Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH:11][CH2:12][CH2:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][CH2:19][NH:20][S:21]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.Cl>O.C(Cl)Cl>[OH:11][CH2:12][CH2:13][C:14]1[CH:32]=[CH:31][C:17]([CH2:18][CH2:19][N:20]([C:1](=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[S:21]([C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)(=[O:23])=[O:22])=[CH:16][CH:15]=1
Reactant: CCCCCCCC(=O)Cl
Reactant: O=S(=O)(NCCc1ccc(CCO)cc1)c1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)N(CCc1ccc(CCO)cc1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
A solution of 2.63 g. (16 mmole) octanoyl chloride in 25 ml. methylene chloride is slowly added dropwise at 0° C. to a mixture of 5.5 g. (16 mmole) 4-chlorobenzenesulphonic acid-4-(2-hydroxyethyl)-phenethylamide], 1.8 g. (18 mmole) triethylamine and 100 ml. methylene chloride. The reaction mixture is then maintained for 1 hour at 0° C. and for a further 2 hours at ambient temperature. It is subsequently shaken out with dilute hydrochloric acid and water, dried with anhydrous sodium sulphate and evaporated. After chromatography with silica gel/methylene chloride, there are obtained 3.8 g. (51% of theory) of the desired product: m.p. 55° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][C:3]=1[N:15]1[C:19](=[O:20])[C:18]2[CH2:21][CH2:22][CH2:23][CH2:24][C:17]=2[C:16]1=[O:25].[CH2:26]([NH2:32])[C:27]1[O:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)=[CH:4][C:3]=1[NH:15][C:16](=[O:25])[C:17]1[CH2:24][CH2:23][CH2:22][CH2:21][C:18]=1[C:19]([NH:32][CH2:26][C:27]1[O:31][CH:30]=[CH:29][CH:28]=1)=[O:20]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(OC2CCCC2)c(Cl)cc1F
Reactant: NCc1ccco1
Solvent: CC#N
Product: O=C(NCc1ccco1)C1=C(C(=O)Nc2cc(OC3CCCC3)c(Cl)cc2F)CCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.8 %

Procedure:
N-(2-Fluoro-4-chloro-5-cyclopentyloxyphenyl)-3,4,5,6-tetrahydrophthalimide (1.00 g, 2.75 mmol), furfurylamine (0.320 g, 3.29 mmol), and acetonitrile (25 ml) as a solvent were placed into a round bottom flask (50 cc) and stirred for 2 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, and the precipitated crystals were isolated by filtration. The crystals were washed with hexane and dried to obtain N-(2-fluoro-4-chloro-5-cyclo-pentyloxyphenyl)-N'-furfuryl-3,4,5,6-tetrahydrophthalamide as light brown crystals (0.860 g, 68.0% yield).
Reaction SMILES: [NH2:1][C:2]1[C:3](Cl)=[N:4][C:5]([CH3:9])=[N:6][C:7]=1[Cl:8].[NH3:11]>C(O)(C)C>[Cl:8][C:7]1[N:6]=[C:5]([CH3:9])[N:4]=[C:3]([NH2:11])[C:2]=1[NH2:1]
Reactant: N
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Solvent: CC(C)O
Product: Cc1nc(N)c(N)c(Cl)n1
Temperature: 150 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A 200 mL stainless steel Parr vessel was loaded with 5-amino-4,6-dichloro-2-methylpyrimidine (7.2 g, 40 mmol) and 2 M ammonia in isopropanol (100 mL), and then was sealed and heated at 150° C. for 16 h. HPLC analysis indicated complete conversion. The mixture was concentrated in vacuo, and the residue was suspended in a mixture of H2O (10 mL) and isopropanol (35 mL). This was stirred at 50° C. for 1 h and then was cooled to room temperature. The precipitate was collected by suction filtration, washed sparingly with isopropanol, then air dried on the filter to afford 6-chloro-4,5-diamino-2-methylpyrimidine (5.8 g, 91%) as a brown powder, which was used without further purification in the next step.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[N:1]1([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)CBr
Reactant: c1ccc2c(c1)CCN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCc2ccccc21
Temperature: 80 °C
Yield: 73.2 %

