Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:20][CH3:21])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>C(OCC)(=O)C.CO>[CH3:24][N:25]([CH3:27])[CH:26]=[CH:2][C:1]([C:4]1[CH:5]=[C:6]([N:10]([CH2:20][CH3:21])[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CCN(c1cccc(C(C)=O)c1)S(=O)(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN(c1cccc(C(=O)C=CN(C)C)c1)S(=O)(=O)c1ccccc1
Yield: 96 %

Procedure:
1.05 g (3.46 mmol) of N-(3-acetyl-phenyl)-N-ethyl-benzenesulfonamide were dissolved in 10 ml of N,N-dimethylformamide dimethylacetal and the resultant solution was refluxed for 18 hours. The excess of volatile reagent was removed by reduced pressure distillation to yield a crude which was chromatographied over silica gel using a gradient of ethyl acetate/methanol as eluent. 1.2 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethyl-benzenesulfonamide as a yellowish-white solid were obtained (yield 96%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:11](Cl)(=[O:13])=[O:12])[CH:7]=[CH:8][C:9]=1[Cl:10])([O-:3])=[O:2].ClCCl.[CH2:18]([NH2:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>C(N(CC)CC)C>[CH2:18]([NH:34][S:11]([C:6]1[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)(=[O:13])=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]
Reactant: CCCCCCCCCCCCCCCCN
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCNS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Yield: 89 %

Procedure:
To a mixture of 800 g of 3-nitro-4-chlorobenzenesulfonyl chloride and 1,000 ml of dichloromethane, was added dropwise a dichloromethane solution containing 600 g of hexadecylamine and 251 ml of triethylamine. After completion of the reaction, the reaction solvent was removed by distillation under reduced pressure. The residue was dissolved in 3,000 ml of methanol under heating, followed by gradually cooling to precipitate crystals, which were collected by filtration and dried to give 1,020 g (88%) of the noted compound.
Reaction SMILES: [OH-].[K+].[C:3]([C:7]1[CH:8]=[C:9]([O:17][C@H:18]([CH3:23])[C:19]([O:21]C)=[O:20])[CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)([CH3:6])([CH3:5])[CH3:4].Cl>O.O1CCCC1>[C:3]([C:7]1[CH:8]=[C:9]([O:17][C@H:18]([CH3:23])[C:19]([OH:21])=[O:20])[CH:10]=[C:11]([C:13]([CH3:14])([CH3:15])[CH3:16])[CH:12]=1)([CH3:4])([CH3:5])[CH3:6]
Reactant: COC(=O)[C@@H](C)Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(C(C)(C)C)cc(C(C)(C)C)c1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of 2.0 g (36 mmol) of potassium hydroxide in water (100 mL) and tetrahydrofuran (100 mL) was added 11.48 g (36 mmol) of methyl (2R)-2-(3,5-di-t-butylphenyloxy)propanate (13). The reaction mixture was allowed to stir overnight at room temperature. The reaction mixture was acidified to pH 2 with concentrated hydrochloric acid and the resulting solution was extracted with diethyl ether (3×200 mL). The combined extracts were washed with an aqueous saturated sodium chloride solution (1×300 mL) and dried (MgSO4). Filtration and concentration resulted in a yellowish sludge. The crude product was purified by precipitation from hexane at -78° C. to afford 8.2 g (75%) of (2R)-2-(3,5-di-t-butylphenyloxy)propanoic acid (14) as an off-white crystalline material: 1H NMR (CDCl3) δ1.29 (s, 18 H), 1.64-1.66 (d, 3 H), 4.56-4.82 (q, 1 H), 6.75 (s, 2 H), 7.06 (s, 1 H); 13C NMR (CDCl3) δ177.7, 156.8, 152.5, 116.2, 109.7, 72.3, 35.0, 31.4, 18.4.
Reaction SMILES: [C:1]1([S:7]([N:10]2[CH2:12][CH:11]2[C:13]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=3[CH3:28])[CH2:17][CH2:16]2)=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[I-].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>>[C:1]1([S:7]([N:10]2[CH2:12][CH:11]([C:13]([N:15]3[CH2:16][CH2:17][N:18]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[CH3:28])[CH2:19][CH2:20]3)=[O:14])[N:38]([C:35]3[CH:36]=[CH:37][C:32]([F:31])=[CH:33][CH:34]=3)[C:39]2=[O:40])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CN3S(=O)(=O)c3ccccc3)CC2)c1
Agent: [I-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4)C(=O)N3c3ccc(F)cc3)CC2)c1

