Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]>N1CCCCC1.CN(C=O)C>[NH2:1][C@@H:2]([C:7]([NH2:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)C[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(N)=O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)C[C@@H](N)C(N)=O

Procedure:
Polymer-bound D-Leu-NH2: FMOC-protected Rink amide resin (30 g, 0.61 mmol/g, 18 mmol) was treated with piperidine/DMF solution (250 mL). The mixture was shaken at rt for 24 h, drained, washed with DMF (5×200 mL), CH2Cl2 (5×200 mL) and dried under vacuum. The resin was then treated with FMOC-D-Leu-OH (22 g, 62 mmol), 1-hydroxybenzotriazole hydrate (2.5 g, 18 mmol), 1,3-diisopropylcarbodiimide (9.8 mL, 62 mmol), and DMF (250 mL). The mixture was shaken for 20 h, drained, washed with DMF (4×200 mL), DMF-water (1:1, 3×200 mL), DMF (3×200 mL), MeOH (3×200 mL), CH2Cl2 (3×200 mL) and dried. The completion of reaction and the loading of the resin-bound FMOC-D-Leu-NH2 (0.56 mmol/g) were determined by the treatment of 52 mg of the resin with 10% (v/v) TFA/CH2Cl2 (2 mL) to give 11 mg of FMOC-D-Leu-NH2. The resin-bound FMOC-D-Leu-NH2 was deprotected with 20% (v/v) piperidine/DMF solution (250 mL) to give polymer-bound D-Leu-NH2 (20 g).
Reaction SMILES: F[C:2]1[CH:14]=[CH:13][C:5]([C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])=[C:4]([CH3:15])[CH:3]=1.[C:16]1([OH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:15][C:4]1[CH:3]=[C:2]([O:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=[CH:13][C:5]=1[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]
Reactant: Cc1cc(F)ccc1C(=O)OC(C)(C)C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(Oc2ccccc2)ccc1C(=O)OC(C)(C)C
Temperature: 130 °C
Reaction time: 12 h
Yield: 84.1 %

Procedure:
To a solution of tert-butyl 4-fluoro-2-methylbenzoate (1 g, 4.8 mmol) in methylsulfinylmethane (45 mL) were added phenol (0.43 g, 4.6 mmol) and potassium carbonate (1.24 g, 9 mmol). Then the mixture was stirred at 130° C. for 12 hours. The reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (50 mL). The organic phase was separated, washed with water (20 mL). The organic phase was separated and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether/ethyl acetate=10:1) to give tert-butyl 2-methyl-4-phenoxybenzoate (1.1 g, 86%) as a yellow solid. LRMS (M+H+) m/z: calcd 284.14. found 284.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.P([O-])([O-])(O)=[O:23].[Na+].[Na+].Cl([O-])=O.[Na+]>C(O)(C)(C)C.O>[C:1]([O:5][C:6]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]([OH:23])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=P([O-])([O-])O
Reactant: CC(C)(C)OC(=O)Oc1ccccc1C=O
Agent: CC=C(C)C
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)Oc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
21.5 g (93.8 mmol) of 2-(tert-butoxycarbonyloxy)-benzaldehyde and 80 ml (750 mmol) of 2-methyl-2-butene are diluted in 250 ml of tert-butanol. A solution containing 28.1 g (234 mmol) of sodium hydrogenphosphate and 29.7 g (328 mmol) of sodium chlorite in 75 ml of water is added dropwise to the reaction medium, which is stirred at ambient temperature for 2 hours. The mixture is evaporated under reduced pressure and the residue is dissolved in dichloromethane. The organic phase is washed with water, dried over magnesium sulphate, filtered and concentrated. The white solid obtained is precipitated from heptane at 0° C. The precipitate is filtered off and then rinsed with heptane and dried. 15.8 g of 2-(tert-butoxycarbonyloxy)benzoic acid are obtained in the form of a white powder with a yield of 70%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12].[CH3:15][C:16]1[CH:17]=[CH:18][C:19](S(O)(=O)=O)=[CH:20][CH:21]=1.[CH3:26][N:27]([CH:29]=[O:30])C>>[NH2:6][C:5]1[C:17]2[C:16](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]([O:30][C:29]2[CH:10]=[CH:2][N:1]=[C:26]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[NH:7][N:6]=[C:5]4[C:11]([O:13][CH3:14])=[O:12])[N:27]=2)=[CH:3][CH:4]=1
Reactant: COC(=O)c1n[nH]c2ccc(N)cc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CN(C)C=O
Product: COC(=O)c1n[nH]c2ccc(Nc3nccc(Oc4ccc(N)c5ccccc45)n3)cc12
Temperature: 25 °C

