Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:15])=O)=[CH:10][CH:11]=2)[N:6]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:32][C@@H:33]([CH2:47][C:48]1[CH:53]=[C:52]([F:54])[CH:51]=[C:50]([F:55])[CH:49]=1)[C@H:34]([OH:46])[CH2:35][NH:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[CH:39]=1>ClCCl>[C:1]([C:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([NH:32][C@@H:33]([CH2:47][C:48]3[CH:49]=[C:50]([F:55])[CH:51]=[C:52]([F:54])[CH:53]=3)[C@H:34]([OH:46])[CH2:35][NH:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([CH2:44][CH3:45])[CH:39]=3)=[O:15])=[CH:10][CH:11]=2)[N:6]([CH2:16][CH2:17][CH2:18][CH3:19])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1cc(C(C)=O)c2ccc(C(=O)O)cc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CCCCn1cc(C(C)=O)c2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Reaction time: 2 h
Yield: 77.8 %

Procedure:
3-Acetyl-1-butyl-1H-indole-6-carboxylic acid (0.322 g) was dissolved in dichloromethane (15 mL). 1,1′-Carbonyldiimidazole was added (0.171 g). The mixture was stirred for 2 h and then a mixture of (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.250 g) in dichloromethane (15 mL) was added. After stirring overnight, the mixture was partitioned between dichloromethane, water, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel using MeOH/dichloromethane (4/96) to give 3-acetyl-1-butyl-N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-1H-indole-6-carboxamide (0.335 g). MS (ESI+) for C34H39F2N3O3+H1 m/z 576.30 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)[O:4][N:3]=1.[OH-].[Li+]>O1CCOCC1.O.C(O)(C)C>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[O:4][N:3]=1
Reactant: COC(=O)c1ccc(-c2nc(C)no2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Solvent: CC(C)O
Product: Cc1noc(-c2ccc(C(=O)O)cc2)n1
Temperature: 25 °C

Procedure:
Methyl 4-(3-methyl-1,2,4-oxadiazol-5-yl)benzoate (J. R. Young and R. J. DeVita, Tetrahedron Lett., 1998, 39, 3931) was dissolved in a mixture of dioxan (110 ml), water (70 ml) and isopropanol (30 ml), and lithium hydroxide (1.38 g) was added. The mixture was stirred at room temperature for ca 5 h and then the mixture was acidified to ca pH 4 by addition of Amberlyst 15 H+ resin. The resin was removed by filtration and the filtrate was concentrated in vacuo. The solid white precipitate which was obtained was collected by filtration, washed with water on the filter and dried in vacuo at 40° C. for 48 h to give the title compound (D18) (4.23 g).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33].Cl>C(Cl)Cl>[CH:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6](=[CH:16][C:17]3[N:22]=[C:21]([NH:23][S:32]([CH3:31])(=[O:34])=[O:33])[CH:20]=[CH:19][CH:18]=3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)n1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
Mix 6-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-pyridin-2-ylamine (70 mg, 0.235 mmol), triethylamine (68 μL, 0.470 mmol), N,N-dimethylaminopyridine (3 mg, 0.024 mmol), and methanesulfonyl chloride (19 μL, 0.247 mmol) in CH2Cl2 (2 mL). Stir at room temperature overnight and add 150 □L triethylamine and 40 μL methanesulfonyl chloride. Stir at room temperature for 6 h and add 1.00N aqueous HCl (1 mL). Load mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge, then elute, collect, and concentrate 45 mL CH2Cl2. Dissolve crude product in THF (5 mL), add 1.0M tetrabutylammonium fluoride (0.25 mL), and heat to reflux for 1 h. Cool to room temperature and dilute with H2O and brine. Extract into ethyl acetate, dry (MgSO4) and concentrate organics. Chromatograph on silica gel (10 g), eluting with 20% to 35% ethyl acetate/hexanes to afford 61 mg (69%) of the title compound as a yellow oil. MS (ES) 377 (M+H), 375 (M−H); BPLC shows 96% purity.
Reaction SMILES: C([Si](C(C)C)(C(C)C)N1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1)(C)C.[S:30]1C=CC(B(O)O)=C1>>[S:30]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]([CH:16]=[C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:18]=3)[CH:15]=2)=[CH:6]1
Reactant: CCOC(=O)c1cn2cc(-c3ccn([Si](C(C)C)(C(C)C)C(C)C)c3)ccc2n1
Reactant: OB(O)c1ccsc1
Product: CCOC(=O)c1cn2cc(-c3ccsc3)ccc2n1

