Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:9]=[C:8](F)[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1.[CH2:16]([OH:18])C>>[NH2:3][C:4]1[N:9]=[C:8]([O:18][CH3:16])[N:7]=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[N:5]=1
Reactant: Nc1nc(F)nc(OC(F)(F)F)n1
Reactant: CCO
Agent: [H-]
Agent: [Na+]
Product: COc1nc(N)nc(OC(F)(F)F)n1
Reaction time: 0.25 h

Procedure:
2.3 g (0.093 mol) of 97% strength sodium hydride were added a little at a time to 300 ml of ethanol at from 20 to 35° C. and stirring was carried out until dissolution was complete, which took 15 minutes. 18.5 g (0.093 mol) of 2-amino-4-fluoro-6-trifluoromethoxy-1,3,5-triazine were then added at 0° C. in the course of 10 minutes, while stirring and stirring was continued for 1 hour at 0° C. and overnight at 22° C. The mixture was evaporated down under reduced pressure, after which the residue was taken up in methylene chloride and the solution was extracted with water and dried. Evaporation gave 17.9 g (85.9% of theory) of the title compound of melting point 69°-91° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][OH:40])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[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].[CH2:41](Br)[CH:42]=[CH2:43]>CN(C)C=O.O>[CH2:3]([O:19][CH2:20][CH:21]([CH2:39][O:40][CH2:43][CH:42]=[CH2:41])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[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: C=CCBr
Reactant: CCCCCCCCCCCCCCCCOCC(CO)OCCCCCCCCCCCCCCCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOCC(COCCCCCCCCCCCCCCCC)OCCCCCCCCCCCCCCCC
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
Sodium hydride (1.78 g. of 50 wt. % dispersion in mineral oil, 37 mmoles) was added at 60° C. to a solution of 1,2-di-O-(n-hexadecyl)-glycerol (10 g., 18.5 mmoles) in N,N-dimethylformamide (100 ml.), and the resulting solution stirred for 20 minutes at 60° C. Allyl bromide (4.47 g., 37 mmoles) was then added dropwise and the resulting mixture stirred for 3 hours at 90° C., cooled, cautiosly diluted with water (200 ml.) to quench the reaction, and extracted with ether (3×150 ml.). The combined ether extract was washed with saturated aqueous sodium chloride solution, dried (MgSO4), filtered and evaporated in vacuo to an oil, which was purified by silica gel chromatography (elution with benzene) [10 g., 93% yield, oil, n.m.r. (CDCl3) δ 5.66-6.16 (m, 1, --OCH2CH=CH2), 5.25 (d of doublets, 2, --OCH2CH=CH2) and 4.03 (d, 2, --OCH2CH=CH2)].
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:26][C:17]3[C:18]4[NH:22][C:21](=[O:23])[NH:20][C:19]=4[CH:24]=[CH:25][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[F:27][C:28]1[CH:41]=[CH:40][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[O:33])=[CH:30][CH:29]=1>CS(C)=O.C(OCC)(=O)C>[F:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([CH:34]2[CH2:39][CH2:38][N:37]([CH2:12][CH:13]3[O:26][C:17]4[C:16](=[CH:25][CH:24]=[C:19]5[NH:20][C:21](=[O:23])[NH:22][C:18]5=4)[O:15][CH2:14]3)[CH2:36][CH2:35]2)=[O:33])=[CH:40][CH:41]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4[nH]c(=O)[nH]c4c3O2)cc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(c1ccc(F)cc1)C1CCN(CC2COc3ccc4[nH]c(=O)[nH]c4c3O2)CC1
Temperature: 90 °C

