Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[CH:24]=3)[CH:16]3[CH:12]([CH2:13][N:14](C(OC=C)=O)[CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl>O1CCOCC1.C(OC(C)C)(C)C>[ClH:1].[Cl:29][C:25]1[CH:24]=[C:23]([C:8]2([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[CH:16]3[CH:12]([CH2:13][NH:14][CH2:15]3)[C:11](=[O:22])[CH2:10][CH2:9]2)[CH:28]=[CH:27][CH:26]=1
Reactant: C=COC(=O)N1CC2C(=O)CCC(c3cccc(Cl)c3)(c3cccc(Cl)c3)C2C1
Agent: Cl
Solvent: CC(C)OC(C)C
Solvent: C1COCCO1
Product: O=C1CCC(c2cccc(Cl)c2)(c2cccc(Cl)c2)C2CNCC12
Temperature: 60 °C
Reaction time: 6 h
Yield: 144.6 %

Procedure:
(3aRS,7aRS)-7,7-bis-(3-chlorophenyl)-2-vinyloxycarbonyl-4-perhydroisoindolone (1.5 g) is treated with a 6N solution (7.4 cc) of hydrochloric acid in dioxane for 2 hours at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is heated for 1 hour in solution in ethanol at 60° C. and then stirred for 6 hours at 25° C. The solution is concentrated to dryness under reduced pressure (2.7 kPa) and the meringue obtained is solidified in isopropyl ether. The precipitate is drained and washed with isopropyl ether and then dried to give 7,7-bis-(3-chlorophenyl)-4-perhydroisoindolone hydrochloride (1 g).
Reaction SMILES: [CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:14]([O:16]CC)=O)[S:13][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3].O.[NH2:20][NH2:21]>C(O)C>[CH2:1]([N:4]1[CH2:10][CH2:9][C:8]2[CH:11]=[C:12]([C:14]([NH:20][NH2:21])=[O:16])[S:13][C:7]=2[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: NN
Reactant: CCCN1CCc2cc(C(=O)OCC)sc2CC1
Solvent: CCO
Solvent: O
Product: CCCN1CCc2cc(C(=O)NN)sc2CC1

Procedure:
13.0 gm (0.0486 mol) of ethyl 5,6,7,8-tetrahydro-6-propyl-4H-thieno[2,3-d]azepine-2-carboxylate were dissolved in 15 ml of absolute ethyl alcohol, and the solution was refluxed for 3 hours with 14 ml (0.23 mol) of 80% hydrazine hydrate. After cooling, the mixture was concentrated by evaporation in vacuo, and the residue was recrystallized from isopropyl alcohol.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH3:12][NH2:13].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:13][CH3:12])(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CN
Solvent: O
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccccc1Br
Temperature: 0 °C

Procedure:
2-Bromobenzenesulfonyl chloride (manufactured by Fluorochem Co., 25 g) was dissolved in tetrahydrofuran (40 mL), and under stirring at 0° C., 40% methylamine aqueous solution (TCI, 25 mL) was added dropwise thereto over ten minutes. After stirring the mixture at room temperature for 2 hours and 40 minutes, water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. To the residues, hexane and a small amount of ethyl acetate were added, followed by stirring. Solids were filtered to obtain the target compound (23.26 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][C:34]#[N:35])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH:36]O.[OH-].[Na+]>CO>[NH2:35][C:34](=[O:36])[CH2:33][C:19]1[CH:18]=[CH:17][C:16]([NH:15][C:13]([C:10]2([C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][O:3][C:4]=4[CH:9]=3)[CH2:11][CH2:12]2)=[O:14])=[CH:21][C:20]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=1
Reactant: OO
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 24 %

