Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na+].[CH3:2][C:3]([CH3:10])([CH3:9])[C:4](=O)[C:5]([O-:7])=[O:6].Cl.[NH2:12][OH:13]>O>[CH3:2][C:3]([CH3:10])([CH3:9])[C:4](=[N:12][OH:13])[C:5]([OH:7])=[O:6]
Reactant: NO
Reactant: CC(C)(C)C(=O)C(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC(C)(C)C(=NO)C(=O)O
Yield: 81.2 %

Procedure:
163 g (1 mole) 93.5% trimethylpyruvic acid sodium salt and 69.5 g (1 mole) hydroxylamine hydrochloride were dissolved at 40° C. in 450 ml water. The product crystallized out during slow cooling under agitation. After 1.5 h agitation in an ice bath the crystals were filtered off, washed with 150 ml ice water, dried in a vacuum at 60° C., and then further dried in a vacuum desiccator over phosphorus pentaoxide to constant weight. 117.8 g trimethylpyruvic acid oxime (81% yield) in the form of colorless crystals were obtained.
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.CC1(C)C(C)(C)OB([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:23](/[C:20]1[CH:21]=[CH:22][C:17]([C:2]2[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=2)=[CH:18][CH:19]=1)=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1(C)OB(c2ccc(/C=C/c3ccccc3)cc2)OC1(C)C
Reactant: Nc1ncccc1Br
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: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(/C=C/c2ccccc2)cc1

Procedure:
Pd(dppf)Cl2 (0.141 g) was added to a mixture of (E)-1-bromo-4-styrylbenzene (1.00 g), potassium acetate (1.14 g) and 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.03 g) in DMF (dry) (10 ml). The mixture was stirred at 90° C. under nitrogen for 12 hr. The insoluble solid was removed by filtration through Celite pad (eluted with EtOAc). The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate. Activated-carbon powder and silica-gel were added and the mixture was shaken, sonicated and filtered through silica-gel/Celite pad (eluted with EtOAc). The filtrate was concentrated in vacuo to give the crude (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane. Tetrakis(triphenylphosphine)palladium(0) (0.186 g) was added to a suspension of 3-bromopyridin-2-amine (0.557 g), the prepared (E)-4,4,5,5-tetramethyl-2-(4-styrylphenyl)-1,3,2-dioxaborolane and sodium carbonate (1.02 g) in DME (20 mL) and water (4 mL) and the mixture was stirred at 80° C. under nitrogen overnight. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (532 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)CC)C>C1COCC1.[Cu]I>[F:1][C:2]1[CH:3]=[C:4]([C:15]#[C:14][Si:11]([CH3:13])([CH3:12])[CH3:10])[C:5]([NH2:8])=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1ncc(F)cc1I
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cc(F)cnc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.3 %

Procedure:
A solution of 5-fluoro-3-iodo-pyridin-2-ylamine (4 g, 16.8 mmol) in THF (50 mL) and trimethylsilylacetylene (4.7 mL, 33.6 mmol) is treated with PdCl2(PPh3)4 (353 mg, 0.5 mmol), CuI (96 mg, 0.5 mmol) and triethylamine (7 mL, 50.4 mmol) and stirred at rt for 2 h. The mixture is filtered through Celite and concentrated. The residue is purified by silica gel chromatography eluting with 10%-35% EtOAc in heptane to afford 5-fluoro-3-trimethylsilanylethynyl-pyridin-2-ylamine (3.3 g, 94%). MS: 209 (M+H); 1H NMR (300 MHz, CDCl3): δ 7.90 (d, 1H), 7.30 (m, 1H), 4.89 (s, NH2, 2H), 0.25 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][CH:8]([C:12](O)=O)[C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.C(OC(=O)C)(=O)C>O>[CH2:12]=[C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:16][CH:15]=1)[C:9]([OH:11])=[O:10]
Reactant: COc1ccc(CC(C(=O)O)C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C=C(Cc1ccc(OC)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Methoxybenzylmalonic acid, (20.2 g., 0.09 mol) was suspended in N,N,N1,N1 -tetramethylmethanediamine (45 ml). Acetic anhydride (45 ml) was added dropwise, keeping the temperature below 45° C. by cooling in an ice-bath as necessary. The resulting clear solution was stirred for 11/2 hour at ambient temperature and then was poured into ice and water. The white solid product was collected, combined with comparable product from a second 0.083 mol run, and dried at 0.1 mm at room temperature to give 22.4 g. (68%) of product, m.p. 88°-91° C. A sample recrystallized from ether-petroleum ether melted at 90°-93° C.
Reaction SMILES: [N+]1([O-:7])C=CC=CC=1.[CH2:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N:15]=1)=[O:12])[CH3:9].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[CH2:8]([O:10][C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Br:20])[N+:15]=1[O-:7])=[O:12])[CH3:9]
Reactant: CCOC(=O)Nc1cccc(Br)n1
Reactant: [O-][n+]1ccccc1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)Nc1cccc(Br)[n+]1[O-]
Yield: 62 %

