Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C1OC=CC=1)C1C=CC=CC=1.[C:14]([C:17]1[O:18][CH:19]=[CH:20][CH:21]=1)(=[O:16])[CH3:15].BrC1C=CC=CC=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1Br>>[O:18]1[CH:19]=[CH:20][CH:21]=[C:17]1[C:14]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[O:30][CH3:29])([OH:16])[CH3:15]
Reactant: COc1ccccc1Br
Reactant: CC(=O)c1ccco1
Agent: OC(c1ccccc1)c1ccco1
Solvent: Brc1ccccc1
Product: COc1ccccc1C(C)(O)c1ccco1

Procedure:
(±)1-(2-Furyl)-1-(2-methoxyphenyl)ethanol (b.p. 115°-118° C./0.15 mm.Hg; m.p. 64°-66° C.) was prepared by the procedure hereinbefore described in (i) for the preparation of (±) 2-α-hydroxybenzylfuran but replacing the furfuraldehyde by 2-acetylfuran [described by Levine et al, J.A.C.S. 71, 1208,(1949)] and the bromobenzene by 2-methoxybromobenzene.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)[CH3:3].[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([N:23]3[CH2:28]CNC[CH2:24]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1>C1(C)C=CC=CC=1>[NH:14]1[C:22]2[C:17](=[CH:18][C:19]([N:23]3[CH2:28][CH2:1][N:2]([CH2:4][C:5]4[C:13]5[C:8](=[N:9][CH:10]=[CH:11][CH:12]=5)[NH:7][CH:6]=4)[CH2:3][CH2:24]3)=[CH:20][CH:21]=2)[CH:16]=[CH:15]1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: c1cc2cc(N3CCNCC3)ccc2[nH]1
Solvent: Cc1ccccc1
Product: c1cnc2[nH]cc(CN3CCN(c4ccc5[nH]ccc5c4)CC3)c2c1
Yield: 31.8 %

Procedure:
A mixture of 3-dimethylaminomethyl-1H-pyrrolo[2,3-b]pyridine (0.23 g, 1.33 mmol) and 1-(5-indolyl)piperazine (0.27 g, 1.34 mmol) in toluene (20 ml) was heated at reflux for 16 h under nitrogen. The mixture was allowed to cool and the solid present collected. Purification by flash chromatography, eluting with 90:8:1 dichloromethane/methanol/ammonia, twice gave the title compound (0.14 g, 32%) as a white solid. Recrystallisation from methanol afforded needles, m.p. 232.5°-233° C.; (Found: C, 72.14; H, 6.29; N, 21.07. C20H21N5.0.1H2O requires C, 72.09; H, 6.41; N, 21.02%); δH (DMSO-d6) 2.56 (4H, m, 2×piperazinyl CH2), 3.02 (4H, m, 2×piperazinyl CH2), 3.69 (1H, s, CH2N), 6.27 (1H, m, 3'-H), 6.83 (1H, dd, J 8.8, 2.1 Hz, 6'-H), 6.97 (1H, m, 2'-H), 7.05 (1H, dd, J 7.8, 4.6 Hz, 5-H), 7.22 (2H, m, 4'-H, 7'-H), 7.38 (1H, d, J 2.1 Hz, 2-H), 8.06 (1H, dd, J 7.8, 1.4 Hz, 4-H), 8.20 (1H, dd, J 4.6, 1.4 Hz, 6-H), 10.77 (1H, br s, NH), and 11.46 (1H, br s NH); m/z (CI+, NH3) 322 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[H-].[Na+].Br[CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[N:13]([CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Nc2cc(Br)cn(C)c2=O)n[nH]1
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2cc(Br)cn(C)c2=O)nn1CCO[Si](C)(C)C(C)(C)C
Yield: 59.6 %