Procedure:
Indoline (1.07 g, 8.98 mmol), ethyl bromoacetate (1.20 ml, 10.8 mmol), potassium carbonate (2.10 g, 15.2 mmol) were added to dimethylformamide (14 ml), and the mixture was heated at 80° C. for 30 minutes. The reaction mixture was cooled to room temperature and diluted with ethyl acetate, and then washed with water and dried over sodium sulfate. Insoluble solids were removed by filtration and the filtrate was evaporated under reduced pressure. The resulting oil was purified by silica gel column chromatography (ethyl acetate-hexane) to obtain the title compound as yellow oil (1.35 g, yield: 73%).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]([F:25])([F:24])[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][C:13]([F:12])([F:24])[F:25])=[O:23]
Reactant: O=C=Nc1ccccc1OC(F)(F)F
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1OC(F)(F)F
Yield: 59.6 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N′-(2-trifluoromethyloxyphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-trifluoromethoxyphenylisocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(0.69 g, 60%). EI-MS m/z 358(M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][C@H:4]([OH:19])[CH2:5][O:6][C:7]([CH3:18])([CH3:17])[CH2:8][N:9]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[N:10]1.C(OCC)(=O)C.[H][H]>[Pd].C(O)C>[NH2:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:7]([CH3:18])([CH3:17])[O:6][CH2:5][C@@H:4]([OH:19])[CH2:3][N:2]([CH3:1])[CH3:20])[N:10]=1
Reactant: CN(C)C[C@H](O)COC(C)(C)Cn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CN(C)C[C@H](O)COC(C)(C)Cn1ccc(N)n1
Yield: 86.9 %

Procedure:
Compound (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol was prepared by reacting 1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-3-nitro-1H-pyrazole (0.39 g, 1.62 mmol), isopropyl alcohol (6 mL), and dimethylamine (3 mL, 6 mmol, 2 M in dioxane) under microwave conditions at 130° C. for 15 min. The mixture was extracted with dichloromethane and water. The organic layer was separated and the solvent evaporated under reduced pressure to yield (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.4 g, 87%). This compound was reduced under the following conditions. The mixture of (S)-1-dimethylamino-3-[1,1-dimethyl-2-(3-nitro-pyrazol-1-yl)-ethoxy]-propan-2-ol (0.39 g, 1.66 mmol), ethyl acetate (30 mL), ethanol (30 mL) was added to a Parr bottle with 10% Pd/C (0.22 g) and subjected hydrogen gas (20 psi) for 2 h under the Parr Shaker Apparatus conditions. Work up by filtration via a glass membrane filter paper, solvent was removed under reduced pressure to afford (S)-1-[2-(3-amino-pyrazol-1-yl)-1,1-dimethyl-ethoxy]-3-dimethylamino-propan-2-ol as an oil (0.37 g, 97.5%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][C:7]1[CH:21]=[CH:20][C:10]([O:11][C:12]([CH3:19])([CH3:18])[C:13]([O:15]CC)=[O:14])=[CH:9][CH:8]=1)[C:2]([CH3:4])=[O:3].[CH2:22](O)[CH3:23].[OH-].[K+].[ClH:27]>O>[Cl:27][C:23]1[CH:22]=[CH:8][C:7]([CH:21]=[CH:4][C:2]([NH:1][CH2:5][CH2:6][C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12]([CH3:18])([CH3:19])[C:13]([OH:15])=[O:14])=[CH:20][CH:21]=2)=[O:3])=[CH:6][CH:5]=1
Reactant: Cl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNC(C)=O)cc1
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)(Oc1ccc(CCNC(=O)C=Cc2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
A solution of 119.1 g. (0.407 mol) ethyl 2-[4-(2-acetaminoethyl)-phenoxy]-2-methylpropionate in 750 ml. ethanol is mixed with a solution of 224.4 g. (4.00 mol) potassium hydroxide in 800 ml. water and heated under reflux for 8 hours. While cooling, there are then added exactly 4.00 mol hydrogen chloride (for example, in the form of 2 N hydrochloric acid), cooling is intensified and, after some time, the crystals which separate out are filtered off with suction. These are washed with water and dried; there are obtained 48.4 g. of product (53% of theory) which melts, with decomposition, at 274° C. From the mother liquor there are obtained, after distilling off the ethanol and cooling, a further 32.5 g. (36% of theory) of product with a melting point of 263°-270° C. The crude 2-[4-(2-aminoethyl)-phenoxy]-2-methylpropionic acid obtained is recrystallised from ethanol and water (4:1 v/v) and then has a melting point of 284° C. The corresponding hydrochloride has a melting point of 187°-189° C.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH2:5]([SH:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>CO.C(#N)C=C>[CH2:5]([S:12][CH2:3][CH2:2][C:1]#[N:4])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=CC#N
Reactant: SCc1ccccc1
Solvent: CO
Solvent: CCN(CC)CC
Product: N#CCCSCc1ccccc1
Reaction time: 0.17 h
Yield: 97.5 %