Procedure:
A mixture of 0.60 g (1.6 mmole) of (8R)-1,3,7,8-tetrahydro-8-[[[(4 methylphenyl)sulfonyl]oxy]methyl]-2H-[1,4]dioxino[2,3-e]benzimidazol-2-one and 1.7 g (8.0 mmole) of 4-(4-fluorobenzoyl)piperidine in 30 mL of DMSO was heated at in 90° C. under nitrogen for 5 hours. The reaction was allowed to come to room temperature, diluted to 500 mL with ethyl acetate, washed with 500 mL portions of saturated aqueous sodium bicarbonate and water, dried over sodium sulfate, filtered and evaporated in vacuum. The residue was column chromatographed on silica gel with 2% methanol in chloroform as eluant and the product fractions evaporated to give the free base as a colorless oil. This was recrystallized from ethanol with the addition of 4 N isopropanolic HCl to give 0.13 g of the (S)-enantiomer of the title compound. A second recrystallization from ethanol gave 0.095 g of the product as a white solid hydrochloride, hydrate, m.p. 250-256° C. (d).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:5])=[O:3])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc2ccccc2n1CCc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cc2ccccc2n1CCc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
480 mg (1.5 mmol) of 1-[2-(4-Chloro-phenyl)-ethyl]-1H-indole-2-carboxylic acid ethyl ester was dissolved in 5 ml of dioxan and 5 ml of 2N aqueous sodium hydroxide was added. The reaction was heated to 60° C. for 2 h, then was cooled to 0° C. The solution was diluted with 10 ml of water and the pH of the solution was adjusted to between 2 and 3 by the addition of concentrated aqueous HCl, whereupon the product precipitates. The product was filtered off and dried under reduced pressure. Yield: 390 mg MS (Cl+): m/e=300, chloro pattern.
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]#[C:24][CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH2:22]([N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1])[C:23]#[C:24][CH3:25]
Reactant: CC#CCBr
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
8-Chlorotheophylline (4.9 g) and potassium carbonate (5 g) were dissolved in N,N-dimethylformamide (100 ml), and 1-bromo-2-butyne (2.4 ml) was added thereto. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate, and washed with water. Insoluble white solid was collected through filtration, and washed with ethyl acetate to give 3.8 g of 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione. Then, the resulting 7-(2-butynyl)-8-chloro-1,3-dimethyl-3,7-dihydropurine-2,6-dione (1.8 g) and 1-piperazine carboxylic acid tert-butyl ester (3.7 g) were stirred at 150° C. for 1 hour. After cooling to room temperature, the reaction mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, and dried over an hydrous magnesium sulfate. The solvent was removed by distillation at reduced pressure. The residue was purified by silica gel column chromatography to obtain 1.6 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:4).
Reaction SMILES: O(C)[Na].[CH3:4][O:5][CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O.[NH2:15][C:16]([NH2:18])=[O:17]>CCO>[OH:13][C:11]1[NH:18][C:16](=[O:17])[NH:15][C:7](=[O:9])[C:6]=1[O:5][CH3:4]
Reactant: NC(N)=O
Reactant: COC(=O)C(OC)C(=O)OC
Agent: CO[Na]
Solvent: CCO
Product: COc1c(O)[nH]c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 99 %

Procedure:
The NaOCH3 (8.5 g, 157 mmole), was added to a stirred solution of dimethyl 2-methoxymalonate (10.2 g, 62.91 mmole), urea (2.5 g, 41.7 mmole), and EtOH (80 ml). The reaction mixture was heated to 100° C. for 4 hrs, then the reaction was evaporated to remove the solvent. Water was added to the mixture and then concentrated HCl was added. The pH of the mixture was adjusted to ca. 3˜4. The mixture was filtered and wash water and acetone. After drying in vacuo, it gave a product (99%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:14])=[O:13])=[N+]=[N-].[H][H]>[Pd].C(O)C>[NH2:1][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[S:12]([N:15]([CH3:17])[CH3:16])(=[O:13])=[O:14]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN

Procedure:
A mixture of 2-(azidomethyl)-5-fluoro-N,N-dimethylbenzenesulfonamide (3.57 g, 13.8 mmol) and 5% palladium on carbon (0.89 g, 25% w/w) in absolute ethanol (100 mL) was stirred under a balloon of hydrogen gas for one hour. The reaction was filtered through a small pack of celite and the filtrate was concentrated in vacuo to a yellow oil. The crude material was purified by preparative HPLC. (Gilson semi preparative HPLC system using a Waters Delta pak column (3(10×40 mm I.D.)cartridges, C18, 15 μm pore size) eluting with 5-95% acetonitrile/water (0.1% TFA) at 30 ml/min) to afford the desired product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:6][C:5]=1[O:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH3:17]
Reactant: C1CCNC1
Reactant: COCCCCOc1cc(C)ccc1C(=O)OC
Product: COCCCCOc1cc(CN2CCCC2)ccc1C(=O)OC

