Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH2:19][OH:20]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:18][CH2:19][OH:20])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCO)cc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 59.2 %

Procedure:
4-nitrophenol (10 g) was dissolved in DMF (100 ml), potassium carbonate (12.9 g) and 2-bromoethanol (10.8 g) were added to the mixture, and the mixture was stirred for 16 hours at 90° C. After cooling to room temperature, the mixture was filtered, and the solvent was removed under reduced pressure. The obtained residue was added to water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 2-(4-nitrophenoxy)ethanol (7.8 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].I[CH3:27].[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH3:27])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
500 mg (1.44 mmol) of Compound 27 obtained in Example 27 was dissolved in 30 ml of dimethylformamide under argon atmosphere and the solution was cooled on ice. 0.27 ml of iodomethane and 63 mg of sodium hydride (60% oil dispersion) were added, the mixture was stirred at the same temperature for 1 hour and the temperature was raised to room temperature to stir for additional 2 hours. Water was added to the reaction solution and the mixture was extracted twice with ethyl acetate. The organic layer was washed once with water and once with an aqueous saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, the solvent was distilled off and the tan residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:2) to give 2-[4-(N-acetyl-N-methylamino)-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[C:4]=1[C:5]([OH:7])=[O:6].[OH-].[Na+].S(OC)(O[CH3:24])(=O)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[F:1][C:2]([F:16])([F:17])[C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:13])([F:15])[F:14])[C:4]=1[C:5]([O:7][CH3:24])=[O:6]
Reactant: O=C(O)c1c(C(F)(F)F)cccc1C(F)(F)F
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)c1c(C(F)(F)F)cccc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 6 g of 2,6-bis-trifluoromethyl-benzoic acid, 60 ml of tetrahydrofuran and 11.58 ml of a 2N sodium hydroxide solution was stirred for 30 minutes at 20° C. and after the reaction medium was cooled to 0° C., 4.26 ml of dimethyl sulfate were added. The mixture was stirred for 1 hour at 20° C. and another 2.1 ml of dimethyl sulfate were added. The reaction mixture was stirred for 24 hours at 20° C. and was then poured into an aqueous solution of sodium bicarbonate, extracted with isopropyl ether, then with ethyl acetate, dried, filtered, rinsed and brought to dryness. After chromatographing on silica (eluant hexane-ethyl acetate (9-1)), 5.59 g of the desired product were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C@H:10]([CH3:12])[C@H:9]([N:13]([CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14](=[O:21])[C:15]([OH:20])([CH3:19])[C:16]([NH2:18])=[O:17])[C:8](=[O:30])[N:7]([CH2:31][CH:32]=[O:33])[C:6]=2[CH:34]=1.[BH4-].[Na+].C(OC(=O)C)C.CCCCCCC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C@H:10]([CH3:12])[C@H:9]([N:13]([CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[C:14](=[O:21])[C:15]([OH:20])([CH3:19])[C:16]([NH2:18])=[O:17])[C:8](=[O:30])[N:7]([CH2:31][CH2:32][OH:33])[C:6]=2[CH:34]=1
Reactant: C[C@H]1Oc2ccc(F)cc2N(CC=O)C(=O)[C@H]1N(CC(F)(F)C(F)(F)F)C(=O)C(C)(O)C(N)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[C@H]1Oc2ccc(F)cc2N(CCO)C(=O)[C@H]1N(CC(F)(F)C(F)(F)F)C(=O)C(C)(O)C(N)=O
Yield: 32.9 %

