Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:12])[C@@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([CH:7]=[O:8])=[O:6].[CH2:13]([OH:24])[CH:14]1[O:20][C:18](=[O:19])[CH:17]([OH:21])[CH:16]([OH:22])[CH:15]1[OH:23]>>[CH2:1]([OH:12])[C@@H:2]([OH:11])[C@@H:3]([OH:10])[C@H:4]([OH:9])[C:5]([C:7]([OH:19])=[O:8])=[O:6].[CH2:16]([OH:22])[C@@H:15]([OH:23])[C@H:14]1[O:20][C:18](=[O:19])[C:17]([OH:21])=[C:13]1[OH:24]
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=C1OC(CO)C(O)C(O)C1O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Product: O=C1O[C@H]([C@H](O)CO)C(O)=C1O

Procedure:
Very generally, the invention provides, in combination with a process employing hydrogen peroxide, a co-process which acts as a source of the hydrogen peroxide and provides, along with it, a useful co-product. D-glucose is enzymatically oxidized at one of the first and second carbons to produce hydrogen peroxide and an intermediate product. The other of the first and second carbons of the intermediate product is then enzymatically oxidized to produce hydrogen peroxide and 2-keto-D-gluconic acid. In one form of the invention, the intermediate product is D-glucosone. In another form of the invention, the intermediate product is D-glucono-δ-lactone. In this latter case, the 2-keto-D-gluconic acid is produced as a mixture with D-isoascorbic acid.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:11]([NH2:13])[CH3:12]>>[CH2:11]([NH:13][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1)[CH3:12]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCN
Product: CCNc1ncccc1[N+](=O)[O-]
Temperature: 105 °C
Yield: 106.2 %

Procedure:
A stirred mixture of 2-chloro-3-nitropyridine (50.0 g, 0.32 mol), ethylamine (33.5 g, 0.74 mol), and xylenes (85 mL) was heated at 105° C. in a sealed vessel for three hours. After cooling, the solvent was removed in vacuo, and water was added to the residue. The product was extracted with methylene chloride, dried (sodium sulfate), and concentrated in vacuo to give 56.8 g of the title compound as a brown oil, suitable for use in the next reaction.
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:15])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH2:14])[C:10]([CH3:13])=[N:11][CH:12]=1.C(#N)C.Cl.[Cl:20][C:21]([NH2:23])=[NH:22]>C(O)(=O)C>[ClH:20].[ClH:1].[ClH:20].[CH3:15][N:3]([CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:14][C:21]([NH2:23])=[NH:22])[C:10]([CH3:13])=[N:11][CH:12]=1
Reactant: N=C(N)Cl
Reactant: Cc1ncc(CCCN(C)C)cc1N
Agent: Cl
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1ncc(CCCN(C)C)cc1NC(=N)N
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 136.9 %