Procedure:
Acrylonitrile (21.4 g) was added dropwise to a solution of benzyl mercaptan (49.6 g) and triethylamine (4 ml) in methanol (400 ml). This addition lead to an exothermic reaction and the temperature of the reaction mixture was allowed to rise from room temperature to 35° C. After 10 minutes the reaction was almost complete as shown by TLC, there being a trace of unreacted thiol still present. Additional acrylonitrile (0.5 g) was then added to consume the last of the thiol. After a further 10 minutes the solution was evaporated to give the title compound 69.0 g as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1.[CH2:24]=O.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:24][N:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:6](=[O:11])[C:5]2=[C:12]1[C:20]2[C:15](=[CH:16][C:17]([N:21]([CH3:23])[CH3:22])=[CH:18][CH:19]=2)[CH2:14][O:13]1
Reactant: CN(C)c1ccc2c(c1)COC2=C1C(=O)Nc2ccc(Cl)cc21
Reactant: C1CCNCC1
Reactant: C=O
Solvent: CCO
Product: CN(C)c1ccc2c(c1)COC2=C1C(=O)N(CN2CCCCC2)c2ccc(Cl)cc21
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A mixture of 5-Chloro-3-(5-dimethylamino-3H-isobenzofuran-1-ylidene)-1,3-dihydro-indol-2-one (400 mg, 1.22 mmol), paraformaldehyde (91 mg, 3.05 mmol) and piperidine (156 mg, 1.83 mmol) in 20 mL of EtOH was stirred at reflux for overnight and cooled to room temperature. The solid which formed on cooling was collected by filtration, washed with EtOH (5 mL) and dried under vacuum to give the title compound (500 mg, 97%) as bright yellow crystals.
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:23])[C:7](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:8](=O)[CH2:9][CH2:10]C)#[N:2].[NH2:24][C:25]([CH2:37][CH3:38])=[CH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28].[CH3:39]CO>>[CH2:30]([O:29][C:27]([C:26]1[CH:13]([C:14]2[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:23])=[C:8]([CH2:9][CH3:10])[NH:24][C:25]=1[CH2:37][CH2:38][CH3:39])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCC(N)=CC(=O)OCc1ccccc1
Reactant: CCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Reactant: CCO
Product: CCCC1=C(C(=O)OCc2ccccc2)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(CC)N1

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxohexanoic acid 2-cyanoethyl ester (16.3 g, 50 mmol) and benzyl 3-amino-2-pentenoate (11.3 g, 55 mmol) in 250 ml of EtOH was refluxed for 36 hrs. After the solvent was removed in vacuo, the residue was dissolved in 250 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-6-ethyl-1,4-dihydro-4-(4-nitrophenyl)-2-propylpyridine was obtained as a yellow oil (25.1 g, 98%).
Reaction SMILES: [C:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:7][CH2:6]1)(O)=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[OH2:56].[NH3:57]>C(OCC)(=O)C.CN(C=O)C>[C:1]([CH2:4][C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]([N:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([NH:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[F:34])=[O:26])[CH:20]=3)[CH2:15]2)=[O:13])[CH2:7][CH2:6]1)(=[O:56])[NH2:57]
Reactant: N
Reactant: O=C(O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1
Reactant: O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: NC(=O)C[C@H]1CC[C@H](OC(=O)N2CCc3cc(NC(=O)Nc4ccccc4F)ccc3C2)CC1

Procedure:
A DMF (15 mL) solution of trans-6-[3-(2-fluoro-phenyl)-ureido]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid 4-carboxymethyl-cyclohexyl ester (527 mg) obtained in Example 2, HOBt (166 mg), EDCI (236 mg), and ammonia water (0.5 mL) was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed with a saturated aqueous solution of sodium bicarbonate and saturated brine, then dried, and concentrated. The residue was purified by chromatography (NH silica gel, dichloromethane/methanol=30:1→5:1) to obtain a solid. This solid was recrystallized (isopropanol) to obtain the title compound (89 mg, 17%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][OH:22])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[N:10]=[N:11][C:12](Cl)=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:14]=1.[C:23]([O-])(=[O:25])[CH3:24].[Na+].C(O)(=[O:30])C>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][CH2:21][O:22][C:23](=[O:25])[CH3:24])[CH:5]=[C:6]([Cl:19])[C:7]=1[O:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:30])[NH:11][N:10]=1
Reactant: CC(C)c1cc(Oc2c(Cl)cc(CCO)cc2Cl)nnc1Cl
Reactant: CC(=O)[O-]
Reactant: CC(=O)O
Agent: [Na+]
Product: CC(=O)OCCc1cc(Cl)c(Oc2cc(C(C)C)c(=O)[nH]n2)c(Cl)c1
Temperature: 114 °C
Yield: 100 %

