Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])([O-:7])=[O:6].N1C=CC=CC=1.C[Si](C)(C)[N:23]1[CH2:27][CH2:26][CH2:25][C:24]1=[O:28]>C1C=CC=CC=1>[N+:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][C:24]([N:23]1[CH2:27][CH2:26][CH2:25][C:1]1=[O:2])=[O:28])([O-:7])=[O:6]
Reactant: C[Si](C)(C)N1CCCC1=O
Reactant: O=C(Cl)Cl
Reactant: O=[N+]([O-])c1ccccc1O
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C1CCCN1C(=O)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.2 %

Procedure:
To a solution of phosgen (6.12 g, 61.8 mmol) in anhydrous benzene (30 ml) was dropwise added under ice-cooling a solution of 2-nitrophenol (8.60 g, 61.8 mmol) and purified pyridine (4.88 g, 61.8 mmol) in anhydrous benzene (20 ml). The mixture was stirred for 30 min. at room temperature. From the reaction solution were separated precipitates by filtration, and a filtrate was evaporated under reduced pressure to give a colorless oily material. The oily material was dissolved in anhydrous benzene (20 ml), to which was added a solution of 1-trimethylsilyl-2-pyrrolidinone (4.00 g, 25.4 mmol) in anhydrous benzene (10 ml). The mixture was stirred at room temperature for 30 min. The reaction mixture was evaporated under reduced pressure to dryness to give a solid material. The desired product was separated using column chromatography on silica gel (eluted with chloroform-acetone 30:1→3:1). Recrystallization from ethanol afforded 1.98 g of colorless prisms. Yield 31.1%
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.C(=O)=O.CC(C)=O.[CH3:20][C:21]1[CH:25]=[C:24]([CH3:26])[O:23][N:22]=1.Br[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([C:41]2[O:42][CH2:43][CH2:44][N:45]=2)=[CH:37][CH:36]=1>O1CCCC1>[O:42]1[CH2:43][CH2:44][N:45]=[C:41]1[C:38]1[CH:39]=[CH:40][C:35]([O:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:26][C:24]2[O:23][N:22]=[C:21]([CH3:20])[CH:25]=2)=[CH:36][CH:37]=1
Reactant: Cc1cc(C)on1
Reactant: BrCCCCCCOc1ccc(C2=NCCO2)cc1
Agent: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(C)=O
Product: Cc1cc(CCCCCCCOc2ccc(C3=NCCO3)cc2)on1
Temperature: -55 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a stirring solution of 48.6 g (0.48 moles) diisopropylamine in 520 ml tetrahydrofuran (THF) at -5° C. (ice/acetone bath) was added 185 ml of 2.6M n-butyllithium (0.48 moles) under nitrogen. The addition was complete after 30 minutes and the pale yellow solution was maintained at -5° to +5° C. for an additional 30 minutes. The ice/acetone bath was replaced by Dry Ice/acetone and when the internal temperature reached -55° C., 46.6 g (0.48 moles) 3,5-dimethylisoxazole was added dropwise over 20 minutes. This solution was allowed to stir an additional 30-40 minutes at -55° C. or lower. A solution containing 135 g (0.41 moles) 2-[4-(6-bromohexyloxy)phenyl]-4,5-dihydro-oxazole dissolved in 400 ml THF was added dropwise (via nitrogen pump) over 35 minutes. The temperature during the addition was kept below -50° C. by carefully controlling the rate of the addition. The heavy suspension was stirred for an additional hour. The Dry Ice bath was removed and the reaction was quenched by dropwise addition of 10 ml water. The reaction mixture was allowed to warm to about 5°-10° C. and then poured into 1 liter water and 1 liter ethyl acetate. The aqueous layer was set aside and the organic layer was washed once with water and brine. The extract was dried over magnesium sulfate and evaporated to near dryness under water vacuum. The crude crystalline product was dissolved in 600 ml warm acetonitrile, filtered thru a pad of solka floc and allowed to crystalize at room temperature. After two hours, the heavy crystalline precipitate was cooled to 10° C. and filtered to give 108 g (76%) 5-{7-[4-(4,5-dihydro-2-oxazolyl)phenoxy]heptyl}-3-methylisoxazole, m.p. 97°-98° C., after drying 24 hrs at 60° C.
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O-])(=[O:13])[CH3:12].[Na+].C(OC(=O)C)(=O)C.O>CCCCCC>[CH3:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]2[C:2]=1[O:1][C:11](=[O:13])[CH:12]=[CH:4]2
Reactant: CC(=O)[O-]
Reactant: Cc1cccc(C=O)c1O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: Cc1cccc2ccc(=O)oc12
Temperature: 177.5 °C
Yield: 53.9 %