Procedure:
The 2-(4-methoxybutoxy)-4-(pyrrolidin-1-ylmethyl)-benzoic acid methyl ester that is used is prepared in a manner analogous to that described in Example 30Aa) from 2-(4-methoxybutoxy)-4-methyl-benzoic acid methyl ester and pyrrolidine, with subsequent purification of the crude product by FC (eluants C and M): brown-black oil, Rf (N)=0.22.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:13](C=O)([CH2:14][OH:15])[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:27]([Mg]Br)=[CH2:28]>C1COCC1>[CH:27]([CH:14]([OH:15])[C@H:13]1[O:12][C@@H:11]([N:18]2[CH:26]=[C:24]([CH3:25])[C:22](=[O:23])[NH:21][C:19]2=[O:20])[CH2:10][C@@H:9]1[O:8][Si:1]([C:4]([CH3:6])([CH3:5])[CH3:7])([CH3:2])[CH3:3])=[CH2:28]
Reactant: C=C[Mg]Br
Reactant: Cc1cn([C@H]2C[C@H](O[Si](C)(C)C(C)(C)C)[C@@](C=O)(CO)O2)c(=O)[nH]c1=O
Solvent: C1CCOC1
Product: C=CC(O)[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
3'-O-t-Butyldimethylsilyl thymidine 4'-aldehyde (5.0 g; azeotroped twice with toluene, 25 ml) was dissolved in dry THF (60 ml) and cooled to -78° C., followed by addition of 1.0M solution of vinylmagnesium bromide (2.5 eq.) in THF. The reaction mixture was stirred for 30 minutes and then quenched with saturated aqueous NH4Cl, diluted with ethyl acetate, washed with water (2×100 ml) and then with brine. Then the organic layer was dried. The title compound was purified by flash chromatography using 30% ethyl acetate/hexane, affording a 43% yield of the desired alcohol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[F:1][C:2]1[CH:7]=[C:6]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)(=[O:33])=[O:32])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCCC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCCC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)pyrrolidine. MS (ESI): mass calcd. for C20H19FN4O2S, 398.12; m/z found, 399.2 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.28 (d, J=1.4, 1H), 8.12-8.08 (m, 1H), 8.0-7.94 (m, 1H), 7.71-7.65 (m, 2H), 7.62-7.56 (m, 1H), 7.42-7.39 (m, 1H), 7.34-7.27 (m, 2H), 2.94 (t, J=6.7, 4H), 1.81-1.69 (m, 4H).
Reaction SMILES: Cl.Cl.Cl.[NH:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:9]=[C:8]([CH3:18])[N:7]=1)[NH2:5].C(N(C(C)C)CC)(C)C.[CH3:28][C:29]([C:31]1[CH:36]=[CH:35][C:34]([N:37]([CH3:39])[CH3:38])=[CH:33][CH:32]=1)=O>C(O)C>[CH3:38][N:37]([CH3:39])[C:34]1[CH:35]=[CH:36][C:31]([C:29](=[N:5][NH:4][C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]=[C:8]([CH3:18])[N:7]=2)[CH3:28])=[CH:32][CH:33]=1
Reactant: CC(=O)c1ccc(N(C)C)cc1
Reactant: Cc1nc(NN)cc(-c2ccccc2)n1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CC(=NNc1cc(-c2ccccc2)nc(C)n1)c1ccc(N(C)C)cc1
Yield: 17.9 %

Procedure:
To a solution of 4-hydrazino-2-methyl-6-phenylpyrimidine trihydrochloride (300 mg, 0.97 mmol) and diisopropylethylamine (0.17 mL, 0.97 mmol) in ethanol (10 mL) was added 4-dimethylaminoacetophenone (158 mg, 0.97 mmol). The resultant reaction mixture was heated at reflux overnight. The reaction mixture was diluted with dIH2O and the pH was adjusted to 1-2 and washed with ethyl acetate. The pH of the aqueous layer was adjusted to 9-10 and was extracted with ethyl acetate. The combined extracts were concentrated in vacuo and the residue crystallized from ethyl acetate:hexanes. 60 mg (18%) of the title compound was isolated as a yellow solid. HPLC Purity: 98%.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.CN1CCOCC1.Cl.Cl.[CH3:41][N:42]1[CH:46]=[CH:45][N:44]=[C:43]1[CH2:47][NH2:48].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:48][CH2:47][C:43]1[N:42]([CH3:41])[CH:46]=[CH:45][N:44]=1)=[O:5]
Reactant: Cn1ccnc1CN
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cn1ccnc1CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 8 h
Yield: 1.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol) was dissolved in DMF (1 mL) prior to the addition of 4-methylmorpholine (0.046 mL, 0.417 mmol), C-(1-methyl-1H-imidazol-2-yl)-methylamine dihydrochloride (13.91 mg, 0.125 mmol), and BOP (55.4 mg, 0.125 mmol). The reaction mixture was stirred overnight and then purified via preparative LCMS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 methanol:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 methanol:water with 10-mM ammonium acetate; Gradient: 50-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow rate=20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give (R/S)-2-hydroxy-N-((1-methyl-1H-imidazol-2-yl)methyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (4.9 mg, 0.001 mmol, 13% yield): LCMS=525.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.24 (2 H, m), 7.70 (4 H, t, J=8.03 Hz), 7.52-7.64 (3 H, m), 7.00 (1 H, d, J=1.25 Hz), 6.88 (1 H, d, J=1.51 Hz), 5.18 (1 H, s), 4.40-4.58 (2 H, m), 3.60 (3 H, s); Analytical LCMS: column: Mac-mod Halo C18, 4.6×50 mm, 2.7-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.05% TFA; Mobile Phase B: 90:10 acetonitrile:water with 0.05% TFA; Temperature: 45° C.; Gradient: 0-100% B over 4 minutes, flow rate=4 mL/min, product retention=2.0 min.
Reaction SMILES: [C:1]([C:4]1[C:5]([N+:13]([O-])=O)=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([NH2:9])=[O:8])(=[O:3])[NH2:2]>C(O)C.[Pd]>[NH2:13][C:5]1[C:6]([C:7](=[O:8])[NH2:9])=[CH:10][CH:11]=[CH:12][C:4]=1[C:1]([NH2:2])=[O:3]
Reactant: NC(=O)c1cccc(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1cccc(C(N)=O)c1N
Reaction time: 5 h
Yield: 50 %

