122 ml of tetrahydrofuran, and to the solution were added 5.8 g of lithium chloride and 5.2 g of sodium borohydride under ice cooling. The reaction mixture was stirred at a room temperature for 18 hours, and after the addition of 500 ml of saturated sodium chloride aqueous solution, extracted twice with 300 ml of chloroform. The extract was dried over magnesium sulfate and concentrated under a reduced pressure to obtain 25.4 g of the title compound as colorless crystals
Reaction SMILES: Cl[CH:2]([C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[CH2:57][CH2:56]2)=[CH:51][CH:50]=1)[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[O:9][C@@H:10]1[CH2:15][C@H:14]([CH2:16][O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:13]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:12]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:11]1[O:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(OCC)(=O)C>C(Cl)Cl.C(O)(=O)C.[Zn]>[CH:55]1([C:52]2[CH:51]=[CH:50][C:49]([CH2:2][C:3]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[O:9][C@@H:10]3[CH2:15][C@H:14]([CH2:16][O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C@@H:13]([O:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[C@H:12]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C@H:11]3[O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:54][CH:53]=2)[CH2:56][CH2:57]1
Reactant: ClC(c1ccc(C2CC2)cc1)c1ccncc1O[C@@H]1C[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: c1ccc(COC[C@H]2C[C@@H](Oc3cnccc3Cc3ccc(C4CC4)cc3)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 67 %

Procedure:
In a nitrogen stream, zinc (0.14 g, 2.14 mmol) was added to a solution of 4-[chloro-(4-cyclopropylphenyl)-methyl]-3-((1R,2S,3S,4R,5R)-2,3,4-trisbenzyloxy-5-benzyloxymethyl-cyclohexyloxy)pyridine (0.22 g, 0.28 mmol) in methylene chloride (4.1 mL) and acetic acid (12.4 mL), and the mixture solution was stirred at room temperature for 14 hours. To the reaction mixture was added ethyl acetate and the mixture was washed with a saturated hydrogencarbonate aqueous solution and dried (anhydrous magnesium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:1)] to obtain the title product (0.14 g, 67%).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([CH3:9])[N:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[C:5]=1[CH3:19])(=[O:3])[CH3:2].Cl[C:21](=[O:28])[CH2:22][CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[CH3:27][O:26][C:24](=[O:25])[CH2:23][CH2:22][C:21]([C:8]1[C:4]([C:1](=[O:3])[CH3:2])=[C:5]([CH3:19])[N:6]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH3:18])=[CH:14][CH:15]=2)[C:7]=1[CH3:9])=[O:28]
Reactant: CCOc1ccc(-n2c(C)cc(C(C)=O)c2C)cc1
Reactant: COC(=O)CCC(=O)Cl
Product: CCOc1ccc(-n2c(C)c(C(C)=O)c(C(=O)CCC(=O)OC)c2C)cc1

Procedure:
Utilizing the general procedure outlined in EXAMPLE 1, 3-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)pyrrole (771 mg, 3.0 mmol) and methyl 4-chloro-4-oxobutyrate (0.56 mL, 4.5 mmol) reacted to give 4-[4-acetyl-2,5-dimethyl-1-(4-ethoxyphenyl)-1H-pyrrol-3-yl]4-oxo-butyric acid methyl ester as a white solid: 1H NMR (CDCl3, 500 MHz) δ 7.06 (d, 2H), 6.98 (d, 2H), 4.08 (q, 2H), 3.67 (s, 3H), 3.03 (t, 211), 2.74 (t, 2H), 2.41 (s, 3H), 2.11 (s, 3H), 2.06 (s, 3H), 1.45 (t, 3H); MS (ESI) 372 (M+H)+.
Reaction SMILES: C([Li])CCC.[Br-].[OH:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:35]=O>C1COCC1>[CH3:30][O:31][C:32]1[CH:33]=[C:34](/[CH:35]=[CH:10]/[CH2:9][CH2:8][OH:7])[CH:37]=[CH:38][C:39]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: OCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(C=O)ccc1OCc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(/C=C/CCO)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34 %

Procedure:
n-Butyllithium (1.55M in hexane, 194 ml) was added dropwise to a stirred suspension of (3-hydroxypropyl)triphenylphosphonium bromide (60.3 g) in dry THF (375 ml) cooled to 0° under nitrogen. The resulting blood-red solution was stirred at 0° for 15 min and then a solution of 3-methoxy-4-(phenylmethoxy)benzaldehyde (36.3 g) in dry THF (50 ml) was added dropwise over 15 min. The mixture was stirred at 0° for 30 min, allowed to warm up to room temperature, stirred for a further 2 h and then the reaction quenched by the addition of 2N hydrochloric acid (100 ml). The THF was removed in vacuo at 40°, the aqueous residue extracted with ethyl acetate (350 ml) and the organic layer washed with 2N HCl (200 ml). The aqueous phase was extracted with further ethyl acetate (150 ml), the organic layers combined, washed with 8% sodium bicarbonate solution (200 ml) and dried. Concentration afforded a product which was purified by FCC eluting with System B (1:2) yielding the title compound as a cream powder (14.5 g) m.p. 57°-61°
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][CH2:10]I)[CH3:2].[Br:14]CCCCBr.[H-].[Na+]>C1COCC1>[CH2:1]([O:3][C:4](=[O:13])[CH:5]([CH3:12])[O:6][CH2:7][CH2:8][CH2:9][CH2:10][Br:14])[CH3:2]
Reactant: CCOC(=O)C(C)OCCCCI
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)OCCCCBr