Procedure:
This product is prepared under conditions similar to those described for the preparation of Intermediate 15 (step 15.1), replacing the 1-(triisopropylsilyl)pyrrole-3-boronic acid with thiophene-3-boronic acid (catalyst: dichlorobis(triphenylphosphine)palladium).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:8]([S:10]SCC)[CH3:9]>[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4].C1(C)C(C)=CC=CC=1>[CH2:8]([S:10][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[OH:7])[CH3:9]
Reactant: CCSSCC
Reactant: Oc1ccccc1
Agent: [Zr+4]
Agent: [Cl-]
Solvent: Cc1ccccc1C
Product: CCSc1ccccc1O
Temperature: 150 °C
Reaction time: 2 h
Yield: 44.1 %

Procedure:
A mixture of phenol (87.5 g, 0.93 moles), xylene (100 ml), and zirconium tetrachloride (6.0 g, 0.026 moles) was heated to reflux under a slow nitrogen stream. The xylene was distilled through a 10 inch Vigreux column. The distillation was continued over a 2 hour period until the reaction mixture reached 177° C. Approximately 10 g of phenol was distilled with the xylene. The reaction mass was cooled to 150° C., and ethyl disulfide (62.0 g, 0.50 moles) was added. The reaction mixture was heated to 152° C., then heated slowly over a 5 hour period to 180° C., and finally held at 180° C. for an additional 10 hours. Ethyl mercaptan was removed continuously by distillation. The reaction mixture was cooled to 100° C., then vacuum distilled at 100 mm mercury until the pot temperature reached 200° C. to give 70.8 g of distillate. GC analysis indicated the distillate contained 34.0 g of ortho-(ethylthio)phenol (44% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1.C(N(C(C)C)C(C)C)C.Br[CH2:35][C:36]1[C:37]([CH2:42]Br)=[CH:38][CH:39]=[CH:40][CH:41]=1>CN(C)C=O>[CH2:42]1[C:37]2[C:36](=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][N:1]1[CH2:2][C:3]1[N:7]=[C:6]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]4[CH2:23][CH2:24][C@H:13]4[C:12]=23)[O:5][N:4]=1
Reactant: BrCc1ccccc1CBr
Reactant: NCc1noc(-c2ncn3c2[C@@H]2CCN2C(=O)c2ccccc2-3)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2-n2cnc(-c3nc(CN4Cc5ccccc5C4)no3)c2[C@@H]2CCN12
Yield: 60.8 %

