Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].[CH:31]1[C:43]2[CH:42]([CH2:44][O:45][C:46]([NH:48][C@H:49]([C:54]3[CH:59]=[CH:58][C:57](O)=[CH:56][CH:55]=3)[C:50]([O:52][CH3:53])=[O:51])=[O:47])[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:35]=2[CH:34]=[CH:33][CH:32]=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:26]([O:25][C:24]([NH:23][CH2:22][CH2:21][O:20][C:57]1[CH:58]=[CH:59][C:54]([C@@H:49]([NH:48][C:46]([O:45][CH2:44][CH:42]2[C:43]3[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=3[C:36]3[C:41]2=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:47])[C:50]([O:52][CH3:53])=[O:51])=[CH:55][CH:56]=1)=[O:30])([CH3:27])([CH3:29])[CH3:28]
Reactant: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(O)cc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)c1ccc(OCCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
To a solution of 0.465 g (1.77 mmol) of triphenylphosphine in 10 mL of THF was added 0.286 g (1.77 mmol) of tert-butyl N-(2-hydroxyethyl)-carbamate followed by 0.476 g (1.18 mmol) of methyl (2R)-{[(9H-fluoren-9-ylmethoxy)carbonyl]amino}(4-hydroxyphenyl)ethanoate and 0.279 mL (1.77 mmol) of diethyl azodicarboxylate. The reaction was stirred overnight at room temperature and then concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:3) to give 0.383 g of methyl (2R)-(4-{2-[(tert-butoxycarbonyl)amino]ethoxy}phenyl){[(9H-fluoren-9-ylmethoxy)carbonyl]amino}ethanoate as a white solid. Electrospray Mass Spec 547.2 (M+)+
Reaction SMILES: [C:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[H][H]>C(O)(=O)C.[Pt]=O>[CH:1]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: [H][H]
Reactant: O=C(O)c1nccc2ccccc12
Agent: O=[Pt]
Solvent: CC(=O)O
Product: O=C(O)C1NCCc2ccccc21
Yield: 63 %

Procedure:
To a solution of isoquinoline-1-carboxylic acid (12.5, 0.072 mole) in 185 ml of glacial acetic acid was added 2 g of platinum oxide and the suspension was hydrogenated at room temperature under 60 psi hydrogen pressure in a Parr hydrogenation apparatus for 24 h. The reaction mixture was filtered though a filter pad (Celite) to remove the catalyst and the filtrate was evaporated to dryness in vacuo. The solid residue was triturated with water, filtered and dried to yield 8 g (63% yield) of DL-1,2,3,4-tetrahydroisoquinolin-1-carboxylic acid. FD-Mass spectrum 178 (MH+);
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]([Cl:19])[CH:13]=2)[C:8]=1[C:9]([NH2:11])=[O:10])([OH:3])=[O:2].[CH3:20]O>>[Cl:19][C:14]1[CH:13]=[C:12]([N:7]2[C:8]([C:9]([NH2:11])=[O:10])=[C:4]([C:1]([O:3][CH3:20])=[O:2])[CH:5]=[N:6]2)[CH:17]=[C:16]([Cl:18])[CH:15]=1
Reactant: CO
Reactant: NC(=O)c1c(C(=O)O)cnn1-c1cc(Cl)cc(Cl)c1
Product: COC(=O)c1cnn(-c2cc(Cl)cc(Cl)c2)c1C(N)=O

