Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[C:15]([N:19]5[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]5)[CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC2C3C(C(=O)N(C4C=C[C:44]([O:47]C)=CC=4)N=3)=CNC=2C=1>>[CH3:44][O:47][C:4]1[CH:5]=[CH:6][C:1]([N:7]2[C:25](=[O:26])[C:10]3=[CH:11][NH:12][C:13]4[CH:14]=[C:15]([N:19]5[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]5)[CH:16]=[CH:17][C:18]=4[C:9]3=[N:8]2)=[CH:2][CH:3]=1
Reactant: COc1ccc(-n2nc3c4ccc(N)cc4[nH]cc-3c2=O)cc1
Reactant: O=c1c2c[nH]c3cc(N4CCNCC4)ccc3c-2nn1-c1ccccc1
Product: COc1ccc(-n2nc3c4ccc(N5CCNCC5)cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure for 14a using 13c. 1H-NMR (DMSO-d6) δ (ppm): 3.04 (4H, br), 3.75 (3H, s), 3.90 (4H, br), 6.8 (1H, m), 7.26 (2H, m), 7.42 (1H, m), 7.87 (1H, d, J=8.79 Hz), 8.05 (2H, d, J=9.06 Hz), 8.62 (1H, br). m/z 376.4 (MH+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.C(=O)([O-])[O-].[F:16][C:17](=[C:22]([F:24])[F:23])[CH2:18][C:19](Cl)=[O:20]>ClCCl.O>[F:16][C:17](=[C:22]([F:24])[F:23])[CH2:18][C:19]([NH:1][C:2]1[N:3]=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([O:8][CH3:9])[N:7]=1)=[O:20]
Reactant: COc1cc(OC)nc(N)n1
Reactant: O=C(Cl)CC(F)=C(F)F
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Product: COc1cc(OC)nc(NC(=O)CC(F)=C(F)F)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 10.7 %

Procedure:
To an ice-cooled stirred suspension of 2-amino-4,6-dimethoxypyrimidine (1.55 g, 10 mmol) in dichloromethane (50 mL) and potassinm carbonate (2.76 g, 20 mmol) in water (20 mL) was added 3,4,4-trifluoro-3-butenoyl chloride (3.17 g, 20 mmol). The reaction mixture was stirred in cold for 10 min and at r.t. for 15 min. The organic layer was washed with 3N HCl (2×25 mL), saturated sodium bicarbonate (25 mL) and brine, and dried. Evaporation of the solvent gave 0.296 g (10%) of the title compound as a white solid. m.p. 127°-130° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][CH:6]=1)(=[O:4])[CH2:2][CH3:3].[N+:15]([O-])([OH:17])=[O:16].O>OS(O)(=O)=O>[N+:15]([C:7]1[CH:6]=[C:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH:10]=[CH:9][C:8]=1[NH:11][C:12](=[O:14])[CH3:13])([O-:17])=[O:16]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)c1ccc(NC(C)=O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: CCC(=O)c1ccc(NC(C)=O)c([N+](=O)[O-])c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
To a solution of N-(4-propionylphenyl)acetamide (1.91 g, 10 mmol) in 20 mL of concentrated H2SO4 was added 2 mL 98% HNO3 over 10 minutes while maintain the temperature at −10° C. After stirring for 0.5 h, the mixture was poured into 100 mL of cold water. The precipitate was collected by filtration and washed with water to give the crude product (1.18 g, 50%), which was used directly in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][OH:39])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.B(F)(F)F.CCOCC.O1CCCC1.[OH-].[Na+]>C1(OC)C=CC=CC=1.C(O)(=O)C.O.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][OH:39])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(N)n3)[C@H]2SC1
Temperature: 10 °C
Reaction time: 0.33 h
Yield: 34.9 %