Procedure:
1.5 g (4.65 mmol) of (S)-1-(3-aminomethyl-1,2,4-oxadiazol-5-yl)-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, 20 ml of N,N-dimethylformamide, 4 ml (13.9 mmol) of N-ethyldiisopropylamine and 1.3 g (4.9 mmol) of α,α'-dibromo-o-xylene were stirred at room temperature for 1 hour. The reaction solution was evaporated, the residue was dissolved in methylene chloride and chromatographed on 50 g of silica gel while eluting with methylene chloride/ethyl acetate 1/1. There were obtained 1.2 g (61%) of (S)-12,12a-dihydro-1-(3-isoindolin-2-ylmethyl-1,2,4-oxadiazol-5-yl)-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepin-9-one, which was converted into the hydrochloride of m.p. 210°-213°.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH3:28])[C:15]2[C:20]([NH:21][C:22]3(OCC)[CH2:24][CH2:23]3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH3:28])[C:15]2[C:20]([NH:21][CH:22]3[CH2:23][CH2:24]3)=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(Nc2cccnc2N(C)C2CCN(Cc3ccccc3)CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(c1ncccc1NC1CC1)C1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
A mixture of 1-benzyl-4-[N-methyl-N-(3-(1-ethoxycyclopropylamino)-2-pyridinyl)amino]piperidine (EXAMPLE 123, 178 mg) in dry tetrahydrofuran (4.7 ml) under nitrogen is treated with lithium aluminum hydride (18 mg), and the resulting mixture is stirred at 20°-25° for 1 hr, quenched with saturated aqueous ammonium chloride (5 ml), diluted with water (30 ml) and methylene chloride (20 ml), and filtered through diatomaceous earth. The layers of the filtrate are separated, the aqueous phase is extracted with methylene chloride (2×10 ml), and the combined organic phase is washed with saline (10 ml), dried over sodium sulfate and concentrated under reduced pressure. The crude product is then chromatographed (silica gel 230-400 mesh, 40 g; eluting with a gradient of methanol/methylene chloride (2.5/97.5-5/95)) to give the title compound, NMR (CDCl3) 7.75, 7.31. 7.24, 7.21, 6.92, 4.92, 3.50, 3.04, 2.89, 2.62, 2.35, 1.99, 1.70, 0.75 and 0.51δ.
Reaction SMILES: Cl.[F:2][C:3]([F:21])([F:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]([NH2:19])[NH:16][N:15]=1)(=[O:13])=[O:12].[C:22](OCC)(=[O:27])[CH2:23][C:24]([CH3:26])=O>CO>[F:21][C:3]([F:2])([F:20])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][S:11]([C:14]1[N:18]=[C:17]2[N:19]=[C:24]([CH3:26])[CH:23]=[C:22]([OH:27])[N:16]2[N:15]=1)(=[O:12])=[O:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1nc(S(=O)(=O)Nc2ccccc2C(F)(F)F)n[nH]1
Agent: Cl
Solvent: CO
Product: Cc1cc(O)n2nc(S(=O)(=O)Nc3ccccc3C(F)(F)F)nc2n1
Reaction time: 120 h

Procedure:
A solution of 1 ml of 12N hydrochloric acid in 250 ml of methanol was added to a mixture of 20.0 g (65.1 mmol) of N-(2-trifluoromethylphenyl)-5-amino-1,2,4-triazole-3-sulfonamide and 9.2 ml (72.2 mmol) of ethyl acetoacetate and the mixture heated to reflux with stirring. After about 5 days, most but not all of the starting material was found to have reacted by thin layer chromatrography. The sollution was chilled and the precipitate that formed was collected by filtration, washed with cold methanol and dried to obtain 16.5 g (67.9 percent of theory) of the title compound as a white solid hemihydrate melting at 245°-7° C.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][C@H:11]1[C:19]2[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=2)[CH2:13][C@H:12]1[OH:21].[C:22]1(=O)[O:27][C:25](=[O:26])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(C)C=CC=CC=1>>[Cl:20][C:16]1[CH:15]=[C:14]2[C:19](=[CH:18][CH:17]=1)[C@@H:11]([N:10]1[C:25](=[O:26])[C:24]3[C:23](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:22]1=[O:27])[C@@H:12]([OH:21])[CH2:13]2
Reactant: N[C@H]1c2ccc(Cl)cc2C[C@H]1O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1c2ccc(Cl)cc2C[C@@H]1O
Temperature: 25 °C

