Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[NH:8][NH2:9]>CC(O)C>[OH:1][CH:6]1[CH2:5][O:4][CH2:3][CH:2]1[NH:9][NH:8][C:7]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)NN
Reactant: C1OCC2OC12
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NNC1COCC1O
Temperature: 90 °C
Reaction time: 72 h

Procedure:
3,4-epoxytetrahydrofuran (3.33 mL) and t-butyl carbazate (6.14 g) were dissolved in 2-propanol (15 mL), and the solution was heated to 90° C. After three days, t-butyl carbazate (6.3 g) was further added. After heating with stirring for further two days, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Xylene was added to the residue, and the mixture was concentrated again under reduced pressure. The residue was partitioned by adding chloroform and brine. The organic layer was dried over anhydrous magnesium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate/n-heptane, 50% to 100%) to give the title compound (5.78 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7])#[CH:2].I[C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2.C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[CH3:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[C:1]#[C:2][C:15]1[CH:16]=[N:17][C:18]2[C:23]([CH:24]=1)=[CH:22][CH:21]=[CH:20][CH:19]=2
Reactant: Ic1cnc2ccccc2c1
Reactant: C#Cc1cc(C(=O)OC)ccc1C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C)c(C#Cc2cnc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 3-ethynyl-4-methylbenzoate (0.341 g, 2 mmol), 3-iodoquinoline (0.5 g, 2 mmol), Pd(PPh3)4 (0.11 g, 0.01 mmol), CuI (0.179 g, 0.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol) in DMF (15 ml) was stirred at ambient temperature for 12 hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n-hexane) to provide methyl 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoate.
Reaction SMILES: Cl.[CH2:2]1[CH:6]2[CH2:7][NH:8][CH2:9][CH:5]2[CH2:4][N:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].C(N([CH2:22][CH3:23])CC)C>C(Cl)(Cl)Cl>[CH2:7]1[CH:6]2[CH2:2][N:3]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH:5]2[CH2:9][N:8]1[C:10]([O:12][CH2:13][C:23]1[CH:22]=[CH:2][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)OCc3ccccc3)CC2C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate hydrochloride (10 g, 0.04 mol; see Preparation A above) and triethylamine (14 mL, 0.1 mol) were mixed in CHCl3 (100 mL). N-benzyloxy-carbonyloxy succinimide (11 g, 0.044 mol), dissolved in CHCl3 (100 mL), was added at 0–5° C. The mixture was allowed to slowly reach room temperature and was stirred at rt for 5 h. The reaction mixture was washed with water, dried (Na2SO4) and evaporated, giving the sub-title compound in quantitative yield.
Reaction SMILES: [N:1]([C@H:4]1[C@H:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1>[NH2:1][CH:4]1[CH:8]([OH:9])[CH2:7][N:6]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:5]1
Reactant: [N-]=[N+]=N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@H]1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1CN(C(=O)OCc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 7 h
Yield: 100 %

Procedure:
A mixture of racemic trans-benzyl 3-azido-4-hydroxypyrrolidine-1-carboxylate (2.96 g, 11.29 mmol) (Method 195) and triphenylphosphine (3.11 g, 11.85 mmol) in THF (25 mL) was stirred at rt for 7 h. Water (2 mL, 111 mmol) was then added and the mixture then stirred at 50° C. overnight. The mixture was then concentrated under reduced pressure, and the residue was purified via silica gel chromatography (100% DCM to 37:3:60/methanol:Et3N:DCM) to yield the title compound (2.96 g, 11.29 mmol) as an oil. 1H NMR (400 MHz, Dichloromethane-d2) δ ppm 7.38-7.19 (m, 5 H), 5.02 (s, 2 H), 3.89 (brs, 1 H), 3.62 (dd, 2 H), 3.29-3.15 (m, 2 H), 3.12-3.01 (m, 1 H); m/z 236.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[Br:15][CH2:16][C:17](Br)=[O:18].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:17](=[O:18])[CH2:16][Br:15])[CH:3]=1
Reactant: Nc1cccnc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CBr)Nc1cccnc1
Reaction time: 2 h