Procedure:
The procedure of Example 3 was repeated except that Step 2 relating to the oxidation to the pyridine-oxide was changed, whereby a chloroform solution of 2-ethoxycarbonylamino-6-bromopyridine was treated with m-chloroperbenzoic acid as the oxidizing agent for 9 days at room temperature, giving a 62% yield of 2-ethoxycarbonylamino-6-bromopyridine-1-oxide.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([OH:23])[CH:10]([NH2:22])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[F:24][C:25]([F:36])([F:35])[C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]([OH:23])[CH:10]([NH:22][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][C:26]([C:25]([F:24])([F:35])[F:36])=[CH:27][CH:28]=2)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:7][CH:8]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
To a solution of (1RS,2SR)-1-(4-fluorophenyl)-1-hydroxy-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (200 mg, 0.57 mmol) in ethyl acetate (5 ml) were added 4-(trifluoromethyl)benzoyl chloride (179 mg, 0.86 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 1 hr. The reaction solution was diluted with water (50 ml), and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1). Recrystallization from ethyl acetate-hexane gave the title compound (171 mg, 62%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])[C@@H:19]([OH:21])[CH3:20])[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][O:15][CH2:16][C@H:17]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)[C@@H:18]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])[C@@H:19]([OH:21])[CH3:20])[C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: COC(=O)[C@H](COC[C@H](Cc1ccc(C)cc1)[C@@H](OCC(C)C)[C@H](C)O)NC(=O)OC(C)(C)C
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C[C@@H](COC[C@H](NC(=O)OC(C)(C)C)C(=O)O)[C@@H](OCC(C)C)[C@H](C)O)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
To a solution of (S)-methyl 2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methylbenzyl)pentyl)oxy)propanoate (2.06 g, 4.28 mmol) in aqueous THF (16 THF:5 H2O; 21 mL total volume) was added LiOH—H2O (0.54 g, 12.83 mmol) and the reaction was stirred for 4 h at room temperature. The reaction was diluted with H2O (50 mL) and the majority of the THF was removed on the rotovap. The aqueous residue was acidified with 2 N HCl and extracted with CH2Cl2 (6×50 mL) until the aqueous phase was nearly clear. The combined organic extracts were washed with brine (2×50 mL), dried over Na2SO4, filtered, and concentrated to a colorless oil (1.96 g). The oil was purified by RP flash chromatography (C18; 0→85% CH3CN/H2O) to give (S)-2-((tert-butoxycarbonyl)amino)-3-(((2S,3R,4S)-4-hydroxy-3-isobutoxy-2-(4-methyl-benzyl)pentyl)oxy)-propanoic acid (1.71 g, 85%) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.05 (m, 4H), 6.57 (s, 2H), 5.47 (d, J=8.1 Hz, 1H), 4.44 (m, 1H), 3.92 (m, 1H), 3.77 (m, 1H), 3.58 (m, 1H), 3.41 (d, J=7.2 Hz, 1H), 3.24 (m, 4H), 2.91 (dd, J=13.7, 4.0 Hz, 1H), 2.46 (dd, J=13.7, 10.8 Hz, 1H), 2.31 (s, 3H), 2.10 (dd, J=6.8, 3.3 Hz, 1H), 1.81 (dp, J=13.2, 6.6 Hz, 1H), 1.44 (s, 9H), 1.25 (d, J=6.2 Hz, 3H), 0.91 (dd, J=6.7, 2.7 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ 171.72, 153.71, 135.81, 133.44, 127.15, 127.02, 81.61, 78.33, 76.81, 69.13, 68.31, 67.08, 51.93, 40.98, 31.48, 27.16, 26.42, 19.12, 17.65, 17.58, 17.38; ESIMS m/z 491 ([M+Na]+).
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH2:16][CH2:15]3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[I:29]N1C(=O)CCC1=O.C(Cl)Cl>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([O:11][C:12]2[C:13]([I:29])=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][C@@H:17]([C@:22]2([CH3:28])[CH2:26][O:25][C:24](=[O:27])[NH:23]2)[CH2:16][CH2:15]3)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2)CC[C@H]([C@]2(C)COC(=O)N2)C3)CC1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3c(c2I)CC[C@H]([C@]2(C)COC(=O)N2)C3)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of (R)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one (100 mg, 0.000259 mol), N-iodosuccinimide (65.4 mg, 0.000290 mol) and zirconium tetrachloride (9.1 mg, 0.000039 mol) in methylene chloride (2.13 mL, 0.0332 mol) was stirred at rt under Ar in a vial for 3 h. The precipitate was filtered off and the residue was purified with silica gel chromatography eluted is with EtOAc/hexane (0 to 40%) to give (R)-4-((S)-6-(trans-4-tert-butylcyclohexyloxy)-5-iodo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one as a solid (130 mg, 98%). 1H NMR shows 1.6:1 mixture of 5-iodo and 7-iodo isomers. LCMS: Rf=2.40min 512.39 ([M+1], 30%).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([CH:9]([OH:26])[C@@H:10]([C:23]([OH:25])=[O:24])[N:11]([CH3:22])[S:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])=[CH:7][CH:6]=1.[N+](=[CH2:31])=[N-]>C(OCC)(=O)C.C(OCC)C>[CH3:31][O:24][C:23](=[O:25])[C@H:10]([CH:9]([OH:26])[C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:28][CH:27]=1)[N:11]([CH3:22])[S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20]
Reactant: C=[N+]=[N-]
Reactant: COCOc1ccc(C(O)[C@@H](C(=O)O)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCOc1ccc(C(O)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Reaction time: 0.17 h