Procedure:
1.00 g (2.0 mmol N-[(6R,7S)-2-Fluoro-6-methyl-8-oxo-9-(2-oxo-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide in 30 ml tetrahydrofurane were reduced with 0.09 g (2.0 mmol) sodium borohydride. Chromatography on silicagel with ethylacetate/heptane 0:100 to 100:0 yielded 0.33 g (34%) N-[(6R,7S)-2-fluoro-9-(2-hydroxy-ethyl)-6-methyl-8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-2-hydroxy-2-methyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamide, MS m/e (%): 502.0 (M+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:18][I:19]>CC(=O)CC>[I-:19].[CH3:18][N+:15]1[CH:16]=[CH:17][C:12]([C:9]2[O:10][C:11]3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=2)=[CH:13][CH:14]=1
Reactant: COc1cccc2cc(-c3ccncc3)oc12
Reactant: CI
Solvent: CCC(C)=O
Product: COc1cccc2cc(-c3cc[n+](C)cc3)oc12
Product: [I-]
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(7-methoxy-2-benzofuranyl)pyridine (66 g), methyl iodide (56.7 g) and 2-butanone (800 ml) was stirred at 50° C. for 4 hours, cooled to room temperature, filtered and the resulting solid was washed with 2-butanone to provide 1-methyl-4-(7-methoxy-2-benzofuranyl)pyridinium iodide, m.p. 225°-227° (dec.). The quaternary salt (90 g) was dissolved in methanol (1 l) and a solution of NaBH4 (40 g) in H2O (250 ml) was added dropwise. The mixture was stirred at ambient temperature for 3 hours, concentrated and the residual aqueous layer was extracted with DCM. The extracts were combined, washed with brine and concentrated to give 1-methyl-4-(7-methoxy-2-benzofuranyl)-1,2,3,6-tetrahydropyridine.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C@:14]3([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].N1C=CC=CC=1.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C@:14]3([CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][N:17]([S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)OC(C)(C)C)CCNCCS3(=O)=O)s2)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)N1CC[C@](CC(=O)OC(C)(C)C)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 39919.5 %

Procedure:
To a solution of tert-butyl 2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (7.91 g) and pyridine (30 ml) in chloroform (15 ml) was added a solution of propanesulfonyl chloride (5.02 mg) in chloroform (15 ml) at 0° C. The resulting mixture was stirred for 3 hours at 0° C. Ethyl acetate (200 ml) was added and the solution was washed with 1N hydrochloric acid (150 ml) for two times, saturated sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated to give a brown gum. The gum was dissolved in ethyl acetate (75 ml) and silica gel (12 ml) was added to the solution. The silica gel was removed by filtration, and the resulting filtrate was evaporated. Silica gel column chromatography (eluent: ethyl acetate/hexane from 13/27 to 9/11) afforded tert-butyl 2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetate (7.81 g) as an yellowish solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[CH:16]=[N:17][NH:18]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[I:25]I>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:15]=2[C:16]([I:25])=[N:17][NH:18]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]ncc23)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3[nH]nc(I)c23)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A solution of 4-[4-(t-butoxycarbonyl)piperazin-1-yl]-1H-indazole (5.00 g, 16.5 mmol) in N,N-dimethylformamide is treated with powdered potassium hydroxide (1.85 g, 33.07 mmol) and iodine (4.61 g, 18.2 mmol), stirred at room temperature for 16 h, diluted with ethyl acetate and quenched with 15% aqueous sodium metabisulfite. The phases are separated and the aqueous phase is extracted with ethyl acetate. The extracts and the organic phase are combined, washed with brine, dried over sodium sulfate and concentrated in vacuo to afford a crude solid. This solid is purified by column chromatography (silica gel, 10:90 to 15:85 to 20:80 ethyl acetate/hexanes) to afford the title product as a yellow solid, 2.40 g (35% yield) identified by HNMR and mass spectral analyses.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24])=O)(C)(C)C.Cl>O1CCOCC1>[CH2:26]([O:25][C:23]([C@@H:9]1[CH2:10][C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:12][C:13](=[O:14])[NH:8]1)=[O:24])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: COc1ccc(C2=CC(=O)N(C(=O)OC(C)(C)C)[C@H](C(=O)OCc3ccccc3)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2=CC(=O)N[C@H](C(=O)OCc3ccccc3)C2)cc1
Reaction time: 1 h