Procedure:
A solution of 5-bromo-1-methyl-3-(5-methyl-1H-pyrazol-3-ylamino)pyridin-2(1H)-one 112a (1.08 g, 3.8 mmol) in anhydrous DMF (10 mL) was treated with 60% dispersion of NaH in mineral oil (0.17 g, 4.3 mmol) while stirring under nitrogen. After effervescence the reaction was stirred for an additional 30 min. At this time the reaction was treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (15-1) (0.908 g, 3.8 mmol) and continued to stir under nitrogen for 10 hours. After reaction water (50 mL) was added slowly and the mixture was filtered. The filtrate was concentrated under reduced pressure and the residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate to afford 161a (1 g, 35%), which was used directly without further purification. LCMS: (M+H)+ 443.
Reaction SMILES: O.O.[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C(O)C.[F:16][C:17]([F:25])([F:24])[C:18]([CH2:20][C:21](=O)[CH3:22])=O>CCOCC>[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]2[N:10]=[C:21]([CH3:22])[CH:20]=[C:18]([C:17]([F:25])([F:24])[F:16])[N:9]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)CC(=O)C(F)(F)F
Reactant: N=C(N)c1ccc(O)cc1
Solvent: CCOCC
Solvent: CCO
Solvent: O
Product: Cc1cc(C(F)(F)F)nc(-c2ccc(O)cc2)n1

Procedure:
In a pressure tube a mixture of 17.2 g of 4-hydroxybenzamidine dihydrate, 60 ml of ethanol and 14.6 ml of trifluoroacetylacetone is heated for 18 hours at a bath temperature of 110°. The mixture is then stirred with 200 ml of ether, a small amount of precipitate is filtered off with suction and the filtrate is extracted with two portions of 2N sodium hydroxide solution. The alkaline solution is treated with carbon, filtered and then 400 ml of ethyl acetate and 160 ml of 2N hydrochloric acid are added to pH 1. The organic phase is separated off, washed with water, dried over sodium sulphate and concentrated by evaporation. The residue is recrystallised from ether/hexane yielding 2-(4-hydroxyphenyl)-4-methyl-6-(trifluoromethyl)-pyrimidine having a melting point of 131°-132° C.
Reaction SMILES: CO[C:3]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]([CH:10]=[CH:11][CH2:12][CH3:13])[N:4]=1.[Cl-:14].[NH4+:15]>CO>[ClH:14].[CH:10]([CH:5]1[NH:4][C:3](=[NH:15])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[CH:11][CH2:12][CH3:13]
Reactant: [NH4+]
Reactant: [Cl-]
Reactant: CCC=CC1CCCCC(OC)=N1
Solvent: CO
Product: CCC=CC1CCCCC(=N)N1
Product: Cl
Yield: 101.6 %

Procedure:
The product of Example 327 (1.5 g, 8 mmol) in 85 mL of MeOH was reacted with ammonium chloride (0.36 g, 6.8 mmol) by the method of Example 27 to yield 1.4 g (83%) of the title material.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:15]=[CH:16][C:17]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[C:18]([CH2:20]O)[CH:19]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:32]([NH2:36])([CH3:35])([CH3:34])[CH3:33]>CN1C(=O)CCC1.C(Cl)Cl>[C:32]([NH:36][CH2:20][C:18]1[CH:19]=[C:14]([NH:13][C:7]2[C:6]3[C:11](=[CH:12][C:3]([Cl:2])=[CH:4][CH:5]=3)[N:10]=[CH:9][CH:8]=2)[CH:15]=[CH:16][C:17]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)([CH3:35])([CH3:34])[CH3:33]
Reactant: OCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Reactant: CC(C)(C)N
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CC(C)(C)NCc1cc(Nc2ccnc3cc(Cl)ccc23)ccc1N1CCOCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.2 %

Procedure:
To a suspension of {5-[(7-chloroquinolin-4-yl)amino]-2-(morpholin-4-yl)phenyl}methanol hydrochloride (compound of step C of example 31) (0.105 g, 0.26 mmol) in 4 mL of NMP at 0° C. was added thionyl chloride (90 μL, 1.23 mmol). The reaction mixture was warmed up to room temperature and stirred for 3 h. The reaction mixture was then slowly added to tert-butylamine (0.81 mL, 7.75 mmol) in 1 mL of NMP at 0° C. and then stirred at room temperature for 2 h. This solution was diluted in 100 mL of CH2Cl2 and washed with a saturated aqueous solution of NaHCO3. The organic layer was dried over MgSO4, filtered, evaporated and purified by flash chromatography (Et2O/MeOH/NH4OH//90/10/1 then 80/20/1) to yield expected compound as a yellow solid (103 mg, 92% yield). LC-MS: m/z (ESI) 425.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[N:16]=O.[CH:18]([N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)=O.P(Cl)(Cl)(Cl)=O>C(Cl)(Cl)(Cl)Cl>[N:20]1([C:18]2[NH:16][C:3]3[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=CN1CCOCC1
Reactant: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: CCCn1c(=O)c2[nH]c(N3CCOCC3)nc2n(CCC)c1=O
Reaction time: 12 h