Procedure:
The suspension of 2-Hydroxy-3-methyl benzaldehyde (30 gm, 0.220 mole) and anhydrous Sodium acetate (45 gm, 0.55 mole) in Acetic anhydride (45 gm, 0.44 mole) was heated at 175-180° C. for 6 hours. The reaction mixture was cooled; water (150 ml) and Hexane (60 ml) were added. It was stirred for an hour and filtered. The obtained solid was stirred with Diethyl ether (30 ml). Finally the suspension was filtered and dried to give 19 gm desired product.
Reaction SMILES: [C:1]([C:5]([CH3:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2-].[Na+].[C:10](OCC)(=[O:12])[CH3:11]>>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5](=[O:6])[CH2:7][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)C(C)(C)C
Reactant: CCOC(C)=O
Agent: [NH2-]
Agent: [Na+]
Product: CC(=O)CC(=O)C(C)(C)C

Procedure:
Methyl t-butyl ketone was condensed with ethyl acetate in the presence of sodamide to yield 5,5-dimethyl-2,4-hexanedione. This material was reacted with phosphorus pentachloride to yield the divinyl chloride, which was in turn dehydrohalogenated with sodamide to give 5,5-dimethyl-1,3-hexadiyne. This alkyne was then dimerized using the procedure of Hay (see e.g. Hay, A. S., J. Org. Chem. 27, 3320 (1962)), using copper(I) chloride-tetramethylethylenediamine (TMEDA) complex as the catalyst, to yield the desired t-butyl endcapped tetrayne. The tetrayne melted at 99° C. and decomposed between 130° C. and 140° C. It is also stable to moderate pressures; exposure to 40 kbar pressure for one hour caused no changes in the IR spectrum, and at 60 kbar only about 2% graphitization was seen.
Reaction SMILES: [F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([C:15](OCC)=[O:16])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1.CC(C[AlH]CC(C)C)C.O.[OH-].[Na+].O>ClCCl>[F:1][C:2]1[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([CH3:20])=[C:12]([CH2:15][OH:16])[C:13]([I:14])=[C:8]2[CH:7]=[CH:6]1
Reactant: CCOC(=O)c1c(C)nc2c(ccn2Cc2cccc(F)c2F)c1I
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1nc2c(ccn2Cc2cccc(F)c2F)c(I)c1CO
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
To a solution of ethyl 1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (10 g, 21.92 mmol) in dichloromethane (DCM) (160 mL) at −55° C. under nitrogen atmosphere was added dropwise DIBAL-H (129 mL, 129 mmol) (1M/toluene) in ˜20 min and then the mixture was allowed to warm to 0° C. in 1 h and stirred at 0° C. for 1.5 h. The mixture was cooled to −20° C. and water (5.2 mL) was added dropwise followed by 15% NaOH/water (5.2 mL) and water (12.9 ml) and stirring at ambient temperature continued for 30 min. The mixture was filtered through celite washing with dichloromethane. The filtrate was concentrated and dried in vacuo to provide (1-(2,3-difluorobenzyl)-4-iodo-6-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)methanol (8.76 g, 19.67 mmol, 90% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.70 (t, J=6.05 Hz, 1 H), 2.82 (s, 3 H), 4.99 (d, J=6.05 Hz, 2 H), 5.51 (s, 2 H), 6.32 (d, J=3.52 Hz, 1 H), 6.81-6.89 (m, 1 H), 6.90-7.00 (m, 1 H), 7.07 (dd, J=9.67, 1.86 Hz, 1 H), 7.19 (d, J=3.52 Hz, 1 H); LCMS (m/z) ES+=415 (M+1).
Reaction SMILES: [CH:1]([C:3]1[C:4]([OH:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])=O.C1(C)C=CC(C2C(C([NH:28][NH2:29])=O)=CC=CC=2)=CC=1.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34](S(O)(=O)=O)=[CH:33][CH:32]=1>CO>[OH:13][C:4]1[C:3]([CH:1]=[N:28][NH:29][C:34]2[CH:35]=[CH:36][C:31]([CH3:41])=[CH:32][CH:33]=2)=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: Cc1ccc(-c2ccccc2C(=O)NN)cc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COC(=O)c1cccc(C=O)c1O
Solvent: CO
Product: COC(=O)c1cccc(C=NNc2ccc(C)cc2)c1O
Temperature: 22.5 °C
Reaction time: 14 h

