Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:20]1[CH2:30][CH2:29][C@@H:28]([O:31][Si:32]([CH:39]([CH3:41])[CH3:40])([CH:36]([CH3:38])[CH3:37])[CH:33]([CH3:35])[CH3:34])[C:23]2=[N:24][CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21]1>C(Cl)Cl>[F:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=1[C@@H:20]1[CH2:30][CH2:29][C@@H:28]([O:31][Si:32]([CH:36]([CH3:38])[CH3:37])([CH:39]([CH3:41])[CH3:40])[CH:33]([CH3:34])[CH3:35])[C:23]2=[N+:24]([O-:9])[CH:25]=[CH:26][CH:27]=[C:22]2[CH2:21]1
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2cccnc21)(C(C)C)C(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)Cc2ccc[n+]([O-])c21)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
mCPBA (1.239 g, 5.53 mmol) was added to the CH2Cl2 (30 mL) solution of (6R,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine (2.17 g, 5.03 mmol) at rt. The reaction was stirred at room temperature overnight. The solvent was removed via vacuum. The product was purified by flash column eluted with ethyl acetate in hexane from 0 to 50% to 85%. The product was obtained by flushing the column with 85% ethyl acetate in hexane (1.572 g, 69%). MS(ESI)[M+H+]=448.21; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.14 (br.s., 1H) 6.94-7.11 (m, 2H) 6.84-6.92 (m, 2H) 6.66-6.72 (m, 1H) 6.42 (t, J=4.28 Hz, 1H) 4.04 (dd, J=14.73, 4.41 Hz, 1H) 3.73-3.88 (m, 1H) 2.96 (dd, J=14.48, 5.41 Hz, 1H) 2.50 (d, J=5.79 Hz, 1H) 2.13-2.25 (m, 2H) 1.80-1.94 (m, 1H) 1.18-1.32 (m, 3H) 1.09 (d, J=7.55 Hz, 9H) 1.00 (d, J=7.55 Hz, 9H).
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].Cl.[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][Cl:14])[N:12]=1>Cl>[ClH:14].[ClH:1].[NH2:7][C:8]1[S:9][CH:10]=[C:11]([CH2:13][S:5][CH2:4][CH2:3][NH2:2])[N:12]=1
Reactant: NCCS
Reactant: Nc1nc(CCl)cs1
Agent: Cl
Product: NCCSCc1csc(N)n1

Procedure:
Cysteamine hydrochloride (5.65 g; 50.0 mmoles) and 2-amino-4-chloromethylthiazole hydrochloride (9.25 g; 50.0 mmoles) were dissolved in 70 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 105°. After 64 hours of heating the mixture was evaporated under reduced pressure and the residue triturated with acetone. The collected product was re-triturated with ethanol, filtered and dried to yield the title compound, mp 170°-200°.
Reaction SMILES: [O:1]1[CH2:7][CH2:6][C:5](=[O:8])[NH:4][CH2:3][CH2:2]1.S(OC)(O[CH3:13])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:13][O:8][C:5]1=[N:4][CH2:3][CH2:2][O:1][CH2:7][CH2:6]1
Reactant: O=C1CCOCCN1
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC1=NCCOCC1
Temperature: 150 °C
Yield: 97.6 %

Procedure:
To a solution of 1,4-oxazepan-5-one (0.091 g, 0.793 mmol) in DCM (2 mL) in a screw-cap vial was added dimethyl sulfate (0.1 g, 0.793 mmol) to give a colorless solution. The reaction was heated to 150° C. for 5 minutes. Potassium carbonate (200 mg) was added and the vial was capped and shaken. The reaction was filtered through a glass frit and solvent was removed under reduced pressure to give a clear oil (100 mg) that was used without further purification. LCMS (+ESI) m/z: 130.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][C:8]2[CH:10]=[C:11]3[O:16][CH2:15][O:14][C:12]3=[CH:13][C:7]=2[C:6]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[CH:19][CH:18]=2)=[N:5][N:4]1[C:26](=[O:29])[NH:27][CH3:28].O.NN>C(O)C.[Ni]>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:6]2[C:7]3[CH:13]=[C:12]4[O:14][CH2:15][O:16][C:11]4=[CH:10][C:8]=3[CH2:9][CH:3]([CH2:2][OH:1])[N:4]([C:26](=[O:29])[NH:27][CH3:28])[N:5]=2)=[CH:18][CH:19]=1
Reactant: CNC(=O)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1CO)OCO3
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: CNC(=O)N1N=C(c2ccc(N)cc2)c2cc3c(cc2CC1CO)OCO3
Reaction time: 0.5 h
Yield: 88 %