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine (20.0 g) in ethyl acetate (100 ml) was added diazomethane in diethyl ether (80 ml). After stirring for 10 minutes, the solvent was removed in vacuo. The residue was put on a silica gel column (MERCK 7734:500 g) and eluted with chloroform to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine methyl ester. (threo isomer: 8.82 g, erythro isomer: 6.63 g)
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[F:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[C:27](=O)[CH:26]([CH3:32])[CH2:25]2.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:27]3[C:28]4[C:24](=[CH:23][C:22]([F:21])=[CH:30][CH:29]=4)[CH2:25][CH:26]3[CH3:32])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC1Cc2cc(F)ccc2C1=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC1Cc2cc(F)ccc2C1Nc1ccc(F)c([C@@]2(C)N=C(N)N(C)C(=O)C2(C)C)c1

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-5-fluoro-2-methyl-indan-1-one using decaborane yielded a mixture of isomers of the title compound as a white solid. MS (ESI): m/z=427.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:8][C:6]1[CH:7]=[C:2]([N:23]2[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]2)[N:3]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:5]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cn(-c2cc(Cl)nc(N[C@@H](C)c3ccc(F)cc3)n2)cn1
Temperature: 100 °C
Reaction time: 17 h
Yield: 26.7 %

Procedure:
200 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine and 63 mg of 4-methylimidazole were dissolved in 2 ml of dimethylformamide, and 193 mg of potassium carbonate was added thereto, and the mixture was stirred at 100° C. for 17 hours. The reaction solution was diluted with water, and then subjected to extraction with ethyl acetate. The organic layer was washed in turn with water and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 62 mg of the objective compound as a white solid.
Reaction SMILES: [C:1]1([O:7][C:8]2[C:12]([F:14])([F:13])[C:11]([F:16])([F:15])[C:10]([F:18])([F:17])[C:9]=2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B([O-])([O-])[O-].Cl.[H][H]>[C].[Pd]>[CH:1]1([O:7][CH:8]2[CH2:9][C:10]([F:17])([F:18])[C:11]([F:15])([F:16])[C:12]2([F:13])[F:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: [H][H]
Reactant: FC1(F)C(Cl)=C(Oc2ccccc2)C(F)(F)C1(F)F
Agent: [Pd]
Agent: Cl
Agent: [O-]B([O-])[O-]
Product: FC1(F)CC(OC2CCCCC2)C(F)(F)C1(F)F

Procedure:
605 g (2 mol) of 2-chloro-3,3,4,4,5,5-hexafluorocyclopentenyl phenyl ether are suspended in 500 ml of pH 9 buffer (borate/HCl) in a 1.3 1 autoclave and hydrogenated over 50 g of palladium-carbon at 7020 -80° C. using 80 bar of hydrogen. The mixture is worked up analogously to Example 7 and 2,2,3,3,4,4-hexafluorocyclopentyl cyclohexyl ether is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]O)=[C:6]([F:8])[CH:7]=1.[BrH:12].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][Br:12])=[C:6]([F:8])[CH:7]=1
Reactant: OCc1c(F)cc(Br)cc1F
Reactant: Br
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc(Br)cc(F)c1CBr
Yield: 98 %