Procedure:
A solution of 1.1 g (6 mmol) of the aldehyde of Example 2 in 30 ml of anhydrous methanol was reacted with 0.9 g (6 mmol) of p-toluenebenzohydrazide with acid catalysis (para-toluenesulfonic acid). After the reaction mixture had been stirred for approximately 14 hours at 20 to 25° C., it was freed from the solvent. 1.9 g of the title compound, which corresponded to 99% of theory, were obtained from the residue. (m.p. 134-137° C.)
Reaction SMILES: N[CH:2](C1C=CC(OC)=C(OC)C=1)CC(O)=O.[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:19][C:20]([OH:22])=[O:21]>>[NH2:17][CH:18]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:25][CH:24]=1)[CH2:19][C:20]([O:22][CH3:2])=[O:21]
Reactant: COc1ccc(C(N)CC(=O)O)cc1OC
Reactant: NC(CC(=O)O)c1ccc(OCc2ccccc2)cc1
Product: COC(=O)CC(N)c1ccc(OCc2ccccc2)cc1

Procedure:
The title compound was prepared following the method for preparing Intermediate 6 except that 3-amino-3-(3,4-dimethoxy-phenyl)propionic acid was substituted with 3-amino-3-(4-benzyloxy phenyl)propionic acid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH2:9])=N)[CH:2]=1.[ClH:10].[Cl:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-:20].[K+]>C(O)C>[ClH:11].[N:14]1([CH2:13][CH2:12][O:20][N:9]=[C:7]([Cl:10])[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: ClCCN1CCCCC1
Reactant: [OH-]
Reactant: N=C(N)c1cccnc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: ClC(=NOCCN1CCCCC1)c1cccnc1
Yield: 23.5 %

Procedure:
After dissolving 6.45 g (47.0 mmoles) of 3-pyridinecarboxamidine in 120.4 ml of 0.83N potassium hydroxide solution in ethanol under stirring, 8.65 g (47.0 mmoles) of 1-(2-chloroethyl)piperidine hydrochloride are added under stirring, then the reaction mixture is boiled under reflux for 4 hours. The precipitated potassium chloride is filtered off, the filtrate is clarified by activated carbon and evaporated. The residue is dissolved in 100 ml of chloroform, and the organic solution is washed 3 times with 100 ml of 1N sodium hydroxide solution each, then with 50 ml of water. The organic phase is dried over sodium sulfate and evaporated. The residue is purified by column chromatography (adsorbent: recrystallized from ether to give 2.69 g (23.5%) of the aimed product, m. p.: 81-83° C. (from ether).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1N1CCCC1
Reaction time: 16 h
Yield: 13 %