Procedure:
A 1.5 g portion of the compound of Example 2 was suspended in 30 ml of methanol, and hydrogen chloride gas was bubbled through the suspension for 1 minute. Then 30 ml of methanol was added over a 5 minute period while the addition of gas was continued. Then the mixture was heated under reflux for 2 hours, and was cooled and filtered. The solids were collected and dried to obtain 1.15 g of the desired product, m.p. 220°-222°.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH2:16][CH3:17])[C:3](=[O:15])[C:4]([N:6]1[CH:10]([C:11]([O:13]C)=[O:12])[CH2:9][O:8][CH2:7]1)=[O:5].[Li+].[OH-]>CO>[CH3:1][C:2]([CH3:18])([CH2:16][CH3:17])[C:3](=[O:15])[C:4]([N:6]1[CH:10]([C:11]([OH:13])=[O:12])[CH2:9][O:8][CH2:7]1)=[O:5]
Reactant: CCC(C)(C)C(=O)C(=O)N1COCC1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CCC(C)(C)C(=O)C(=O)N1COCC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
Dissolved methyl 3-(3,3-dimethyl-2-oxopentanoyl)-1,3-oxazolidine-4-carboxylate (3) (0.6 g, 2.33 mM) in MeOH (25 ml) and added LiOH (1M in water, 10 ml, 10 mM). Stirred this mixture overnight at room temperature. Evaporated and partitioned the residues between EtOAc (50 ml) and 2N HCl (50 mL). Extracted the aqueous layer twice more with EtOAc (2×25 ml). Combined extracts, washed with brine (50 ml), dried with anhydrous magnesium sulfate, filtered and evaporated. A clear oil product (0.49 g, 86%) was obtained. Anal. (C11H17NO5) C, H, N.
Reaction SMILES: [CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][NH:19]1)=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1.[CH:29](=[NH:33])OCC.[OH-].[Na+]>O1CCOCC1>[CH3:1][CH:2]([CH3:28])[CH:3]([NH:15][C:16]([CH:18]1[CH2:22][CH:21]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][N:19]1[CH:29]=[NH:33])=[O:17])[CH:4]1[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:12])[CH:6]([S:13][CH3:14])[O:5]1
Reactant: CCCCCC1CNC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)C1
Reactant: CCOC=N
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCCC1CC(C(=O)NC(C(C)C)C2OC(SC)C(O)C(O)C2O)N(C=N)C1
Reaction time: 0.5 h
Yield: 5.3 %

Procedure:
A stirred suspension of 4-pentyl-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (153 mg, 0.34 mmol, 1 equiv) and ethyl formimidate (Aldrich) (44 mg, 0.40 mmol, 1.2 equiv) in dioxane (1 mL) was treated with 1M aqueous NaOH (0.74 mL, 0.74 mmol, 2.2 equiv). After 1 h additional ethyl formimidate (44 mg, 0.40 mmol, 1.2 equiv) was added to the reaction mixture, and stirring was continued for 30 min. The reaction mixture was frozen and lyophilized. The lyophilized powder was purified by column chromatography to furnish the title compound (8 mg): TLC Rf=0.48 CHCl3/MeOH/32% aqueus AcOH (5:3:1); MS (ESPOS): 447.7 [M+H]+, 469.7 [M+Na]+; MS (ESNEG): 481.6 [M−H+HCl]−.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[N:7]12[CH2:14][CH2:13][CH2:12][C:11]1([CH2:15][N:16]([C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([O:29][CH3:30])=[CH:21][CH:20]=1)C=O)[CH2:10][CH2:9][CH2:8]2.O>C1COCC1>[N:7]12[CH2:14][CH2:13][CH2:12][C:11]1([CH2:15][NH:16][C:19]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]([O:29][CH3:30])=[CH:21][CH:20]=1)[CH2:10][CH2:9][CH2:8]2
Reactant: COc1ccc(N(C=O)CC23CCCN2CCC3)c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(NCC23CCCN2CCC3)c2ccccc12
Yield: 65.6 %