Procedure:
To a mixture of 3-aminopyridine (11 g.) and triethylamine (13.0 g.) in dry ethyl acetate (300 ml.) was added a solution of bromoacetyl bromide (26.0 g.) in dry ethyl acetate (26 ml.) over a period of 30 minutes with stirring at 0° to 5° C. and stirring was continued for an additional 2 hours at the same temperature. To the reaction mixture was added a chilled aqueous solution of sodium bicarbonate. After shaking well, the ethyl acetate layer was separated, washed successively with water, an aqueous solution of sodium bicarbonate and water, dried and then concentrated. There was obtained concentrate (200 ml.) containing the title compound. Thus obtained concentrate was used directly in the next step reaction without further purification.
Reaction SMILES: [N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10](=[O:17])[C:11]#[C:12][C:13](O)([CH3:15])[CH3:14])[CH:7]=[CH:6][C:5]=12.C(NCC)C.C([OH:25])C>>[N:1]1[S:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:17][C:13]([CH3:14])([CH3:15])[C:12](=[O:25])[CH:11]=3)[CH:7]=[CH:6][C:5]=12
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1ccc2nsnc2c1
Solvent: CCNCC
Product: CC1(C)OC(c2ccc3nsnc3c2)=CC1=O
Reaction time: 3 h
Yield: 83 %

Procedure:
To a stirred solution of 1-(benzo[c][1,2,5]thiadiazol-5-yl)-4-hydroxy-4-methylpent-2-yn-1-one (0.6 g, 2.597 mmol) in ethanol (10 mL), a solution of diethyl amine (0.189 g, 2.597 mmol) in EtOH (5 mL) was added dropwise at RT. The reaction mixture was then stirred for additional 3 h. The ethanol was then removed, and the mixture further diluted with EtOAc (10 mL). The combined organic layers were washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford 5-(benzo[c][1,2,5]thiadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.5 g, 83%) as a light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[C:11]=1[O:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[Cl:21])[C:5]([O:7][CH3:8])=[O:6].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1>N1C=CC=CC=1.C1(C)C=CC=CC=1>[Cl:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[O:12][C:11]1[C:10]([O:22][CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[NH:1][S:40]([C:37]1[CH:36]=[CH:35][C:34]([O:33][CH3:32])=[CH:39][CH:38]=1)(=[O:42])=[O:41]
Reactant: COC(=O)c1cc(N)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NS(=O)(=O)c2ccc(OC)cc2)c(Oc2cc(OC)ccc2Cl)c(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
135 mg of methyl 3-amino-4-(2-chloro-5-methoxy-phenoxy)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate were dissolved in pyridine (3 ml), treated while cooling with ice with a solution of 111 mg of 4-methoxy-benzenesulphonyl chloride in toluene (1 ml) and subsequently stirred at RT for 20 hours. The reaction mixture was poured on to ice/3M HCl, the product was extracted with ethyl acetate and the organic phase was washed with water and dried over magnesium sulphate. After removing the solvent there was obtained methyl 4-(2-chloro-5-methoxy-phenoxy)-3-(4-methoxy-benzenesulphonylamino)-5-[2-(tetrahydro-pyran-2-yloxy)-ethoxy]-benzoate as a foam.
Reaction SMILES: [C:1]([CH2:9][C:10](=[O:12])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:15][N:16]([CH:18]=[C:9]([C:10](=[O:12])[CH3:11])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:17]
Reactant: CC(=O)CC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Product: CC(=O)C(=CN(C)C)C(=O)c1ccccc1

Procedure:
A stirred solution of benzoylacetone (16.2 g) and dimethylformamide dimethylacetal (16.2 ml) was heated on an oil bath at 80° C. for 40 minutes. Volatile materials were removed under vacuum and the residue was crystallised from ether to give 2-(dimethylaminomethylene)-1-phenyl-1,3-butanedione (mp 81°-83° C.).
Reaction SMILES: [CH:1]([C:3]1[N:10]2[C:6]([S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:5][C:4]=1[CH3:15])=[O:2].[CH3:16][Mg]Br.C(O)(=O)C>O1CCCC1>[OH:2][CH:1]([C:3]1[N:10]2[C:6]([S:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)=[N:5][C:4]=1[CH3:15])[CH3:16]
Reactant: C[Mg]Br
Reactant: Cc1nc2sc3ccccc3n2c1C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1nc2sc3ccccc3n2c1C(C)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-Formyl-2-methylimidazo[2,1-b]benzothiazole, 4.3 g, was suspended in 40 ml of dry tetrahydrofuran. Under ice cooling, a tetrahydrofuran solution (0.02 mol) of methyl magnesium bromide was added to the suspension in a nitrogen flow followed by stirring at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was acidified with diluted acetic acid. The solvent was removed under reduced pressure followed by extraction with ethyl acetate. The residue obtained from the ethyl acetate phase was crystallized with ether to give 4.1 g of the title compound.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:32]([O:34]C)=[O:33])[CH:26]=[CH:25]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH-].[K+]>C(O)CCC>[C:1]12([C:11]3[CH:12]=[C:13]([C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[CH:28]=[C:27]([C:32]([OH:34])=[O:33])[CH:26]=[CH:25]5)[CH:14]=[CH:15][C:16]=3[O:17][CH2:18][CH2:19][CH2:20][OH:21])[CH2:10][CH:5]3[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]3)[CH2:8]1)[CH2:2]2
Reactant: COC(=O)c1ccc2cc(-c3ccc(OCCCO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CCCCO
Product: O=C(O)c1ccc2cc(-c3ccc(OCCCO)c(C45CC6CC(CC(C6)C4)C5)c3)ccc2c1
Temperature: 100 °C
Yield: 88.7 %