Procedure:
|2-Fluoronitrobenzene (2.82 g, 20 mmol) was mixed with pyrrolidine (1.56 g, 22 mmol), and potassium carbonate (5.5 g, 40 mmol) in DMF (10 mL). After beating for 16 hours, the mixture was filtered and the filtrate evaporated in vacuo to an oil. This oil was treated with water (10 mL) and dichloromethane (100 mL). The organic phase was collected, dried (MgSO4), filtered, and evaporated to give 1-(2-nitrophenyl)pyrrolidine (0.5 g). The crude product was reduced using 5% palladium on carbon (0.1 g) in ethanol (30mL) and hydrogen at 40 psi for 2 hours. The solution was filtered through celite to remove catalyst and the filtrate evaporated in vacuo to give 2-(1-pyrrolidino)aniline (0.33 g). The crude product was coupled with CMI, under conditions described in the general procedure for CM couplings, to give N-(4,5-dihydro-1H-imidazol-2-ylmethyl)-2-(1-pyrrolidinyl)aniline.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7](Cl)[C:6]([CH3:10])=[CH:5][N:4]=1.[CH3:11][NH2:12].C(Cl)Cl.CO>C(O)C>[CH3:1][S:2][C:3]1[N:8]=[C:7]([NH:12][CH3:11])[C:6]([CH3:10])=[CH:5][N:4]=1
Reactant: CSc1ncc(C)c(Cl)n1
Reactant: CN
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: CNc1nc(SC)ncc1C

Procedure:
Prepared from 2-methylsulphenyl-4-chloro-5-methyl-pyrimidine by reacting with methylamine in ethanol at 100° C., melting point: 134° C., Rf value: 0.35 (silica gel; methylene chloride/methanol=40:1)
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH:2]=[CH2:3].[I:6]I.[Na].[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([S:17]([O-:19])=[O:18])=[CH:13][CH:12]=1>C(Cl)Cl.[Cl-].[Na+].O.O>[I:6][CH:2]([CH2:3][S:17]([C:14]1[CH:13]=[CH:12][C:11]([O:10][CH3:9])=[CH:16][CH:15]=1)(=[O:19])=[O:18])[C:1]([OH:5])=[O:4]
Reactant: COc1ccc(S(=O)[O-])cc1
Reactant: C=CC(=O)O
Reactant: II
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(S(=O)(=O)CC(I)C(=O)O)cc1
Yield: 24.3 %

Procedure:
Added water (0.85 grams, 0.85 ml) followed by the acrylic acid (3.42 grams, 3.25 ml), then I2 (12.04 grams, 47.41 mmol) to a slurry of sodium (4-methoxybenzenesulfinate (9.11 grams, 46.94 mmol) in methylene chloride (150 ml). Added more methylene chloride (100 ml) so slurry could stir. Stirred at room temperature for weekend. Washed reaction solution with 1N Na2S2O3 (aq) (3×150 ml) until organic layer was colorless. Washed organic layer with brine. Dried (MgSO4), filtered and concentrated in vacuo, to give 4.23 grams (25%) of crude 2-iodo-3-(4-methoxyphenylsulfonyl)propionic acid.
Reaction SMILES: C(OC([N:8]1[C:12]2=[C:13]([Cl:25])[N:14]=[CH:15][C:16]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9]1)=O)(C)(C)C.[CH3:27][O:28][C:29]1[C:30]([NH2:35])=[CH:31][CH:32]=[CH:33][CH:34]=1.CS(O)(=O)=O>O1CCOCC1.CO>[ClH:25].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH:35][C:13]1[N:14]=[CH:15][C:16]([C:17]([N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[O:18])=[C:11]2[C:10]([CH3:26])=[CH:9][NH:8][C:12]=12
Reactant: COc1ccccc1N
Reactant: Cc1cn(C(=O)OC(C)(C)C)c2c(Cl)ncc(C(=O)N3CCOCC3)c12
Agent: CS(=O)(=O)O
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccccc1Nc1ncc(C(=O)N2CCOCC2)c2c(C)c[nH]c12
Product: Cl
Temperature: 180 °C