Procedure:
7.9 g (0.033 mol) of 6-amino-5-nitroso-1,3-dipropyluracil and 5.0 g (0.049 mol) of N-formylmorpholine are dissolved in 40 ml of carbon tetrachloride. At ambient temperature, 7.5 g (0.049 mol) of phosphorus oxychloride are added, the mixture is heated to reflux temperature for one hour and left to stand at ambient temperature for about 12 hours. The oil which separates off on the surface is removed, dissolved in 50 ml of dichloromethane and poured onto ice together with the remaining solution, which has been concentrated by half. After neutralisation of the aqueous phase the organic phase is separated off and the aqueous phase is extracted with dichloromethane. From the combined organic phases the title compound is obtained, after drying and evaporation, as a crystalline residue which is recrystallised from ethanol.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:32][CH3:33])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[N:28]=[C:27]([C:29](O)=[O:30])[CH:26]=[CH:25][CH:24]=3)=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:58][C:59]1[CH:60]=[C:61]([CH2:66][NH2:67])[CH:62]=[CH:63][C:64]=1[CH3:65]>ClCCl.CCOC(C)=O>[Br:58][C:59]1[CH:60]=[C:61]([CH2:66][NH:67][C:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:32][CH3:33])=[O:22])[N:28]=2)=[O:30])[CH:62]=[CH:63][C:64]=1[CH3:65]
Reactant: Cc1ccc(CN)cc1Br
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(C)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
6-[({[1,6-Diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-2-pyridinecarboxylic acid (2 g, 4.42 mmol) was partially dissolved in dichloromethane (100 mL), and HBTU (1.676 g, 4.42 mmol) was added followed sequentially by [(3-bromo-4-methylphenyl)methyl]amine (0.884 g, 4.42 mmol), and TEA (1.232 mL, 8.84 mmol). The mixture was allowed to stir under argon over night at room temperature. The reaction was not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was added and the mixture was again stirred overnight. The reaction was still not complete so additional HBTU (0.167 g, 0.44 mmol) and [(3-bromo-4-methylphenyl)methyl]amine (0.088 g, 0.44 mmol) was again added and the mixture was stirred overnight. The reaction mixture was taken up in EtOAc (100 mL) and washed 3× with water (50 mL). Solid was recovered and washed with water and ethyl acetate. Drying the solid under vacuum gave N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (1.97 g, 2.95 mmol, 66.7% yield). The ethyl acetate layer was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated to give another batch. This batch was taken up in methylene chloride and absorbed on Isolute® Sorbent (Biotage, Uppsala, Sweden; http://www.biotage.com/) and purified with a Combiflash on an 80 g silica column eluted with 0-10% DCM/MeOH. Product fractions were combined and evaporated to give N-[(3-bromo-4-methylphenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (704 mg, 0.987 mmol, 22.34% yield) as a white solid. LC-MS m/z 435 (M+H)+, 0.94 min (ret time).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:28])[C:20]3[CH:25]=[CH:24][C:23]([I:26])=[C:22]([CH3:27])[CH:21]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].CS(C)=O.[NH2:35][CH2:36][C:37]1[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=1>C(#N)C>[I:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:35][CH2:36][C:37]4[CH:38]=[N:39][CH:40]=[CH:41][CH:42]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:28])=[CH:21][C:22]=1[CH3:27]
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)ccc1I
Reactant: NCc1cccnc1
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)ccc1I
Yield: 96.1 %