Procedure:
A 1 L, three-neck, round-bottom flask equipped with an overhead stirrer, a reflux condenser, an N2 inlet tube, and a temperature probe was charged with 5-(3-(dimethylamino)propyl)-2-methylpyridin-3-amine hydrochloride (25 g, 0.109 mol). Acetonitrile (275 mL, 11 vol) was added to it followed by acetic acid (25 mL, 1 vol). The initial suspension turned into a clear solution after the addition of acetic acid. Chloroformamidine hydrochloride (15.6 g, 0.136 mol, 1.25 equiv) was added to the solution resulting in a suspension. The reaction was heated at 40° C. for 30 min and at 50° C. for another 30 min. Then the temperature was raised to 60° C. and the reaction was continued at this temperature. After 1-2 h at 60° C., the reaction mixture became turbid and after 3-4 h, solid started separating out. The reaction was continued at 60° C. for 20 h and was judged complete by LC-MS analysis. The reaction was cooled to ambient temperature and the solid was collected by filtration (N2 flow was used during the filtration). The filter cake was washed with acetonitrile (50 mL, 2 vol). The solid was dried under high vacuum overnight to obtain N-{5-[3-(Dimethylamino)propyl]-2-methylpyridin-3-yl}guanidine trihydrochloride (32.1 g, 85% recovery) as a light brown solid. Elemental analysis Calcd: C, 41.81; H, 7.02; Cl, 30.85; N, 20.32. Found: C, 41.09; H, 6.72; Cl, 31.51; N, 20.47. 1H NMR (500 MHz, D2O)S ppm: 8.57 (s, 1H), 8.45 (s, 1H), 3.22-3.19 (m, 2H), 2.90 (t, 2H, J=10 Hz), 2.86 (s, 6H), 2.69 (s, 3H), 2.15-2.07 (m, 2H); ESI-MS m/z 236 (M+H, 100%).
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([OH:24])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:37]([O-:40])([O-])=O.[K+].[K+].[CH3:43]N(C=O)C>>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[C:14]2[N:18]([CH3:19])[C:17]3[CH:20]=[C:21]([O:24][CH2:43][CH2:37][OH:40])[CH:22]=[CH:23][C:16]=3[S:15]2)[S:10][C:9]1=[N:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[NH:34][CH2:35][CH3:36])[C:29]#[N:30])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(O)cc3N2C)C(=O)N1Cc1ccccc1
Reactant: CN(C)C=O
Agent: [K+]
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2Sc3ccc(OCCO)cc3N2C)C(=O)N1Cc1ccccc1
Temperature: 75 °C
Reaction time: 72 h

Procedure:
To a solution of the product of Example 57 in DMF were added K2CO3 and 3-bromoethanol and the resulting suspension was heated to 75° C. with stirring under nitrogen for 72 h. Solid was removed by filtration and washed by DMF. Evaporation of solvent gave a crude, which was purified by chromatography on silica gel eluting with MeOH-DCM (5:95) to afford the title compound (0.58 g). 1H-NMR indicated one isomer. 1H-NMR (DMSO-d6): δ 7.62 (1H, d), 7.29-7.39 (5H, m), 7.14 (1H, d), 7.02 (1H, d), 6.84 (1H, dd), 5.75 (1H, d), 5.11 (2H, s), 4.97 (1H, t), 4.87 (1H, t), 4.05 (2H, t), 3.80 (3H, s, 3.71 (2H, m), 3.05 (2H, m), 0.99 (3H, t); MS (ESI): 558 (MH+).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([O:9]C(C)(C)C)=[O:8]>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(/C=C(\C(=O)OC(C)(C)C)c2cccs2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: O=CO
Product: CCOC(=O)c1c(/C=C(\C(=O)O)c2cccs2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
Combine (E)-2-(thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester and formic acid (96%, 20 mL). After 2 hours, evaporate in vacuo to obtain a residue. Triturate with pentane containing a small amount of diethyl ether to obtain a solid. Recrystallize the solid from cyclohexane/ethyl acetate/acetone, filter, and dry to give the title compound: mp 184°-187° C. (dec). 1H NMR (DMSO-d6) δ 13.2 (br s, 1H), 7.92 (d, 1H, J=1.7 Hz), 7.80 (d, 2H, J=8.4 Hz), 7.60 (s, 1H), 7.57 (d, 1H, J=1.7 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.40 (dd, 1H, J=4.7, 1.5 Hz), 6.84-6.8 (m, 2H), 4.14 (q, 2H, J=7.1 Hz), 2.37 (s, 3H), 1.13 (t, 3H, J=7.1 Hz). Elemental Analysis calculated for C25H19Cl2NO6S2 : C, 53.20; H, 3.39; N, 2.48. Found: C, 53.30; H, 3.40; N, 2.41.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:25]([C:22]3[CH:21]=[CH:20][C:19]([O:18][C:17]([F:16])([F:29])[F:30])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)N2CCNCC2)cn1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)CC2)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 20.1 %