Procedure:
A solution of Intermediate E2 (1.60 g, 5.90 mmol), methyl 5-amino-1H-indazole-3-carboxylate (1.35 g, 7.07 mmol) and p-TSA (2.24 g, 11.8 mmol) in DMF (30 mL) was stirred at 60° C. for 16 hr. The reaction mixture was cooled to RT and was partitioned between EtOAc (100 mL) and saturated aq. NaHCO3 (100 mL). The layers were separated and the organic extract was washed with water (2×100 mL) and brine (2×100 mL) and then dried and evaporated in vacuo. The residue was purified by trituration with acetonitrile to afford the title compound Intermediate B16 as a brown solid (0.937 g, 87% pure by HPLC, 33%); Rt 1.67 min (Method 2, acidic); m/z 427 (M+H)+ (ES+). The material was used in subsequent steps without additional purification.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.P(Cl)(Cl)(Cl)(Cl)[Cl:11]>O>[CH2:8]([O:7][C:1](=[O:6])[CH:2]=[C:3]([Cl:11])[CH3:5])[CH3:9]
Reactant: CCOC(=O)CC(C)=O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: CCOC(=O)C=C(C)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a stirred mixture of ethyl acetoacetate (15.0 g, 0.12 mol) in petroleum ether (30 mL) under a nitrogen atmosphere was added phosphorus pentachloride (12.7 g, 0.06 mol) gradually. After addition was complete the mixture was stirred at 25° C. for 1 h. Upon completion of the reaction water (50 mL) was added in small portions, transferred to a separatory funnel and the layers separated, followed by washing the aqueous layer with petroleum ether (2×50 mL). The combined petroleum ether extracts were washed with a 20% potassium carbonate solution, followed by a saturated sodium chloride solution and dried over magnesium sulfate. The combined organic layers were concentrated to give a yellow oil. Distillation of the residue yielded 3-chloro-but-2-enoic acid ethyl ester (7.4 g 43%) as a clear oil: LR-ES-MS m/z calculated for C6H9ClO2 [M]+ 148, observed [M+H]+ 149.
Reaction SMILES: [C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][NH:21][CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:23]([S:25]([N:28]1[CH2:31][C:30](=[CH:32][C:33]#[N:34])[CH2:29]1)(=[O:27])=[O:26])[CH3:24].C1CCN2C(=NCCC2)CC1>CN(C)C=O.C1CCN2C(=NCCC2)CC1>[C:1]([O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:30]4([CH2:32][C:33]#[N:34])[CH2:31][N:28]([S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH2:29]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CCS(=O)(=O)N1CC(=CC#N)C1
Reactant: CC(C)(C)C(=O)OCn1ccc2c(-c3cn[nH]c3)ncnc21
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCS(=O)(=O)N1CC(CC#N)(n2cc(-c3ncnc4c3ccn4COC(=O)C(C)(C)C)cn2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To a suspension of [4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]methyl pivalate (19, 10.0 g, 33.4 mmol) and 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 6.22 g, 33.4 mmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 20 mL) was added DBU (254 mg, 1.67 mmol, 0.05 equiv) drop wise to keep the reaction temperature between 15-25° C. After adding DBU, the reaction mixture became homogeneous within 90 min. The reaction mixture was stirred for 3 h at room temperature. When HPLC showed that the reaction was deemed complete, the reaction mixture was quenched with water (120 mL) and acetonitrile (80 mL). The resulting mixture was stirred at room temperature for an additional 30 min. The solids were collected by filtration, washed with a mixture of acetonitrile and water (2/3 by volume, 2×20 mL), and dried in vacuum oven at 40-45° C. for 24 h to afford crude (4-(1-(3-(cyanomethyl)-1-(ethylsulfonyl)azetidin-3-yl)-1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl pivalate (20, 14.5 g, 16.2 g theoretical, 89.5% yield) as white solids, which was found to be sufficiently pure (>98.0% by HPLC) for the subsequent reaction without further purification. For 20: 1HNMR (CDCl3, 300 MHz), δ 8.87 (s, 1H), 8.43 (s, 1H), 8.37 (s, 1H), 7.51 (d, 1H, J=3.6 Hz), 6.76 (d, 1H, J=3.6 Hz), 6.26 (s, 2H), 4.64 (d, 2H, J=9.6 Hz), 4.25 (d, 2H, J=9.6 Hz), 3.41 (s, 2H), 3.09 (q, 2H, J=7.6 Hz), 1.42 (t, 3H, J=7.6 Hz), 1.17 (s, 9H) ppm; C22H27N7O4S (MW, 485.56), LCMS (EI) m/e 486 (M++H).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14](Br)[CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C1(C)C=CC=CC=1>C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]1([C@H:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=3)[CH:13]=2)=[O:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(C(=O)N[C@H](C)c2ccccc2)cc1Br
Reactant: COc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc(C(=O)N[C@H](C)c3ccccc3)ccc2C)cc1
Temperature: 25 °C
Yield: 67.1 %