Procedure:
To a solution of 2,2,2-trichloro-1-[10-(4-iodo-3-methylbenzoyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl]ethanone of Step B (1 g, 1.74 mmol) in dry acetonitrile (30 mL) at room temperature under nitrogen was added dimethyl sulfoxide (0.62 mL, 8.72 mmol) followed by 3-(aminomethyl)pyridine (0.36 mL, 3.49 mmol) and the reaction mixture heated to reflux for 36 hours. The cooled reaction mixture was concentrated in vacuo to a small volume then partitioned between ethyl acetate (50 mL) and 1 M sodium hydroxide (50 mL). The organic layer was separated, washed with water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using ethyl acetate as solvent afforded a white foam (0.94 g). Recrystallization from ethyl acetate/hexane gave the title compound (0.77 g, 79%) as white solid, m.p. 176-177° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH:7]=[N:8][OH:9])[C:4]([CH3:11])([CH3:10])[O:3]1.[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:9][N:8]=[C:7]([Cl:13])[C@H:5]1[C:4]([CH3:11])([CH3:10])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC1(C)O[C@@H](C=NO)C(C)(C)O1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(S)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75.1 mmol) was dissolved in DMF (200 mL) and cooled in an ice bath. 1-Chloropyrrolidine-2,5-dione (10.0 g, 75.1 mmol) was added and the reaction was stirred overnight while slowly warming to ambient temperature. The pale yellow solution was poured into water (1.5 L) and extracted with EtOAc. The organic layers were washed with water and brine, dried, filtered and concentrated. The residue was purified over silica gel (40% EtOAc in hexanes) to afford (R)-N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol, 79.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[CH:4]=[N:5][OH:6].[Cl:15]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:7][C:3]=1[C:4]([Cl:15])=[N:5][OH:6]
Reactant: ON=Cc1cc(C(F)(F)F)ccc1F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: ON=C(Cl)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
To a solution of 643 mg (3.10 mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde oxime in 5 mL of dimethyl formamide (DMF) was added 456 mg (3.41 mmol) of N-chlorosuccinimide (see K.-C. Liu, B. R. Shelton, and R. K. Howe, J. Org. Chem. 1980, 45, 3916). The reaction mixture was stirred at room temperature overnight, and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation to give 675 mg (2.79 mmol) of pure white crystalline 2-fluoro-5-trifluoromethyl-N-hydroxybenzene-carboximidoyl chloride.
Reaction SMILES: N#N.[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]([OH:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]>C(C#N)(C)=O.O=[Mn]=O>[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([C:17](=[O:19])[CH3:18])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4].[N+:3]([C:6]1[CH:10]=[CH:9][N:8]([CH2:11][C:12]2[O:16][C:15]([CH:17]=[O:19])=[CH:14][CH:13]=2)[N:7]=1)([O-:5])=[O:4]
Reactant: CC(O)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Agent: O=[Mn]=O
Agent: CC(=O)C#N
Agent: N#N
Product: CC(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Product: O=Cc1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-[5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-yl]-ethanol (6.50 g, 27.40 mmol) in AcCN (269.0 mL) was treated at rt with MnO2 (15.881 g, 164.40 mmol) and the reaction mixture was stirred at rt for 16 h before being filtered through Celite. The solvent was removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a mixture with 5-(3-nitro-pyrazol-1-ylmethyl)-furan-2-carbaldehyde. TLC: rf (50:50 hept-EA)=0.20. LC-MS-conditions 02: tR=0.83 min. 1H NMR (400 MHz, CDCl3) characteristic signals δ 2.47 (s, 3H), 5.46 (s, 2H), 6.61 (d, J=3.5 Hz, 1H), 6.95 (d, J=2.3 Hz, 1H), 7.16 (d, J=3.5 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=O)[CH:16]=1.Cl.[NH2:23][OH:24].C(N(CC)CC)C>C(O)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([O:11][CH2:12][O:13][CH3:14])[CH:8]=[CH:7][C:6]=1[C:15]1[CH2:20][CH2:19][CH2:18][C:17](=[N:23][OH:24])[CH:16]=1
Reactant: NO
Reactant: COCOc1ccc(C2=CC(=O)CCC2)c(OCOC)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: COCOc1ccc(C2=CC(=NO)CCC2)c(OCOC)c1
Reaction time: 3 h
Yield: 98 %

Procedure:
3-[2,4-Bis(methoxymethoxy)phenyl]-2-cyclohexen-1-one (200 mg), hydroxylamine hydrochloride (72 mg) and triethylamine (0.14 ml) were heated under reflux in ethanol (10 ml). After 3 hr, the cooled reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over magnesium sulfate and evaporated in vacuo to furnish the title compound as an oil (206 mg, 99%). m/z (ES+) 308 (M+H)+.
Reaction SMILES: C([NH:11][C:12](=[N:47]C(OCC1C=CC=CC=1)=O)[NH:13][CH2:14][CH2:15][CH2:16][C@@H:17]([C:34]([NH:36][C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=1)[CH3:38])=[O:35])[NH:18][C:19](=[O:33])[CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(OCC1C=CC=CC=1)=O.CC(O)=O.[ClH:62]>[Pd].CO>[ClH:62].[C:21]1([CH:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:19]([NH:18][C@H:17]([C:34]([NH:36][C@@H:37]([C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[CH3:38])=[O:35])[CH2:16][CH2:15][CH2:14][NH:13][C:12](=[NH:11])[NH2:47])=[O:33])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc([C@@H](C)NC(=O)[C@H](CCCNC(=NC(=O)OCc2ccccc2)NC(=O)OCc2ccccc2)NC(=O)C(c2ccccc2)c2ccccc2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc([C@@H](C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)C(c2ccccc2)c2ccccc2)cc1