Procedure:
3-Carbamoyl-2-nitrobenzamide (0.6 g, 0.0029 mol) was dissolved in ethanol (50 ml) and the solution stirred with 5% palladium on charcoal catalyst (0.1 g) under a hydrogen atmosphere at 50 p.s.i. (3.45 bar) and 50° C. for 5 hours. The catalyst was removed by filtration, the solvent evaporated under vacuum and the residue crystallized from water to give the title compound as a grey solid (0.26 g, 50%), m.p. 284-288° C.
Reaction SMILES: [CH2:1]([C:3]([CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])=[CH:4][C:5](=[N:16][OH:17])[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:2].ClC1C=CC=C(C(OO)=[O:31])C=1.C(Cl)(Cl)Cl>CC(C)=O>[CH2:1]([C:3]([CH:18]([N+:20]([O-:22])=[O:21])[CH3:19])=[CH:4][C:5](=[N:16][OH:17])[CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N+:12]([O-:31])[CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:2]
Reactant: CCC(=CC(CNC(=O)c1cccnc1)=NO)C(C)[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: ClC(Cl)Cl
Product: CCC(=CC(CNC(=O)c1ccc[n+]([O-])c1)=NO)C(C)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A mixture of N-(4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-yl)-3-pyridinecarboxamide (306 mg), 3-chloroperbenzoic acid (323 mg), chloroform (15 ml) and acetone (40 ml) was stirred at room temperature for 10 hours. The resulting precipitates were collected and washed with acetone to give N-(4-ethyl-2-hydroxyimino-5-nitro-3-hexen-1-yl)-3-pyridinecarboxamide 1-oxide.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](O)=[CH:5][C:6](=O)[C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1.Cl.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][NH2:26])[CH:21]=[CH:22][C:23]=1[Cl:24]>CCO>[ClH:17].[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[N:26]=1)=[O:15]
Reactant: COC(=O)C(O)=CC(=O)c1cccnc1
Reactant: NNc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1cc(-c2cccnc2)n(-c2ccc(Cl)c(Cl)c2)n1
Temperature: 0 °C
Yield: 128 %