Procedure:
In analogy to example 2, (RS)-(1-benzenesulfonyl-aziridin-2-yl)-[4-(2,5-dimethyl-phenyl)-piperazin-1-yl]-methanone (example 2, step 3) was reacted with sodium iodide and 4-fluorophenyl isocyanate to give the title compound as a colorless solid. MS: 537.0 ([M+H]+)
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=[N:5]1)[CH3:3].[B-](F)(F)(F)[F:15].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1.C(#N)C>C(O)(=O)C>[F:15][C:7]1[CH:6]=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1ccnn1C(C)C
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1c(F)cnn1C(C)C
Temperature: 100 °C

Procedure:
A microwave vial was charged with ethyl 1-(1-methylethyl)-1H-pyrazole-5-carboxylate (0.15 g) and Selectfluor™ (0.38 g) followed by acetonitrile (3 ml) and acetic acid (1 ml). The mixture was heated at 100° C. under microwave irradiation for 180 min. Selectfluor™ (0.076 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. Further Selectfluor™ (0.15 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. Further Selectfluor (0.38 g) was added and the mixture heated at 100° C. under microwave irradiation for 60 min. The solvent was removed in vacuo and the residue was partitioned between DCM (15 ml) and water (15 ml) and separated using a hydrophobic frit. The aqueous layer was extracted with dichloromethane (2×5 ml) and the combined organic layers were concentrated in vacuo. Purification by chromatography on silica gel (20 g silica cartridge), eluting with a gradient of 0-50% DCM in cyclohexane over 20 minutes gave the title compound (100 mg) as a colourless oil.
Reaction SMILES: CC(C)=O.C(=O)=O.C([O:15][CH2:16][C@@H:17]([CH2:28][N:29]1[CH:34]=[C:33]([CH3:35])[C:32](=[O:36])[N:31](C(=O)C2C=CC=CC=2)[C:30]1=[O:45])[C@H:18]([O:20][Si](C(C)(C)C)(C)C)[CH3:19])C1C=CC=CC=1.B(Cl)(Cl)Cl>ClCCl>[CH3:35][C:33]1[C:32](=[O:36])[NH:31][C:30](=[O:45])[N:29]([CH2:28][C@@H:17]([C@H:18]([OH:20])[CH3:19])[CH2:16][OH:15])[CH:34]=1
Reactant: Cc1cn(C[C@H](COCc2ccccc2)[C@@H](C)O[Si](C)(C)C(C)(C)C)c(=O)n(C(=O)c2ccccc2)c1=O
Agent: ClB(Cl)Cl
Agent: O=C=O
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cc1cn(C[C@H](CO)[C@@H](C)O)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 70.7 %

Procedure:
To a cold (−77° C., acetone/dry ice bath) solution of 5 (2.0 g, 3.72 mmol) in 100 ml of anhydrous dichloromethane was added (via syringe) 38 ml of 1M BCl3 in dichloromethane over 5 min. The reaction was stirred for 6 hrs until no more changes were observed by HPLC analysis and then quenched by adding a mixture of pyridine (26 ml) and methanol (54 ml) over 5 min. The reaction mixture was allowed to warm up to room temperature and concentrated. The resultant material was re-dissolved in methanol (100 ml) and co-evaporated twice with triethylamine (10 ml) to remove pyridine. The residue was suspended in dichloromethane and filtered to remove some triethylammonium chloride. The solid were washed with dichloromethane and the combined filtrates were concentrated and then chromatographed on silica eluting with 10% methanol in dichloromethane. Concentration of the pure product fractions afforded 0.6 g (70%) of nucleoside 6. 1H NMR (DMSO-d6): δ 11.19 (s, 1H), 7.46 (s, 1H), 4.56 (d, J=4.8 Hz, 1H), 4.50 (t, J=5.1 Hz, 1H), 3.83 (m, 1H), 3.73 (m, 1H), 3.57 (m, 1H), 3.38 (m, 2H), 1.75 (s, 3H), 1.73 (m, 1H). 1.10 (d, J=6.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][C:10]=2[CH3:19])[O:3]1.[Br:21]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:21][CH2:19][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]=1[B:4]1[O:3][C:2]([CH3:20])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2ccccc2c1B1OC(C)(C)C(C)(C)O1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC1(C)OB(c2c(CBr)ccc3ccccc23)OC1(C)C
Temperature: 75 °C
Reaction time: 14 h
Yield: 101.8 %

