Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19]Br)=[CH:15][CH:14]=2)=[N:11][N:12]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:37][NH2:38]>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:30])[CH2:28][CH3:29])[CH2:23][CH2:22]2)=[N:6][C:7]=1[C:8]1[O:9][C:10]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][NH:38][CH3:37])=[CH:15][CH:14]=2)=[N:11][N:12]=1
Reactant: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CBr)cc4)o3)n2)CC1
Reactant: CN
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCC(=O)N1CCC(c2cnc(N)c(-c3nnc(-c4ccc(CNC)cc4)o3)n2)CC1
Temperature: 65 °C

Procedure:
A solution of 1-[4-[5-amino-6-[5-[4-(bromomethyl)phenyl]-1,3,4-oxadiazol-2-yl]pyrazin-2-yl]-1-piperidyl]propan-1-one and Na2CO3 (114 mg, 1.1 mmol) in tetrahydrofuran was treated with a solution of methylamine (1.3 mL of 2 M, 2.5 mmol) in THF and heated at 65° C. for 30 minutes. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude material was purified via reverse phase HPLC (1-50% CH3CN/5 mM HCl) to provide 1-(4-(5-amino-6-(5-(4-((methylamino)methyl)phenyl)-1,3,4-oxadiazol-2-yl)pyrazin-2-yl)piperidin-1-yl)propan-1-one.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[CH:4]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH:20]2[CH2:25][CH2:24][N:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)=[O:19])=[CH:14][CH:13]=1.[Cl-].[NH4+]>O1CCCC1>[F:10][C:5]1[CH:4]=[C:3]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)([CH:20]2[CH2:25][CH2:24][N:23]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[OH:19])[CH:8]=[CH:7][C:6]=1[F:9]
Reactant: O=C(c1ccc(F)cc1)C1CCN(S(=O)(=O)c2ccccc2)CC1
Reactant: Fc1ccc(Br)cc1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)N1CCC(C(O)(c2ccc(F)cc2)c2ccc(F)c(F)c2)CC1
Reaction time: 1 h
Yield: 98.2 %

Procedure:
A three-necked round bottom flask, equipped with a mechanical stirrer, flushed with nitrogen, and containing 3.74 g (0.154 mole) of magnesium turnings, was dried with a Bunsen burner. After the flask had cooled, 600 ml of tetrahydrofuran was added. To this mechanically stirred mixture was slowly added a solution of 29.4 g (0.152 mole) of 4-bromo-1,2-difluorobenzene in 50 ml of tetrahydrofuran. The mixture was stirred for 1 hour, and 45.11 g (0.13 mole) of (4-fluorophenyl)[1-(phenylsulfonyl)-4-piperidinyl]methanone was added as a solid. The solution was stirred at ambient temperatures for 3 hours and was poured into an icy aqueous solution of ammonium chloride. The aqueous mixture was extracted with methylene chloride, dried over magnesium sulfate, and the solvent was removed in vacuo. The residue was recrystallized from methylene chloridehexane to give 58.89 g (82.9%) of the title compound. A small sample was recrystallized from a mixture of methylene chloride-ether-hexane to give an analytically pure sample of the title compound, mp 97°-99° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][SH:12])[CH:2]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][S:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])[CH:2]=1
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: SCCCNCc1cccnc1
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCCN1Cc1cccnc1
Yield: 48.4 %

Procedure:
A mixture of N-(3-pyridylmethyl)3-aminopropanethiol (1.8 g), 1-nitro-2,2-bis(methylthio)ethylene (1.7 g) and ethanol (40 ml) was heated under reflux for 5 hours under a nitrogen stream. After the reaction, about 2/3 by volume of ethanol was distilled off under reduced pressure. Ether was added little by little to the reaction mixture to precipitate crystals. The crystals were collected by filtration, and washed with a mixture of ethanol and ether to give the desired 3-(3-pyridylmethyl)2-nitromethylenetetrahydro-2H-1,3-thiazine (1.2 g).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]4)=[C:9]3[N:8]=[C:7](S(C)(=O)=O)[C:6]=2[C:26]#[N:27])[CH2:3][CH2:2]1.C1(NC2N3N=CC(C=C4C(=O)NC(=O)N4)=C3N=C(S(C)=O)C=2C#N)CC1.[Cl:54][C:55]1[CH:56]=[C:57]([C@H:61]([NH2:63])[CH3:62])[CH:58]=[CH:59][CH:60]=1>C(O)(C)C>[Cl:54][C:55]1[CH:56]=[C:57]([CH:61]([NH:63][C:7]2[C:6]([C:26]#[N:27])=[C:5]([NH:4][CH:1]3[CH2:3][CH2:2]3)[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:15]4[C:19](=[O:20])[NH:18][C:17](=[O:21])[NH:16]4)=[C:9]3[N:8]=2)[CH3:62])[CH:58]=[CH:59][CH:60]=1
Reactant: CS(=O)(=O)c1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N
Reactant: C[C@@H](N)c1cccc(Cl)c1
Agent: CS(=O)c1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N
Solvent: CC(C)O
Product: CC(Nc1nc2c(C=C3NC(=O)NC3=O)cnn2c(NC2CC2)c1C#N)c1cccc(Cl)c1
Temperature: 90 °C