Procedure:
0.57 g (1.21 mmol) of the ester obtained in Example 7 in suspension in 30 ml of n-butanol is treated with 400 mg of potassium hydroxide. The reaction mixture is heated for 3 h at 100° C., then evaporated to dryness, and is taken up in 50 ml of water and washed with ether. The aqueous phase is acidified to pH=1 with concentrated HCl and extracted with 600 ml of ether. The organic phase is washed with water, dried over magnesium sulphate, filtered and evaporated to give 0.49 g (90%) of the expected acid which melts at 277°-279° C.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1I)[CH3:2].C(N(CC)CC)C.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18].[NH4+].[Cl-]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]([NH2:9])[S:6][C:7]=1[C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH3:2]
Reactant: CCc1nc(N)sc1I
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCc1nc(N)sc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Under a stream of Ar the above prepared 4-ethyl-5-iodo-thiazol-2-ylamine (1.67 g, 6.57 mmol) was dissolved in 40 mL of acetonitrile and treated successively with triethylamine (2.73 mL, 3 eq.), Cul (0.125 g, 0.1 eq.), (Ph3P)2PdCl2 (0.46 g, 0.1 eq.) and ethynyltrimethylsilane (2.73 mL, 3 eq.). The flask was closed with a septum and allowed to stir for 15 h at ambient temperature. The reaction mixture was then poured onto icewater/NH4Cl, twofold extracted with ethyl acetate, washed with water and brine, dried over sodium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/AcOEt=7/3) afforded finally 0.598 g of the title compound as brown viscous oil, contaminated with some des-iodo-compound.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][OH:4].[OH:5][C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:17](Cl)=[O:18])[C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1>O1CCOCC1>[OH:4][CH2:3][CH2:2][NH:1][C:17]([C:11]1[C:12](=[O:16])[O:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([OH:5])[CH:15]=2)=[O:18]
Reactant: O=C(Cl)c1cc2ccc(O)cc2oc1=O
Reactant: NCCO
Solvent: C1COCCO1
Product: O=C(NCCO)c1cc2ccc(O)cc2oc1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 52.2 %

Procedure:
To a cold, stirred solution of 3.05 grams (g) [0.05 mole (mol)] of 2-aminoethanol in 30 milliliters (ml) of dioxane was added a suspension of 2.2 g (0.01 mol) of 7-hydroxycoumarin-3-carbonyl chloride [Sherman et al, Anal. Chem. 40:803(1968)] in 75 ml of dioxane. The mixture was stirred at 0° C. for 30 minutes, during which time a thick oil precipitated that solidified upon scratching with a spatula. The dioxane was decanted and the precipitate dissolved in water. Adjustment of the pH of the aqueous solution to 7.0 with glacial acetic acid resulted in precipitation of a tan solid. The solid precipitate was recrystallized from water to give 1.3 g (52% yield) of N-(2-hydroxyethyl)-7-hydroxycoumarin-3-carboxamide as a white solid with a melting point of 244°-245° C. Elemental analysis and infrared spectral data for the product are given below:
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20](Cl)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:27]([O:34][C:35]1[CH:36]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH:38]=[CH:39][CH:40]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:24]([CH3:25])=[CH:23][C:18]2[N:19]=[C:20]([C:37]3[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH:36]=3)[S:21][C:17]=2[C:16]=1[Br:26])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1(C)OB(c2cccc(OCc3ccccc3)c2)OC1(C)C
Reactant: Cc1cc2nc(Cl)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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: [K+]
Solvent: C1COCCO1
Product: Cc1cc2nc(-c3cccc(OCc4ccccc4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 95 °C
Yield: 58.1 %