Procedure:
A suspension of 1.02 g (2.56 mmol) of 8-hydroxymethyl-7-methylcarbamoyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxolo[4,5-h][2,3]benzodiazepine (stage C) in 40 ml of ethanol is mixed with 0.45 ml (9 mmol) of 98% hydrazine hydrate and RaNi catalyst while being stirred. After 30 minutes, the catalyst is filtered off, and the solution is concentrated by evaporation. The residue is recrystallized in ethanol, and 0.83 g (88%) of product with a melting point of 136-138° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([S:26][CH3:27])[CH2:23][C:22]1([F:25])[F:24].ClC1C=C(C=CC=1)C(OO)=[O:33]>ClCCl>[NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]1([S:26]([CH3:27])=[O:33])[CH2:23][C:22]1([F:24])[F:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1(c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)CC1(F)F
Solvent: ClCCl
Product: CS(=O)C1(c2c(C#N)nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2N)CC1(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 8.5 %

Procedure:
To a solution of Example 74 (100 mg, 0.23 mmol) in dichloromethane (5 ml) was added 3-chloroperoxybenzoic acid (77%, 53 mg, 0.25 mmol). The reaction mixture was stirred at room temperature for 18 h, diluted with dichloromethane (10 ml) and washed with saturated aqueous sodium hydrogencarbonate solution (2×5 ml). The organic layer was separated, dried (MgSO4) and concentrated in vacuo. The residue was dissolved in acetonitrile/dimethyl sulphoxide (1:1, 1 ml) and purified by automated preparative liquid chromatography (Gilson system, 250 mm×30 mm Phenomenex LUNA C18(2) 101m column) using an acetonitrile:water gradient [45:55 to 95:5]. The appropriate fractions were concentrated in vacuo to give the titled compound (9 mg) and a second diastereoisomer, Example 126
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](SC)=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].[CH:22]([Zn])([CH3:24])[CH3:23]>CCOCC.C1COCC1.[Cl-].[Cl-].[Zn+2].[Ni](Cl)Cl.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([CH:22]([CH3:24])[CH3:23])=[C:9]([C:18]#[N:19])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CC(C)[Zn]
Reactant: CCOC(=O)c1sc(SC)c(C#N)c1-c1ccc(I)cc1
Agent: Cl[Ni]Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)c1sc(C(C)C)c(C#N)c1-c1ccc(I)cc1
Temperature: 60 °C
Yield: 25 %