Procedure:
In a 1 L round bottom flask, N,N-diisopropylethylamine (15.2 mL, 0.0871 mol) was added to a suspension of (1S,2R)-1-amino-5-chloroindan-2-ol (16.0 g, 0.0871 mol) and phthalic anhydride (14.2 g, 0.0958 mol) in toluene (473 mL, 4.44 mol), and the reaction mixture was heated at reflux for 18 hours. The reaction was cooled to room temperature, at which point a large amount of solid precipitated. The solid, which was the desired product, was filtered, rinsed with EtOAc and collected. The filtrate was cooled to 0° C., filtered and the solid was rinsed with EtOAc and combined with the first batch. The filtrate was transferred to a separatory funnel and diluted with H2O (200 mL). The layers were separated, and the aqueous layer was extracted EtOAc (3×200 mL). The combined organic layers were washed 1× brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting off-white solid was suspended in EtOAc, the large chunks were broken up with sonication, and the suspension was cooled to 0° C. The solid was filtered and combined with the previous 2 batches. The filtrate was concentrated in vacuo, and the resultant white solid was suspended one final time in Et2O (100 mL), filtered and combined with the previous 3 batches. The total yield of all four batches of solid was 25.3 g (92%). LCMS: (FA) ES+ molecular ion 314, major ionization 167; 1H NMR (400 MHz, DMSO) δ 7.83 (s, 4H), 7.33 (s, 1H), 7.27 (d, J=8.2, 1H), 7.19 (dd, J=2.0, 8.1, 1H), 5.52 (d, J=7.4, 1H), 5.34 (d, J=5.2, 1H), 4.64 (dt, J=6.9, 12.7, 1H), 3.21 (dd, J=7.4, 16.1, 1H), 3.02 (dd, J=6.1, 16.1, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]([C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:2].C(N(CC)CC)C.[SH2:32]>N1C=CC=CC=1>[CH2:22]([O:21][C:19](=[O:20])[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:24])([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17](=[S:32])[NH2:18])=[CH:15][CH:16]=1)[NH:6][C:7](=[O:9])[CH3:8])[CH3:23]
Reactant: S
Reactant: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Cc1ccc(C(N)=S)cc1)(NC(C)=O)C(=O)OCC
Reaction time: 18 h
Yield: 80 %

Procedure:
Into a solution of 10.0 g (30 mmoles) of N-acetyl-4-cyano-α-(ethoxycarbonyl)phenylalanine ethyl ester and 3.5 g (35 mmoles) of triethylamine in 250 ml of pyridine, hydrogen sulfide gas is introduced until the solution is saturated. The reaction mixture is then stirred at 25° for 18 hours, followed by evaporation of the solvent. The residue is slurried with 50 ml of carbon disulfide for 1 hour and the resulting crystalline solid recovered by filtration to yield 8.7 g (24 mmoles, 80%) of N-acetyl-α-ethoxycarbonyl-4-thiocarbamoylphenylalanine ethyl ester, m.p. 168°-172°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:23](/[CH:24]=[CH:25]/[C:26]2[CH:34]=[CH:33][C:29]([C:30]([O-:32])=[O:31])=[CH:28][CH:27]=2)=[CH:22][C:12]2[C:13]3([CH3:21])[CH:18]([OH:19])[C:17]([CH3:20])([C:11]=2[CH:10]=1)[CH2:16][CH2:15][CH2:14]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+]>C(O)C.C1COCC1>[CH2:1]([O:8][C:9]1[C:23](/[CH:24]=[CH:25]/[C:26]2[CH:27]=[CH:28][C:29]([C:30]([OH:32])=[O:31])=[CH:33][CH:34]=2)=[CH:22][C:12]2[C:13]3([CH3:21])[CH:18]([OH:19])[C:17]([CH3:20])([C:11]=2[CH:10]=1)[CH2:16][CH2:15][CH2:14]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1cc2c(cc1/C=C/c1ccc(C(=O)[O-])cc1)C1(C)CCCC2(C)C1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCCCCOc1cc2c(cc1/C=C/c1ccc(C(=O)O)cc1)C1(C)CCCC2(C)C1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
1.255 g of (E)-4-[2-[(5RS,9SR, 10RS)-3-heptyloxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl]vinyl]benzoate were dissolved in 30 ml of ethanol/THF=1/1 and treated with 2.56 ml of 3N NaOH. The mixture was stirred at room temperature for 5 hours, then poured into ice/conc. HCl, extracted with ethyl acetate, washed with water, dried over Na2SO4 and evaporated. Recrystallization from hexane/ethyl acetate yielded 873 mg of (E)-4-[2-[(5RS,9SR,10RS)-3-heptyloxy-10-hydroxy-5,9-dimethyl-6,7,8,9-tetrahydro-5,9-methano-5H-benzocyclohepten-2-yl]vinyl]benzoic acid as yellow crystals of melting point 89-90° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=O)=[CH:4][CH:3]=1.B.CSC.Cl>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:7]=1
Reactant: CCCCCCCNC(=O)Cc1ccc(Cl)cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCCCCNCCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
2-(4-Chlorophenyl)-N-heptylacetamide (1.045 g, 3.902 mmol) was dissolved in THF (10 ml) and was cooled to 0° C. under argon atmosphere. (Methylthio)methane compound with borane (1:1) (0.741 g, 9.756 mmol) was added and the mixture was refluxed for 5 hours. After the mixture was cooled to room temperature, 5 ml HCl (10%) was gently added and was stirred overnight. The solvent was removed by evaporation. EtOAc (20 ml) was added and the organic phase was washed with K2CO3 (2M, 2×20 ml). The crude was purified by flashcromatography (started with isocratic heptane/EtOAc 50/50 and then the EtOAc concentration was increased to 100%, (silica gel 60 0.004-0.063 mm). The product containing fractions was pooled and the EtOAc was removed by evaporation to give 0.609 g of N-[2-(4-chlorophenyl)ethyl]-N-heptylamine (yield 61.5%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:12]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][CH2:18][CH2:17][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCN1CCCC1
Solvent: ClCCl
Product: O=S(=O)(NCCN1CCCC1)c1ccc(Br)cc1
Reaction time: 3 h