Procedure:
A mixture of 47.3 g (176 mmol) of 4,4,5,5-tetramethyl-2-(2-methyl-1-naphthyl)-1,3,2-dioxaborolane, 33.0 g (185 mmol) of NBS (N-Bromosuccinimide) and 0.17 g of benzoyl peroxide in 340 ml of CCl4 was stirred at 75° C. for 14 h. Thereafter the reaction mixture was cooled to room temperature, filtered through glass frit (G3), and the filtrate was evaporated to dryness. This procedure gave 62.2 g (99%) of beige solid. Anal. calc. for C17H20BBrO2: C, 58.83; H, 5.81. Found: C, 59.00; H, 5.95. 1H NMR (CDCl3): 8.30 (m, 1H, 8-H), 7.84 (d, J=8.3 Hz, 1H, 4-H), 7.79 (m, 1H, 5-H), 7.43-7.52 (m, 3H, 3,6,7-H), 4.96 (s, 2H, CH2Br), 1.51 (s, 12H, CMe2CMe2).
Reaction SMILES: C(N(CC)CC)C.[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]=O)=[N+:9]=[N-:10].[NH2:19][C:20]1[C:27]([Cl:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=1[Cl:29]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[N:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1/[CH:17]=[N:19]/[C:20]1[C:21]([Cl:29])=[CH:22][C:23]([C:24]#[N:25])=[CH:26][C:27]=1[Cl:28])=[N+:9]=[N-:10]
Reactant: [N-]=[N+]=Nc1ccncc1C=O
Reactant: N#Cc1cc(Cl)c(N)c(Cl)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cc(Cl)c(/N=C/c2cnccc2N=[N+]=[N-])c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triethylamine (8.9 mL, 64.2 mmol) was added to a cooled (0° C.) mixture of 4-azidopyridine-3-carbaldehyde (3.2 g, 21.4 mmol) and 4-amino-3,5-dichlorobenzonitrile (4.0 g, 21.4 mmol) in DCM (80 mL) under nitrogen. Titanium tetrachloride (1M, 12.8 mL, 12.8 mmol) was added and then the reaction mixture was stirred for 1 hour at 0° C. After warming to room temperature, the reaction was stirred for an additional 2 h and then concentrated under reduced pressure. The residue was suspended in toluene and filtered though a pad of Celite®. The filtrate was concentrated to dryness under reduced pressure to afford the title compound as an orange solid. This crude material was employed in the next step without further purification or analysis.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:7]2[NH:8][C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1.[CH2:18](Br)[C:19]#[CH:20].O>CN(C)C=O>[F:3][C:4]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:7]2[N:8]([CH2:20][C:19]#[CH:18])[C:9](=[O:12])[CH2:10][O:11][C:6]=2[CH:5]=1
Reactant: O=C1COc2cc(F)c([N+](=O)[O-])cc2N1
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)COc2cc(F)c([N+](=O)[O-])cc21
Temperature: 0 °C
Reaction time: 6 h
Yield: 69.9 %