Procedure:
To lithium aluminum hydride (1.76 g, 46.3 mmol) in THF (43 ml), 1-[N-(1-Azabicyclo[3.3.0 ]octan-5-yl )methyl-N-formylamino]-4-methoxynaphthalene (3.00 g, 9.26 mmol) in THF (15 ml) was added dropwise at room temperature. After refluxed for 1 hour, the reaction mixture was cooled and chilled water was added dropwise. Formed solids were removed by filtration and the filtrate was concentrated in vacuo and purified by chromatography to afford the desired compound (1.80 g, 62.7%), as a pale yellow liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Br[C:11]1[C:12](=[O:24])[N:13]([C:17]([CH:21]([CH3:23])[CH3:22])([CH3:20])[C:18]#[N:19])[C:14](=[O:16])[CH:15]=1>C(O)C>[C:18]([C:17]([N:13]1[C:12](=[O:24])[CH:11]=[C:15]([NH:1][C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH2:4][OH:5])[C:14]1=[O:16])([CH3:20])[CH:21]([CH3:22])[CH3:23])#[N:19]
Reactant: Nc1ccccc1CO
Reactant: CC(C)C(C)(C#N)N1C(=O)C=C(Br)C1=O
Solvent: CCO
Product: CC(C)C(C)(C#N)N1C(=O)C=C(Nc2ccccc2CO)C1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To o-aminobenzyl alcohol, (2 g, 0.0125 mol) and 3-bromo-α-isopropyl-α-methyl-2,5-dioxo-3-pyrroline-1-acetonitrile (2.7 g, 0.01 mol) is added absolute ethanol (100 ml) containing 3 g of 5 A pulverized sieves. The mixture is stirred for 20 hours at room temperature. The solvent is removed and the residue is purified through a silica gel dry column, eluant ether-hexane (2:1). Starting bromomaleimide is first recovered, followed by a bright yellow solid 1.89 g (60%), mp 39°-45° C. Anal. calcd. for C17H19N3O3 : C, 65.16; H, 6.11; N, 13.41. Found: C, 65.94; H, 6.21; N, 12.87.
Reaction SMILES: [OH-:1].[K+].OO.[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]#[N:16])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]>O>[C:5]([N:9]1[C:13]([NH2:14])=[C:12]([C:15]([NH2:16])=[O:1])[CH:11]=[N:10]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: [OH-]
Reactant: CC(C)(C)n1ncc(C#N)c1N
Agent: OO
Agent: [K+]
Solvent: O
Product: CC(C)(C)n1ncc(C(N)=O)c1N
Temperature: 0 °C
Reaction time: 4 h
Yield: 75.1 %

Procedure:
To a mixture of water (500 ml) and 85% KOH (37.91 g) at 0° C. was added 30% H2O2 (49.4 ml, 483 mmol), followed by 1-tert-butyl-5-amino-1H-pyrazole-4-carbonitrile (15.83 g, 96.5 mmol). The reaction mixture was stirred for four hours at 0° C. and then at room temperature for 1 hour. A yellow precipitate had formed which was collected by filtration and air dried to afford 13.2 g (75%) of 1-tert-butyl-5-amino-1H-pyrazole-4-carboxamide, m.p. 193-195° C.
Reaction SMILES: [Li][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.CN(OC)[C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1.Cl>C1COCC1.CCOCC>[CH3:20][O:19][C:13]1[CH:12]=[C:11]([CH2:10][C:9]([C:2]2[S:3][CH:4]=[CH:5][CH:6]=2)=[O:21])[CH:16]=[CH:15][C:14]=1[O:17][CH3:18]
Reactant: COc1ccc(CC(=O)N(C)OC)cc1OC
Reactant: [Li]c1cccs1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2cccs2)cc1OC
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
2-Lithiothiophene (1.0 M in THF, 33.0 mL, 33.0 mmol, Aldrich Chemical Co.) was added dropwise to N-methyl-N-methoxy-(3,4-dimethoxyphenyl)acetamide (5.26 g, 22.0 mmol) in anhydrous THF at -78° C. The reaction was allowed to proceed 90 min., then diluted with 100 mL Et2O and poured into 1 N aq. HCl. The aqueous phase was extracted with Et2O and the combined organic fraction was washed with brine, dried (Na2SO4), and concentrated in vacuo. Flash chromatography (25% EtOAc/hexanes) yielded 2.91 g (50%) 2-(3,4-dimethoxyphenyl)-1-(thien-2-yl)ethanone as a brown oil. MS 263 (M+H)+, 280 (M+NH4)+.
Reaction SMILES: [CH2:1](OC1C=C(C=CC=1O)C(O)=O)C1C=CC=CC=1.[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1O)[CH2:30][Br:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([CH3:1])[CH:34]=1)[CH2:30][Br:31])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(O)c1ccc(O)c(OCc2ccccc2)c1
Reactant: Oc1ccc(CBr)cc1OCc1ccccc1
Product: Cc1cc(CBr)cc(OCc2ccccc2)c1