Procedure:
Add dropwise isopropylzinc solution (ZnCl2 1M in Et2O (10.5 ml) and isopropylzinc 2M in THF (10.5 ml) previously mixed at 10° C. under N2 atmosphere) to a mechanically stirring suspension of 4-cyano-3-(4-iodo-phenyl)-5-methylsulfanyl-thiophene-2-carboxylic acid ethyl ester (1.5 gr, 3.5 mmol) and 1,3-bis-(diphenylphosphino)propane nickel (II) chloride (380 mg, 0.71 mmol) in dry THF (35 ml) and heat the resulting mixture 60° C. for 1 hour. Cool the reaction to room temperature and remove solvents in vacuo. Purify the solid by chromatography on silica gel (eluting with 10-80% Ethyl acetate/hexane) to provide the title compound in 25% yield: Mass spectrum (EI+): m/z 426 (M++1).
Reaction SMILES: [CH:1]1([S:4]([NH:7][C:8]([C:10]2([NH:15][C:16]([CH:18]3[CH2:22][CH:21]([O:23][C:24]4[CH:29]=[CH:28][N:27]=[C:26](Cl)[N:25]=4)[CH2:20][CH:19]3[C:31]([N:33]([CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=C)[CH3:34])=[O:32])=[O:17])[CH2:12][CH:11]2[CH:13]=C)=[O:9])(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:41]([NH2:44])([CH3:43])[CH3:42]>C1COCC1.ClCCCl>[CH:41]([NH:44][C:26]1[N:25]=[C:24]([O:23][CH:21]2[CH2:22][CH:18]3[CH:19]([C:31](=[O:32])[N:33]([CH3:34])[CH2:35][CH2:36][CH2:37][CH2:38][CH:39]=[CH:13][CH:11]4[C:10]([C:8]([NH:7][S:4]([CH:1]5[CH2:3][CH2:2]5)(=[O:6])=[O:5])=[O:9])([NH:15][C:16]3=[O:17])[CH2:12]4)[CH2:20]2)[CH:29]=[CH:28][N:27]=1)([CH3:43])[CH3:42]
Reactant: C=CCCCCN(C)C(=O)C1CC(Oc2ccnc(Cl)n2)CC1C(=O)NC1(C(=O)NS(=O)(=O)C2CC2)CC1C=C
Reactant: CC(C)N
Solvent: ClCCCl
Solvent: C1CCOC1
Product: CC(C)Nc1nccc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)n1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
Compound 10f (30 mg, 0.05 mmol) and isopropylamine (excess) in THF (10 ml) was heated in a microwave oven at 110° C. for 30 min and then left at ambient temperature for 16 hrs. The solvent was stripped of and the residue was redissolved in DCE (15 ml) and degassed with nitrogen. Hoyeda-Grubbs II catalyst (7 mg) was added and the mixture was heated in a microwave oven at 150° C. for 10 min. The mixture was concentrated to dryness and purified by prep. HPLC-MS-UV which gave the pure title compound (3.1 mg), (M+H)+=589.2.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]=2)[CH2:3]1.[H][H]>C(O)C.[Pd]>[NH2:12][C:9]1[CH:8]=[N:7][C:6]([N:4]2[CH2:3][CH:2]([OH:1])[CH2:5]2)=[CH:11][CH:10]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccc(N2CC(O)C2)nc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(N2CC(O)C2)nc1
Yield: 34.8 %

Procedure:
A suspension of 0.34 g (1.74 mmol) of 2-(3-hydroxyazetidin-1-yl)-5-nitropyridine, prepared in the preceding stage, and of 9 mg of Pd/C at 10% in 10 ml of ethanol is stirred vigorously at 20° C. under 5 atmospheres of hydrogen for 4 hours. After this period of time, the mixture is filtered through a celite buffer and then concentrated under reduced pressure. The resulting product is purified by silica column chromatography, elution being carried out with a mixture of dichloromethane and methanol. 0.1 g of the expected product is thus obtained, which product will be used as it is in the subsequent synthesis.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CC([O-])=O.[Na+]>CN(C)C=O>[C:3]1([CH:2]=[CH:1][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Brc1ccccc1
Reactant: C=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C(=Cc1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
Dimethylformamide (Aldrich) was used in anhydrous form. All the aryl bromides, iodobenzene and alkene substrates were purified before use (Aldrich). 6.0 mmol each of styrene and bromobenzene, 6.6 mmol of NaOAc (base) were mixed with 50 ml of DMF (dimethylformamide). 20 ml of this solution was placed in a 50 ml round bottom-flask equipped with a magnetic stirring bar and condenser connected to a vacuum line. The solution was flushed five times with nitrogen using a vacuum nitrogen cycle. The catalysts prepared in Example 12, generations 0 through 4, were then added. The autoclave was placed in an oil bath and the 120° C. was reached by stirring on a hot plate. After the appropriate reaction time, the reaction was allowed to cool to room temperature. The resulting solution was filtered to remove the catalyst. The filtrate was extracted with diethyl ether (4×40 ml), and the ether extracts were washed with brine and distilled water, followed by drying over magnesium sulfate. The product, trans stilbene, was analyzed by 1H NMR spectroscopy and/or gas chromatography, and identified by comparison of spectral results with literature data. Results are shown in Tables 6-7 below. The yields of stilbene was significantly less when generation 3 and 4 dendrimer complexes are used as catalysts. The best turnovers in terms of molecules of trans-stilbene formed per mol of palladium was achieved with the generation 2 catalyst.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH3:19])[CH:4]=[C:5]2[C:11]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[N:9][CH2:8][C:7](=[O:18])[NH:6]2.[Br:20]Br.C([O-])(O)=O.[Na+]>CO>[Br:20][C:4]1[N:3]([CH3:19])[C:2]([CH3:1])=[C:11]2[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][CH2:8][C:7](=[O:18])[NH:6][C:5]=12
Reactant: Cc1c2c(cn1C)NC(=O)CN=C2c1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1c2c(c(Br)n1C)NC(=O)CN=C2c1ccccc1
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
3,7-dihydro-6,7-dimethyl-5-phenylpyrrolo[3,4-e][1,4]diazepin-2(1H)-one (5.0 g, 0.020 mole) is dissolved in methanol (150 ml) and the obtained solution is cooled to -60° C. and stirred during the addition of a solution of bromine (3.4 g, 0.021 mole) in methanol (10 ml). After 20 minutes at -60° C., the reaction mixture is poured into an aqueous solution of NaHCO3 (1.5% w/v, 750 ml). The precipitate which forms is recovered by filtration and crystallized from methanol yielding 4.2 g of the compound of the title. M.p. 200°-2° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:18]=[CH:17][C:8]([CH:9]=[CH:10][C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])=[CH:7][C:6]=1[NH2:19])[CH:2]=[CH2:3].[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[C@H:26]([C:35](O)=[O:36])[CH2:25]1)(=[O:22])[CH3:21].NC1C=C(C=CC=1)C=CC(OCC=C)=O>>[C:20]([S:23][C@@H:24]1[CH2:28][N:27]([C:29]([O:31][CH2:32][CH:33]=[CH2:34])=[O:30])[C@H:26]([C:35](=[O:36])[NH:19][C:6]2[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:18][CH:17]=[C:8](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH:15]=[CH2:16])=[O:12])[CH:7]=2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1C(=O)O
Reactant: C=CCOC(=O)C=Cc1ccc(OCC=C)c(N)c1
Agent: C=CCOC(=O)C=Cc1cccc(N)c1
Product: C=CCOC(=O)/C=C/c1ccc(OCC=C)c(NC(=O)[C@@H]2C[C@H](SC(C)=O)CN2C(=O)OCC=C)c1