Procedure:
To a solution of (S)-2-(7-bromo-2-chloro-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (130 mg, 0.282 mmol) in dioxane, was added 3-benzyloxyphenylboronic acid pinacol ester (105 mg, 0.338 mmol), Pd(PPh3)4 (16 mg, 0.014 mmol), 2N K2CO3 (700 μL). The reaction mixture in sealed tube was heated at 95° C. for 1.5hs. Then the reaction was cooled down. The reaction mixture was washed by sat. NaHCO3, and extracted by EtOAc. The organic phase was filtered, concentrated down, purified by silica gel column, eluting by 0-50% EtOAc in hexanes to give the product (100 mg, 58%). LCMS-ESI+: calc'd for C32H36BrNO4S: 610.2 (M+H+); Found: 610.2 (M+H+).
Reaction SMILES: [O:1]=[C:2]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)[C:3](Cl)=[O:4].[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1>C(Cl)(Cl)Cl>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:3](=[O:4])[C:2](=[O:1])[C:6]2[S:7][CH:8]=[CH:9][CH:10]=2)[CH2:14][CH2:13]1
Reactant: O=C(Cl)C(=O)c1cccs1
Reactant: CN1CCC(CO)CC1
Solvent: ClC(Cl)Cl
Product: CN1CCC(COC(=O)C(=O)c2cccs2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of oxo-thiophen-2-yl-acetyl chloride (31.5 mmol) at 0 to 5° C. in chloroform (60 ml) is added a solution of (1-Methyl-piperidin-4-yl)-methanol (4.07 g, 31.5 mmol) in chloroform (60 ml), dropwise maintaining the temperature below 5° C. The resulting mixture is stirred for 2 hours at room temperature. Washing with 10% potassium carbonate solution, water and then drying over magnesium sulphate, filtration and evaporation gives the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([CH3:44])=[N:22][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:24]=4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1>Cl.C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([CH3:44])=[N:22][NH:23][CH:24]=4)=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1n[nH]cc1-c1ccc(C2(c3ccc(Cl)cc3)CCNCC2)cc1
Reaction time: 2.33 h

Procedure:
A suspension of 4-(4-chloro-phenyl)-4-[4-(3-methyl-1-trityl-1H-pyrazol-4-yl)-phenyl]-piperidine (178 mg, 0.30 mmol) in 5N hydrochloric acid (5 mL), THF (5 mL) and methanol (5 mL) was stirred for 140 minutes. The organic solvents were removed in vacuo then the resulting solution was diluted with 2N HCl and washed with ether. The aqueous phase was basified by addition of sodium hydroxide pellets then extracted with ethyl acetate. This organic extract was washed with brine, dried (MgSO4), filtered and concentrated to give a residue which was purified by column chromatography (SiO2), eluting with a gradient of 2M ammonia in methanol (5% to 7.5%) and dichloromethane. The product was further purified by preparative HPLC to give the title compound which was converted to its dihydrochloride salt (84 mg, 80%); LCMS (PS-A3) Rt 6.86 min [M+H]+ 352. 1H NMR (Me-d3-OD) δ 2.55 (3H, s), 2.70-2.75 (4H, m), 3.22-3.27 (4H, m), 7.35-7.41 (4H, m), 7.47-7.54 (4H, m), 8.32 (2H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClC(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][Br:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(Br)c1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cccc(Br)c1CBr
Yield: 45 %

Procedure:
A mixture of 3-bromo-o-xylene (15 g, 81 mmol), N-bromo succinimid (15.1 g, 85.1 mmol), dibenzoylperoxid (0.65 g) and tetrachloromethane (150 ml) was refluxed for 5 hours. After filtration the filtrate was washed with sodium hydrogensulfite and water. The organic layer was dried over sodium sulfate and evaporated in vacuo. Chromatography (SiO2) (petroleum ether:ethyl acetate, 100:4) gave a 16.8 g fraction of a mixture containing 45% of the title compound. This mixture was used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:7]=[C:6]([CH2:8]O)[N:5]([CH3:10])[N:4]=1)[CH3:2].P(Br)(Br)[Br:12]>C(Cl)Cl>[Br:12][CH2:8][C:6]1[N:5]([CH3:10])[N:4]=[C:3]([CH2:1][CH3:2])[CH:7]=1
Reactant: BrP(Br)Br
Reactant: CCc1cc(CO)n(C)n1
Solvent: ClCCl
Product: CCc1cc(CBr)n(C)n1
Reaction time: 2 h