Procedure:
The mixture of 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfonyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile and 7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)-5-(methylsulfinyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile (20 mg) was mixed with (R)-1-(3-chlorophenyl)ethanamine (33 mg) in i-propanol (0.5 mL). The reaction mixture was heated at 90° C. in the microwave for 1 hour. The reaction was cooled to room temperature and concentrated under vacuum. The residue was diluted with water, filtered and washed with water followed by 20% ethanol/water mixture. The solid was dried under high vacuum to give 2 mg of the product, 5-(1-(3-chlorophenyl)ethylamino)-7-(cyclopropylamino)-3-((2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidine-6-carbonitrile. LCMS (M+1=463)
Reaction SMILES: [CH2:1]([N:6]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:14])[CH2:2][CH2:3][CH:4]=C.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCCC1.O.[Os](=O)(=O)(=O)=O>[O:14]=[C:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:6]1[CH2:1][CH2:2][CH2:3][CH:4]=[O:16]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCCCN1CCCCCCC1=O
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=CCCCN1CCCCCCC1=O
Reaction time: 0.08 h
Yield: 84.5 %

Procedure:
Osmium tetroxide (17 mg, 0.07 mmole) was added to 1-pent-4-enyl-azocan-2-one (5.52 g, 28.3 mmole) in a mixture of tetrahydrofuran (100 mL) and water (50 mL) under ambient water bath cooling. The mixture was stirred for 5 minutes and solid sodium periodate (15.11 g, 70.65 mmole) was added in portions over 15 minutes. The reaction mixture was stirred for 3 hours and filtered. The filtrate was concentrated, saturated with solid sodium chloride, and extracted with methylene chloride. The organic phase was dried (magnesium sulfate) and concentrated. Purification by silica gel chromatography, eluting with chloroform, gave 4-(2-oxo-azocan-1-yl)-butyraldehyde (4.72 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])=[C:4]([NH:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:45])=CC=1>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[S:45])[C@@H:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])=[C:4]([NH:29][C:30]2[CH:35]=[CH:34][N:33]=[CH:32][N:31]=2)[CH:3]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)C(=O)Nc1ccc(F)cc1Nc1ccncn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc2[nH]cnc12)C(=S)Nc1ccc(F)cc1Nc1ccncn1
Yield: 12.2 %

Procedure:
(S)—N-[4-Fluoro-2-(pyrimidin-4-ylamino)phenyl]-2-[9-(tetrahydro-pyran-2-yl)-9H-purin-6-ylamino]propionamide (88 mg, 0.18 mmol) and Lawesson's reagent (298 mg, 0.74 mmol) were heated at reflux in THF (4 mL) under nitrogen for 16 h. Further Lawesson's reagent (150 mg, 0.37 mmol) was added and the reaction refluxed for a further 24 h. The reaction mixture was cooled, diluted with EtOAc (30 mL) and extracted with 1M HCl (2×5 mL). The aqueous extracts were basified with Na2CO3 and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (Na2SO4), concentrated in vacuo and purified by column chromatography (Si—PCC, gradient 0-10% (9:1 MeOH/0.880 NH3) in DCM to give the title compound as a colourless gum, (9 mg, 12%). LCMS (Method B): RT 1.88 min [M+H]+ 410.09
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].CC(C)=O.[I-:15].[Na+]>C(Cl)Cl>[I:15][CH2:2][CH:3]([CH3:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)CCl
Reactant: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCOC(=O)CC(C)CI