Procedure:
To a solution of 1 (2.90 g, 14.0 mmol) in EtOH (60 mL, anhydrous) was added 3,4-dichlorophenyl hydrazine hydrochloride (3.29 g, 15.4 mmol). The solution was heated to reflux for 30 min and then cooled to 0° C. The precipitate was collected by filtration and washed with H2O and MeOH to yield 2 (3.79 g, 70%) as an off-white powder.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.[Cl:12][C:13]1[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([CH2:20]Cl)[C:14]=1[CH3:22].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]2[N:9]([CH2:20][C:15]3[C:14]([CH3:22])=[C:13]([Cl:12])[C:18]([CH3:19])=[CH:17][N:16]=3)[N:10]=[CH:11][C:3]=12
Reactant: Nc1nc(Cl)c2cn[nH]c2n1
Reactant: Cc1cnc(CCl)c(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cnc(Cn2ncc3c(Cl)nc(N)nc32)c(C)c1Cl
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-1H-pyrazolo[3,4-d]pyrimidin-6-ylamine (158 mg), crude 4-chloro-2-chloromethyl-3,5-dimethyl-pyridine (204 mg), Cs2CO3 (660 mg) and DMF was heated to 80° C. for 1.5 h, diluted with EtOAc and washed with water. The crude material was concentrated and suspended in MeOH/DCM. Filtration gave a 2:1 mixture of regioisomers which was further purified by preparative silica gel plate (EtOAc 100%). The major (less polar) isomer corresponded to the title compound. R.t. 5.45 min. 1H-NMR (CDCl3) δ 8.22 (s, 1H), 7.90 (s, 1H), 5.57 (s, 2H), 5.28 (s, 2H), 2.43 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [C:1]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[C:25]([NH2:30])[CH:24]=1.FC(F)(F)C(O)=O>O1CCCC1>[NH2:30][C:25]1[CH:24]=[C:23]([F:22])[CH:28]=[CH:27][C:26]=1[NH:29][C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][NH:11][C:1](=[O:10])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:21][CH:20]=1
Reactant: O=C(C=Cc1ccccc1)NCc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(F)cc1N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(F)ccc1NC(=O)c1ccc(CNC(=O)C=Cc2ccccc2)cc1
Temperature: 45 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
To a suspension of 0.29 g (1.78 mmol) of N,N′-carbonyldiimidazole in tetrahydrofuran (15 ml) is added 0.50 g (1.78 mmol) of 4-[N-cinnamoylaminomethyl]benzoic acid, followed by stirring at 45° C. for 1 hour. After cooling, the reaction mixture is added to a separately prepared tetrahydrofuran (10 ml) solution including 0.28 g (2.22 mmol) of 4-fluoro-1,2-phenylenediamine and 0.20 g (1.78 mmol) of trifluoroacetic acid at room temperature. After reaction at room temperature for 16 hours, the deposited white solid is collected by filtration, washed with tetrahydrofuran, and then dried to give the title compound (0.45 g, 65%). 1H NMR (300 MHz, DMSO-d6): δppm: 4.42 (2H, d), 4.92 (2H, br.s), 6.62 (1H, t), 6.78 (2H, m), 7.01 (1H, t), 7.32 (5H, m), 7.54 (5H, m), 8.76 (1H, br.t), 9.58 (1H, br.s). IR (KBr) cm−1: 3306, 1618, 1517, 1308, 745. HRMS calcd for C23H20N3O2F: 389.4292. Found: 389.4294. MA calcd for C23H20N3O2F: C, 70.94%; H, 5.18%; N, 10.79%. Found: C, 70.72%; H, 5.18%; N, 10.88%.
Reaction SMILES: [CH3:1][C:2]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])([CH3:5])[CH:3]=[CH2:4].ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[CH2:7]([O:6][C:2]([CH:3]1[CH2:4][O:31]1)([CH3:1])[CH3:5])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(C)(C)OCCCCCCCCCCCCCCCC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCOC(C)(C)C1CO1
Reaction time: 8 h
Yield: 93.8 %

Procedure:
A mixture of 36.5g of 1-[(1,1-dimethyl-2-propenyl)oxy]hexadecane, 23.92 g of m-chloroperbenzoic acid and 225 ml of methylene chloride was stirred overnight. A 7 g portion of m-chloroperbenzoic acid was added, then the mixture was stored in a chill room for 56 hours. This mixture was filtered. The filtrate was washed with dilute aqueous sodium bisulfite, then saturated aqueous sodium bicarbonate, dried and the solvent removed, giving 36 g of the desired compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=S)[CH3:2].Cl.Cl.[NH2:17][CH:18]([CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:19]([NH:21][C:22]1([C:31]#[N:32])[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:23]1)=[O:20]>>[CH2:1]([O:3][C:4](=[O:14])[NH:5][C:6](=[N:17][CH:18]([C:19](=[O:20])[NH:21][C:22]1([C:31]#[N:32])[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][CH3:30])[CH2:26][CH2:27]1)[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: CCOC(=O)NC(=S)N1CCOCC1
Reactant: CCCN1CCC(C#N)(NC(=O)C(N)CC2CCCCC2)CC1
Agent: Cl
Product: CCCN1CCC(C#N)(NC(=O)C(CC2CCCCC2)N=C(NC(=O)OCC)N2CCOCC2)CC1

Procedure:
The title compound was prepared starting from (Morpholine-4-carbothioyl)-carbamic acid ethyl ester and 2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamide bis hydrochloride salt according to the procedure from Example 76, step b, except that the compound was first purified by chromatography over silica gel using 9:1 methylene chloride:methanol as the eluant prior to reverse phase HPLC purification. MS, m/z 505=M+1.