Procedure:
A solution of 5-Bromo-2-hydroxymethyl-1,3-difluoro-benzene (0.89 g, 4.0 mmol) and 30 wt % of hydrogen bromide in acetic acid was stirred at room temperature for 90 minutes before it was poured into 80 ml of water. The mixture was extracted with pentane (3×50 ml) and the combined organic layers were washed with water (3×20 ml), dried over MgSO4 and concentrated at low pressure to afford the desired product (10.0 g, 98% yield). 1H NMR (CDCl3) δ: 4.47 (s, 2H), 7.09-7.10 (m, 1H), 7.12-7.13 (m, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N:19]([O-])=[O:20].[Na+].C(OCC)C>C(O)=O>[Cl:1][CH2:2][CH2:3][N:4]([N:19]=[O:20])[C:5]([NH:7][C@@H:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=N[O-]
Reactant: O=C(NCCCl)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=CO
Product: O=NN(CCCl)C(=O)N[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O

Procedure:
To a solution of 300 mg of 1-(2-chloroethyl)-3-(β-D-galactopyranosyl)urea in 2 ml of 99% formic acid was slowly added 150 mg of sodium nitrite in an ice-bath under stirring. The mixture was stirred for 1 hour under ice-cooling to complete the nitrosation. The reaction mixture was admixed with 50 ml of ethyl ether to deposit an oily substance. The ethyl ether phase was separated from the oily substance by decantation. The operation of adding ethyl ether to and separating the ethyl ether phase from the oily substance by decantation was repeated three times, using 50 ml, 20 ml and 20 ml of the ether, respectively. Thereafter, the oily substance was taken up into 30 ml of methyl alcohol, and the resultant solution was admixed with 3 ml of Amberlite IR-120 (H+ form). The admixture was filtered to remove cation-exchange resin, and the filtrate was concentrated under a reduced pressure, depositing crystals of the titled compound. Yield 210 mg (63.6%). mp. 145° C (decomposition with foaming). [α]D21.0 +13.0° (c 0.5, H2O).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@H:11]3[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][C@H:10]3[CH2:9][NH:8][C:7](=[O:22])[C:6]=2[CH:23]=1.I[CH3:25].[H-].[Na+].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C@@H:11]3[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:14][C@H:10]3[CH2:9][N:8]([CH3:25])[C:7](=[O:22])[C:6]=2[CH:23]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC(=O)c3cc(F)ccc3[C@@H]2C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccc(F)cc2C1=O
Reaction time: 2 h

Procedure:
To a suspension of Example 224A (3.8 g, 11.9 mmol) and iodomethane (2.1 g, 15 mmol) in tetrahydrofuran (15 mL) was added NaH (0.6 g, 60%, 15 mmol) in portions at 0° C. The mixture was stirred for 2 hours and water was then added. The precipitates were collected to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.33 (m, 1H), 7.29 (m, 1H), 7.28 (m, 1H), 3.69 (m, 1H), 3.60 (m, 1H), 3.54 (m, 1H), 3.35 (m, 2H), 3.17 (m, 1H), 3.10 (s, 3H), 3.00 (m, 1H), 2.16 (m, 1H), and 1.43 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[C:10]([O:15][CH3:16])(=[O:14])[C:11]([CH3:13])=O>>[CH3:16][O:15][C:10](=[O:14])[C@H:11]([CH3:13])[NH:5][C:4]1[CH:6]=[CH:7][C:8]([Cl:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: COC(=O)C(C)=O
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: COC(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1

Procedure:
Following General Procedure A above and using 3,4-dichloroaniline (Aldrich) and methyl pyruvate (Aldrich), the title compound was prepared as an oil. The reaction was monitored by tlc on silica gel (Rf=0.55 in 25% EtOAc/hexanes) and purification was by flash chromatography (silica gel using 25% EtOAc/hexanes as the eluant).
Reaction SMILES: [C:1]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:2][CH2:3][CH:4]=CCCC.CSC.C[OH:17]>>[CH2:11]([O:10][C:1](=[O:9])[CH2:2][CH2:3][CH:4]=[O:17])[CH3:12]
Reactant: CCCC=CCCC(=O)OCC
Reactant: CO
Solvent: CSC
Product: CCOC(=O)CCC=O
Temperature: -60 °C
Reaction time: 4 h