Procedure:
Mix ethyl 4-chloro-3-methylbutyrate (80 g), acetone (400 mL) and sodium iodide (100 g). Reflux for 8 hours, cool and add methylene chloride (400 mL). Filter and evaporate the filtrate to a residue. Partition the residue between methylene chloride (200 mL) and water (200 mL). Separate the organic phase, dry (MgSO4) and evaporate to an oil. Purify by distillation to give the title compound.
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:29]2[N:30]=[C:31]([NH:34]C(=O)C(F)(F)F)[S:32][CH:33]=2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[CH2:3][CH2:2]1.O.O.O.C([O-])(=O)C.[Na+]>O.O1CCCC1>[NH2:34][C:31]1[S:32][CH:33]=[C:29]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([NH:9][C@@H:10]2[C:27](=[O:28])[N:12]3[C:13]([C:24]([OH:26])=[O:25])=[C:14]([CH2:17][S:18][C:19]4[S:20][CH:21]=[N:22][N:23]=4)[CH2:15][S:16][C@H:11]23)=[O:8])[N:30]=1
Reactant: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2[C@H](NC(=O)C(=NOC3CC3)c3csc(NC(=O)C(F)(F)F)n3)C(=O)N12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C(=NOC2CC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CSc4nncs4)CS[C@H]23)cs1
Reaction time: 8 h

Procedure:
To a suspension of 7β-[2-cyclopropyloxyimino-2-(2-trifluoroacetamidothiazol-4-yl)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid syn isomer) (1.1 g) in a mixture of water (23.5 ml) and tetrahydrofuran (2 ml) was added sodium acetate trihydrate (2.35 g) at ambient temperature. The mixture was stirred at the same temperature overnight to give a clear solution. The solution was washed with ethyl acetate and adjusted to pH 2 with 1N hydrochloric acid. The mixture was extracted with tetrahydrofuran twice. The extract was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with ethyl acetate to give 7β-[2-(2-amino- thiazol-4-yl)-2-(cyclopropyloxyimino)acetamido]-3-(1,3,4-thiadiazol-2-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (780 mg) as a solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C:19]1=[O:23])=[O:17])([CH3:14])([CH3:13])[CH3:12].[CH3:24][CH:25]([CH3:29])[CH2:26][CH:27]=[O:28].B(F)(F)F.CCOCC>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:22][CH2:21][CH:20]([CH:27]([OH:28])[CH2:26][CH:25]([CH3:29])[CH3:24])[C:19]1=[O:23])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)CC=O
Reactant: CC(C)(C)OC(=O)N1CCCC1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: FB(F)F
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(O)C1CCN(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add lithium bis(trimethyl silyl)-amide (1.0 M in THF, 148 mL, 148 mmol) to a solution of 2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (25.0 g, 134 mmol) in THF (450 mL) at −78° C. and stir under nitrogen for 2 hours. Add 3-methyl-butyraldehyde (17.5 mL, 162 mmol) followed by boron trifluoride diethyl etherate (20.5 mL, 162 mmol) and continue to stir at −78° C. for 2 hours. Warm the mixture to room temperature, quench with saturated aqueous ammonium chloride (250 mL) and extract with EtOAc (3×). Dry the combined organics (Na2SO4), filter and concentrate under reduced pressure. Divide the crude product into two equal portions and purify each portion by silica gel chromatography, eluting with 0-40% EtOAc in hexanes to provide 3-(1-hydroxy-3-methyl-butyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester, diastereomer 1 (12.5 g, 34%) (D1) as the first eluting isomer, MS (m/z)=216.0 (M−56), and 3-(1-hydroxy-3-methyl-butyl)-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester, diastereomer 2 (3.87 g, 11%) (D2) as the second eluting isomer. MS (m/z)=216.0 (M−56)
Reaction SMILES: C1(C)C=CC(S(O[CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:22]3[S:23][CH:24]=[CH:25][CH:26]=3)=[O:21])=[CH:16][CH:15]=2)[C:12]#[N:13])(=O)=O)=CC=1.[Na].[SH:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.O>COCCOC>[S:31]1[C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=[C:30]1[S:29][CH:11]([C:14]1[CH:15]=[CH:16][C:17]([C:20]([C:22]2[S:23][CH:24]=[CH:25][CH:26]=2)=[O:21])=[CH:18][CH:19]=1)[C:12]#[N:13]
Reactant: Cc1ccc(S(=O)(=O)OC(C#N)c2ccc(C(=O)c3cccs3)cc2)cc1
Reactant: Sc1nc2ccccc2s1
Agent: [Na]
Solvent: O
Solvent: COCCOC
Product: N#CC(Sc1nc2ccccc2s1)c1ccc(C(=O)c2cccs2)cc1
Reaction time: 0.5 h
Yield: 67 %