Procedure:
4-bromo-benzenesulfonyl chloride (3.36 g, 13.1 mmol, 1 equiv) was dissolved in 50 mL DCM and treated with TEA (9.16 mL, 65.7 mmol, 5 equiv). To this, while stirring the solution, was added 2-pyrrolidin-1-yl-ethylamine (3 g, 26.3 mmol, 2 equiv). After 3 h, reaction was poured onto DCM/water mixture and washed once. The aqueous phase was back extracted once with fresh DCM. Organic phases were combined, washed once with brine and dried over sodium sulfate. Filtration followed by rotary evaporation provided desired product. White needles (3.92 g, 90%). Rf=0.35 (10% MeOH/DCM)
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH:8]([O:21][CH3:22])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[CH:28]=[O:29].O>C1(C)C=CC=CC=1.O1CCCC1.C(OCC)(=O)C>[CH3:22][O:21][CH:8]([O:7][CH3:6])[C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[C:10]=1[CH:28]([OH:29])[C:27]1[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:25]([O:24][CH3:23])[CH:26]=1
Reactant: COc1ccc(C=O)cc1OC
Reactant: COc1cc(C(OC)OC)cc(OC)c1OC
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(O)c2c(C(OC)OC)cc(OC)c(OC)c2OC)cc1OC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 97.4 %

Procedure:
136 ml of a 1.6M n-butyl lithium solution in toluene are added to a solution of 48.5 g of 3,4,5-trimethoxybenzaldehyde dimethyl acetal in 485 ml of tetrahydrofuran under stirring at 0° C. for about 20 minutes. The mixture is further stirred at 0° C. for 30 minutes, and 33.2 g of 3,4-dimethoxybenzaldehyde are added thereto. After stirring the mixture at 0° to 10° C. for 2 hours, 780 ml of water and 780 ml of ethyl acetate are added thereto. After shaking the mixture, the organic layer is separated therefrom, washed with water and evaporated under reduced pressure to remove solvent. 79.5 g of 2-(3,4-dimethoxy-α-hydroxybenzyl)-3,4,5-trimethoxybenzaldehyde dimethyl acetal are thereby obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[CH2:16])[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.C([O:29]O)(C)(C)C>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:24])([C:15]2([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[O:29][CH2:16]2)[CH2:9][N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: C=C(c1ccc(F)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1
Reactant: CC(C)(C)OO
Solvent: c1ccccc1
Product: OC(Cn1cncn1)(c1ccc(F)cc1)C1(c2ccc(F)cc2)CO1
Temperature: 25 °C
Yield: 62 %

