Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]1.O[Li].O>C1COCC1.CO>[F:17][C:2]([F:1])([F:16])[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]1
Reactant: CCOC(=O)C1CCN(CCC(F)(F)F)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1CCN(CCC(F)(F)F)CC1
Reaction time: 15 h
Yield: 99.1 %

Procedure:
To a solution of ethyl 1-(3,3,3-trifluoropropyl)piperidine-4-carboxylate (3.30 g, 13.0 mmol) in THF (40 mL) and MeOH (40 mL) was added LiOH—H2O (1.64 g, 39.1 mmol). The reaction was allowed to stir for 15 h at which time the solution was filtered to remove undissolved solids and the filtrate concentrated. The resulting material was diluted with water (10 mL), made to pH 5 with HCl (conc), then concentrated in vacuo to yield a white solid (2.9 g, 150%). Mass Spectrum: Calcd for C9H15NF3O2(M+H): 226. Found: 226.
Reaction SMILES: [CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@@H:13]4[CH2:15][O:16][P:17]([OH:20])([O:19][C@H:12]4[C@H:11]3[OH:21])=[O:18])[C:5]=2[N:6]=1.C(O)C(N)(CO)C[OH:26].CN1C(=O)N(C)C(=O)C2NC=NC1=2.CN1C(=O)N(C)C(=O)C2NC=NC1=2.C(N)CN.SCCO.C>>[CH:1]1[N:2]=[C:3]([NH2:22])[C:4]2[N:9]=[CH:8][N:7]([C@@H:10]3[O:14][C@H:13]([CH2:15][O:16][P:17]([OH:20])([OH:19])=[O:18])[C@@H:12]([OH:26])[C@H:11]3[OH:21])[C:5]=2[N:6]=1
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@@H]2COP(=O)(O)O[C@H]2[C@H]1O
Reactant: NC(CO)(CO)CO
Agent: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: OCCS
Solvent: NCCN
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O
Reaction time: 2.5 h

Procedure:
Samples of cAMP standards (0-10 pmol) are added to each test tube containing the incubation buffer (trizma base 0.1 M; aminophylline 8.0 mM; 2-mercaptoethanol 6.0 mM, pH 7.4) and [3H]-cAMP in a total volume of 0.5 mL. The binding protein, previously prepared from beef adrenals, is added to the samples previously incubated at 4° C. for 150 min. and, after the addition of charcoal are centrifuged at 2,000 g for 10 min. The clear supernatant (0.2 mL) is mixed with 4 mL of atomlight in a LS-1800 Beckman scintillation counter.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:29]=[CH:28][C:22]3[C:23](=[O:27])[CH:24]=[CH:25][O:26][C:21]=3[C:20]=2[CH2:30][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:10][CH:9]=[CH:8][C:7]=1[O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46].O1C2C(=CC=CC=2)C(=O)C=C1>[Pd].CO.C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:49])[CH2:4][CH2:5][C:6]1[C:7]([O:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]([O:47][CH3:48])=[O:46])=[CH:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:29]=[CH:28][C:22]2[C:23](=[O:27])[CH2:24][CH2:25][O:26][C:21]=2[C:20]=1[CH2:30][CH2:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(=O)ccoc3c2CCCc2ccccc2)c1CCC(=O)OC
Agent: [Pd]
Agent: O=c1ccoc2ccccc12
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)CCCCCOc1cccc(CCCCCCOc2ccc3c(c2CCCc2ccccc2)OCCC3=O)c1CCC(=O)OC
Yield: 38 %

Procedure:
A 1.0 g (1.49 mmol) sample of 2-[(6-methoxy-6-oxohexyl)oxy]-6-[6-[[4-oxo-8-(3-phenylpropyl)-4H-1-benzopyran-7-yl]oxy]hexyl]benzenepropanoic acid methyl ester from the preceding example was catalytically hydrogenated over 10% palladium on carbon, in 30 mL of 1:1 methanol-ethyl acetate, at room temperature and 1 atmosphere, using thin-layer chromatography to monitor the reduction of the starting chromone. The catalyst was filtered and the filtrate was concentrated in vacuo giving an oily product which was purified by flash-chromatography. There was obtained 0.38 g (38%) of the title chromanone as a colorless oil.
Reaction SMILES: Cl.C([CH2:4][C:5]([NH2:7])=[O:6])C.[CH2:8](N(CC)CC)[CH3:9].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[CH2:8]([O:6][C:5](=[N:7][C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:4])[CH3:9]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCC(N)=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: ClCCl
Product: CCOC(C)=NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.4 %