Procedure:
To a solution of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (5 g) in a mixture of anisole (20 ml) and acetic acid (5 ml) was added dropwise boron trifluoride etherate (5 ml) at 10° C. After stirring for 20 minutes at 10° C., the reaction mixture was poured into a mixture of tetrahydrofuran (100 ml), ethyl acetate (100 ml) and water (100 ml), and then adjusted to pH 6.0 with 20% aqueous sodium hydroxide. The resultant aqueous layer was separated and washed with ethyl acetate under keeping the pH value at 6.0. This solution was subjected to chromatography on aluminum oxide. The fractions eluted with 3% aqueous sodium acetate were collected and adjusted to pH 4.0 with 10% hydrochloric acid. This solution was further chromatographed on nonionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries). The fractions eluted with 20% aqueous acetone were collected, concentrated in vacuo and adjusted to pH 2.0 with 10% hydrochloric acid. The resultant precipitate was collected by filtration and dried in vacuo to give 7-[2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (1.23 g).
Reaction SMILES: CC1(C)C[O:5][C:4]([C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[N:28]([CH2:29][CH2:30][O:31][CH2:32][CH3:33])[C:27]5[CH:34]=[CH:35][CH:36]=[CH:37][C:26]=5[N:25]=4)[CH2:20][CH2:19]3)=[CH:12][CH:11]=2)([CH3:9])[CH3:8])=N1.Cl.[OH-].[Na+].C([O:44]C(=O)C)C>C(O)CCC>[CH2:32]([O:31][CH2:30][CH2:29][N:28]1[C:27]2[CH:34]=[CH:35][CH:36]=[CH:37][C:26]=2[N:25]=[C:24]1[CH:21]1[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][C:13]2[CH:12]=[CH:11][C:10]([C:7]([CH3:9])([CH3:8])[C:4]([OH:44])=[O:5])=[CH:15][CH:14]=2)[CH2:23][CH2:22]1)[CH3:33]
Reactant: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C4=NC(C)(C)CO4)cc3)CC2)nc2ccccc21
Reactant: CCOC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCO
Product: CCOCCn1c(C2CCN(CCc3ccc(C(C)(C)C(=O)O)cc3)CC2)nc2ccccc21
Yield: 87 %

Procedure:
In a reaction vessel, 2-[1-(2-{4-[1-(4,4-dimethyl-4,5-dihydro-oxazol-2-yl)-1-methyl-ethyl]-phenyl}-ethyl)-piperidin-4-yl]-1-(2-ethoxy-ethyl)-1H-benzoimidazole (4.4 g) prepared in the Example 18 and hydrochloric acid aqueous solution (50 mL) were introduced, and the mixture was stirred with reflux. After the reaction was completed, sodium hydroxide solution was added to control the pH to 7. Ethylacetate (50 mL) was added to separate a layer, and the organic layer was condensed under reduced pressure. And, butanol (9 mL) was added and dissolved by heating. And then, it was cooled to precipitate crystals, and the crystals were filtered under reduced pressure to obtain 2-[4-(2-{4-[1-(2-ethoxy-ethyl)-1H-benzoimidazol-2-yl]-piperidin-1-yl}-ethyl)-phenyl]-2-methyl-propionic acid (3.43 g, yield 87%, HPLC purity 99% or more).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][NH2:13])([O-:3])=[O:2].[C:17]1([N:27]=[C:28]=[S:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>ClCCl>[C:17]1([NH:27][C:28]([NH:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][C:6]2[CH:14]=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[S:29])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: NCCCCCOc1cccc([N+](=O)[O-])c1
Solvent: ClCCl
Product: O=[N+]([O-])c1cccc(OCCCCCNC(=S)Nc2cccc3ccccc23)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of 5-(3-nitro-phenoxy)-pentylamine (867 mg, 3.87 mmol) in dichloromethane (5 mL) was added 1-naphthyl isothiocyanate (788 mg, 4.26 mmol) at room temperature. The reaction mixture was stirred at room temperature overnight. After removal of the solvent, the residue was purified by silica gel column chromatography to give 1-naphthalen-1-yl-3-[5-(3-nitro-phenoxy) -pentyl]-thiourea (1.3 g, 3.18 mmol, 82%) as a yellow gel.
Reaction SMILES: [CH3:1][S:2]([CH2:5][C:6]([OH:8])=O)(=[O:4])=[O:3].O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH2:41])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:31][C:32]1[C:33]([F:42])=[C:34]2[C:40]([NH:41][C:6](=[O:8])[CH2:5][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:39][NH:38][C:35]2=[N:36][CH:37]=1
Reactant: CS(=O)(=O)CC(=O)O
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CC(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
2-(Methylsulfonyl)acetic acid (601 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 (50 mL) was added. The resulting suspension was filtered, and the solid was rinsed with DCM and water. After drying, N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)acetamide (503 mg, 66.1% yield) was obtained as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1>CC(O)=O.[Pd]>[CH3:1][N:2]([CH3:10])[CH:3]1[CH2:9][CH2:8][CH:6]([NH2:7])[CH2:5][CH2:4]1
Reactant: CN(C)c1ccc(N)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CN(C)C1CCC(N)CC1
Yield: 22.8 %