Procedure:
To a mixture of N-((1R)-1-phenylethyl)(3-bromo-4-methylphenyl)carboxamide (1.38 g, 4.32 mmol) and 4-methoxyphenylboronic acid (0.53 g, 4.32 mmol) in 10 mL of 2M Na2CO3 aq. soln and 20 mL of toluene was bubbled through N2 for 5 min. Catalyst Pd(PPh3)4 (0.36 g, 0.314 mmol) was then added and the mixture was heated to 80 C for 19 hours under N2. The reaction mixture was cooled to RT and was diluted with 100 mL of EtOAc and 50 mL of water. The organic layer was separated and washed with 50 mL of brine, and dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (CHCl3 to EtOAc) to provide yellow solid (1.0 g, 2.9 mmol, 92%).
Reaction SMILES: F[C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[O:22]1[CH2:23][CH2:24][N:19]([C:2]2[CH:18]=[CH:17][C:5]([C:6]([C:8]3[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=3)=[O:7])=[CH:4][CH:3]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: O=C(c1ccc(F)cc1)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(c1ccc(N2CCOCC2)cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 91.3 %

Procedure:
A mixture containing 4-(4-fluorobenzoyl)-nitrobenzene (1.96 g, 8 mmol), morpholine (0.84 g, 9.6 mmol), and potassium carbonate (1.33 g, 9.6 mmol) in dimethyl sulfoxide (15 mL) was heated to 100–110° C. for 12 hours. The reaction mixture was cooled to room temperature and diluted with cold water, and filtered. The crude product was washed several times with water and dried to give 4-(4-morpholinobenzoyl)-nitrobenzene (2.28 g, 91%), m.p. 173–175° C., and was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[O:16])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1.C[Mg]Br.[CH2:20]1COC[CH2:21]1>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([CH:15]([OH:16])[CH2:20][CH3:21])=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: C1CCOC1
Reactant: COc1cccc(-c2ccc(C=O)nc2)c1
Agent: C[Mg]Br
Solvent: CCOC(C)=O
Product: CCC(O)c1ccc(-c2cccc(OC)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To a solution of 5-(3-methoxyphenyl)picolinaldehyde (0.75 g, 3.5 mmol), in THF (7 mL) was added methyl magnesium bromide (0.17 g, 8.8 mmol) under nitrogen at −40° C./ The reaction was brought to rt and then stirred at rt for 2 h. The contents were diluted with ethyl acetate (150 mL), quenched with ammonium chloride solution (100 mL), the organic layer washed with brine solution (2×100 mL), the layers separated, the organic layer was dried over sodium sulphate and distilled off to get the crude product. The compound was purified by flash chromatography (100-200 microns; 15% ethyl acetate in hexane) to give 1-(5-(3-methoxyphenyl)pyridin-2-yl)propan-1-ol (450 mg, 53% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.04 (d, 1H), 7.52 (d, 1H), 7.38 (t, 1H), 7.26 (s, 1H), 7.23 (d, 1H), 6.95 (d, 1H), 5.28 (d, 1H), 4.54 (q, 1H), 3.81 (s, 3H), 1.7 (m, 1H), 1.8 (m, 1H), 0.86 (t, 3H); LC-MS m/z calcd for [M+H]+ 244.13. found 244.0.