Procedure:
To a solution of 1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (may be prepared as described in Description 14) (100 mg, 0.487 mmol) in DMF (10 ml) was added 4-[(trifluoromethyl)oxy]benzenesulfonyl chloride (152 mg, 0.585 mmol). Finally DIPEA (0.255 ml, 1.462 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Solvent was removed by evaporation, the residue was dissolved in ethyl acetate and the solution extracted with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness and the residue was purified by MDAP to yield the title compound (42 mg) as a white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].[H-].[Na+].[Cl:18][C:19]1[CH:34]=[CH:33][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=2)=[O:24])=[CH:21][CH:20]=1>COCCOC.O>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([C:25]2[CH:32]=[CH:31][C:28]([CH2:29][N:1]3[CH:5]=[CH:4][C:3]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]3[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:27][CH:26]=2)=[O:24])=[CH:33][CH:34]=1
Reactant: CCOC(=O)c1cc[nH]c1C(=O)OCC
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1ccn(Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c1C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.8 %

Procedure:
Under argon gas, diethyl 1H-pyrrole-2,3-dicarboxylate (4.79 g) was dissolved in DME (100 ml) and the solution was cooled to 0° C. Then, sodium hydride (990 mg) was added and the mixture was stirred at room temperature for 0.5 hour, after which it was cooled to 0° C. again. To this reaction mixtrue was added 4-(4-chlorobenzoyl)benzyl bromide (8.53 g) and the mixture was stirred at room temperature for 14 hours. This reaction mixture was diluted with water and extracted with ethyl acetate (500 ml) and the organic layer was washed with NaHCO3 /H2O (300 ml) twice and saturated aqueous NaCl solution (100 ml) once, and dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (stationary phase 250 g; hexane: ethyl acetate=6:1→1:1) to provide 9.56 g (yield 96%) of the title compound. 1H-NMR (CDCl3) δ: 1.26(3H,t,J=7.1Hz), 1.35(3H,t,J=7.0Hz), 4.26(2H,q,J=7.1Hz), 4.30(2H,q,J=7.1 Hz),5.49(2H,s), 6.57(1H,d,J=3.OHz), 6.88(1H,d,J=3.2Hz), 7.19(2H,d,J=8.4Hz), 7.45(2H,d,J=8.6Hz), 7.72(4H,d,J=8.8Hz).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=1.Cl[CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]([CH3:27])[CH3:26])=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].C(C1C=CC(C=O)=CC=1)(C)C.O=P(Cl)(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH:25]([C:22]1[CH:21]=[CH:20][C:19]([C:15]2[O:16][C:17]([CH3:18])=[C:13]([CH2:12][O:1][C:2]3[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([CH3:10])[CH:3]=3)[N:14]=2)=[CH:24][CH:23]=1)([CH3:27])[CH3:26]
Reactant: Cc1cc(O)ccc1C=O
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Agent: CC(C)c1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)ccc1C=O

Procedure:
In analogy to the procedure described in example 120 f], 4-hydroxy-2-methyl-benzaldehyde (for the preparation of 4-hydroxy-2-methyl-benzaldehyde see: H. H. Hodgson, T. A. Jenkinson, J. Chem. Soc. 1929, 469, 1639-1641) was reacted with 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole (prepared from 4-isopropyl-benzaldehyde and diacetyl monoxyme followed by treatment with POCl3 in analogy to the procedures described in examples 21 a] and b]) in the presence of potassium carbonate to yield 4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-benzaldehyde. 4-[2-(4-Isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-benzaldehyde was reacted with (ethoxy-ethoxy-carbonyl-methyl)-triphenyl-phosphonium chloride [for the preparation of (ethoxy-ethoxycarbonyl-methyl)-triphenyl-phosphonium chloride see: K. K. Bach, H. R. El-Seedi, H. M. Jensen, H. B. Nielsen, I. Thomson, K. B. G. Torssell, Tetrahedron 1994, 50, 7543-7556] in the presence of DBU in analogy to the procedure described in example 120 c] to give 2Z-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid ethyl ester, which was further saponified in analogy to the procedure described in example 120 f] to yield 2Z-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-acrylic acid as light green solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]2[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=2)([CH3:12])[CH3:11])=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[CH:3]=1.[CH2:30]([CH2:32][NH2:33])[OH:31]>C([O-])(O)=O.[Na+]>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:4]1[CH:3]=[C:2]([NH:33][CH2:32][CH2:30][OH:31])[N:7]=[CH:6][C:5]=1[N:8]([CH3:22])[C:9](=[O:21])[C:10]([C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[C:15]([Cl:20])[CH:14]=1)([CH3:11])[CH3:12]
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(Cl)cc1-c1ccccc1Cl
Reactant: NCCO
Agent: O=C([O-])O
Agent: [Na+]
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)c1cnc(NCCO)cc1-c1ccccc1Cl
Temperature: 25 °C
Yield: 54 %