Procedure:
Prepared according to the method described in Example 1(g) above from (R)-Nω,Nω '-bis(Cbz)-N2 -(diphenylacetyl)-(S)-N-[1-(4-methoxyphenyl)ethyl]-arginine amide (2.8 g; from step (e) above), 10% Pd/C (1.5 g), and, instead of HOAc, MeOH (225 mL) and concentrated HCl (21 mL) under hydrogen, 18 hours reaction time, which gave the crude product (1.8 g). Crystallization from MeOH:diethyl ether then from isopropanol:diethyl ether afforded the sub-title compound as a white solid (0.75 g).
Reaction SMILES: [CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([OH:48])=O)[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:60]2[N:61]=[CH:62]C=CC=2N=N1.CNC.C1COCC1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[CH2:1]([O:19][C@H:20]1[C@H:24]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]/[CH:34]=[CH:35]\[CH2:36]/[CH:37]=[CH:38]\[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:23][N:22]([CH2:44][CH2:45][C:46]([N:61]([CH3:62])[CH3:60])=[O:48])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)O)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCC/C=C\C/C=C\CCCCCCCCO[C@@H]1CN(CCC(=O)N(C)C)C[C@H]1OCCCCCCCC/C=C\C/C=C\CCCCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
The 3-((3R,4R)-3,4-bis((9Z,12Z)-octadec-9,12-dienyloxy)pyrrolidin-1-yl)propanoic acid (63 mg, 0.094 mmol) obtained in Example 57 was dissolved in chloroform (2 mL), and stirred overnight at room temperature after adding O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU; Aldrich; 71 mg, 0.187 mmol), a 2 mol/L dimethylamine THF solution (0.234 mL, 0.469 mmol), and diisopropylethylamine (0.082 mL, 0.469 mmol). The aqueous layer was extracted with ethyl acetate after adding a saturated sodium bicarbonate aqueous solution to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=100/0 to 95/5) to give compound 58 (60.7 mg, 92.6%).
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][CH:48]([CH3:52])[C:49](Cl)=[O:50].O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:49](=[O:50])[CH:48]([CH3:52])[CH3:47])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(C)C(=O)Nc1cccc(-c2n[nH]c3ccc(-c4nc[nH]n4)cc23)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 4.4 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.190 g, 0.33 mmol) in pyridine (2 mL) was added 2-methylpropanoyl chloride (0.042 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.005 g, 5% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.02 (s, 1H), 8.65 (s, 1H), 8.21 (s, 1H), 8.10 (br s, 1H), 7.78 (d, 1H), 7.65 (m, 2H), 7.45 (t, 1H), 2.63 (m, 1H), 1.19 (d, 6H); ES-MS (m/z) 347 [M+1]+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][N:12]=1.[C:29]1([N:35]2[CH:39]=[C:38]([NH2:40])[CH:37]=[N:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>O1CCOCC1>[CH3:25][O:24][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15]2[C:14]([N+:26]([O-:28])=[O:27])=[CH:13][N:12]=[C:11]([NH:40][C:38]3[CH:37]=[N:36][N:35]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:39]=3)[N:16]=2)=[CH:19][CH:20]=1
Reactant: COc1ccc(Nc2nc(Cl)ncc2[N+](=O)[O-])cc1
Reactant: Nc1cnn(-c2ccccc2)c1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Nc2nc(Nc3cnn(-c4ccccc4)c3)ncc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
284 g (19.0 mmol) Diisopropylethylamine are added to a solution of 561 mg (2.00 mmol) (2-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine and 350 mg (2.00 mmol) 1-phenyl-1H-pyrazol-4-ylamine in 6 ml dioxane. The mixture is stirred for 16 hours at room temperature. Then water is added to the reaction mixture, the resulting precipitate is filtered off, washed with water and dried under vacuum giving N4-(4-methoxy-phenyl)-5-nitro-N2-(1-phenyl-1H-pyrazol-4-yl)-pyrimidine-2,4-diamine as yellow crystals; HPLC/MS (B): 2.50 min, [M+H] 404.