Procedure:
A mixture of 68 g of 4-dimethylaminoaniline and 34 g of 5% palladium-on-charcoal in 250 ml of AcOH is hydrogenated at a temperature of 75°-90° C. under a pressure of 50 bar. The catalyst is filtered off and washed with water and the filtrate is evaporated under vacuum. The residue is taken up with water, rendered alkaline by the addition of concentrated NaOH, extracted with AcOEt and dried over Na2SO4 and the solvent is evaporated off under vacuum. The oil obtained is distilled under reduced pressure to give 16.2 g of the expected product in the form of an oil. B.p.=102°-110° C. under 20 mm Hg.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:13][CH:14]=1.O>CN1C(=O)N(C)CCC1.C1COCC1>[C:15]1([C:12]2[O:13][CH:14]=[C:10]([CH2:9][O:4][CH2:3][CH2:2][CH2:1][OH:5])[N:11]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: ClCc1coc(-c2ccccc2)n1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCCN(C)C1=O
Product: OCCCOCc1coc(-c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1,3-Propanediol (3.6 mL, 50 mmol) is dissolved in 10% DMPU in THF and cooled to 0° C. Sodium hydride is added portionwise (60%, 400 mg, 10 mmol). The contents are stirred for 10 min at 0° C., warmed to r.t. and stirred for another 10 min. 4-Chloromethyl-2-phenyl-oxazole (2.0 g, 10 mmol, EXAMPLE 21) is added, and the contents heated to 60° C. for 4 days. The reaction is cooled to r.t., poured into water (200 mL) and extracted with ethyl acetate (2×200 mL). The organic fractions were pooled and washed with brine (2×200 mL), dried over MgSO4, filtered and reduced under vacuum to an oil. The crude material was purified by flash chromatography (silica, 2% methanol in dichloromethane) to give the title compound. MS (ESI) 234 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:24])[N:6]=1)=[O:4].[NH2:25][C@H:26]([CH2:28][OH:29])[CH3:27].N12CCCNC1=NCCC2>C1(C)C=CC=CC=1>[OH:29][CH2:28][C@@H:26]([NH:25][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[N:7]([CH3:24])[N:6]=1)=[O:4])[CH3:27]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)n(C)n1
Reactant: C[C@H](N)CO
Agent: C1CN=C2NCCCN2C1
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccn2)c1COc1cc(C(=O)N[C@@H](C)CO)nn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a solution of 1-methyl-5-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-1H-pyrazole-3-carboxylic acid methyl ester (80 mg, 0.24 mmol) and L-alaninol (24 mg, 0.32 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (14 mg, 0.1 mmol) and the reaction was stirred at room temperature under argon overnight. The mixture was evaporated and purification by chromatography (silica, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (87 mg, 96%) which was obtained as a colorless oil. MS: m/e=372.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[Br:21]Br.OS([O-])=O.[Na+]>C(O)(=O)C>[Br:21][C:20]1[CH:19]=[C:6]([CH:5]=[CH:4][C:3]=1[O:2][CH3:1])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][CH:9]=1
Reactant: COc1ccc(Cc2ccc(NS(C)(=O)=O)cc2)cc1
Reactant: BrBr
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cc2ccc(NS(C)(=O)=O)cc2)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.1 %

Procedure:
A round bottom was charged with N-[4-(4-Methoxy-benzyl)-phenyl]-methane sulfonamide (8) (1.4 g, 4.8 mmol), acetic acid (15 mL) and slow addition of bromine (5 minute period, 0.23 mL, 5.2 mmol). The reaction mixture was stirred at room temperature overnight. To the yellow homogeneous reaction mixture 15% w/v of aq. NaHSO3 (50 mL) was added. The reaction mixture formed a white precipitate. The reaction mixture was stirred for 30 minutes. Then the solid was collected, rinsed several times with water and dried in vacuo to provide 961.9 mg (56% yield) of product (9).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12]Br)=[CH:7][CH:6]=1)[CH3:2].[CH3:16][C:17]1[NH:21][C:20](=[O:22])[C:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:18]=1.C(=O)([O-])[O-].[K+].[K+].C1CCCCC1.C(OCC)(=O)C>CC(C)=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][N:21]2[C:20](=[O:22])[C:19]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:18]=[C:17]2[CH3:16])=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Reactant: CC1=NC(c2ccccc2)(c2ccccc2)C(=O)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(C(=O)CN2C(=O)C(c3ccccc3)(c3ccccc3)N=C2C)cc1
Temperature: 70 °C
Yield: 48.1 %