Procedure:
A solution of 0.14 g (0.29 mmol) N-[6-chloro-4-(2-chloro-phenyl)-pyridin-3-yl]-2-(3,5-dichloro-phenyl)-N-methyl-isobutyramide and 4 ml ethanolamine was stirred at 130° for 9 h. After cooling to ambient temperature, the solution was poured into 20 ml 0.5N NaHCO3-solution and extracted three times with 30 ml CH2Cl2. The combined organic layers were dried (Na2SO4), filtered and evaporated. The residue was purified by flash-chromatography (SiO2, CH2Cl2/ethyl acetate 1:3) to give 0.08 g (54%) of the title compound as a white foam.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4](=[N:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[CH:12]=2)[C:5]([NH2:8])=[N:6][N:7]=1.C(N(CC)CC)C.S(O[CH2:36][CH2:37][O:38][CH2:39][CH2:40]OS(C1C=CC(C)=CC=1)(=O)=O)(C1C=CC(C)=CC=1)(=O)=O.C(OCC)(=O)C>CN(C=O)C>[F:17][C:13]1[CH:12]=[C:11]([NH:10][N:9]=[C:4]2[C:3]([CH2:2][N:1]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[N:7][N:6]=[C:5]2[NH2:8])[CH:16]=[CH:15][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC1=NN=C(CN2CCOCC2)C1=NNc1cccc(F)c1
Temperature: 87 °C
Yield: 17.1 %

Procedure:
To a mixture of 5-(aminomethyl)-4-(3-fluorophenylhydrazono)-3-amino-4H-pyrazole (60 mg, 0.25 mmole) and triethylamine (71 μL, 0.512 mmole) in 3 mL of anhydrous DMF was added solid di(2-tosyloxyethyl)ether (108 mg, 0.25 mmole). The reaction was heated at 87° C. for 5-6 hours, and was then worked up by the addition of saline and ethyl acetate. The crude material was purified by preparative TLC (CH2Cl2:CH3OH=15:1) to yield 13 mg of the title compound as a yellow powder. MS (m/z, ES+): 305 (M+1, 100%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 7.53 (m, 1H), 7.40 (m, 2H), 7.03 (m, 1H), 6.45 (br s, 2H), 3.97 (s, 2H), 3.74 (m, 4H), 2.65 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.Cl.[C:14]1([C:20]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:28]3[CH:24]([CH2:25][NH:26][CH2:27]3)[S:23][CH2:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>ClCCl>[C:29]1([C:20]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:28]3[CH:24]([CH2:25][N:26]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])[CH2:27]3)[S:23][CH2:22][CH2:21]2)[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: c1ccc(C2(c3ccccc3)CCSC3CNCC32)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1CC(=O)N1CC2SCCC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 92.6 %