Procedure:
A mixture of 7-chloro-3-methyl-4-(1-morpholin-4-yl-methanoyl)-pyrrolo[2,3-c]pyridine-1-carboxylic acid tert-butyl ester (120 mg), o-anisidine (71 ul), and methanesulfonic acid (41 μl) in 1,4-dioxane (2 ml) was heated under microwave conditions at 180° C. for 30 minutes. The solid mass obtained was dissolved in methanol, transferred to a round bottom flask and evaporated. The residue was dissolved in dichloromethane (40 ml) and washed with 5% sodium hydrogen carbonate solution (2×10 ml) and water (2×10 ml). The organic layer was dried (MgSO4) and evaporated to give a brown oil. The residue was purified by Biotage chromatography over silica gel (9 g), eluting with hexane followed by 25% ethyl acetate/hexane followed by 50% ethyl acetate/hexane. The residue was dissolved in ethyl acetate (10 ml) and treated with a solution of 1M hydrochloric acid in diethyl ether (10 drops). The resultant solid precipitate was then filtered off, sucked dry then dried at 40° C. under vacuum to afford the title compound (56 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:19](O)=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1>CN(C=O)C.C(Cl)Cl>[F:5][C:6]([F:23])([F:22])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]([C:19]([Cl:3])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
Thionyl chloride (3.6 ml) was added to a clear solution of 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carboxylic acid (0.025 mol) in DMF (1 ml) and DCM (100 ml). The mixture was stirred and refluxed for one hour. The solvent was evaporated. DCM (50 ml) was added to the residue, then evaporated, yielding 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbonyl chloride (intermediate 5).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:34][CH2:35][CH2:36][N:37]4[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: NCCN1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCN4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-(2-aminoethyl)-piperidine. ES-MS m/e (%): 497 (M+H+, 100).
Reaction SMILES: O=[CH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:5]=1[O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26].[N:33]1C=CC=CC=1.FC(F)(F)C(ONC(=O)C(F)(F)F)=O>C1(C)C=CC=CC=1>[C:2]([CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:15][C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:17])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:5]=1[O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26])#[N:33]
Reactant: COC(=O)C(NC(=O)c1ccccc1)c1ccc(CC=O)c(OC(=O)c2ccccc2)c1
Reactant: c1ccncc1
Agent: O=C(NOC(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1ccccc1
Product: COC(=O)C(NC(=O)c1ccccc1)c1ccc(CC#N)c(OC(=O)c2ccccc2)c1

Procedure:
A solution of methyl 4-(2-oxoethyl)-α-[(phenylcarbonyl)amino]-3-[(phenylcarbonyl)oxy]benzeneacetate from Preparation 9 above in toluene containing pyridine (2.3 eq) is treated with O,N-bistrifluoroacetyl hydroxyl amine (1.0 eq). The resulting solution is allowed to stir until no starting material remains. The reaction mixture is washed with saturated eq NaHCO3 solution, dried (MgSO4), and concentrated. The product of the formula 15 above is purified by silica gel chromatography.
Reaction SMILES: [F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1I.[F:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([O:23][CH3:24])[CH:15]=1>CCCCCCC.CCOC(C)=O>[F:1][CH:2]([F:12])[CH2:3][NH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[C:17]1[CH:18]=[CH:19][C:14]([F:13])=[CH:15][C:16]=1[O:23][CH3:24]
Reactant: COc1cc(F)ccc1B(O)O
Reactant: FC(F)CNc1cnccc1I
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)ccc1-c1ccncc1NCC(F)F

Procedure:
The title compound was prepared in analogy to example 72, from (2,2-difluoro-ethyl)-(4-iodo-pyridin-3-yl)-amine and 4-fluoro-2-methoxyphenylboronic acid (CAS RN 179899-07-1) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light brown solid (78%). MS (ESI): m/z=283.18 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][NH:11][CH:12]=1)=[O:7])[CH3:4].[CH3:13]I>O1CCCC1>[CH2:3]([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([CH3:13])[CH:12]=1)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(C)c1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81.5 %