Procedure:
To a solution of 1.8 g of (S)-4-(4-methoxy-phenyl)-6-oxo-3,6-dihydro-2H-pyridine-1,2-dicarboxylic acid 2-benzyl ester 1-tert-butyl ester in 15 ml of 1,4 dioxane are added 1.2 ml of 4N hydrochloric acid in 1,4 dioxane at room temperature. The reaction mixture is stirred for 1 hour and concentrated under reduced pressure to afford the title compound as an off white solid. Rf=0.1 (EtOAc-heptane 1:1); Rt=3.94.
Reaction SMILES: [Br:1][CH:2]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:3]([C:5]1([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=2)[CH2:8][CH2:7][CH2:6]1)=O.[NH:23]1[CH2:27][CH2:26][NH:25][C:24]1=[S:28].C(O)C>C(O)(=O)C>[BrH:1].[Cl:16][C:11]1[CH:10]=[C:9]([C:5]2([C:3]3[N:25]4[CH2:26][CH2:27][N:23]=[C:24]4[S:28][C:2]=3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8][CH2:7][CH2:6]2)[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: O=C(C(Br)c1ccccc1)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: S=C1NCCN1
Solvent: CC(=O)O
Solvent: CCO
Product: Br
Product: Clc1ccc(C2(C3=C(c4ccccc4)SC4=NCCN43)CCC2)cc1Cl
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenylethanone (3.8 g), imidazolidine-2-thione (0.97 g), ethanol (70 ml) and acetic acid (40 ml) was heated under reflux for 20 hours then allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue was crystallised from ethanol. The resulting product was collected by filtration, washed with ethanol (10 ml) and dried in vacuo at 100° C. to give 3-[1-(3,4-dichlorophenyl)cyclobutyl]-2-phenyl-5,6-dihydroimidazo[2,1-b]thiazole hydrobromide as a pale brown solid (1.43 g), m.p. 280° C. (decomposes).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[CH2:13]([O:20][C:21]([NH:23][CH2:24][C:25](O)=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C)C=O>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:22])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 3 grams of (3-Amino-propyl)-carbamic acid tert-butyl ester in 15 ml of dimethylformamide was added 3 grams of N-benzyloxycarbonyl glycine, 4.7 mL of N-methylmorpholine and 5.06 grams of TBTU. The reaction was cooled to 0 degrees C. for 30 minutes then allowed to stir at room temperature overnight. The volatiles were removed under reduced pressure and the resulting material was dissolved in ethyl acetate and washed with 10% citric acid. The aqueous was extracted an additional two times with ethyl acetate, combined and washed with water, saturated aqueous sodium bicarbonate, water, brine and dried over MgSO4. The volatiles were removed under reduced pressure and the resulting material was crystallized from EtOAc/hexane affording 4.55 grams of the desired product as a tan solid. LRMS found 388.3=(M+Na)+
Reaction SMILES: [C:1]([C:4]1[N:9]=[CH:8][C:7]([CH:10](OS(C)(=O)=O)[CH2:11][N:12]2[C:20]3[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[C:14]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]2=3)=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[N-:32]=[N+:33]=[N-:34].[Na+]>CN(C=O)C.O>[N:32]([CH:10]([C:7]1[CH:6]=[CH:5][C:4]([C:1]([NH2:2])=[O:3])=[N:9][CH:8]=1)[CH2:11][N:12]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]1=2)=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc2c(c1)c1c(n2CC(OS(C)(=O)=O)c2ccc(C(N)=O)nc2)CCN(C)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC(N=[N+]=[N-])c2ccc(C(N)=O)nc2)CCN(C)C1
Temperature: 100 °C
Yield: 51.1 %