Procedure:
When 3-benzyloxy-4-hydroxybenzoic acid is used as a starting material and similarly reduced and brominated, 3-benzyloxy-4-hydroxybenzyl bromide used in Example 33 can be obtained.
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)C1C=CC=CC=1)([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[CH:6]([N:9]([C:16]1[CH:21]=[CH:20][C:19]2[O:22][CH2:23][O:24][C:18]=2[CH:17]=1)[C:3](=[O:4])[CH2:2][Br:1])([CH3:8])[CH3:7]
Reactant: CC(C)N(c1ccccc1)c1ccc2c(c1)OCO2
Reactant: O=C(Br)CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C(=O)CBr)c1ccc2c(c1)OCO2
Reaction time: 8 h

Procedure:
Bromoacetyl bromide (6.0 mL) in methylene chloride (100 mL) is added dropwise to a 0° C. solution of N-Isopropyl-N-(3,4-methylenedioxy-phenyl) aniline, prepared as in Part A, (12.0 g) in methylene chloride (100 mL) and triethylamine (9.41 mL) and the resultant mixture is allowed to attain RT overnight. The reaction mixture is washed with 1N hydrochloric acid (3×80 mL), water (2×80 mL), brine (80 mL), dried, (MgSO4) and concentrated in vacuo to afford crude N-Isopropyl-N-(3,4-methylenedioxy-phenyl) bromoacetamide (16.3 g) as a black mobile oil which is used without further purification: 1H NMR (300 MHz, CDCl3) δ6.82 (d, 1H, J=8.2), 6.61 (m, 2H), 4.90 (m, 1H, J=6.8), 3.58 (s, 2H), 1.07 (m, 6H).
Reaction SMILES: [C:1]([O:24][C:25]1[CH:30]=[CH:29][C:28](C2C=CC(F)=CC=2F)=[CH:27][C:26]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].OC1C=C([C:54]([F:57])([F:56])[F:55])C=CC=1C(O)=O>>[C:1]([O:24][C:25]1[CH:30]=[C:29]([C:54]([F:57])([F:56])[F:55])[CH:28]=[CH:27][C:26]=1[C:39]([O:41][CH2:42][CH3:43])=[O:40])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Oc1ccc(-c2ccc(F)cc2F)cc1C(=O)OCC
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)Oc1cc(C(F)(F)F)ccc1C(=O)OCC

Procedure:
Ethyl 2-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-4-(trifluoromethyl)benzoate was prepared in a similar fashion as ethyl 4-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoyloxy)-2′,4′-difluorobiphenyl-3-carboxylate, using the appropriate 2-hydroxy-4-(trifluoromethyl)benzoic acid starting material. Mass calculated for C32H39F3O4=544.64; found: [M+Na]+=567.3.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28]([NH:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)=[CH:17][CH:16]=1)=[O:29]
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1ccc(-c2coc(-c3ccccc3)n2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccc(-c2coc(-c3ccccc3)n2)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.3 %

Procedure:
to a solution of 4-(2-phenyloxazol-4-yl)benzenamine (299 mg, 1266 μmol) and pyridine (500 μl, 6131 μmol) dissolved in 4 mL dichloromethane at room temperature was added 2,4-dichlorobenzoyl chloride (177 μl, 1266 μmol) all at once. The reaction was stirred at room temperature for 1 hour then concentrated under reduced pressure, taken up in heptane and concentrated again under reduced pressure to afford a yellow solid. The solid was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic extract was dried over magnesium sulfate, filtered and the filtrate concentrated under reduced pressure to afford a yellow solid. The product was purified by preparative reversed phase HPLC. Combination of fractions containing product were concentrated under reduced pressure to afford a colorless solid (100 mg, 19%). ESI+ m/z=409.0 [MH]+.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:4]=1)#[N:2].[CH2:19]([NH2:22])[CH2:20][CH3:21]>>[C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6]([NH:22][CH2:19][CH2:20][CH3:21])=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[N:4]=1)#[N:2]
Reactant: CCCN
Reactant: Cc1ccc(-c2nc(C#N)c(C#N)nc2Cl)cc1
Product: CCCNc1nc(C#N)c(C#N)nc1-c1ccc(C)cc1
Yield: 74 %