Procedure:
5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide (58 mg, 0.12 mmol), H2O2 (30 wt % solution in water, 36 μL, 1.2 mmol), and NaOH (10 wt % in water, 0.15 mL, 0.42 mmol) were dissolved in MeOH (1.2 mL) and stirred at 25° C. for 2 hours. The reaction was filtered and purified by reverse phase HPLC to yield 2′-(2-amino-2-oxoethyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-N,N-dimethylbiphenyl-4-carboxamide (14 mg, 23%). ESI-MS m/z calc. 485.2, found 486.5 (M+1)+; Retention time 2.54 minutes.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([OH:26])=[S:25])=[C:15]([C:18]4[S:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[C:35]([O:41][CH2:42]I)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37].O>CN(C)C(=O)C.C(OCC)(=O)C>[C:1]1([CH2:7][C:8]([NH:10][C@@H:11]2[C:27](=[O:28])[N:13]3[C:14]([C:24]([O:26][CH2:42][O:41][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37])=[S:25])=[C:15]([C:18]4[S:19][C:20]([CH3:23])=[N:21][N:22]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(=O)OCI
Reactant: Cc1nnc(C2=C(C(O)=S)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nnc(C2=C(C(=S)OCOC(=O)C(C)(C)C)N3C(=O)[C@@H](NC(=O)Cc4ccccc4)[C@H]3SC2)s1
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
To a solution of 7β-(2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylic acid (492 mg) in N,N-dimethylacetamide (4 ml) was added cesium carbonate (200 mg) under ice-cooling, stirred at the same temperature for 1.5 hours. To the mixture was added iodomethyl pivalate (297 mg), stirred for 1 hour at the same temperature. To the mixture were added water (50 ml) and ethyl acetate (50 ml). The organic layer was separated, washed with water and saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was triturated with diethyl ether to give pivaloyloxymethyl 7β-(2-phenylacetamido)-3-(5-methyl-1,3,4-thiadiazol-2-yl)thio-3-cephem-4-carboxylate (492 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[CH3:18][N+:19](C)=C(N(C)C)O.C(N(CC)CC)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44](C)=[C:43]([NH2:48])[C:42]=1N>CN(C)C=O>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([NH:19][CH3:18])=[C:43]([NH:48][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)CCN(C(=O)c1ccc(C)c(N)c1N)c1ccccn1
Reactant: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c(NC(=O)CNC(=O)OC(C)(C)C)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
19.2 g (0.11 mol) of N-tert.butyloxycarbonylglycine were dissolved in 175 ml of dimethylformamide, mixed with 35.2 g (0.11 mol) of O-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate, 11.0 g of triethylamine and 34.2 g (0.10 mol) of 3-amino-4-methyl-amino-benzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)-amide and stirred for 2.5 hours at ambient temperature. Then the reaction solution was mixed with 5 l of ice water and stirred for 2 hours. The grey precipitate formed was filtered off, washed with water, dried and recrystallised from ethyl acetate with the addition of activated charcoal. Yield: 39.85 g (80% of theory), C25H33N5O6 (499.6) Rf value: 0.55 (silica gel; methylene chloride/ethanol=19:1)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[CH:22][N:21]=[C:20]([C:24]([O:26][CH3:29])=[O:25])[CH:19]=2)[CH2:14][C@H:13]1[O:27][CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO[C@@H]1CN(c2cc(C(=O)O)ncn2)CC[C@@H]1NC(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)ncn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
cis(±)-6-(4-{[(Benzyloxy)carbonyl]amino}-3-methoxypiperidin-1-yl)pyrimidine-4-carboxylic acid obtained in Example (174b) (420 mg, 1.09 mmol) was dissolved in DMF (10 mL). Potassium carbonate (180 mg, 1.3 mmol) and methyl iodide (185 mg, 1.3 mmol) were added, and the mixture was stirred at room temperature overnight. Potassium carbonate (180 mg, 1.3 mmol) and methyl iodide (185 mg, 1.3 mmol) were further added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=40/1, 20/1, 10/1) to obtain 112 mg of the title compound as a brown oily substance (26%).
Reaction SMILES: [CH2:1]([CH:4]([CH2:7][OH:8])[CH2:5][OH:6])[CH2:2][CH3:3].[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O>C1(C)C=CC=CC=1>[CH2:1]([CH:4]1[CH2:7][O:8][CH:13]([C:12]2[CH:15]=[CH:16][CH:17]=[C:10]([F:9])[CH:11]=2)[O:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: O=Cc1cccc(F)c1
Reactant: CCCC(CO)CO
Solvent: Cc1ccccc1
Product: CCCC1COC(c2cccc(F)c2)OC1
Yield: 32.6 %

Procedure:
2-Propyl-1,3-propanediol (138.0 g; 1.17 mol) and 3-fluorobenzaldehyde (138.0 g; 1.11 mol) were dissolved in toluene (1.5 liters), and PTS (7 g) was added. The mixture was refluxed for 3 hours while being dehydrated with a Dean-Stark's device. The resultant reaction mixture was washed sequentially with saturated sodium bicarbonate solution and saturated brine, and then dried over magnesium sulfate. Subsequently, the solvent was evaporated. The residue was recrystallized twice from heptane, to thereby obtain 81.2 g (362 mmol) of 5-propyl-2-(3-fluorophenyl)-1,3-dioxane. The yield of the compound from 3-fluorobenzaldehyde was 32.6%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11]/[C:10](=[CH:26]\N(C(C)C)C(C)C)/[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH2:11][C@H:10]([CH3:26])[C:9]1=[O:34])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)N(/C=C1\C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O)C(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: C[C@@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@H]1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Temperature: 25 °C