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH:21]N1C(=O)CCC1=O.C(N(CC)CC)C.C1(=O)NC(=O)CC1>O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].O>[C:1]([OH:19])(=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: O=C1CCC(=O)N1O
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: CCCCCCCCCCCCCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.5 g of stearoyl chloride was dissolved in 2 ml of 1,4-dioxane, and 0.29 g of N-hydroxysuccinimide and 0.1 ml of triethylamine were added, and the mixture was stirred at room temperature for 3 h. 1 ml of water was added to the mixture, and the pH was adjusted to 5 by addition of alkali. 60 μl of a succinimide-activated stearic acid solution were mixed with 2.5 ml of hirudin solution (21 mg/ml in 0.1 M sodium carbonate pH 9) and 2.5 ml of dioxane, and the mixture was incubated at room temperature with stirring for 12 h. The mixture was then purified by preparative RP-HPLC (see Example 2). The derivatives elute at 48% B, 54% B, 62% B and 74% B. The specific acitivities were 9,600 U/mg, 12,400 U/mg, 12,800 U/mg and 840 U/mg.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:7]F.[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[Na+]>C(#N)C>[F:9][C:10]([F:16])([F:15])[S:11]([O-:14])(=[O:13])=[O:12].[F:7][N+:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccncc1
Reactant: FF
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: F[n+]1ccccc1
Temperature: -40 °C

Procedure:
To a 100 ml anhydrous acetonitrile solution containing 10 g (0.126 mole) of pyridine a mixed gas of fluorine and nitrogen was introduced at a rate of 90 ml/min. at -40° C. under vigorous stirring. The amount of the fluorine gas introduced amounted to 0.18 mole. Subsequent to the fluorine introduction, 22 g (0.128 mole) of sodium trifluoromethanesulfonate as a XM reactant was added to the reaction solution after which the resultant reaction solution was maintained at -40° C. for 5 hours under stirring. Subsequently, the solvent, after filtering sodium fluoride, was distilled off and the resultant residue was recrystallized from methylene chloride to give 17.5 g (yield: 71%) of N-fluoropyridinium trifluoromethanesulfonate. The product thus obtained was repurified with methylene chloride/acetonitrile to recover 13.8 g (yield: 56%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C(O[C:27](=[O:29])[CH3:28])(=O)C>>[C:17]([N:1]([C:27](=[O:29])[CH3:28])[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][CH:11]([CH3:22])[N:10]([C:16](=[O:21])[CH3:15])[N:9]=2)=[CH:4][CH:3]=1)(=[O:19])[CH3:18]
Reactant: CC1Cc2cc3c(cc2C(c2ccc(N)cc2)=NN1)OCO3
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N(C(C)=O)c1ccc(C2=NN(C(C)=O)C(C)Cc3cc4c(cc32)OCO4)cc1
Yield: 84.6 %