Procedure:
2,3-Dicyano-5-chloro-6-p-tolylpyrazine (1.00 g; 0.0039 mole) and 0.46 g (0.0078 mole) of n-propylamine were worked up in the same way as in Example 13, and then recrystallized from toluene to afford 0.80 g (yield 74%) of 2,3-dicyano-5-n-propylamino-6-p-tolylpyrazine.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([OH:13])[C:9]1=[O:14])=[O:6])[CH3:3].Br[C@@H:17]([CH2:34][O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:18]([O:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:15][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]1[C@H:11]([CH3:12])[N:10]([O:13][CH:17]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:18]([O:20][CH:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:9]1=[O:14])=[O:6])[CH3:3]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)[C@@H](Br)COCc1ccccc1
Reactant: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1OC(COCc1ccccc1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
To a solution of (3S-trans)-[[(1,1-dimethylethoxy)carbonyl]amino]-4-methyl-1-hydroxy-2azetidinone (55 mg, 0.26 mmol) and (S)-2-bromo-3-(phenylmethoxy)propanoic acid, diphenylmethyl ester (110 mg, 0.26 mmol) in dimethylformamide (1 ml) was added potassium carbonate (100 mg, 1 mmol). The resulting slurry was stirred for three hours at room temperature, quenched with hydrochloric acid (1N, 10 ml) and extracted with ether (20 ml). The organic layer was washed twice with dilute hydrochloric acid (1N, 2×10 ml), with saturated sodium chloride solution (20 ml), dried over magnesium sulfate and evaporated at reduced pressure. Purification of the product by preparative thin layer chromatography afforded the title compound (108 mg) as a mixture of diastereomers.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][O:12][C:13]1[CH:14]=[C:15]([C:19]2([OH:25])[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]2)[CH:16]=[CH:17][CH:18]=1>>[OH:25][C:19]1([C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][CH3:11])[CH:14]=2)[CH2:24][CH2:23][CH2:22][N:21]([C:5]([C:4]2[CH:3]=[C:2]([CH3:1])[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:20]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: Cc1cccc(C(=O)Cl)c1
Product: COc1cccc(C2(O)CCCN(C(=O)c3cccc(C)c3)C2)c1

Procedure:
The compound of Example 8 was prepared according to the general preparation protocol A from 3-methylbenzoyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([OH:19])=O)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([Cl:23])=[O:19])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C

Procedure:
To an ice cooled methylene chloride solution of 1-[(Benzyloxy)carbonyl]piperidine-3-carboxylic acid (512 mg, 1.95 mmol) under nitrogen was added oxalyl chloride (0.185 mL, 1.95 mmol) and a few drops N,N-dimethylformamide. The reaction flask was warmed slowly to room temperature and after 2 hours the solvent was removed in vacuo. Toluene was added and removed in vacuo (2×) to give the title compound.
Reaction SMILES: Br[CH:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3]1.[CH2:16]([NH:23][CH2:24][CH2:25][NH2:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([O-])(O)=O.[Na+]>CN(C)C=O>[C:12]([C:9]1[CH:10]=[CH:11][C:6]2[O:5][C:4]([CH3:15])([CH3:14])[CH2:3][CH:2]([NH:26][CH2:25][CH2:24][NH:23][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:8]=1)#[N:13]
Reactant: NCCNCc1ccccc1
Reactant: CC1(C)CC(Br)c2cc(C#N)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC(NCCNCc2ccccc2)c2cc(C#N)ccc2O1
Temperature: 25 °C
Reaction time: 48 h
Yield: 216.7 %