Procedure:
To a mixture of 4-(2-bromo-acetyl)-benzoic acid ethyl ester (812 mg, 3 mmol) and 2-methyl-5,5-diphenyl-3,5-dihydro-imidazol-4-one (750 mg, 3 mmol) in 12 mL acetone, potassium carbonate (502 mg, 3.6 mmol) is added and the reaction mixture is heated at 70° C. for 5 min in the microwave oven (Biotage Initiator). The mixture is cooled to room temperature, filtered and the filtrate evaporated to yield the crude product which is subjected to flash chromatography. ISCO Companion CombiFlash, 80 g silica gel, cyclohexane/ethyl acetate, gradient, ethyl acetate 0-100% to yield 4-[2-(2-methyl-5-oxo-4,4-diphenyl4,5-dihydro-imidazol-1-yl)-acetyl]-benzoic acid ethyl ester (635 mg, 45%) as light yellow solid. LC/MS at 254 nm; [M+H] 441; Rt 3.613 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[N:9][C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]=2)=[N:7]1.[CH3:31][S:32]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])=[O:33].CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.O.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]>[CH3:11][C:10]1[N:6]([CH2:5][C:4]2[CH:28]=[CH:29][CH:30]=[C:2]([N:38]3[CH2:39][CH2:40][CH:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:36][CH2:37]3)[CH:3]=2)[N:7]=[C:8]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH:13]=2)[N:9]=1
Reactant: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(Br)c1
Reactant: CS(=O)(=O)C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc(-c2cc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cccc(N2CCC(S(C)(=O)=O)CC2)c1
Temperature: 106 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(1-(3-bromobenzyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoromethoxy)phenyl)-isoxazole (48 mg, 0.1 mmol) in toluene (5 ml) were added 4-(methylsulfonyl)-piperidine (33 mg, 0.2 mmol), Ruphos (4.8 mg, 0.01 mmol), Pd2(dba)3 (9.2 mg, 0.01 mmol) and t-BuONa (19.2 mg, 0.2 mmol). The mixture was stirred under Ar atmosphere at 106° C. for 16 h, then cooled to RT, diluted with H2O (20 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were washed with H2O (10 mL) and brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure; the residue was purified by silica gel chromatography (Petroleum ether:EtOAc=1:1) to give the title compound as a white solid; MS (ES+) C26H26F3N5O4S requires: 561. found: 562[M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.91 (d, J=6.8 Hz, 2H), 7.33 (d, J=6.4 Hz, 2H), 7.25 (m, 1H), 7.10 (s, 1H), 6.89 (d, J=6.4 Hz, 1H), 6.80 (s, 1H), 6.72 (d, J=6.0 Hz, 1H), 5.34 (s, 2H), 3.82 (bd, J=10.0 Hz, 2H), 2.96 (m, 1H), 2.86 (s, 3H), 2.77 (m, 2H), 2.50 (s, 3H), 2.24 (bd, J=10.0 Hz, 2H), 1.95 (m, 2H).
Reaction SMILES: II.[CH:3]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:4].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].Cl>[Zn].O1CCCC1>[C:26]([O:25][C:23](=[O:24])[CH2:22][CH:3]([OH:4])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:12])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=CCCCCCCC(=O)OCc1ccccc1
Agent: Cl
Agent: II
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CCCCCCC(=O)OCc1ccccc1

Procedure:
A stirred suspension of 59 g. (0.75 g-atom) of activated zinc in 500 ml. of dry tetrahydrofuran containing a crystal of iodine is brought to reflux under nitrogen. To this is added slowly a solution of 12.1 g. (0.50 mol.) of benzyl 7-formylheptanoate and 117 g. (0.60 mol.) of t-butyl bromoacetate in 500 ml. of dry tetrahydrofuran. Within a few minutes, the solution becomes cloudy and the iodine color disappears, indicating that the reaction has started. After the addition is complete (30 minutes), the mixture is stirred and refluxed for an additional hour. The cooled solution is then poured into 0.1 N hydrochloric acid and the pH adjusted to 2 with 2 N hydrochloric acid. The excess zinc is filtered off and the filtrate thoroughly extracted with ethyl acetate. The combined extracts are dried and concentrated in vacuo to give crude 3-hydroxydecanedioic acid 10-benzyl ester-1-t-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:10])[CH:6]=[C:7]([CH3:9])[CH:8]=1.CS(O[CH2:16][C@@H:17]1[C@:26]2([CH3:27])[C@H:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][C@:18]1([OH:31])[CH3:30])(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:10][CH2:16][C@@H:17]2[C@:26]3([CH3:27])[C@H:21]([C:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][CH2:25]3)[CH2:20][CH2:19][C@@:18]2([CH3:30])[OH:31])[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: CC1(C)CCC[C@]2(C)[C@@H](COS(C)(=O)=O)[C@](C)(O)CC[C@@H]12
Reactant: COc1cc(C)cc(S)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc(C)cc(SC[C@@H]2[C@@]3(C)CCCC(C)(C)[C@@H]3CC[C@@]2(C)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.2 %