Procedure:
1.3 g (R)-5-Biphenyl-4-ylmethyl-3-[1-dimethylaminometh-(E/Z)-ylidene]-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (7-a, R1=Boc, R6=Me, R7=Me) is added to ethyl acetate (40 ml) at ambient temperature. 0.3 g of 10% Palladium on Carbon (Engelhard 4505) is added to the mixture. The mixture is then pressurised under a hydrogen atmosphere to 2 bar. The mixture is stirred at ambient temperature and 2 bar hydrogen pressure for 3 days. The mixture is then filtered to remove the catalyst and concentrated under reduced pressure. The residue is then purified by column chromatography (ethyl acetate/hexane, 70:30) to afford (3R,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-a, R1=Boc) and (3S,5S)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-pyrrolidine-1-carboxylic acid tert-butyl ester (3-b, R1=Boc). Diastereomer ratio 88.8:11.2 (3-a, R1=Boc: 3-b, R1=Boc) as determined by hplc.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[CH:11](OCC)(OCC)OCC.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH2:31])[CH:26]=[C:27]([O:29][CH3:30])[CH:28]=1>CCCCCC>[CH3:30][O:29][C:27]1[CH:26]=[C:25]([NH:31][CH:11]=[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:9])[CH:24]=[C:23]([O:22][CH3:21])[CH:28]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: COc1cc(N)cc(OC)c1
Reactant: CCOC(OCC)OCC
Solvent: CCCCCC
Product: COc1cc(NC=C2C(=O)OC(C)(C)OC2=O)cc(OC)c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
In a dried 2-necked round bottom flask equipped with reflux condenser and inert atmosphere, 2,2-dimethyl-1,3-dioxane-4,6-dione (5.3 g, 37 mmol) was dissolved in triethyl orthoformate (37 ml, 221 mmol) and the mixture was stirred at 100° C. under nitrogen for 1.5 h. 3,5-dimethoxybenzenamine (5.6 g, 37 mmol) was added and heating continued for 4.5 h. The reaction mixture was cooled down to RT and poured into hexane (50 mL). The solid was filtered off and washed with hexane to afford 5-((3,5-dimethoxyphenylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione as a light yellow solid. MS: W/z=[M+H]+. 308.1 Calc'd for C15H17NO6: 307.3.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][N:8]2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=2)=[CH:4][CH:3]=1
Reactant: Nc1nccc(Cl)n1
Reactant: Cc1n[nH]c2cc(Br)ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2ccnc(N)n2)c2cc(Br)ccc12
Reaction time: 2 h

Procedure:
To a solution of 6-bromo-3-methylindazole (300 mg, 1.42 mmol) in DMF (6 mL) was added NaH (60% oil suspension) (91 mg, 2.27 mmol) at 0° C. The mixture was stirred at RT for 10 min before addition of 4-chloropyrimidin-2-amine (368 mg, 2.84 mmol). Stirring continued at 60° C. for 2 hr. After standing at RT overnight the reaction mixture was quenched by addition of water (10 mL). The mixture was extracted with EtOAc (2×15 mL). During the process of extraction solid formed was removed by suction filtration. The organic layer was washed with water (2×5 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was triturated with EtOAc-heptane (1:1) to give the title intermediate as a white solid: 1H NMR (250 MHz, DMSO) δ 2.53-2.64 (3H, m), 6.69-7.21 (3H, m), 7.43-7.62 (1H, m), 7.76-7.89 (1H, m), 8.18-8.38 (1H, m), 8.92-9.15 (1H, m); LC-MS: m/z=+303.95/305.65 (M+H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[C:9](O)(=O)[CH2:10][C:11](O)=O.[OH-].[NH4+:17]>O>[CH2:10]([C:11]1[NH:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[N:17]=1)[C:9]1[NH:8][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=2[N:7]=1
Reactant: Nc1ccccc1N
Reactant: [NH4+]
Reactant: O=C(O)CC(=O)O
Agent: [OH-]
Solvent: O
Product: c1ccc2[nH]c(Cc3nc4ccccc4[nH]3)nc2c1