Procedure:
1.13 g of N,N'-carbonyldiimidazole are added to a solution, cooled to 0° C., of 1.16 g of 2-methoxyphenylacetic acid in 20 cm3 of dry dichloromethane. The mixture is stirred for 40 minutes at 0° C. and then a solution of 2.15 g of (4aRS,7aRS)4,4-diphenylperhydrothiopyrano[2,3-c]pyrrole hydrochloride and 0.9 cm3 of triethylamine in 20 cm3 of dichloromethane is added. The reaction mixture is stirred for one hour at 0° C. and is then washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid obtained is washed with 30 cm3 of ethyl ether and 30 cm3 of diisopropyl oxide and it is then dried under reduced pressure (2.7 kPa). 2.66 g of (4aRS,7aRS)-4,4-diphenyl-6-[(2-methoxyphenyl)acetyl]perhydrothiopyrano[2,3 -c]pyrrole are obtained in the form of a white solid; melting point 172° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[CH2:14][NH:13][C:12]2=[O:17])=[CH:7][CH:6]=1)[CH3:4].[H-].[Na+].[H][H].[CH2:22](Br)[CH:23]=[CH:24][CH3:25]>C(OCC)C.O>[CH2:22]([O:1][N:2]=[C:3]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[C:15](=[O:16])[CH2:14][NH:13][C:12]2=[O:17])=[CH:9][CH:10]=1)[CH3:4])[CH:23]=[CH:24][CH3:25]
Reactant: CC(=NO)c1ccc(N2C(=O)CNC2=O)cc1
Reactant: [H][H]
Reactant: CC=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CC=CCON=C(C)c1ccc(N2C(=O)CNC2=O)cc1
Reaction time: 2 h

Procedure:
A solution of 0.01 mol of 3-[4-(1-hydroxyiminoethyl)phenyl]hydantoin in diethyl ether is treated with 0.01 mol of sodium hydride. After hydrogen evolution stops, 0.011 mol of crotyl bromide is added. The reaction mixture is stirred for 2 hours. The reaction mixture is then poured into cold water, the layers are separated, and the aqueous layer is extracted with diethyl ether. The combined ether solutions are dried over MgSO4and filtered, and the solvent is removed by rotary evaporator to yield 3-[4-(1-crotyloxyiminoethyl)phenyl]hydantoin.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]3)[CH:5]=[N:6][CH:7]=1.[CH:19]1([B-](F)(F)F)[CH2:21][CH2:20]1.[K+].C1COCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl.O>[CH:19]1([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11]4)[CH:5]=[N:6][CH:7]=2)[CH2:21][CH2:20]1
Reactant: F[B-](F)(F)C1CC1
Reactant: CN1C(=O)Cc2cc(-c3cncc(Br)c3)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: CN1C(=O)Cc2cc(-c3cncc(C4CC4)c3)ccc21
Temperature: 125 °C

Procedure:
To 5-(5-bromo-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one, prepared as described in Example 21, (100 mg, 0.330 mmol) was added potassium cyclopropyltrifluoroborate (50 mg, 0.35 mmol), THF (2 mL), water, (0.66 mL), and tripotassium phosphate (245 mg, 1.155 mmol). The reaction mixture was degassed and placed under an argon atmosphere, and then [1,1′-bis(diphenylphospihino)-ferrocene]-dichloropalladium(II) complexed with dichloromethane (CAS#72287-26-4 13.5 mg, 0.016 mmol) was added. The reaction vessel was sealed and was heated by microwave irradiation at 125° C. for 85 minutes. The reaction mixture was cooled to room temperature, diluted with dichloromethane and filtered through glass wool. The filtrate was further diluted with saturated aqueous sodium bicarbonate and the layers were separated. The aqueous layer was extracted two times with dichloromethane, and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0 to 100%) to afford 5-(5-cyclopropyl-pyridin-3-yl)-1-methyl-1,3-dihydro-indol-2-one; HRMS: (ESI) m/z 265.1345 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 0.72-0.89 (m, 2H), 1.03-1.19 (m, 2H), 1.85-2.11 (m, 1H), 3.27 (s, 3H), 3.61 (s, 2H), 6.92 (d, J=8.1 Hz, 1H), 7.39-7.61 (m, 3H), 8.38 (d, J=1.8 Hz, 1H), 8.60 (d, J=2.0 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[NH:8][C:7]([CH3:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:30])=CC=1.CO.C(Cl)Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[S:30])[NH:8][C:7]([CH3:14])=[C:6]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc2c(=O)[nH]c(C)c(-c3ccccc3)c2c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: CO
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc2c(=S)[nH]c(C)c(-c3ccccc3)c2c1
Yield: 148.2 %