Procedure:
Ethylacetamidate hydrochloride 1.0 g (8.09 mmol) was dissolved in dichloromethane 40 ml at room temperature, added dropwise triethylamine 1.08 ml (16.99 mmol) and stirred for 30 minutes at room temperature. Then, the reacting solution was cooled to 0° C., benzoylchloride 1.03 g (7.35 mmol) was slowly added dropwise in the reacting solution for 10 minutes and stirred for 4 hours at room temperature. After completing the reaction, the reacting solution was washed with water and saturated brine, and then dried with anhydrous magnesium sulfate. Then, the resulting product was filtered under reduced pressure and purified through a flash column chromatography (ethyl acetate:normal hexane=2:8). As a result, N-(1-ethoxy-ethylidene)-benzamide (1.20 g, yield: 86%) was obtained as a liquid phase.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH:10]1([NH2:13])[CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[ClH:1].[O:7]1[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][NH:13][CH:10]2[CH2:12][CH2:11]2)[CH2:5][CH2:6]1
Reactant: NC1CC1
Reactant: ClCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C(CN1CCOCC1)NC1CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
A solution of 100 mg of N-(2-chloroethyl)morpholine and 307 mg of cyclopropylamine in 5 mL of CH3CN was refluxed for 2 h. The mixture was cooled to 25° C. and treated with excess K2CO3. After stirring for 1 h the suspension was filtered and the solvent was evaporated. The residual solvent was removed at high vacuum and the residue was dissolved in a large excess of methanolic HCl. The solvent was evaporated to give 102 mg of the product.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]2[C:13]=1[C:12]1[C@@H:11]([CH2:14][CH:15]([OH:18])[C:16]#[N:17])[CH2:10][CH2:9][C:8]=1[S:7]2.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].N1C=CN=C1>CN(C=O)C.C(Cl)Cl>[Si:23]([O:18][CH:15]([CH2:14][C@H:11]1[CH2:10][CH2:9][C:8]2[S:7][C:6]3[C:13](=[C:2]([Cl:1])[N:3]=[CH:4][N:5]=3)[C:12]1=2)[C:16]#[N:17])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC(O)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(C#N)C[C@H]1CCc2sc3ncnc(Cl)c3c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
To a solution of 3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0^[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]-2-hydroxypropanenitrile (170 mg, 0.61 mmol, 1.00 equiv) in 5 mL of distilled DMF was added tert-butyl(chloro)dimethylsilane (138 mg, 0.92 mmol, 1.50 equiv) and imidazole (124 mg, 1.82 mmol, 3.00 equiv) at room temperature under nitrogen. The resulting solution was stirred for 2 h at ambient temperature and diluted with DCM (30 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 236 mg (99%) of 2-[(tert-butyldimethylsilyl)oxy]-3-[(3R)-12-chloro-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl]propanenitrile as a white solid. MS: m/z 395 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[C:13](/[CH3:20])=[CH:14]/[C:15]([O:17]CC)=[O:16])[CH3:2].[OH-].[K+].O.Cl>C(O)C.O1CCCC1>[CH2:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[C:5]([O:23][CH2:24][O:25][CH3:26])=[C:6]([O:21][CH3:22])[CH:7]=[C:8]2/[C:13](/[CH3:20])=[CH:14]/[C:15]([OH:17])=[O:16])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)c1cc(OC)c(OCOC)c2c(CC)cccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1cccc2c(/C(C)=C/C(=O)O)cc(OC)c(OCOC)c12
Yield: 64.6 %