Procedure:
2.0 g <6.7 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine were refluxed with 40 ml of acetic anhydride for 3 hours, then it was evaporated to dryness under reduced pressure. The crystalline residue was transferred with 25 ml of water to a filter and washed with 5×3 ml of water. After drying 2.79 g of the raw triacetyl derivative were obtained. After washing with 20 ml of isopropanol and drying at 100° C. 2.39 g (84.6%) of the pure aimed product were obtained, m.p. 224°-227° C.
Reaction SMILES: [CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:2]1.Br[CH2:13][CH2:14][CH3:15]>>[CH2:1]1[O:11][C:10]2[CH:9]=[CH:8][C:5]([CH:6]([OH:7])[CH2:13][CH2:14][CH3:15])=[CH:4][C:3]=2[O:2]1
Reactant: CCCBr
Reactant: O=Cc1ccc2c(c1)OCO2
Product: CCCC(O)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared from 3,4-methylenedioxybenzaldehyde of formula 2 (7.5 g, 50 mmol) by subjecting it to Grignard's reaction with 1-bromopropane by the method described in example 1(i) to give 1-(3,4-methylenedioxyphenyl)-n-butanol of formula 3 (9.4 g, 97%). The secondary alcohol (7.8 g, 40 mmol) was subjected to Vilsmeier reaction with dimethyl formamide-phosphorous oxychloride as described in example 1 (ii) to furnish 2-formyl-1-(3,4-methylenedioxyphenyl)-1-butene (5.0 g, 67%). The resulting aldehyde (2.0 g, 10 mmol) was hydrogenated in presence of Pd/C in methanol to furnish after purification corresponding dihydro derivative (1.0 g, 50%) of formula 5. The dihydro derivative of formula 5 was subjected to Wittig reaction as described in example 1 (iii) followed by saponification to produce 5-(3,4-methylenedioxyphenyl)-4-ethyl-4E-pentenoic acid (0.8 g, 86%) of formula 7. The pentenoic acid (0.75 g, 3.0 mmol) of formula 9 after acid chloride formation with thionyl chloride, and reaction with piperidine was purified by column chromatography on silica gel to give 5-(3,4-methylenedioxyphenyl)-4-ethyl-2E-pentenoic acid piperidine amide of formula 1b (0.8 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.CO[CH:11]1[CH2:15][CH2:14][CH:13](OC)O1.C(O)(=O)C>CCCCCC>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([N:6]2[CH:11]=[CH:15][CH:14]=[CH:13]2)=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: Cc1ccc(N)cc1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: Cc1ccc(-n2cccc2)cc1
Temperature: -100 °C
Yield: 40.6 %

Procedure:
The title compound was prepared in analogy to the procedure described in European Patent Application 480204. 4-Methylaniline (30 g, 280 mmol), 2,5-dimethoxytetrahydrofuran (22 g, 166 mmol) and acetic acid (200 mL) were combined under a nitrogen atmosphere and heated at -100° C. for 90 minutes. The solvent was removed under reduced pressure and the residue obtained suspended in hexane and filtered. The filtrate was passed through a pad of silica gel and concentrated in vacuo. The residue obtained was crystallized from methanol to afford 10.6 g (45%) of the title compound. MS (DCI/NH3) m/e 158 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[O:17][CH3:18])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].C(N(CC)CC)C.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C(OCC)(=O)C>[C:26]1([S:32]([NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 17.5 %

Procedure:
A mixture of 3-amino-4-methoxy-N-phenyl-benzamide (0.9726 g, 4.00 mmol), triethylamine (0.56 mL, 4.02 mmol), and benzenesulfonyl chloride (0.51 mL, 4.00 mmol) in ethyl acetate (70 mL) was heated briefly to obtain a solution. The reaction was stirred overnight at room temperature under nitrogen. An additional equivalent of triethylamine and ½ equivalent of benzenesulfonyl chloride was added and the mixture heated to 50-60° C. After 7 hours, the solvent was removed in vacuo and the residue dissolved in ethyl acetate and washed with 1N HCl followed by saturated NaHCO3. The organic layer was filtered, dried with MgSO4, and stripped of solvent by rotary evaporator. Trituration of the residue in hexane/ethyl acetate (4:1) afforded the product (0.268 g); m.p. 190-194° C.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH:12]=[CH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(C1C=CC=CC=1)(=O)C1C=CC=CC=1.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])C.C(Cl)(Cl)Cl>O1CCOC1>[Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13](=[O:15])[CH2:12][C@@H:11]1[CH:30]1[O:33][CH2:34][CH2:35][O:32]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C=CC(=O)O1
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1COCO1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1OC(=O)C[C@@H]1C1OCCO1
Yield: 94 %