Procedure:
Methanesulfonic acid-1-(6-carbamoyl-pyridin-3-yl)-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl ester (300 mg, 0.678 mmol) was dissolved in 5 mL DMF, and sodium azide (88 mg, 1.357 mmol) was added, and the mixture heated at 100° C. for 1 h. The reaction mixture was monitored by LCMS. After completion of reaction, the reaction mixture was cooled to RT and diluted with water (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layer was washed with water (4×40 mL), dried over anhydrous sodium sulfate and concentrated to obtain the crude product that was purified by reverse phase chromatography to yield 5-[1-azido-2-(2,8-dimethyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethyl]-pyridine-2-carboxylic acid amide (135 mg). 1H NMR (CD3OD, TFA salt) δ (ppm): 8.6 (dd, 1H), 8.1 (t, 1H), 7.9 (t, 1H), 7.33 (dd, 1H), 7.26 (s, 1H), 7.06 (t, 1H), 5.3 (t, 1H), 4.7 (dd, 1H), 4.42 (dd, 1H), 4.4 (dd, 2H), 4.3 (m, 1H), 3.8 (m, 1H),3.6 (m, 1H), 3.34 (dd, 1H), 3.1 (d, 3H), 2.4 (s, 3H). Separation by chiral HPLC provides enantiomers V-22a-b.
Reaction SMILES: [CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][O:5][CH:6](CO)CS)[CH3:2].[S:15](=O)(=O)(O)O.[C:20]([O:23][C:24](=O)[CH3:25])(=[O:22])[CH3:21]>O>[CH2:1]([CH:3]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:4][O:5][CH2:6][CH:24]([O:23][C:20](=[O:22])[CH3:21])[CH2:25][SH:15])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: O=S(=O)(O)O
Reactant: CCCCC(CC)COC(CO)CS
Solvent: O
Product: CCCCC(CC)COCC(CS)OC(C)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1 mole of the monothioglycerol ether obtained in Example 1 is diluted with 110 g of acetic anhydride. While cooling with ice water, 15 ml of conc. sulfuric acid are added dropwise to this solution. The temperature should not exceed 40° C. The batch is stirred for 1 hour, diluted with water, and then extracted with ether. The ethereal extract is washed neutral with sodium bicarbonate solution. Distillation at 85° C./4.10-3 torr yields 3-(2-ethylhexyloxy)-2-acetoxy-1-propanethiol as an odourless oil with a SH content of 11.6%.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[Cl:22][C:23]1[C:30]([CH2:31][CH2:32]O)=[C:29]([F:34])[CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>C(Cl)Cl.CCCCCC>[Br:20][CH2:32][CH2:31][C:30]1[C:23]([Cl:22])=[C:24]([CH:27]=[CH:28][C:29]=1[F:34])[C:25]#[N:26]
Reactant: N#Cc1ccc(F)c(CCO)c1Cl
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: N#Cc1ccc(F)c(CCBr)c1Cl
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stirrer was added triphenylphosphine (1.57 g, 6 mmol) and methylene chloride (8 mL). Upon cooling the mixture to −10° C., bromine (0.28 mL, 5.5 mmol) was added dropwise. After 10 min, 2-chloro-4-fluoro-3-(2-hydroxyethyl)benzonitrile (1 g, 5 mmol) in methylene chloride (6 mL) was added and stirring was continued for 20 min while the internal reaction temperature was allowed to warm to 15° C. The mixture was then diluted with hexane (30 mL) and purified via a silica plug [hexane-Et2O (20:1) as eluent]. The combined filtrates were concentrated to furnish the title compound (1.26 g, 96%): 1H NMR (400 MHz, Acetone-d6, δ in ppm) 7.92 (dd, J=6 and 9 Hz, 1H), 7.42 (t, J=9 Hz, 1H), 3.70 (t, J=7 Hz, 2H), 3.13 (dt, J=2 and 7 Hz, 2H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[C:12]([F:17])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]>S(=O)(=O)(O)O>[F:5][C:6]1[C:14]([CH3:15])=[C:13]([F:16])[C:12]([F:17])=[C:11]([N+:1]([O-:4])=[O:2])[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: Cc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1c(F)c(F)c([N+](=O)[O-])c(C(=O)O)c1F
Reaction time: 2 h

Procedure:
To a mixture of 370 ml of conc. sulfuric acid and 61.2 ml of 70% nitric acid, 36.6 g of 2,4,5-trifluoro-3-methylbenzoic acid was added at 55° to 70° C. by portions with stirring. After 2 hours at room temperature, the reaction mixture was poured into ice and extracted with isopropyl ether. The combined extracts were washed with brine, dried and evaporated to give 30.6 g of the desired compound as yellow crystals.
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([C@@H:13]2[O:15][C@H:14]2[CH2:16][CH2:17][CH2:18][C@H:19]([NH:31]C(=O)OCC2C=CC=CC=2)[C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=2[Br:30])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C@H:13]([C@@H:14]2[CH2:16][CH2:17][CH2:18][C@@H:19]([C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[Br:30])[NH:31]2)[OH:15])[CH:4]=[C:3]([C:2]([F:42])([F:1])[F:43])[CH:8]=1
Reactant: O=C(N[C@@H](CCC[C@@H]1O[C@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C(F)(F)F)ccc1Br)OCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O[C@H](c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CCC[C@@H](c2cc(C(F)(F)F)ccc2Br)N1
Temperature: 125 °C
Yield: 69.6 %

Procedure:
To benzyl {(1S)-4-{(2S,3S)-3-[3,5-bis(trifluoromethyl)phenyl]oxiran-2-yl}-1-[2-bromo-5-(trifluoromethyl)phenyl]butyl}carbamate (500 mg, 0.731 mmol) in DMF (2 mL) was added DBU (111 mg, 0.731 mmol). The system was heated to 125° C. for 6 hours. The solvent was removed in vacuo. The reaction was diluted with ethyl acetate and water. The organic was dried over sodium sulfate, filtered and concentrated. The resultant oil was purified by column chromatography to yield (R)-[3,5-bis(trifluoromethyl)phenyl]{(2S,6S)-6-[2-bromo-5-(trifluoromethyl)phenyl]piperidin-2-yl}methanol (280 mg, 0.509 mmol). 1H NMR (500 MHz, CDCl3) δ7.9 (s, 2H), 7.81 (d, J=5.4 Hz, 2H), 7.64 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 5.14 (d, J=8.2 Hz, 1H), 4.51 (m, 1H), 3.16 (m, 1H), 2.06 (m, 1H), 1.95 (m, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.29 (m, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.C(Cl)(Cl)=O.[Cl:10][C:11]1[CH:12]=[C:13]([CH2:17][C:18](=[O:27])[CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=2)[CH:14]=[CH:15][CH:16]=1.CN>C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:18](=[O:27])[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[CH:21]=3)=[CH:3][N:2]([CH3:5])[CH:1]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cc1cccc(Cl)c1)Cc1cccc(Cl)c1
Reactant: CN(C)C=O
Agent: CN
Agent: O=C(Cl)Cl
Solvent: ClC(Cl)Cl
Product: Cn1cc(-c2cccc(Cl)c2)c(=O)c(-c2cccc(Cl)c2)c1
Reaction time: 3 h