Procedure:
A mixture of 6-methoxy-3-methyl-4-phenylisoquinolin-1(2H)-one (0.7 g) and Lawesson's reagent (1.3 g) in 7 mL toluene was heated to reflux for 12 h. After cooling, the reaction was subjected directly to flash chromatography (5% MeOH/CH2Cl2) to give a solid, which was triturated with diethyl ether to provide 1.1 g of 6-methoxy-3-methyl-4-phenylisoquinoline-1(2H)-thione.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH2:26][CH3:27])[C:22]=4[NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:31]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH2:26][CH3:27])[C:22]=4[NH:28][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([C:36]5[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:31]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Brc1cccc(-c2ccccc2)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(CC)c4Nc4cccc(-c5ccccc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-ethyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-phenyl-pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][CH:29]=1)[CH2:12][N:13]([C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[N:14]1[CH:18]=[N:17][N:16]=[CH:15]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].C(C1C=CC(NN2C=NN=C2)=CC=1)#N.CN([CH:49]=[O:50])C>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:27]=[CH:28][C:29]=1[O:50][CH3:49])[CH2:12][N:13]([C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[CH:23][CH:24]=1)[N:14]1[CH:15]=[N:16][N:17]=[CH:18]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N(Cc2cccc(OCc3ccccc3)c2)n2cnnc2)cc1
Reactant: CN(C)C=O
Agent: N#Cc1ccc(Nn2cnnc2)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CN(c2ccc(C#N)cc2)n2cnnc2)cc1OCc1ccccc1
Yield: 44 %

Procedure:
The title compound was prepared by adapting the method for 4-[(3-benzyloxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole using NaH (60% dispersion in oil, 0.22 g, 5.4 mmol), 4-[(4-cyanophenyl)amino]-4H-[1,2,4]triazole (1.0 g, 5.68 mmol) and 4-methoxy-3-benzyloxybenzyl bromide[Meyers, 1989] (1.66 g, 5.4 mmol) in anhydrous DMF (5 mL) to give 4-[(3-benzyloxy-4-methoxybenzyl)(4-cyanophenyl)amino]-4H-[1,2,4]triazole as an off-white solid (0.97 g, 44%) after recrystallisation; mp. 138-141° C.; δH (400 MHz, CDCl3) 3.89 (s, 3H), 4.72 (s, 2H), 5.12 (s, 2H), 6.59 (AA′BB′, 2H), 6.62 (d, J=2, 1H), 6.64 (dd, J=7.8, 2, 1H), 6.79 (d, J=7.8, 1H), 7.28-7.34 (m, 5H), 7.57 (AA′BB′, 2H), 7.74 (s, 2H); LRMS (FAB+) m/z (rel. intensity) 412 (100, [M+H]), 343 (51), 227 (72%); HPLC: tR=2.21 min (94%); HRMS (FAB+): Found 412.1774 C24H22N5O2 requires 412.1776.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].O=S(Cl)[Cl:14]>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1c(F)cccc1F
Reaction time: 0.25 h

Procedure:
A solution of 2,6-difluorobenzoic acid (1.58 g, 10.0 mmol) and SOCl2 (1.1 ml, 15 mmol) were refluxed at 80° C. for 1 hr. Two drops of DMF were added and reflux continued for 15 min. to dissolve any remaining solid. Excess SOCl2 was evaporated in vacuo to give 2,6-difluorobenzoyl chloride as a light yellow oil.