Procedure:
A solution containing 228 mg (0.998 mmol) compound (2a) and 18.0 mg (0.998 mmol) benzophenone in 200 mL [1,3]-dioxolane was irradiated at 20° C. for 5 hours according to the general procedure. Column chromatography (silica gel 35 g, ethyl acetate in hexanes 30%) gave compound (3a) (285 mg, 94%) as a colorless solid, Rf=0.35, [α]25D 18.3°, c 1.3, CHCl3, IR (neat) 2953, 2857, 1778, 1125 cm−1; 1H-NMR (300 MHz, CDCl3) δ: 0.05 (s, 6H), 0.87 (s, 9H), 2.45 (dd, 1H, J=4.2 Hz, J=17.7 Hz), 2.68 (d, 1H, J=17.7 Hz), 2.72-2.79 (m, 1H), 3.65 (dd, 1H, J=2.7 Hz, J=11.4 Hz), 3.86-3.91 (m, 3H), 3.97-4.01 (m, 2H), 4.50 (mc, 1H), 4.88 (d, 1H, J=3.6 Hz). 13C-NMR (75.4 MHz, CDCl3, Dept) δ: 5.52 (+), 18.18 (quat), 25.77 (+), 30.12 (−), 39.67 (+), 64.71 (−), 65.36 (−), 65.47 (−), 80.24 (+), 103.94 (+), 176.55 (quat). C14H26O5Si; Exact Mass: 302.15; Mol. Wt.: 302.44; C, 55.60, H, 8.67, O, 26.45, Si, 9.29.
Reaction SMILES: [F-].[K+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[C:14]=2I)=[O:12])=[CH:6][C:5]=1[C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34]>[Cu]I.CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:17]([CH3:18])[N:16]=[C:15]([O:19][CH:20]([F:22])[F:21])[C:14]=2[C:33]([F:35])([F:34])[F:32])=[O:12])=[CH:6][C:5]=1[C:24](=[O:31])[NH:25][CH2:26][C:27]([F:30])([F:29])[F:28]
Reactant: Cn1nc(OC(F)F)c(I)c1C(=O)Nc1ccc(Cl)c(C(=O)NCC(F)(F)F)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cu]I
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nc(OC(F)F)c(C(F)(F)F)c1C(=O)Nc1ccc(Cl)c(C(=O)NCC(F)(F)F)c1
Temperature: 80 °C
Yield: 13.5 %

Procedure:
36.2 mg (0.19 mmol) of copper(I) iodide and 8.8 mg (0.15 mmol) of potassium fluoride are initially introduced in a heat-dried vial under argon, and 4 ml of N,N-dimethylformamide and 70.0 mg (0.12 mmol) of N-{4-chloro-3-[(2,2,2-trifluoroethyl)carbamoyl]phenyl}-3-(difluoromethoxy)-4-iodo-1-methyl-1H-pyrazole-5-carboxamide and 36.0 mg (254 μmol) of trifluoromethyltrimethylsilane are added. The reaction mixture is degassed in the ultrasound, flushed with argon and the closed vial is heated at 80° C. for two hours. The reaction solution is poured onto water and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, filtered and concentrated by evaporation on a rotary evaporator. Chromatographic purification on silica gel gives 8.00 mg of N-{4-chloro-3-[(2,2,2-trifluoroethyl)carbamoyl]phenyl}-3-(difluoromethoxy)-1-methyl-4-(trifluoromethyl)-1H-pyrazole-5-carboxamide (13%).