Procedure:
1.191 g of O-(p-toluenesulfonyl)-p-(2-thienylcarbonyl)mandelonitrile was dissolved in 5 ml of DME, and the solution was stirred in an argon atmosphere under ice cooling. Sodium salt of 2-mercaptobenzothiazole (567 mg) was added, and the mixture was stirred under ice cooling for 45 minutes, and then at room temperature for 30 minutes. Water (30 ml) was added, and the mixture was extracted with 30 ml of methylene chloride three times. The extract was washed with 20 ml of water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was separated by column chromatography (silica gel; methylene chloride) to afford 788 mg (yield 67%) of alpha-(2-benzothiazolylthio)[p-(2-thienylcarbonyl)phenyl] acetonitrile as a viscous oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11]O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.ClCCl>[Cl:15][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: ClCc1ccc2ccccc2c1

Procedure:
To 1.26 mol of naphth-2-yl-methanol in 1.5 liters of toluene there are slowly added 3.8 mol of thionyl chloride. The mixture is then heated at reflux for two hours. After cooling, the solvent is evaporated off. The crude product is taken up in toluene twice and evaporated. The oil obtained is taken up in dichloromethane, washed and dried. After filtering and evaporating, the oil obtained is distilled to yield the expected product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([CH3:14])(=[N:10][N+:11]([O-:13])=[O:12])=[O:9])[CH:5]=[CH:6][CH:7]=1.[Br:15][C:16]1[C:17]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])=[N:18][C:19](Cl)=[N:20][CH:21]=1.Cl.C([O-])(O)=O.[Na+]>C(#N)C.O1CCOCC1>[Br:15][C:16]1[C:17]([NH:23][C@H:24]([CH3:27])[CH2:25][OH:26])=[N:18][C:19]([NH:1][C:2]2[CH:3]=[C:4]([S:8]([CH3:14])(=[N:10][N+:11]([O-:13])=[O:12])=[O:9])[CH:5]=[CH:6][CH:7]=2)=[N:20][CH:21]=1
Reactant: C[C@H](CO)Nc1nc(Cl)ncc1Br
Reactant: CS(=O)(=N[N+](=O)[O-])c1cccc(N)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC#N
Product: C[C@H](CO)Nc1nc(Nc2cccc(S(C)(=O)=N[N+](=O)[O-])c2)ncc1Br