Procedure:
Allyl 4-allyloxy-3-aminocinnamate was condensed with (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-carboxypyrrolidine by the method described in example 1 for allyl 3-aminocinnamate to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(6-allyloxy-3-(E-2-allyloxycarbonyl-1-ethenyl)phenylcarbamoyl)pyrrolidine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:30])[CH2:4][NH:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=2)[N:9]=[C:8]([N:17]2[CH2:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]2)[CH:7]=1.C([O-])(=O)C.[K+].[N:36]#[C:37]Br.Cl>O.CO>[NH2:36][C:37]1[O:30][CH:3]([CH2:4][NH:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[N:9]=[C:8]([N:17]3[CH2:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[S:20](=[O:29])(=[O:28])[CH2:19][CH2:18]3)[CH:7]=2)[CH2:2][N:1]=1
Reactant: N#CBr
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(O)CN)c2c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3CN=C(N)O3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.4 %

Procedure:
A mixture of 1-amino-3-{[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]amino}propan-2-ol (80 mg, 0.18 mmol, prepared in analogy to Example 9-7) and potassium acetate (89 mg, 0.91 mmol) in a mixture solution of methanol and water (7 ml, V/V=6/1) was added cyanogen bromide (89 mg, 0.84 mmol) at 0° C. After being stirred at room temperature for 3 hours, the mixture was stirred further with concentrated hydrochloric acid (3 mL) for 1 hour, and then concentrated in vacuo. The residue was dissolved in a saturated aqueous solution of sodium bicarbonate (10 mL) and extracted with dichloromethane (15 mL×3). The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash column (10% methanol in dichloromethane) to afford 32 mg of the desired product as a white solid. MS obsd. (ESI+) [(M+H)+] 452, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.92-7.87 (m, J=4.6 Hz, 2 H), 7.72 (s, 1 H), 7.65-7.62 (t, J=3.7 Hz, 1 H), 7.49-7.45 (t, J=3.9 Hz, 1 H), 7.32 (d, J=2.1 Hz, 1 H), 7.23 (d, J=2.1 Hz, 1 H), 6.85 (t, J=2.6 Hz, 1 H), 6.46 (brs, 2 H), 6.10 (s, 1 H), 5.10 (s, 2 H), 4.82-4.77 (m, J=4.8 Hz, 1 H), 4.49 (brs, 2 H), 3.75 (m, 1 H), 3.63 (s, 2 H), 3.52 (m, 3 H), 2.35 (s, 3 H).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=1)[NH2:3].CN(C)/[CH:14]=[CH:15]/[C:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:26])[CH3:25])=[CH:20][CH:19]=1)=O>>[CH3:25][N:24]([CH3:26])[C:21]1[CH:22]=[CH:23][C:18]([C:16]2[N:2]([C:4]3[CH:9]=[C:8]([C:10]#[N:11])[CH:7]=[CH:6][N:5]=3)[N:3]=[CH:14][CH:15]=2)=[CH:19][CH:20]=1
Reactant: N#Cc1ccnc(NN)c1
Reactant: CN(C)/C=C/C(=O)c1ccc(N(C)C)cc1
Agent: Cl
Product: CN(C)c1ccc(-c2ccnn2-c2cc(C#N)ccn2)cc1
Yield: 69 %