Procedure:
The aminoformylating reagent was made by adding 30 g. of dimethylformamide dropwise to 20 g. of phosgene in 150 ml. of chloroform at 0° C. A 10 g. portion of 1,3-bis(3-chlorophenyl)-2-propanone in 50 ml. of chloroform was then added. The mixture was stirred for 3 hours, after which 50 ml. of 40% aqueous methylamine was added. Chloroform was then evaporated from the mixture, and 200 ml. of ethanol and 50 ml. of additional 40% aqueous methylamine were added. The mixture was then stirred under reflux overnight. In the morning, the product was extracted as described in the example above, and chromatographed on a silica gel column with ethyl acetate containing successively larger quantities of methanol. The product, 3,5-bis(3-chlorophenyl)-1-methyl-4(1H)-pyridone, 0.85 g., melted at 164°-167° C.
Reaction SMILES: [CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([O:28][CH3:29])=[CH:23][C:22]=3[CH3:30])(=[O:20])=[O:19])[C@H:8]([CH2:16][NH2:17])[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=2[O:2]1.C[Si](C#N)(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(OCC)(=O)C>C(#N)C>[CH2:1]1[O:34][C:33]2[CH:32]=[CH:31][C:5]([CH2:6][N:7]([S:18]([C:21]3[C:22]([CH3:30])=[CH:23][C:24]([O:28][CH3:29])=[CH:25][C:26]=3[CH3:27])(=[O:20])=[O:19])[C@H:8]([CH2:16][NH:17][S:42]([CH3:41])(=[O:44])=[O:43])[C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])=[CH:4][C:3]=2[O:2]1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CN)C(=O)OC(C)(C)C)c(C)c1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](CNS(C)(=O)=O)C(=O)OC(C)(C)C)c(C)c1
Reaction time: 8 h
Yield: 122.7 %

Procedure:
To a mixture of tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-amino-propionate (1.02 g, 2.0 mmol), with trimethylsilyl cyanide (0.7 ml, 5.2 mmol) in dry acetonitrile (15 ml) was added methanesulfonyl chloride (0.18 ml, 2.3 mmol) and the material was stirred overnight. Ethyl acetate (80 ml) was added and the material was partitioned with aqueous hydrochloric acid (1.5%, 80 ml). The organic phase was collected and washed with an equal volume of brine; The aqueous phases were back extracted with ethyl acetate (2×80 ml) and the organic phases combined, dried (MgSO4), filtered and condensed to provide tert-butyl 2(R)-[(3,4-methylendioxybenzyl)-(2,6-dimethyl-4-methoxybenzenesulfonyl)amino]-3-methanesulfonylamino-propionate as a pale yellow semi-viscous oil (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:19])[CH2:10][NH:11]C(OC(C)(C)C)=O.O1CCOCC1.[ClH:27]>>[ClH:27].[CH3:1][O:2][C:3](=[O:20])[C@@H:4]1[CH2:8][CH2:7][CH2:6][N:5]1[C:9](=[O:19])[CH2:10][NH2:11]
Reactant: COC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H]1CCCN1C(=O)CN
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
N-t-Butyloxycarbonyl-glycyl-L-proline methylester (21.3 g, 74.4 m mole) and 4N hydrogen chloride dioxan solution (150 ml) were mixed, and shaked to dissolve the solid material. It was stirred for 1 hour at room temperature. The solvent was well-distilled off under reduced pressure to obtain the solid glycyl-L-proline methylester hydrochloride (16.4 g, 73.9 m mole, yield: 99%). The product was very hygroscopic and gave a single spot with Rf =0.45 by silica gel thin layer chromatography (developing solvent, n-butanol:acetic acid:water=4:2:2, colour forming method: spraying of 0.1% ninhydrin and heating).