Procedure:
To a flask were added 20 g polyphosphoric acid. After heating to 90 C under nitrogen, a mixture of 5.0 g 1,2-phenylenediamine and 2.4 g malonic acid were added. The reaction mixture was heated to 180 C for 4 hours, then cooled to 150 C and poured into 40 ml water. The mixture was basified with aqueous ammonium hydroxide. After cooling to 5 C, the product was filtered off and washed with water. The solid was reslurried in 200 ml hot acetonitrile, cooled, filtered and dried leaving 2.7 g of a gray solid.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[O:9])[CH2:2]2.[Br-].[Cl-].[NH4+].C[C:14]1[CH:19]=[CH:18][C:17](COC(NNC(C2C=NC=CN=2)=O)=O)=[CH:16][CH:15]=1.C1C[O:37][CH2:36]C1>O>[OH:9][C:3]1([C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:37][CH3:36])[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: C1CCOC1
Reactant: Cc1ccc(COC(=O)NNC(=O)c2cnccn2)cc1
Reactant: O=C1CN2CCC1CC2
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: COc1ccccc1C1(O)CN2CCC1CC2

Procedure:
A solution of 3-quinuclidinone (3.97 g, 31.7 mmol) in THF (15 mL) was added dropwise to a solution of 2-methoxyphenylmagneisum bromide [prepared from 2-bromoanisole (3.76 mL, 28.9 mmol), iodine (2 crystals) and magnesium (0.77 g, 31.7 mmol) in THF (10 mL)] cooled in an ice/water bath. After 3 h at room temperature a saturated aqueous solution of ammonium chloride (50 mL) was added. The resulting mixture (pH10) was diluted with H2O (50 mL) and extracted with dichloromethane (4×50 mL). The combined organic extracts were washed with brine, dried over magnesium sulphate and evaporated to a light yellow oil. The crude product was purified by chromatography through silica-gel using dichloromethane/methanol/ammonia (89:10:1) as eluent to give the title compound as a colourless oil (1.02 g); 1H NMR (360 MHz, CDCl3) δ 1.45-1.65 (3H, m), and 2.32 (1H, m, 5 and 8-CH2), 2.44 (1H, br, OH); 2.46 (1H, m, 4-CH), 2.81 (2H, t, J=8 Hz) and 2.93 (1H, m) and 3.10 (1H, m 6 and 7-CH2), 3.29 (1H, d, J=15 Hz, 2-CH), 3.40 (1H, d, J=15 Hz, 2-CH), 3.91 (3H, s, OME), 6.98 (2H, m, Ar-H), 7.27 (2H, m, Ar-H); m/z 233 (M+).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)(O)[CH2:16][C@H:12]1[C:13]([OH:15])=[O:14])([O:3]CC1C=CC=CC=1)=O.C(CC(Cl)=S)(=O)C.[C:33]([S:36][C:37]1(C(O)=O)C(C(=O)C)=CCN1CC1OC=CC=1)(=[O:35])[CH3:34]>>[C:33]([S:36][CH2:37][C:1]([N:11]1[CH2:18][C:17]([CH2:20][C:21]2[O:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C@H:12]1[C:13]([OH:15])=[O:14])=[O:3])(=[O:35])[CH3:34]
Reactant: O=C(O)[C@@H]1CC(O)(Cc2ccco2)CN1C(=O)OCc1ccccc1
Reactant: CC(=O)SC1(C(=O)O)C(C(C)=O)=CCN1Cc1ccco1
Agent: CC(=O)CC(=S)Cl
Product: CC(=O)SCC(=O)N1CC(Cc2ccco2)=C[C@H]1C(=O)O

Procedure:
4-[(2-Furyl)methyl]-3,4-dehydro-L-proline from part (a) is reacted with 2-acetylthioacetyl chloride according to the procedure of Example 3 (b) to yield (2S)-1-[2-(acetylthio)-1-oxoethyl]-4-[(2-furyl)methyl]-2,5-dihydro-1H-pyrrole-2-carboxylic acid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15](O)=[O:16])[N:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:37][C:38]1[CH:39]=[C:40]([C:44]2[NH:48][C:47](=[O:49])[O:46][N:45]=2)[CH:41]=[CH:42][CH:43]=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:30]=[CH:29][CH:28]=[CH:27][C:9]=3[N:10]([CH2:19][C:20]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)=[O:21])[C:11](=[O:18])[N:12]([CH2:14][C:15]([NH:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([C:44]4[NH:48][C:47](=[O:49])[O:46][N:45]=4)[CH:39]=3)=[O:16])[N:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1cccc(-c2noc(=O)[nH]2)c1
Reactant: O=C(O)CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(CN1N=C(C2CCCCC2)c2ccccc2N(CC(=O)C2CCCC2)C1=O)Nc1cccc(-c2noc(=O)[nH]2)c1
Temperature: 0 °C