Procedure:
2,3-Bis(4-fluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-3-butene-2-ol (1.0 g) was dissolved in 50 ml of anhydrous benzene and stirred under nitrogen. To this solution was added 0.012 g of vanadium acetonyl-acetonate. The solution was then refluxed and tert-butyl hydroperoxide (0.44 g dissolved in 5 ml of anhydrous benzene) was added dropwise over 10 minutes. The reaction was refluxed for one additional hour and then cooled to ambient temperature. The benzene was removed in vacuo and the residue chromatographed on silica gel (2% MeOH/CH2Cl2). This yielded a total of 650 mg of diastereomeric products in a 3:1 ratio. Further chromatography resulted in the separation of the diastereomers. The major isomer was a waxy white solid. NMR (CDCl3 /TMS) δ 2.60 (d, J=6 Hz, 1H); 3.48 (d, J=6 Hz, 1H); 4.70 (q, J=7 Hz, 2H); 5.25 (s, 1H); 6.8-7.3 (m, 8H); 7.55 (s, 1H); 7.90 (s, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:18]#[N:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[OH-:21].[Na+]>S(=O)(=O)(O)O>[CH2:1]([O:3][C:4](=[O:20])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2([C:18](=[O:21])[NH2:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(NC2(C#N)CCCCC2)cc1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)c1ccc(NC2(C(N)=O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
550 mg (2.02 mmol) of 4-(1-cyanocyclohexylamino)-benzoic acid ethyl ester are dissolved in 20 ml of concentrated sulfuric acid. The reaction medium is stirred at room temperature for 5 hours. The reaction medium is poured gently onto ice, the pH is brought to 12 with sodium hydroxide, and the resulting mixture is extracted with ethyl acetate. The organic phases are combined and washed with water. They are dried over sodium sulfate. The solvents are evaporated off. The product is chromatographed on silica gel (60/40 heptane/ethyl acetate). The product 4-(1-carbamoyl-cyclohexylamino)benzoic acid ethyl ester is obtained in the form of a white solid.
Reaction SMILES: [N:1]1([C:24]([CH3:26])=[O:25])[CH2:23][CH2:22][CH2:21][C@H:2]1[C:3]([NH:5][C@H:6]([C:18]([OH:20])=O)[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].S(C1C=CC(C)=CC=1)([O-])(=O)=O.[NH2:38][CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[N:1]1([C:24]([CH3:26])=[O:25])[CH2:23][CH2:22][CH2:21][C@H:2]1[C:3]([NH:5][C@H:6]([C:18]([NH:38][CH2:39][C:40]([O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:41])=[O:20])[CH2:7][CH2:8][CH2:9][NH:10][C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])=[O:4]
Reactant: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Reactant: NCC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(=O)N1CCC[C@H]1C(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
5.6 g of Ac-Pro-Orn(Boc)-OH, 5.0 g of the tosylate of H-Gly-OBzl and 2.0 g of HOBt are dissolved in 50 ml of DMF, cooled to 0° C., and 1.9 ml of NEM and 3.4 g of DCC in 5 ml of DMF are added. The mixture is stirred at 0° C. for one hour, and at room temperature overnight. After the urea has been removed by filtration, the solvent is removed by evaporation in vacuo, and the residue is chromatographed on silica gel (system 4). 6.1 g (yield: 79%) of Ac-Pro-Orn(Boc)-Gly-OBzl remain as an oil. Rf (system 4)=0.75; MS (FAB): 519 (M+1).