Procedure:
To a solution of compound 4 (500 mg, 3.57 mmol) in DCM (20 mL) was added PBr3 (386 mg, 1.43 mmol) was stirred at ° C. for 2 h. The mixture was washed with water, dried over Na2SO4. The solvent was evaporated to give the crude compound which was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([O:14]CC3C=CC=CC=3)=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]>C(O)C.[Pd]>[CH2:1]1[C:4](=[O:5])[N:3]2[C@@H:6]([C:12]([OH:14])=[O:13])/[C:7](/[O:11][C@H:2]12)=[CH:8]/[CH2:9][OH:10]
Reactant: O=C(OCc1ccccc1)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H]1/C(=C/CO)O[C@@H]2CC(=O)N21

Procedure:
Benzyl clavulanate (100 mgs) in ethanol (5 ml) was hydrogenated over 10% Pd/C (30 mgs) for 45 minutes at ambient temperature and atmospheric pressure. The catalyst was filtered, washed with ethanol and the combined filtrates were evaporated in vacuo to give clavulanic acid as an unstable, viscous oil (58 mgs). N.m.r. (C5D5N): 3.05 (d,1,J=18 Hz), 3.60 (dd,1,J1 =18 Hz, J2 =2.5 Hz), 4.75 (d,2,J=7.5 Hz), 5.58 (t,1,J=7.5 Hz), 5.66 (S,1), 6.0δ (d,1,J=2.5 Hz).
Reaction SMILES: [F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[N:23]=[CH:22][CH:21]=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[CH:25]=4)[C:17]=3[CH:18]=[O:19])[C:14](=[O:15])[C:3]=12.[BH4-].[Na+]>CO>[F:1][C:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:4]2[CH2:11][CH2:12][N:13]([C:16]3[C:17]([CH2:18][OH:19])=[C:20]([C:24]4[CH:29]=[C:28]([NH:30][C:31]5[CH:36]=[CH:35][N:34]=[CH:33][N:32]=5)[C:27](=[O:37])[N:26]([CH3:38])[CH:25]=4)[CH:21]=[CH:22][N:23]=3)[C:14](=[O:15])[C:3]=12
Reactant: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2C=O)cc(Nc2ccncn2)c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cn1cc(-c2ccnc(N3CCn4c5c(c(F)c4C3=O)CCCC5)c2CO)cc(Nc2ccncn2)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
A mixture of 146b (79 mg, 0.15 mmol), NaBH4 (22 mg, 0.60), and CH3OH (10 mL) was stirred at 25° C. for 1 h. The mixture was extracted with CH2Cl2 (10 mL×2). The combined CH2Cl2 extract was concentrated under reduced pressure. The residue was purified with reverse-phase prep-HPLC to afford 146 (39 mg, 49%). LCMS: [M+H]+ 516. 1H NMR (500 MHz, CDCl3) δ 8.83 (d, J=2.0, 1H), 8.78 (s, 1H), 8.52 (d, J=5.0, 1H), 8.35 (d, J=5.5, 1 H), 8.12 (s, 1H), 8.03 (d, J=2.0, 1H), 7.36 (d, J=5.0, 1H), 6.76-6.77 (m, 1H), 5.07 (s, 1H), 4.65 (d, J=9.5, 1H), 4.48 (d, J=9.5, 1H), 4.29 (d, J=1.5, 1H), 4.02-4.13 (m, 2H), 3.79 (d, J=6.5, 1H), 3.73 (s, 3H), 2.52-2.58 (m, 4H), 1.85-1.90 (m, 2H), 1.77 (d, J=5.0, 2H)
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11].[H][H]>CC(O)C>[CH3:3][O:4][C@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[OH:11]
Reactant: COC1CCCCC1=O
Reactant: [H][H]
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Product: CO[C@H]1CCCC[C@H]1O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
In a 100 ml autoclave were charged 3.4 ml of a 0.1M solution of potassium hydroxide (0.34 mmol) in 2-propanol, 4.2 mg (0.02 mmol) of (1S,2S)-diphenylethylenediamine, 1.28 g (10.0 mmol) of 2-methoxycyclohexanone, 8.4 mg (0.005 mmol) of Ru2Cl4 [(S)-BINAP]2NEt3, and 6.5 ml of 2-propanol in a nitrogen atmosphere, and hydrogen was introduced therein to 50 atm. The mixture was stirred at 50° C. for 60 minutes and cooled to room temperature. The disappearance of the starting material was confirmed by gas chromatography. The solvent was evaporated under reduced pressure, and the residue was distilled under reduced pressure to obtain (1R,2S)-2-methoxycyclohexanol. The optical purity of the product was found to be 97% d.e. and 92% e.e. by gas chromatography.