Procedure:
The title compound was prepared in 69% yield from 2-hydrazinylpyridine-4-carbonitrile hydrochloride salt (PREPARATION 3) and (2E)-3-(dimethylamino)-1-[4-(dimethylamino)phenyl]prop-2-en-1-one according to the procedure for the preparation of Example 46, part B.
Reaction SMILES: CI.[CH2:3]([O:10][C:11](=[O:26])[CH2:12][CH2:13][C@H:14]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:15]([OH:17])=[O:16])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:27]([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.C(Cl)(Cl)Cl.CO>[C:22]([O:21][C:19]([NH:18][C@@H:14]([CH2:13][CH2:12][C:11]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:26])[C:15]([O:17][CH3:27])=[O:16])=[O:20])([CH3:23])([CH3:25])[CH3:24]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.5 %

Procedure:
Methyl iodide (1.01 mL, 16.3 mmol) was added dropwise to a solution of (2S)-5-(benzyloxy)-2-{[(tert-butoxy)carbonyl]amino}-5-oxopentanoic acid XII (5.00 g, 14.82 mmol) and K2CO3 (2.25 g, 16.3 mmol) in DMF (25 mL) at room temperature The reaction mixture was stirred about 3 h at room temperature before adding additional methyl iodide (1.01 mL, 16.3 mmol). EtOAc was then added to the reaction and washed 3×10% Na2S2O3 and dried over MgSO4. The solvent was removed under reduced pressure and the crude product was purified on a silica gel column (100:1 and then 50:1 CHCl3/MeOH) to give 5-benzyl 1-methyl (2S)-2-{[(tert-butoxy)carbonyl]amino}pentanedioate XIII (4.20 g, 12.23 mmol, 82% yield). ESIMS found for C18H25NO6 m/z 352 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10](=O)[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21](OCC)=[O:22])[CH:14]=1)C>C1COCC1>[OH:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21][OH:22])[CH:16]=[CH:17][CH:18]=1
Reactant: CCOC(=O)CCc1cccc(CCC(=O)OCC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1cccc(CCCO)c1
Temperature: 25 °C
Yield: 80.9 %

Procedure:
A stirred solution of lithium aluminum hydride (1.63 g, 42 mmol) in THF (50 mL) was cooled to 0° C. and the intermediate from Step B (6.0 g, 21 mmol) in THF (50 mL) was added dropwise. After the addition was complete, the reaction mixture was warmed to ambient temperature over 30 minutes. The reaction was quenched by slowly adding 1N HCl (200 mL) and then DCM (400 mL) was added. The organic layer was removed and the aqueous layer was washed with DCM (4×100 mL). The combined organic layers were washed with saturated NaCl (1×100 mL), dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to provide 3.3 g of the title intermediate (81% yield), which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([NH:10][NH2:11])=O)=[C:5]([CH3:7])[N:6]=1.[CH3:12][N:13]=[C:14]=[S:15]>C(O)C>[CH3:1][C:2]1[S:3][C:4]([C:8]2[N:13]([CH3:12])[C:14]([SH:15])=[N:11][N:10]=2)=[C:5]([CH3:7])[N:6]=1
Reactant: CN=C=S
Reactant: Cc1nc(C)c(C(=O)NN)s1
Solvent: CCO
Product: Cc1nc(C)c(-c2nnc(S)n2C)s1
Yield: 47.6 %