Procedure:
A solution of 2-[3,5-dichloro-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (17) (500 mg, 1.38 mmol) in glacial acetic acid (5 mL) was treated with sodium acetate (230 mg, 2.8 mmol) and heated to 114° C. for 24 h. At this time, the reaction mixture was cooled to room temperature and was concentrated under vacuum. The resulting residue was diluted with methylene chloride (25 mL) and was washed with water (10 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (10 mL). The waters layers were combined and extracted with methylene chloride (10 mL). The organic layers were combined and dried with sodium sulfate, filtered, concentrated and dried under high vacuum overnight to afford acetic acid 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-yloxy)-phenyl]-ethyl ester (34) (531 mg, 100%) as a white solid; LRMS for C17H18Cl2N2O4 (M+) m/z=385. Molecular Weight=385.2500; Exact Mass=384.0644
Reaction SMILES: [C:1]1(=[N:7][OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30]([OH:32])=[O:31]>>[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30]([O:32][C:1]1([N:7]=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:31]
Reactant: ON=C1CCCCC1
Reactant: CC(CC(=O)O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: [Pb+4]
Product: CC(CC(=O)OC1(N=O)CCCCC1)C(F)(F)F

Procedure:
1-Nitrosocyclohexyl 4,4,4-trifluoro-3-methylbutanoate was prepared from cyclohexanone oxime, lead tetraacetate and 4,4,4-trifluoro-3-methyl butanoic acid using conditions of General Method 3. 1H NMR (250 MHz, chloroform-d) δ 2.69-2.92 (1H, m), 2.69-2.92 (1H, m), 2.47 (1H, d, 6.5 Hz), 1.71-2.05 (4H, m), 1.42-1.63 (2H, m), 1.27 (3H, d, 6.9 Hz), 1.10-1.39 (2H, m), 0.87 (1H, d, 7.0 Hz), 0.78-0.99 (1H, m).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[CH3:17])[CH2:10]2>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([N:16]([CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:23][CH:24]=1)[CH3:17])[CH2:10]2)(=[O:4])=[O:3]
Reactant: CN(Cc1ccc(N)cc1)C1Cc2ccc(N)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CN(Cc1ccc(NS(C)(=O)=O)cc1)C1Cc2ccc(NS(C)(=O)=O)cc2C1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Methanesulphonyl chloride (0.53 ml) was added to 5-amino-2-[N-(4-aminobenzyl)-N-methylamino]indane (1.1 g) in pyridine and the reaction mixture was stirred at room temperature for 17 hours. The solvent was then removed by evaporation in vacuo and the residue taken up in methylene chloride, washed with aqueous sodium bicarbonate, dried (MgSO4) and evaporated in vacuo. The resulting gum was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% up to 2%). The product-containing fractions were combined and evaporated to dryness in vacuo to give a colourless foam. This foam was dissolved in chloroform and the solution was evaporated to dryness in vacuo to give the title compound as a colourless foam, yield 0.2 g.
Reaction SMILES: [C:1]1([NH:7][OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([Te:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=O)=[CH:13][CH:12]=1>C(Cl)(Cl)Cl>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([Te:17][C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:24][CH:23]=1.[N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:8]
Reactant: COc1ccc([Te](=O)c2ccc(OC)cc2)cc1
Reactant: ONc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc([Te]c2ccc(OC)cc2)cc1
Product: O=Nc1ccccc1
Yield: 90 %
Yield: 88 %

Procedure:
Phenylhydroxylamine (109 mg, 1 mmol) and bis-(p-methoxyphenyl)-telluroxide (376 mg, 1.05 mmol) were stirred in chloroform (4 ml) at room temperature under nitrogen for 0.1 h. Evaporation of the solvent and column chromatography (petroleum ether-ethyl acetate 9:1) gave bis-(p-methoxyphenyl)-telluride (150 mg, 88%) and nitrosobenzene (96 mg, 90%) m.p. 66°-68°).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[SiH4].[S-:12][C:13]#[N:14].[Na+]>C(O)C>[S:12]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:13]#[N:14]
Reactant: O=C(CBr)c1ccccc1
Reactant: N#C[S-]
Agent: [Na+]
Agent: [SiH4]
Solvent: CCO
Product: N#CSCC(=O)c1ccccc1
Reaction time: 5 h