Procedure:
A suspension of sodium hydride (0.06 g) in N,N-dimethylformamide (3 ml) was cooled to 0° C. 7-Fluoro-6-nitro-2H-1,4-benzoxazin-3(4H)-one (0.57 g) was added thereto at 0° to 5° C., and the resultant mixture was stirred for 30 minutes. Propargyl bromide (0.35 g) was added to the mixture, which was gradually heated to room temperature, and the reaction was continued for 6 hours. After addition of water, the resultant mixture was extracted with ethyl acetate, and the extract was washed with water, dried and concentrated. The residue was purified by silica gel thin layer chromatography using a mixture of ethyl acetate and n-hexane (1:1) as an eluent to give 7-fluoro-6-nitro-4-(2-propynyl)-2H-1,4-benzoxazin-3(4H)-one (0.47 g). m.p., 109.1° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=1.[CH3:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[N:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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>[CH3:10][C:11]1[CH:12]=[C:13]([C:2]2[O:6][C:5]([CH3:7])=[C:4]([CH:8]=[O:9])[CH:3]=2)[CH:14]=[N:15][CH:16]=1
Reactant: Cc1oc(Br)cc1C=O
Reactant: Cc1cncc(B(O)O)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1cncc(-c2cc(C=O)c(C)o2)c1
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A mixture of 5-bromo-2-methylfuran-3-carbaldehyde (1.9 g), 5-methyl-3-pyridineboronic acid (1.6 g), tetrakis(triphenylphosphine)palladium(0) (0.6 g), 2N aqueous sodium carbonate solution (12 mL) and 1,2-dimethoxyethane (20 mL) was stirred overnight with refluxing under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane), and crystallized from ethyl acetate/hexane to give the title compound (1.6 g, 81%) as a white crystal.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9](Cl)(=[O:21])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>O1CCCC1>[O:21]=[CH:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C1COCCN1
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=CCCCCCCCCCCCN1CCOCC1

Procedure:
A suspension of 2.30g (57.0 mmol) of sodium hydride (60% oil dispersion) in dry tetrahydrofuran (THF) and 5.0 g (57.0 mmol) of morpholine was refluxed under nitrogen for 30 minutes. After cooling, 12.56 g (57.0 mmol) of dodecanoyl chloride in THF was added dropwise, and the mixture was refluxed 30 minutes. Water was added, and the mixture was extracted with ethyl acetate (EtOAc). The combined organic phase was dried with MgSO4, concentrated in vacuo, and purified by flash chromatography (8:1 hexane/EtOAc) to give N-(oxododecyl)morpholine, as confirmed by NMR & IR spectroscopy.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([NH:9][C:10]2[CH:11]=[N:12][N:13]([CH3:31])[C:14]=2[C@H:15]2[O:21][CH2:20][C@@H:19]([F:22])[C@H:18]([NH:23]C(=O)OC(C)(C)C)[CH2:17][CH2:16]2)=[O:8])[N:6]=1.[F:32][C:33]1[C:38]([O:39][CH3:40])=[CH:37][CH:36]=[C:35]([F:41])[C:34]=1B(O)O>>[NH2:23][C@H:18]1[C@H:19]([F:22])[CH2:20][O:21][C@H:15]([C:14]2[N:13]([CH3:31])[N:12]=[CH:11][C:10]=2[NH:9][C:7]([C:5]2[N:6]=[C:2]([C:34]3[C:35]([F:41])=[CH:36][CH:37]=[C:38]([O:39][CH3:40])[C:33]=3[F:32])[S:3][CH:4]=2)=[O:8])[CH2:16][CH2:17]1
Reactant: Cn1ncc(NC(=O)c2csc(Br)n2)c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@H](F)CO1
Reactant: COc1ccc(F)c(B(O)O)c1F
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnn(C)c3[C@@H]3CC[C@@H](N)[C@H](F)CO3)cs2)c1F

Procedure:
Following the procedure for Example 101 starting from tert-butyl ((3S,4R,7S)-7-(4-(2-bromothiazole-4-carboxamido)-1-methyl-1H-pyrazol-5-yl)-3-fluorooxepan-4-yl)carbamate (Intermediate 99), and replacing 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester with (2,6-difluoro-3-methoxyphenyl)boronic acid gave 229. 1H NMR (400 MHz, DMSO-d6) δ 9.88 (s, 1H), 8.63 (s, 1H), 7.78 (s, 1H), 7.40 (td, J=9.3, 5.1 Hz, 1H), 7.27 (td, J=9.5, 1.9 Hz, 1H), 4.81 (dd, J=10.9, 3.6 Hz, 1H), 4.37 (d, J=47.9 Hz, 1H), 4.24-4.10 (m, 1H), 4.10-3.92 (m, 1H), 3.90 (s, 3H), 3.78 (s, 3H), 3.29-3.19 (m, 1H), 2.11-2.01 (m, 1H), 1.87-1.77 (m, 1H), 1.75-1.66 (m, 2H). LCMS (ES+) m/z 482 (M+1).
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CON(C)[C:20](=[O:23])[CH2:21][CH3:22]>>[C:9]1([C:7]2[O:8][C:4]3[CH:3]=[C:2]([C:20](=[O:23])[CH2:21][CH3:22])[CH:16]=[CH:15][C:5]=3[N:6]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCC(=O)N(C)OC
Reactant: Brc1ccc2nc(-c3ccccc3)oc2c1
Product: CCC(=O)c1ccc2nc(-c3ccccc3)oc2c1