Procedure:
A mixture of 3-methoxy-5-methylbenzenethiol (11) (3.14 g, 20.4 mmol), ((1S,2R,4aS,8aS)-2-hydroxy-2,5,5,8a-tetramethyldecahydronaphthalen-1-yl)methyl methanesulfonate (12) (6.48 g, 20.4 mmol), and Cs2CO3 (19.90 g, 61.08 mmol) in CH3CN (300 mL) was stirred at room temperature for 1 h, then refluxed for 24 h. After cooling, the mixture was concentrated. Purification by chromatography on silica gel (Hexanes/EtOAc, 4:1) gave (1R,2R,4aS,8aS)-1-{[(3-methoxy-5-methylphenyl)sulfanyl]methyl}-2,5,5,8a-tetramethyl-decahydronaphthalen-2-ol (13) (5.70 g, purity ˜75%) as a yellow sticky mass.
Reaction SMILES: [CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[NH:13][CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1.Cl[CH2:23][C:24](=[O:26])[CH3:25]>>[CH:1]1([CH2:5][N:6]2[C:15](=[O:16])[C:14]3[N:13]([CH2:23][C:24](=[O:26])[CH3:25])[CH:12]=[N:11][C:10]=3[N:9]([CH2:17][CH:18]3[CH2:21][CH2:20][CH2:19]3)[C:7]2=[O:8])[CH2:4][CH2:3][CH2:2]1
Reactant: CC(=O)CCl
Reactant: O=c1c2[nH]cnc2n(CC2CCC2)c(=O)n1CC1CCC1
Product: CC(=O)Cn1cnc2c1c(=O)n(CC1CCC1)c(=O)n2CC1CCC1

Procedure:
1,3-Di-cyclobutylmethyl-7-(2-oxopropyl)-xanthine was prepared from 1,3-di-cyclobutylmethyl xanthine and chloroacetone using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 155° C.
Reaction SMILES: C(OC([N:8]1[C@@H:12]([CH2:13][CH2:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[O:16][CH3:17])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][C@@H:12]([CH2:13][CH2:14][CH:15]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[O:16][CH3:17])[CH2:11][OH:10]
Reactant: COC(CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: COC(CC[C@H](N)CO)c1ccc(Cl)cc1

Procedure:
In analogy to example 45c (S)-4-[3-(4-chloro-phenyl)-3-methoxy-propyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with trifluoroacetic acid to give (S)-2-amino-5-(4-chloro-phenyl)-5-methoxy-p entan-1-ol. Yellow oil. MS (ISP): 246.1 ([{37Cl}M+H]+), 244.1 ([{35Cl}M+H]+).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[N:25]=[CH:24][N:23]=[C:22]([O:26][C:27]2[CH:37]=[C:36]([CH3:38])[C:30]3[N:31]([CH3:35])[C:32](=[O:34])[O:33][C:29]=3[CH:28]=2)[CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:35][N:31]1[C:30]2[C:36]([CH3:38])=[CH:37][C:27]([O:26][C:22]3[N:23]=[CH:24][N:25]=[C:20]([N:3]4[CH2:4][CH2:5][CH:6]([N:9]5[C:17]6[C:12](=[N:13][CH:14]=[CH:15][CH:16]=6)[NH:11][C:10]5=[O:18])[CH2:7][CH2:8]4)[CH:21]=3)=[CH:28][C:29]=2[O:33][C:32]1=[O:34]
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: Cc1cc(Oc2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.34 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 100 mg (0.34 mmol) 6-(6-chloro-pyrimidin-4-yloxy)-3,4-dimethyl-3H-benzoxazol-2-one and 0.15 mL (0.86 mmol) DIPEA were combined in 1.8 mL DMF and stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down and the precipitate was suction filtered and dried i. vac.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>O>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[C:30]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of toluene (35 mL) and water (5 mL) was degassed with nitrogen for 30 minutes. A mixture of sodium carbonate (1.9 g, 18.09 mmol), 4-bromobenzaldehyde (0.7 g, 3.72 mmol), 3-trifluoromethoxyphenylboronic acid (2.86 g, 4.78 mmol) and tetrakis triphenyl phosphene palladium(0) (0.9 g, 0.75 mmol) was added to the above degassed water/toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (0.8 g, 80%).