Procedure:
Bromoacetophenone-modified aminopropylsilylated glass surfaces (2.5×7.5 cm; Sigma, Silane-Prep™, S4651) (see Example 13) were coated with a 0.1M solution of sodium thiocyanate in ethanol and incubated for five hours at 50° C. The glass surfaces thus treated were then washed five times using respectively 30 mL of ethanol for 3 minutes each at room temperature. After washing three times for three minutes each using respectively 30 mL of DCM at room temperature, the glass surfaces were dried and stored at 4° C. until further use.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25](Cl)=[CH:26][CH:27]=1)=[O:21].[CH3:29][O:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:9][CH3:10])=[C:4]([F:19])[C:3]=1[C:20]([C:22]1[CH:23]=[N:24][C:25]([NH:36][CH2:35][C:34]2[CH:37]=[CH:38][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:26][CH:27]=1)=[O:21]
Reactant: COc1ccc(CN)cc1
Reactant: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(Cl)nc2)c1F
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC[C@@H](NC(=O)OC(C)(C)C)c1ccc(Cl)c(C(=O)c2ccc(NCc3ccc(OC)cc3)nc2)c1F
Temperature: 50 °C

Procedure:
Step 7—To a solution of tert-butyl N-[(1R)-1-[4-chloro-3-(6-chloropyridine-3-carbonyl)-2-fluorophenyl]propyl]-carbamate (82.8 g, 194 mmol) from Step 6 in DMSO (5 vol) was added 4-methoxybenzylamine (53.1 g, 2 equi Vol). The mixture was heated to 50° C. (external temp) overnight then allowed to cool. The mixture was diluted with EtOAc (30 vol) and washed with 5% citric acid (5 vol), water (5 vol) and brine (5 vol) and concentrated to furnish tert-butyl N-[(1R)-1-[4-chloro-2-fluoro-3-(6-{[(4-methoxyphenyl)methyl]amino}pyridine-3-carbonyl)phenyl]propyl]carbamate as a brown oil, 109 g. m/z: 528.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH:15]1([CH2:18][C:19]#[N:20])[CH2:17][CH2:16]1>C1COCC1>[C:19]([C:18]([CH:15]1[CH2:17][CH2:16]1)=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1)#[N:20]
Reactant: N#CCC1CC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(=C(C#N)C2CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl 4-oxopiperidine-1-carboxylate (2.0 g, 10 mmol) and cyclopropylacetonitrile (0.97 g, 12 mmol) were dissolved in THF (20 mL), heated to reflux, and allowed to stir for 3 hours. The mixture was then cooled to ambient temperature and concentrated in vacuo. The residue was purified by MPLC on silica gel to afford the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:7](=[O:11])[C:6]=2[C:12]=1[CH3:13].[CH2:15](O)[CH2:16][OH:17].C(OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:14])[C:5]2[S:10][CH2:9][CH2:8][C:7]3([O:17][CH2:16][CH2:15][O:11]3)[C:6]=2[C:12]=1[CH3:13]
Reactant: Cc1cc(Br)c(C)c2c1SCCC2=O
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCOCC
Solvent: COC(OC)OC
Product: Cc1cc(Br)c(C)c2c1SCCC21OCCO1

Procedure:
26.06 g (0.096 mol) of the title compound of Step C, 250 mL of ethylene glycol, 170 mL of trimethyl orthoformate (purchased from Aldrich Chemical Company), and 0.06 g of p-toluenesulfonic acid monohydrate were stirred together at 80° C. under nitrogen overnight. The mixture was diluted with 400 mL of diethyl ether. The resulting mixture was washed with a 1:1 mixture of 1N sodium hydroxide:saturated aqueous NaCl (2×600 mL) and then with saturated aqueous NaCl (1×600 mL). The organic layer was dried (Na2SO4), filtered, and evaporated to dryness. The crude product was chromatographed over silica gel eluting with a mixture of ethyl acetate:hexane (1:9) to yield 24.73 g of the title compound of Step D as a solid melting at 97° C. (dec). 1H NMR (CDCl3): δ2.2 (s,3H), 2.3 (m,2H), 2.4 (s,3H), 3.0 (m,2H), 4.15 (m,2H), 4.3 (m,2H), 7.3 (s,1H).