Procedure:
A mixture of sodium hydride (216 mg, 8.57 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was treated with a solution of 1H-pyrazole-4-carboxylic acid ethyl ester (1.0 g, 7.14 mmol) in tetrahydrofuran (10 mL). The reaction was warmed to 25° C. and was stirred at 25° C. for 45 min. At this time, the reaction was treated with methyl iodide (0.67 mL, 10.71 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was cooled to 0° C. and was quenched by the dropwise addition of a saturated aqueous ammonium chloride solution. This mixture was diluted with ethyl acetate (150 mL). The organics were washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 40:60 ethyl acetate/petroleum ether) afforded 1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (897 mg, 81.5%) as a clear oil: 1H NMR (DMSO-d6, 300 MHz) δ8.27 (s, 1H), 7.80 (s, 1H), 4.18 (q, J=7.32 Hz, 2H), 3.85 (s, 3H), 1.24 (t, J =7.32 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][CH3:10])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[S:11](Cl)(=[O:14])(=[O:13])[OH:12].[F:16][C:17]1[C:22](O)=[C:21]([F:24])[C:20]([F:25])=[C:19]([F:26])[C:18]=1[F:27].C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:9][C:4]1[CH:5]=[C:6]([CH3:8])[C:7]([S:11]([O:12][C:22]2[C:21]([F:24])=[C:20]([F:25])[C:19]([F:26])=[C:18]([F:27])[C:17]=2[F:16])(=[O:14])=[O:13])=[C:2]([CH3:1])[CH:3]=1
Reactant: COc1cc(C)cc(C)c1
Reactant: O=S(=O)(O)Cl
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)c(C)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
3,5-Dimethylanisole (3 g, 22.026 mmol) was initially introduced into methylene chloride (60 ml) and the mixture was cooled, and a solution of chlorosulfuric acid (7.3 ml, 110.13 mmol) in methylene chloride (60 ml) was slowly added dropwise at 0° C. After stirring in a cooling bath for 10 min, the reaction solution was added dropwise to 300 ml of ice-water, the phases were separated, the aqueous phase was extracted with methylene chloride (60 ml) and the combined organic phases were washed with saturated sodium chloride solution (50 ml), dried over sodium sulfate and concentrated in vacuo. During this operation, pentafluorophenol (4.05 g, 22.026 mmol) was dissolved in methylene chloride (50 ml) and triethylamine (6.1 ml, 44.053 mmol) and the solution was stirred for 30 min. The freshly prepared sulfonyl chloride, concentrated on a rotary evaporator, was dissolved in methylene chloride (50 ml) and the solution was slowly added dropwise. After the mixture had been stirred at room temperature for 1 h, saturated sodium bicarbonate solution (40 ml) was added, the phases were separated and the organic phase was washed with saturated sodium chloride solution (40 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether/methylene chloride (20:1:2). Yield: 6.06 g (71%)
Reaction SMILES: Cl[CH2:2][C:3](=[O:5])[CH3:4].[Br:6][C:7]1[C:8]([OH:17])=[C:9]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:11][C:12]=1[F:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]([N+:14]([O-:16])=[O:15])[C:8]=1[O:17][CH2:2][C:3](=[O:5])[CH3:4]
Reactant: CC(=O)CCl
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1c([N+](=O)[O-])ccc(F)c1Br
Temperature: 25 °C

Procedure:
Chloroacetone (3.8 g, 3.3 ml, 41 mmol) was added dropwise to a solution of 3-bromo-4-fluoro-2-hydroxy-1-nitrobenzene (4.3 g, 18.2 mmol) in acetone (54 ml) with stirring at ambient temperature. Potassium carbonate (5.8 g, 42 mmol) and potassium iodide (6.0 g, 36.4 mmol), were added and the reaction mixture was heated to reflux temperature for 2 hours. The reaction mixture was then cooled to room temperature, poured onto water (100 ml), and extracted three times with ethyl acetate (150 ml). The combined organic layers were dried over magnesium sulfate, treated with decolorizing charcoal and filtered through diatomaceous earth. Solvent was removed in vacuo to afford a dark brown oil.