Procedure:
A solution of 4-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran (1.50 g, 5.64 mmole, from Example 8, part B) and N-benzylethylenediamine (8.48 g, 10 eq.) containing NaHCO3 (4.80 g, 5 eq.) in N,N-dimethylformamide (30 ml) was stirred for 48 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and distilled H2O. The organic phase was washed with distilled H2O, saturated NaCl solution, dried over Na2SO4 and evaporated in vacuo to obtain 4.10 g of an orange oil. The crude product was chromatographed on silica eluting with 9:1 methylene chloride/methanol (trace of NH4OH) to obtain 0.91 g (48%) of the title compound as a colorless gum. 1H NMR (CDCl3) δ 8.00 (s, 1H). 7.49-7.34 (m, 6H), 6.88 (d, J=8.80 Hz, 1H), 3.93-3.82 (m, 3H), 3.03-2.80 (m, 5H), 2.25 (dd, J=5.57 and 13.20 Hz, 1H), 1.67 (m, 1H), 1.53 (s, 3H), 1.35 (s, 3H); 13C NMR (CDCl3) δ 157.66, 139.89, 132.52, 132.03, 128.43, 128.14, 127.05, 125.55, 119.65, 118.06, 102.89, 76.86, 53.73, 49.38, 49.01, 45.32, 39.25, 36.40, 29.72, 25.02; MS: (M+H)+ @334.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[OH:6][CH:7]1[O:11][C:10](=[O:12])[CH:9]=[CH:8]1.C1(C=CC(O)=CC=1)O>C(Cl)(Cl)Cl>[OH:12][CH:10]1[CH:9]2[CH:8]([C:5]3[CH2:4][C:3]2=[CH:2][CH:1]=3)[C:7](=[O:6])[O:11]1
Reactant: C1=CCC=C1
Reactant: O=C1C=CC(O)O1
Agent: Oc1ccc(O)cc1
Solvent: ClC(Cl)Cl
Product: O=C1OC(O)C2C3=CC=C(C3)C12
Temperature: 20 °C
Reaction time: 17 h

Procedure:
244 ml of cyclopentadiene were slowly added to a mixture of 208 g of 5-hydroxy-2(5H)-furanone, 350 mg of hydroquinone and 1.05 liters of chloroform while keeping the temperature at 45°-47° C. and the mixture was stirred at 20° C. for 17 hours and was evaporated to dryness under reduced pressure. The residue was added to isopropyl ether and the mixture was heated to reflux with stirring and was cooled and vacuum filtered. The solid was dissolved in methylene chloride and the solution was treated with activated carbon and evaporated to dryness under reduced pressure. The residue and isopropyl ether was heated to reflux with stirring and was cooled and vacuum filtered to obtain 325.7 g of racemic 1-hydroxy-3-oxo-1,3,3a,7a-tetrahydro-4,7-methano-isobenzofuran melting at 105° C.
Reaction SMILES: [N:1]1([C:6]([N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[O:7])[CH:5]=[CH:4]N=[CH:2]1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2CNCC[C:17]=2[C:16]=1[CH:25]=[O:26]>O1CCCC1>[N:8]1([C:6]([N:1]2[CH2:2][CH2:22][C:17]3[C:16]([CH:25]=[O:26])=[C:15]([O:14][CH3:13])[CH:24]=[CH:23][C:4]=3[CH2:5]2)=[O:7])[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: COc1ccc2c(c1C=O)CCNC2
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc2c(c1C=O)CCN(C(=O)n1ccnc1)C2
Temperature: 80 °C
Reaction time: 14 h
Yield: 88.2 %

Procedure:
To a solution of freshly dried di-imidazol-1-yl-methanone (276 mg, 1.7 mmol) in anhydrous tetrahydrofuran (20 mL) the solution of 6-methoxy-1,2,3,4-tetrahydro-isoquinoline-5-carbaldehyde (325 mg, 1.7 mmol) in anhydrous tetrahydrofuran (10 mL) was added and the mixture was stirred at 80° C. oil bath for 14 h. The solution was concentrated and the residue was dissolved in dichloromethane, washed with water (2×10 mL), dried over MgSO4 and concentrated. In this manner the title compound (426 mg, 1.50 mmol, 88.2%) was obtained as a brownish yellow foam.
Reaction SMILES: S(=O)(=O)(O)O.C[O:7][CH:8](OC)[CH2:9][CH2:10][CH2:11][S:12][C:13]1[N:17]([CH3:18])[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:15][N:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:18][N:17]1[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:15][N:14]=[C:13]1[S:12][CH2:11][CH2:10][CH2:9][CH:8]=[O:7]
Reactant: COC(CCCSc1nnc(-c2ccccc2)n1C)OC
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cn1c(SCCCC=O)nnc1-c1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
Concentrated sulfuric acid was added to a solution of 3-[(4,4-dimethoxybutyl)thio]-4-methyl-5-phenyl-4H-1,2,4-triazole (20.49 mmol, 6.30 g) in ethanol (50 ml) until cloudy. The mixture was stirred at 40° C. for 2 h and then made alkaline with sodium carbonate and subsequently extracted with ethyl acetate. The organic phase was dried and concentrated, resulting in 4.8 g of the title compound colorless oil.