Procedure:
A solution of ethyl 4-octenoate (34 mL, 173 mmol) in methanol (240 mL) was placed in a 3-neck round bottomed flask and cooled at −60° C., and then O3/O2 was bubbled through the reaction mixture. After 4 hours at ca. −60° C., the reaction mixture had a slight blue tint, and TLC (1:9 ethyl acetate:hexane, stained in phosphomolybdic acid (PMA)) showed no starting material remaining. The reaction mixture was then flushed with O2 for 10 minutes. To the above reaction mixture was added slowly dimethyl sulfide (26 mL, 345 mmol) while maintaining the reaction temperature below −55° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred overnight. Argon was then bubbled through for 2 hours. The reaction mixture was then concentrated in vacuo. Low pressure fractional distillation afforded 4-oxo-butyric acid ethyl ester (14.3 g, 63%, contained a small amount of dimethyl sulfoxide) as a clear, colorless oil. Alternatively, purification can be accomplished using silica gel chromatography (100% hexanes-20% ethyl acetate in hexane). 1H NMR (300 MHz, CDCl3) δ ppm 9.81 (s, 1 H), 4.14 (q, J=7.2 Hz, 2 H), 2.79 (t, J=6.6 Hz, 2 H), 2.62 (t, J=6.6 Hz, 2 H), 1.26 (t, J=7.2 Hz, 3 H).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)=[CH:13][C:12]2=[O:25])=[CH:5][CH:4]=1.[CH2:26]([N:28](CC)[CH2:29][CH3:30])[CH3:27].CS(Cl)(=O)=O.N1CCCC1>C(Cl)Cl>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:28]4[CH2:29][CH2:30][CH2:27][CH2:26]4)=[CH:4][CH:5]=3)[C:12](=[O:25])[CH:13]=2)[CH:20]=1
Reactant: CCN(CC)CC
Reactant: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CO)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: C1CCNC1
Product: O=c1cc(OCc2cccnc2)ccn1CCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 50 mg (0.15 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(pyridin-3-ylmethoxy)-1H-pyridin-2-one (example 11.1a) in 3.0 mL DCM is added 62 μL triethylamine (0.45 mmol) and subsequently 23 μL (0.30 mmol) methanesulfonyl chloride at RT. The reaction mixture is stirred 1 h at RT, and then 25 μL (0.30 mmol) pyrrolidine is added. The mixture is stirred additional 2 h at RT and is directly transferred to a reverse HPLC for purification (Zorbax stable bond, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH:15]([CH:24]=O)[CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C(O)=O.[CH2:33]([NH:35][NH2:36])[CH3:34]>CO>[C:18]1([CH2:17][CH2:16][C:15]2[CH:24]=[N:36][N:35]([CH2:33][CH3:34])[C:14]=2[CH:11]2[CH2:12][CH2:13][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:9][CH2:10]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCNN
Reactant: O=CC(CCc1ccccc1)C(=O)C1CCN(Cc2ccccc2)CC1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCn1ncc(CCc2ccccc2)c1C1CCN(Cc2ccccc2)CC1
Yield: 55 %

Procedure:
di-TFA salt A solution of 1-(1-benzylpiperidin-4-yl)-2-formyl-4-phenyl-1-butanone from Step E (76.5 mg) and ethylhydrazine oxalate (45 mg) in methanol (4 mL) was heated at 45° C. for 15.5 h. The solvent was removed under reduced pressure. The residue was purified by preparative reverse-phase IHPLC using a 9.4×250 mm Semi-preparative Zorbax SB-C18 column with 30-50% acetonitrile gradient in water having 0.5% (v/v) TFA over 15 min at 7.1 mL per min to give the title compound (45 mg) as the faster-eluting, minor isomer.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:3][CH2:4][CH3:5])=[O:2].[C:16](OC(=O)C)(=[O:18])[CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:16]([O:15][C:11]1[CH2:12][CH2:13][CH2:14][C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])(=[O:18])[CH3:17]
Reactant: CCOC(=O)CCCCC1CCCC1=O
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CCCCC1=C(OC(C)=O)CCC1

Procedure:
In the manner described in Example 10, treatment of 2-(4-carbethoxybutyl)cyclopentan-1-one (Example 3) with acetic anhydride and p-toluenesulfonic acid monohydrate gives a yellow oil, b.p. 109°-110°C. (0.37 mm).