Procedure:
A solution of 37 mg (0.17 mmol) of (RS)-S-(3-aminophenyl)-S-methyl-N-nitrosulfoximide in 3 ml of acetonitrile is mixed with 91 mg (0.34 mmol) of (R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and 0.06 ml of a 4 molar solution of hydrochloric acid in dioxane, and it is stirred under reflux overnight. Another 0.05 ml of the 4 molar solution of hydrochloric acid in dioxane is added, and it is refluxed for another 6 hours. After TLC monitoring, it is mixed again with 92 mg (0.34 mmol) of (R)-2-[(5-bromo-2-chloropyrimidin-4-yl)amino]propan-1-ol and refluxed overnight. After cooling, the batch is made basic with saturated NaHCO3 solution and extracted from ethyl acetate. The combined organic phases are dried (Na2SO4), filtered and concentrated by evaporation. The residue that is obtained is purified by chromatography (DCM/EtOH 95:5). 24 mg (0.05 mmol, corresponding to 32% of theory) of the product is obtained (diastereomers A/B 1:1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:25]=[CH:24][C:13]3[C@:14]4([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=3[CH:11]=2)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]4)=[C:6]([C:26]([F:29])([F:28])[F:27])[CH:5]=1)([O-:3])=[O:2].[C:30](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:30][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:7]4[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:26]([F:29])([F:27])[F:28])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3ccc([N+](=O)[O-])cc3C(F)(F)F)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4ccc([N+](=O)[O-])cc4C(F)(F)F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(4-nitro-2-trifluoromethylphenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (48 mg, 0.12 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (40 mg, 0.36 mmol). Methyl iodide (0.022 mL, 0.36 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 35 mg (70%) of the title compound as a white solid. mp 128°-130°. FDMS: m/e=418.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[Li])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OC1C=C(OC)C=CC=1Br)C1C=CC=CC=1.[Li]CCCC>C1COCC1>[CH2:12]([O:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[C:10]([C:2]1[C:3]([C:7]([OH:9])=[O:8])=[CH:4][CH:5]=[CH:6][N:1]=1)=[O:11])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: [Li]c1ccc(OC)cc1OCc1ccccc1
Agent: COc1ccc(Br)c(OCc2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ncccc2C(=O)O)c(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a THF (20 ml) solution of pyridine-2,3-dicarboxylic acid anhydride (1.92 g, 12.9 mmol) was added a THF solution of 2-benzyloxy-4-methoxyphenyllithium (10 ml), which was prepared from 2-benzyloxy-4-methoxyphenyl bromide (3.77 g, 12.9 mmol) and BuLi (1.6M hexane solution, 8.85 ml, 14.2 mmol) at -78° C., at -78° C. over a period of 5 min. The temperature of the mixture was raised to room temperature and the mixture was additionally stirred at the same temperature for 2 h. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between 1N HCl and AcOEt. The organic layer was washed with 1N HCl dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in 1N NaOH and the solution was washed with AcOEt and chloroform. The aqueous layer was acidified with conc. HCl and extracted with AcOEt. The organic layer was washed with 1N HCl and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residual solid was recrystallized from is chloroform-ether to give 2-(2-benzyloxy-4-methoxyphenylcarbonyl)-3-pyridine carboxylic acid (2,03 g) as a colorless solid.
Reaction SMILES: O.O.O.O.O.O.[NH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.Cl.Cl.N1CCNCC1.Br[CH2:22][C:23]1[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=1>CO>[N:7]1([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: C1CNCCN1
Agent: Cl
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(CN2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
A mixtue of 38 g. (0.2 mole) piperazine hexahydrate, 28 g. (0.2 mole) piperazine dihydrochloride and 150 ml. methanol is mixed, while stirring at ambient temperature, with 45 g. (0.2 mole) methyl 4-bromomethylbenzoate. The reaction mixture is left to stand for 2 days and suction filtered from the precipitate. The clear solution is evaporated and the residue is recrystallised from ethanol to give 39 g. (64%) of the desired compound as a monohydrochloride; m.p. 226°-227° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([CH:7]1[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]1)=[O:6].C1CCNCC1.[N+:23]([C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[N+:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([CH:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12]2)=[O:6])=[O:31])=[CH:33][CH:34]=1)([O-:25])=[O:24]
Reactant: CN1CCC(C(=O)c2cccc(N)c2)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc([N+](=O)[O-])cc3)c2)CC1
Yield: 110.5 %

Procedure:
To a mixture of 4-[3-aminobenzoyl]-1-methylpiperidine (50 mg, 0.229 mmol) and (piperidinomethyl)-polystyrene (176 mg, 0.458 mmol) in tetrahydrofuran (1 mL) was added 4-nitrobenzoyl chloride (85 mg, 0.458 mmol) in tetrahydrofuran (1 mL). The reaction mixture was mixed for 18 h at ambient temperature. The reaction mixture was filtered and the filter cake was rinsed with methanol. The filtrate solution was diluted with 10% acetic acid in methanol and poured over a Varian Mega Bond Elut™ strong cation exchange column. The column was rinsed with methanol to remove impurities, then treated with a 7M ammonia in methanol to elute the product from the column. The solvent was evaporated to give 93 mg (>100%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH2:11])=[CH:6][C:5]=1[OH:12].C(Cl)Cl.[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:17](=[O:20])[CH:18]=[CH2:19])=[CH:6][C:5]=1[OH:12]
Reactant: C=CC(=O)Cl
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc(O)c(C(=O)OC)cc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 4-amino-5-chloro-2-hydroxybenzoic acid methyl ester, was added DCM and triethylamine. This mixture was cooled to 0° C. and acryloyl chloride was added dropwise with stirring. After approximately 2 hours, the reaction was quenched by adding MeOH at 0° C. and the resulting mixture was stirred at room temperature for about 15 min and then concentrated in vacuo. DCM and water were added to the residue and this mixture was mixed thoroughly. The layers were separated and the aqueous layer was extracted with DCM. The organic layers were combined, dried (Na2SO4), filtered and the solvent was removed in vacuo to give 4-acryloylamino-5-chloro-2-hydroxybenzoic acid methyl ester. This ester was then combined with Preparation 1, followed by the addition of a THF-MeOH solvent. The mixture was heated and stirred for about 16 hours to provide biphenyl-2-ylcarbamic acid 1-[2-(4-formyl-3-hydroxyphenylcarbamoyl)ethyl]piperidin-4-yl ester was made. Using this ester, and following the procedure described in Example 2 and substituting the appropriate amine, the title compound was prepared. MS m/z [M+H+] calcd for C35H38N4O5, 595.7; found, 595.2.