Procedure:
A 500 mL three-necked-reaction flask was charged with [5-cyclohexyl-1-(2-cyclopentyl-2-oxo-ethyl)-2-oxo-1,2-dihydro-benzo[e][1,2,4]triazepin-3-yl]-acetic acid (32.3 g, 78 mmol), DCM (150 mL) and a few drops of DMF. After cooling to 0° C., oxalyl chloride (8.9 mL, 102 mmol) was added by addition funnel and the mixture warmed to room temperature (over about 30 min). After this time the reaction mixture was concentrated to dryness, then charged with DCM (50 mL) and concentrated again. DCM (150 mL) was added and the reaction mixture cooled to 0° C. 3-(3-Amino-phenyl)-4H-[1,2,4]oxadiazol-5-one (14.6 g, 82 mmol) and DIPEA (41 mL, 235 mmol) in DCM (40 mL) were slowly added to the reaction by addition funnel. The reaction mixture was stirred at room temperature and monitored for starting material consumption (5 h). Upon completion, the reaction mixture was quenched with 2N HCl (140 mL), and washed with DCM (1×100 mL), then after phase separation the organic layer was washed with brine (1×100 mL). The organic layer was separated and dried (Na2SO4, 75 g), filtered and concentrated to yield a light yellow solid after high vacuum. The solid was crystallized from MeCN to yield the title compound as an off white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[S:5][C:4]=1[C:14]([NH2:16])=O.[CH3:17][C:18](=O)[CH2:19][CH3:20].[OH2:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:19]([C:18]1([CH3:17])[N:2]([CH3:1])[C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=3)[S:5][C:4]=2[C:14](=[O:22])[NH:16]1)[CH3:20]
Reactant: CCC(C)=O
Reactant: O
Reactant: CNc1cc(-c2ccncc2)sc1C(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 63 %

Procedure:
A mixture of 3-(methylamino)-5-(pyridin-4-yl)thiophene-2-carboxamide (0.094 g, 0.40 mmol), 2-butanone (3.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 days at 70° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate-tetrahydrofuran (2:1, 100 mL, 50 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. The oil was purified by column chromatography (Combiflash, 12 g silica gel, hexanes to ethyl acetate), then triturated with ethyl acetate-hexanes (1:1), and the precipitate was collected by filtration to afford the title compound (0.0578 g, 63%) as a yellow solid:
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.C([O:17][CH:18](O)[C:19]([F:22])([F:21])[F:20])C.C(O)(=O)C>C1C=CC=CC=1>[CH3:7][O:6][C:4]([CH:3]1[CH:18]([C:19]([F:22])([F:21])[F:20])[O:17][CH:2]=[N:1]1)=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: CCOC(O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: COC(=O)C1N=COC1C(F)(F)F
Temperature: 25 °C

Procedure:
To a solution of methyl isocyanoacetate (4.55 ml) and triethylamine (7.0 ml) in benzene (45 ml) was added trifluoroacetaldehyde ethyl hemiacetal (8 ml) at 0° C. The mixture was stirred at room temperature for an hour and then heated with reflux for 2 hours. The resulting mixture was neutrized with acetic acid, evaporated, diluted with ethyl acetate and washed successively with water (2 times), 10% aqueous sodium hydrogen carbonate and brine. After drying over sodium sulfate, the ethyl acetate extract was filtered and concentrated. The residue was distilled (60° C. /4 mmHg) to give 4-methoxycarbonyl-5-trifluoromethyl-2-oxazoline (5 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:10]([NH:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1ccc(NCc2ccccc2)cc1
Temperature: 85 °C
Yield: 96.5 %

Procedure:
Following general procedure D, a mixture of 4-chloroanisole (1.23 mL, 10 mmol), benzylamine (1.52 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-50% EtOAc/hexanes) to provide the title compound as a yellow oil (2.059 g, 97%). 1H NMR (300 MHz, CDCl3) δ: 7.63-7.52 (m, 5H), 7.06 (d, J=9.0 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 4.46 (s, 2H), 4.05 (s, 1H), 3.92 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 152.6, 143.1, 140.5, 129.2, 128.1, 127.7, 115.4, 114.6, 56.1, 49.5 ppm. IR (neat, cm−1): 3414, 3029, 2832, 1513, 1453, 1235, 1036, 820, 743, 698. Anal. Calcd. for C14H15NO: C, 78.84; H, 7.09. Found: C, 78.61; H, 7.10.