Procedure:
470 mg of ethyl (E)-3-(5-ethyl-3-methoxy-4-methoxymethoxy-1-naphthyl)-2-butenoate was dissolved in 5 ml of ethanol and 5 ml of tetrahydrofuran, to which 350 mg of potassium hydroxide and 2 ml of water were added, followed by refluxing for 1 hour. The reaction mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and evaporated to obtain 280 mg of the titled compound as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](Cl)=[O:31]>C(#N)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[C:9]2[N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=[CH:4][CH:3]=1)=[O:31]
Reactant: CN1CCN(c2cccc3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CN1CCN(c2cccc3ccc(NC(=O)c4cccc(Cl)c4)cc23)CC1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
The title product was prepared following the procedure of example 3 from 7-amino-1-(4-methyl-l-piperazinyl)-naphthalene (0.24 g, 0.995 mmol) and triethylamine (0.146 mL, 1.09 mmol) and 3-chlorobenzoyl chloride (0.138 mL, 1.09 mmol) in acetonitrile (10 mL) with overnight stirring at room temperature. The product was isolated using flash chromatography and trituration from hexane and recrystallization from ethyl acetate (with a seed crystal) to yield 0.076g (20%) of the title compound: mp 147°-148° C. HRMS m/e calculated for C22H22ClN3O; 379.1448. Observed m/e: 379.14473. Analysis calculated for C22H22ClN3O: C, 69.56; H, 5.84; N, 11.06. Found: C, 68.95; H, 5.81; N, 10.96.
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([N+:14]([O-])=O)=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2].O.NN>CO>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([NH2:14])=[CH:9][CH:10]=2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: NN
Solvent: O
Solvent: CO
Product: CC(=O)N1CCc2ccc(N)cc2C1
Yield: 86.8 %

Procedure:
A mixture of 13 (5.1 g, 23 mmol), activated carbon (4.2 g), ferric chloride hexahydrate (2.1 g, 7.6 mmol) and methanol (140 ml) is stirred under refluxing for 20 minutes. To the boiling mixture is added hydrazine hydrate (8.5 g, 265 mmol) dropwise, and the mixture is refluxed for an additional 4 h, cooled and filtered and the residue washed with methanol. The filtrate is concentrated in vacuo and the residue recrystallized from EtOAc to give compound 14 (3.8 g, 85% yield). 1H NMR [300 MHz, (CD3)2SO], a 3:2 mixture of amide conformers doubling most signals, δ 6.80 (1H, d, H-5), 6.40 (1H, d, H-6), 6.33 (1H, s, H-7), 4.89 (2H, br s, NH2), 4.46 (0.8H, s, ArCH2N), 4.41 (1.2H, s, ArCH2N), 3.57 (2H, t, ArCH2CH2N), 2.66 (1.2H, t, ArCH2CH2N), 2.55 (0.8H, t, ArCH2CH2N), 2.06 (1.2H, s, COCH3), 2.05 (1.8H, s COCH3).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[CH2:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH3:1].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=CCCCCCC
Reactant: C=Cc1ccccc1
Product: CCCCCCCC
Product: CCc1ccccc1

Procedure:
The feed stream thus introduced into the reactor is caused to flow downwardly through the reactor in a co-current flow mode, passing through the catalyst bed where the styrene and 1-octene are hydrogenated to yield a product stream comprising ethylbenzene and n-octane, respectively. This product stream is then cooled and separated into gas and liquid products, with the liquid product being analyzed to determine the conversion efficiency of the reactor.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:4][C:3]1([F:15])[F:14].[CH3:16][S:17]([CH2:20][CH2:21][C:22](O)=[O:23])(=[O:19])=[O:18].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:14][C:3]1([F:15])[CH:2]([NH:1][C:22](=[O:23])[CH2:21][CH2:20][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8])[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CC(N)C(F)(F)C1
Reactant: CS(=O)(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CC(NC(=O)CCS(C)(=O)=O)C(F)(F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a reaction flask was added tert-butyl 4-amino-3,3-difluoropyrrolidine-1-carboxylate (1.36 g, 6.12 mmol), 3-(methylsulfonyl)propanoic acid (1.02 g, 6.73 mmol, 1.1 mol eq), DCM (31 mL, 0.4 M), NMM (1.35 mL, 12.2 mmol, 2 mol eq), HOBt (1.31 g, 9.2 mmol, 1.5 mol eq) and EDC-HCl (1.85 g, 9.2 mmol, 1.5 mol eq). The resulting suspension was stirred at ambient temperature under a nitrogen atmosphere for 2 hr. The reaction was diluted with DCM (80 mL), washed with aqueous NaHCO3 (2×30 mL) and the organic layer was dried over Na2SO4 and evaporated to give a residue that was purified via silica flash chromatography eluting with gradients from 100% heptane to 100% ethyl acetate to give the title product as a white foamy solid (1.65 g, 76% yield, >95% purity). 1H NMR (400 MHz, chloroform-d) δ ppm 6.45 (br. s., 1 H) 4.68-4.89 (m, 1 H) 3.94 (dd, J=10.70, 8.62 Hz, 1 H) 3.62-3.86 (m, 2 H) 3.43 (t, J=7.15 Hz, 2 H) 3.18 (br. s., 1 H) 2.97 (s, 3 H) 2.84 (td, J=7.15, 1.96 Hz, 2 H) 1.47 (s, 9 H). 19F NMR (376 MHz, chloroform-d) δ ppm −112.79-−110.52 (m, 1 F) −114.51-−113.30 (m, 1 F). m/z (APCI+) for C13H22F2N2O5S 257.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)[CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]2[C:17]([NH2:18])=[CH:16][N:15]=[C:14]([Cl:21])[N:13]=2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCN(c2nc(Cl)ncc2[N+](=O)[O-])C1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCCN(c2nc(Cl)ncc2N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.4 %