Procedure:
To a 2,4-dimethylthiazole-5-carbohydrazide (Prep26, 23 g, 0.13 mol) in ethanol (100 ml), methyl isothiocyanate (49.1 g, 0.67 mol) was added. The mixture was refluxed overnight. Then the ethanol was partially removed under vacuum and the residue was filtered. The solid was dried under vacuum to afford 14 g of the title compound (y=46%).
Reaction SMILES: C(O)(=O)C[C:3](CC(O)=O)([C:5]([OH:7])=[O:6])[OH:4].[C:14]([OH:22])(=O)[CH:15]([CH2:17][C:18]([OH:20])=O)[OH:16]>>[O:6]=[C:5]1[O:7][C@H:17]([C@H:15]([CH2:14][OH:22])[OH:16])[C:18]([OH:20])=[C:3]1[OH:4]
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: O=C(O)CC(O)C(=O)O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O

Procedure:
The mixture as defined in claim 1 including citric acid, malic acid, an ascorbic acid and other organic acids inherent in fruits to give a titratable acid level of 0.15 to 0.8 percent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21](O)=[O:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:24].[S:25]([C:29]1[CH:30]=[C:31]([NH2:35])[CH:32]=[CH:33][CH:34]=1)(=[O:28])(=[O:27])[NH2:26]>>[S:25]([C:29]1[CH:30]=[C:31]([NH:35][C:21]([C:20]2[CH:19]=[N:18][N:11]3[C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH3:24])[CH:4]=4)=[N:9][C:10]=23)=[O:22])[CH:32]=[CH:33][CH:34]=1)(=[O:27])(=[O:28])[NH2:26]
Reactant: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)O)c3n2)ccc1Cl
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C(=O)Nc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.6) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 510.2 [(M+H)+]; mp 275° C.
Reaction SMILES: [OH:1][CH:2]([C@@H:13]1[CH2:17][CH2:16][CH2:15][N:14]1[C:18](=[O:34])[C@@H:19]1[CH2:23][CH2:22][CH2:21][N:20]1[C:24](=[O:33])[CH2:25][NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.CS(C)=O.C1C=CC=CC=1>C(N(CC)CC)C>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[C:18](=[O:34])[C@@H:19]2[CH2:23][CH2:22][CH2:21][N:20]2[C:24](=[O:33])[CH2:25][NH:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:1])=[CH:10][CH:9]=1
Reactant: COc1ccc(OCC(O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CNc2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COc1ccc(OCC(=O)[C@@H]2CCCN2C(=O)[C@@H]2CCCN2C(=O)CNc2ccccc2)cc1
Yield: 59.3 %

Procedure:
(2S)-2-[1-Hydroxy-2-(4-methoxyphenoxy)ethyl]-1-[N-(N-phenylglycyl)-L-prolyl]pyrrolidine (488 mg) was treated in the same manner as in Example 47-D) using DMSO (3 ml), benzene (1.5 ml), triethylamine (0.73 ml+0.15 ml), and sulfur trioxide-pyridine complex (778 mg) to give 288 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[C:6]([CH:9]=1)[CH:7]=O.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+].C(=O)(O)[O-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][CH2:11][CH2:12][CH:13]=[CH2:14])=[C:6]([CH2:7][NH2:21])[CH:9]=1
Reactant: [BH3-]C#N
Reactant: C=CCCCc1ccc(C)cc1C=O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CO
Product: C=CCCCc1ccc(C)cc1CN
Temperature: 65 °C
Reaction time: 1 h
Yield: 33.5 %

Procedure:
Step AI (5): 5-Methyl-2-(pent-4-enyl)benzaldehyde (170 mg, 0.90 mmol) and ammonium acetate (10.44 g, 135.5 mmol) was dissolved in methanol (35 mL). Sodium cyanoborohydride (341 mg, 5.42 mmol) was added. The reaction mixture was stirred at 65° C. in a high-pressure vessel for 1 h. Aqueous sodium bicarbonate solution was added and the reaction mixture was extracted with DCM. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum. The residue was purified by reverse phase chromatography to give (5-methyl-2-(pent-4-enyl)phenyl)methanamine (57 mg, 33%) as a colorless oil. LC-MS (M+H)+=190.09.