Procedure:
The preparation is carried out analogously to Example 29a from 6-bromo-2-phenyl-benzoxazole and N-methoxy-N-methyl-propionamide.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].Br[C:7]1[C:11](OC)([CH3:12])[CH2:10][CH2:9][C:8]=1[CH3:15].O>CCOCC>[CH2:1]([C:7]1[C:11]([CH3:12])=[CH:10][CH2:9][C:8]=1[CH3:15])[C:2]1[C:3]([CH3:4])=[CH:2][CH2:1][C:3]=1[CH3:4]
Reactant: [Li]CCCC
Reactant: COC1(C)CCC(C)=C1Br
Solvent: O
Solvent: CCOCC
Product: CC1=CCC(C)=C1CC1=C(C)CC=C1C
Reaction time: 0.17 h
Yield: 61 %

Procedure:
One equivalent of n-butyl lithium was added to a solution in which 7.038 g (34.3 mmol) of 2-bromo-3-methoxy-1,3-dimethyl-cyclopentene compound prepared in the example 3 was dissolved in 38 ml of ether at −25° C. nitrogen atmosphere. When white solid was precipitated, the temperature was elevated to 10° C. and the reaction was continued for further 10 minutes. The temperature was lowered to −25° C. and the fulvene compound prepared in the example 2 was added. Completion of reaction is determined by the development of yellow color of the reaction mixture. 50 ml of water was added to the reaction mixture and the solvent was removed using the rotatory evaporator. 50 ml of 2N HCl solution was added to the organic layer extracted with 50 ml of ethyl acetate, and the resulting mixture was vigorously shaked for 2 minutes. Water layer was removed by layer separation and the organic layer was neutralized with 50 ml of a saturated sodium bicarbonate solution. Isolated organic layer was dried over magnesium sulfate, and then the vacuum distillation was preformed to give 4.17 g of yellow 2,2′-methylenebis(1,3-dimethyl-1,3-cyclopentadiene) compound. Yield: 61%.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8](/[CH:10]=C/N(C)C)[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=1)[CH3:2].I([O-])(=O)(=O)=[O:19].[Na+]>O1CCCC1.O>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([CH:10]=[O:19])[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc([N+](=O)[O-])c(/C=C/N(C)C)n1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOc1ccc([N+](=O)[O-])c(C=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of the compound prepared in Example 422 (2.2 g) in tetrahydrofuran (40 mL) was added sodium periodate (5.95 g) in water (40 mL). The mixture was stirred at room temperature overnight. The suspended inorganic solids were filtered out, washed with tetrahydrofuran and the filtrate evaporated in vacuo. The residue was taken in small amount of water and extracted with chloroform, dried, evaporated in vacuo to a brown oil and further dried under high vacuum to afford the title compound (1.6 g) with the following physical data.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[CH:17][C:4]=1[C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.[CH3:25][C:26](=O)[CH2:27][C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[C:4]3[C:3](=[CH:20][C:19]([O:21][CH3:22])=[C:18]([O:23][CH3:24])[CH:17]=3)[N:2]=[C:26]([CH3:25])[C:27]=2[C:28](=[O:34])[CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCCCCC(=O)CC(C)=O
Reactant: COc1ccc(C(=O)c2cc(OC)c(OC)cc2N)cc1OC
Agent: Cl
Product: CCCCCC(=O)c1c(C)nc2cc(OC)c(OC)cc2c1-c1ccc(OC)c(OC)c1