Procedure:
To an ice cooled mixture of 1 g (0.0032 mole) of (rac)-1-(2-chloro-5-nitro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (IV-67), 1.96 mL of trifluoracetic acid and 15 mL of ethyl acetate, was added 2.76 g (0.02 mole) of stannous chloride dihydrate. The mixture was stirred overnight at ambient temperature. The mixture was made basic (pH 14) by the addition of 15% sodium hydroxide solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.086 g of (rac)-1-(5-amino-2-chloro-pyrimidin-4-yl)-piperidine-3-carboxylic acid ethyl ester (V-67).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[C:12](=[CH:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][CH2:14][C:3]=12.C([O-])=O.[NH4+]>[Pd].C(O)(=O)C>[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[C:11](=[O:22])[CH:12]([CH2:15][C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)[CH2:13][CH2:14][C:3]=12
Reactant: Cc1c2n(c3ccccc13)C(=O)C(=Cc1cccnc1)CC2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1c2n(c3ccccc13)C(=O)C(Cc1cccnc1)CC2
Yield: 52.1 %

Procedure:
A solution of 8,9-dihydro-10-methyl-7-[(pyridin-3-yl)-methylene]pyrido[1,2-a]indol-6(7H)-one (520 mg), ammonium formate (568 mg) and 10% palladium on carbon (200 mg) in acetic acid (20 ml) was stirred at 110° C. for 2 hours. After filtration of the catalyst, the filtrate was evaporated in vacuo. The residue was diluted with 10% methanol-chloroform. The solution was washed with 5% aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Purification of the residue with silica gel chromatography (5% methanol-chloroform), followed by recrystallization from ethyl acetate-ether, gave 8,9-dihydro-10-methyl-7-[(pyridin-3-yl)methyl]pyrido[1,2-a]indol-6(7H)-one (273 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.CC1C=CC(S([N:46]=[N+:47]=[N-])(=O)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=[N+:46]=[N-:47])[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:18][C:17]=3[C:30]#[N:31])=[CH:32][CH:33]=2)=[O:10])=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)C(=[N+]=[N-])c1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(C#N)c1
Reaction time: 4 h
Yield: 114 %

Procedure:
tert-Butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)acetate (0.400 g) and 4-methylbenzenesulfonyl azide (0.193 g) were dissolved in 5 ml of acetonitrile and treated with DBU (0.152 ml). The reaction was stirred for 4 hours, then concentrated, diluted with ethyl acetate and washed with water. The organic layer was dried, filtered, concentrated onto silica gel and purified by silica gel chromatography to provide tert-butyl 2-(4-(4-(4-chlorophenethylcarbamoyl)phenoxy)-3-cyanophenyl)-2-diazoacetate (0.48 g) as a bright yellow solid.
Reaction SMILES: [NH:1]([CH3:3])[CH3:2].C[Al](C)C.C1(C)C=CC=CC=1.FC(F)(F)C([NH:19][CH2:20][CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22](OCC)=[O:23])=O>C(Cl)Cl>[NH2:19][CH2:20][CH:21]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([N:1]([CH3:3])[CH3:2])=[O:23]
Reactant: CNC
Reactant: CCOC(=O)C(CNC(=O)C(F)(F)F)c1ccccc1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CN(C)C(=O)C(CN)c1ccccc1
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 69.4 %