Procedure:
The lactic acid ethyl ester and 1,4-dibromo-butane were reacted in THF in the presence of NaH to obtain 7-bromo-2-methyl-3-oxaheptanoic acid ethyl ester and subsequently, the exchange of bromine and iodine was carried out, as described in 4 (d). Boiling point2.3 : 120° - 123° C.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH2:32]([N:34]1[CH2:39][CH2:38][CH:37]([CH2:40][NH2:41])[CH2:36][CH2:35]1)[CH3:33]>>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][NH:41][CH2:40][CH:37]3[CH2:38][CH2:39][N:34]([CH2:32][CH3:33])[CH2:35][CH2:36]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CCN1CCC(CN)CC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Product: CCN1CCC(CNCc2cn(CC3CC3)c(=O)c3ccc(-c4cc(C(=O)NC5CC5)cc(F)c4C)cc23)CC1

Procedure:
The title compound was prepared as a solid according to the method of Example 75 step ii) using product of Example 75 step i) and C-(1-ethyl-piperidin-4-yl)-methylamine.
Reaction SMILES: C(OC([NH:11][C@H:12]([CH3:22])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:11][C@H:12]([CH3:22])[CH2:13][CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: C[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@@H](N)CCC(=O)OC(C)(C)C
Reaction time: 3 h
Yield: 106.3 %

Procedure:
To a solution of tert-butyl (4R)-4-{[(benzyloxy)carbonyl]amino}pentanoate (3.5 g, 11.4 mmol) in methanol (35 ml) was added Pd—C (0.7 g) and the mixture was stirred under a hydrogen atomosphere for 3 hours. Catalyst was-removed by filtration and the solvent was removed in vacuo to give tert-butyl(4R)-4-aminopentanoate (2.1 g).
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]1[CH2:21][CH2:20][N:19](C(OCC3C=CC=CC=3)=O)[CH2:18][CH2:17]1)[C:11](=[O:32])[N:10]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[C:36]([O:42][CH3:43])[CH:35]=1)[C:9]2=[O:44])(=[O:3])[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[CH3:43][O:42][C:36]1[CH:35]=[C:34]([CH:39]=[CH:38][C:37]=1[O:40][CH3:41])[CH2:33][N:10]1[C:9](=[O:44])[C:8]2[C:13](=[CH:14][CH:15]=[C:6]([CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:7]=2)[N:12]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:11]1=[O:32]
Reactant: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCN(C(=O)OCc4ccccc4)CC3)c2=O)cc1OC
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COc1ccc(Cn2c(=O)c3cc(CNC(C)=O)ccc3n(C3CCNCC3)c2=O)cc1OC
Yield: 99.1 %

Procedure:
A mixture of 0.1 g of benzyl 4-{6-[(acetylamino)methyl]-3-(3,4-dimethoxybenzyl)-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl}piperidine-1-carboxylate obtained in stage 5.6, 0.016 g of ammonium formate and 0.018 g of Pd/C (10%) in 2 ml of EtOH purged beforehand with nitrogen is irradiated under a microwave field at 80° C. for 30 min. The mixture is filtered and the filtrate is evaporated under reduced pressure to give 0.077 g of the expected product.
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]1=O.C([O-])(=O)C.[Na+].[CH3:17][NH:18][C:19]([NH2:21])=[S:20]>C(O)(=O)C>[CH3:17][NH:18][C:19]1[S:20][C:2]2[C:7](=[O:8])[CH2:6][C:5]([CH3:10])([CH3:9])[CH2:4][C:3]=2[N:21]=1
Reactant: CNC(N)=S
Reactant: CC1(C)CC(=O)C(Br)C(=O)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CNc1nc2c(s1)C(=O)CC(C)(C)C2
Temperature: 25 °C
Yield: 81.3 %

Procedure:
82 g of 2-bromo-5,5-dimethylcyclohexane-1,3-dione, 40 g of sodium acetate and 50 g of N-methylthiourea are dissolved in 500 ml of acetic acid. The mixture is stirred at room temperature until the weakly exothermic reaction has subsided, and then refluxed for 3 hours. The reaction mixture is then concentrated to one third of its volume in a rotary evaporator, poured into 100 ml of water and cooled to 0° C. The precipitate is collected by filtration and dried in vacuo at 80° C., affording 64 g of 2-methylamino-5,5-dimethyl-7-oxo-4,5-dihydro-6H-benzthiazole with a melting point of 217°-218° C.