Procedure:
According to the same manner as that described in Reference Example 6, 2-amino-3',4',4,5-tetramethoxybenzophenone hydrochloride was reacted with 2,4-nonanedione to give 4-(3,4-dimethoxyphenyl)-3-hexanoyl-6,7-dimethoxy-2-methylquinoline. This compound was recrystallized from ethanol to give colorless prisms. mp. 123°-125° C.
Reaction SMILES: [F:1][CH:2]([F:17])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)[O:5][N:4]=1.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[F:17][CH:2]([F:1])[C:3]1[C:7]([CH3:8])=[C:6]([C:9]2[S:13][C:12]([C:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[O:16])=[CH:11][CH:10]=2)[O:5][N:4]=1
Reactant: C1CCNCC1
Reactant: Cc1c(C(F)F)noc1-c1ccc(C(=O)O)s1
Product: Cc1c(C(F)F)noc1-c1ccc(C(=O)N2CCCCC2)s1
Yield: 72 %

Procedure:
Prepared from 5-(3-Difluoromethyl-4-methyl-isoxazol-5-yl)-thiophene-2-carboxylic acid (Preparative Example 27) and piperidine by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, then chromatographed on silica gel with EtOAc/hexanes (30 then 40%) as eluant to afford product as a colorless solid (110 mg, 72%). 1H NMR (CDCl3) 1.66-1.72 (6, 3 H), 2.35 (s, 3 H), 3.67-3.71 (m, 4 H), 6.79 (t, J=53.2, 1 H), 7.31 (d, J=4.0, 1 H), 7.45 (d, J=4.0, 1 H). 13C NMR 7.7, 24.7, 26.3, ˜46 (br), 39.8 (br), 108.7, 110.3 (t, J=236), 126.8, 128.8, 130.6, 140.6, 158.6 (q, J=30), 162.1, 162.5. 19F NMR −117.4 (J=53.5). LC/MS 6.36 min, [M+1]+ 327.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].I[CH3:15]>C1COCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[O:10][CH3:15])[CH:5]=[O:6]
Reactant: CI
Reactant: Cc1cc(C=O)cc(I)c1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1c(C)cc(C=O)cc1I
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 60.1 %

Procedure:
At 5° C., to a stirred solution of 3-iodo-4-hydroxy-5-methylbenzaldehyde (3.53 g, 13.5 mmol) in THF (67.4 mL) was added 60% sodium hydride/mineral oil (0.701 g, 17.5 mmol). After 0.5 h, to the reaction was added dropwise iodomethane (1.34 mL, 21.6 mmol). After 2 h, the reaction was heated at 60° C. After 3 days, the reaction was cooled to ambient temperature, quenched with H2O (100 mL) and extracted with ether. The ethereal extracts were washed with 1N NaOH (3×), with brine (3×), dried (ACO3) and concentrated. Purification on Biotage KP-Sil eluting with 15% acetone/hexane gave 2.24 g (60%) of the title compound. 1H NMR (DMSO-d6) δ 2.37 (s, 3H), 3.77 (s, 3H), 7.78 (s, 1H), 8.17 (s, 1H), 9.86 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:24]=[N:23][N:22]=3)=[CH:11][CH:10]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1.[CH2:50]([SH:55])[CH2:51][CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:50]([S:55][C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:21]3[NH:22][N:23]=[N:24][N:25]=3)=[CH:13][CH:14]=2)[C:6](=[O:45])[N:5]([CH2:46][CH2:47][CH3:48])[C:4](=[O:49])[CH:3]=1)[CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1=O
Reactant: CCCCCS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCCSc1cc(=O)n(CCC)c(=O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 43 %

Procedure:
A mixture of 6-chloro-3-propyl-1-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]pyrimidine-2,4(1H,3H)-dione (0.5 g), pentylmercaptan (0.12 ml) and potassium carbonate (0.13 g) in acetonitrile (10 ml) was heated under reflux for 4 hours with stirring. The reaction mixture was allowed to cool and the precipitate was removed by filtration. The filtrate was concentrated to dryness. The resulting residue was dissolved in methanol (15 ml) and then 1N hydrochloric acid (1.5 ml) was added to the solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated to dryness and then the residue was extracted with methylene chloride-water. The organic layer was washed with water, dried, and evaporated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless amorphous powders (0.16 g, 43%).