Procedure:
To a stirred 4° C. CH2Cl2 solution (5 mL) containing HNMe2 (180 mg, 4 mmol) under N2, was added 2M AlMe3 in toluene (2 mL, 4 mmol). The reaction was warmed to 20° C. and stirred for five minutes before adding a CH2Cl2 solution (4 mL) containing α-[[(trifluoroacetyl)amino]methyl]benzeneacetic acid, ethyl ester (600 mg, 2.1 mmol). After two days, the reaction was quenched with 1 N aq. HCl, and extracted 3× with EtOAc. The EtOAc fractions were washed with brine, dried over Na2SO4, and concentrated. The crude product was chromatographed on silica gel using 4:1 hexane/EtOAc to elute 380 mg (63%) of the desired trifluoroacetamide which was heated to 60° C. for five hours in MeOH (2 mL) containing 1N aq. NaOH (3 mL). The reaction was diluted with brine, extracted 4× with EtOAc, dried over Na2SO4, and concentrated to yield the title compound as a clear oil (280 mg, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][NH2:12])[O:7][C:6]=2[CH:13]=1.Br[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[O:7][C:6]=2[CH:13]=1
Reactant: O=c1ccc2ccc(OCCCBr)cc2o1
Reactant: NC[C@H]1COc2ccc(O)cc2O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNC[C@H]3COc4ccc(O)cc4O3)cc2o1
Temperature: 86 °C

Procedure:
(S)-2,3-Dihydro-7-hydroxy-1,4-benzodioxin-2-methanamine (3.53 g, 16.2 mmole), 7-(3-bromopropoxy)coumarin (4.17 g, 14.7 mmole), and diisopropylethylamine (5.00 ml, 28.7 mmole) were combined in 300 ml of DMF and heated at 86° C. for 24 hours under a nitrogen atmosphere. The solvent was then removed in vacuum and replaced with dichloromethane. The mixture was washed with an equal volume of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and concentrated in vacuum. The residue was column chromatographed on 300 g of silica gel using first 75% ethyl acetate/dichloromethane and then 2% methanol/dichloromethane as eluant. The product-containing fractions were concentrated in vacuum and the free base redissolved in warm methanol. Five ml of 4N isopropanolic HCl was added, the mixture was brought to a boil on a hot plate and the solvent gradually replaced with isopropanol. Upon cooling, 2.24 g of the title compound precipitated as an white solid, monohydrochloride, m.p. 245°-248° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[SH:7].C(O)C.Cl.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]Cl.C[O-].[Na+]>CO.C(O)(C)C>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[S:7][CH2:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1
Reactant: Cc1occc1S
Reactant: ClCc1ccccn1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CO
Solvent: CC(C)O
Product: Cc1occc1SCc1ccccn1

Procedure:
The 3-furyl sulfides of our invention can also be prepared by reacting 3-furan thiols, e.g. 2-methyl-3-furan thiol with an appropriate aralkyl halide or nitrogen heterocyclic halide, or alkenyl halide or alkylthiolalkyl halide (e.g. bromide or chloride); (i) in the presence of a base such as an alkali metal alkoxide (e.g., sodium methoxide); (ii) at a temperature in the range of 15°-65° C; and (iii) in a suitable solvent, e.g., an anhydrous lower alkanol such as anhydrous methanol, ethanol or isopropanol. Thus, for example, alpha picolyl chloride hydrochloride, when reacted with 2-methyl-3-furan thiol in anhydrous methanol in the presence of sodium methoxide at a temperature of 24° C will yield (2-methyl-3-furyl)(2-pyridylmethyl) sulfide. Thus, as a further example, in a methanol solvent sodium methylate is reacted with 2-methyl-3-furan thiol to form the corresponding mercaptide which is, in turn, reacted with allyl bromide at reflux temperature and 1 atmosphere pressure thereby forming (allyl)(2-methyl-3-furyl) sulfide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[C@@H:10]([NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH2:24][CH3:25]>CC#N.C1COCC1.[Ag-]=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:24][CH3:25])[C@@H:10]([NH:14][C:15]([C:17]2[S:18][C:19]([Cl:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: CCI
Agent: O=[Ag-]
Solvent: CC#N
Solvent: C1CCOC1
Product: CCO[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)c1ccc(Cl)s1

Procedure:
29.1 A solution of 150 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (example 22.4) in 3 ml MeCN and 1 ml THF was treated with 300 mg silver(I) oxide and 0.35 ml iodoethane. The reaction mixture was stirred over night, then was again treated with 300 mg silver(I) oxide and 0.35 ml iodoethane. The reaction mixture was agitated over night at r.t., then filtrated. The filtrate was concentrated. The crude product was purified by chromatography (silica gel; gradient: cyclohexane->EtOAc) to give 90 mg (3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-ethoxy-pyrrolidine-1-carboxylic acid tert-butyl ester as light yellow oil. MS 373.1 ([M−H]−)