Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[K+].[OH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([C:14]1[O:19][CH2:18][CH2:17][O:16][N:15]=1)=[CH:11][O:12][CH3:13].[O:20]([C:27]1[C:32]([F:33])=[C:31](F)[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C)C=O>[O:20]([C:27]1[C:32]([F:33])=[C:31]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:10]([C:14]2[O:19][CH2:18][CH2:17][O:16][N:15]=2)=[CH:11][O:12][CH3:13])[N:30]=[CH:29][N:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC=C(C1=NOCCO1)c1ccccc1O
Reactant: Fc1ncnc(Oc2ccccc2)c1F
Agent: [H-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC=C(C1=NOCCO1)c1ccccc1Oc1ncnc(Oc2ccccc2)c1F
Temperature: 20 °C
Reaction time: 12 h
Yield: 32.8 %

Procedure:
0.119 g of potassium hydride (60% suspension in mineral oil) is added to a solution of 0.7 g (0.00298 mol) of 3-[1-(2-hydroxyphenyl)-2-methoxyethen-1-yl]-5,6-dihydro-1,4,2-dioxazine and 0.6 g (0.00288 mol) of 4-phenoxy-5,6-difluoro-pyrimidine in 10 ml of dimethylformamide at 0° C., and the mixture is then stirred for 12 hours at 20° C. The reaction mixture is poured into water and extracted using ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is chromatographed on silica gel using cyclohexane/ethyl acetate (1:1). 0.4 g (82% of theory) of 3-{1-[2-(4-phenoxy-5-fluoropyrimid-6-yloxy)-phenyl]-2-methoxyethen-1-yl}-5,6-dihydro-1,4,2-dioxazine is obtained.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[N:5]=[C:6]2[S:14][CH:13]=[C:12]([CH3:15])[N:7]2[C:8](=[O:11])[C:9]=1[Br:10])[CH3:3].[C:16]([OH:26])(=[O:25])[C@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[OH:18]>C(O)(C)C>[OH:18][C@@H:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]([O-:26])=[O:25].[Br:10][C:9]1[C:8](=[O:11])[N:7]2[C:12]([CH3:15])=[CH:13][S:14][C:6]2=[N:5][C:4]=1[C@@H:2]([NH3+:1])[CH3:3]
Reactant: Cc1csc2nc(C(C)N)c(Br)c(=O)n12
Reactant: O=C(O)[C@@H](O)c1ccccc1
Solvent: CC(C)O
Product: Cc1csc2nc([C@H](C)[NH3+])c(Br)c(=O)n12
Product: O=C([O-])[C@@H](O)c1ccccc1
Temperature: 72 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
7-(1-Aminoethyl)-6-bromo-3-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one (18.8 g, 65.2 mmol) was dissolved in isopropanol (375 mL) at reflux and then (S)-(+)-mandelic acid (4.84 g, 31.8 mmol) in isopropanol (375 mL) was added dropwise to the amine solution over 35 min. The reaction mixture was allowed to cool to about 72° C. and solid precipitation was observed. The slurry was cooled to room temperature and stirred for 1 hour. The solid product was collected by filtration. The wet cake was washed with isopropanol (100 mL) and dried on the filter under suction for 1 h to give the product (S)-1-(6-bromo-3-methyl-5-oxo-5H-thiazolo[3,2-a]pyrimidin-7-yl)ethanaminium (S)-2-hydroxy-2-phenylacetate (11.9 g) as a white solid. Chiral HPLC analysis was performed on a Lux Cellulose-2, 4.6×250 mm, 5 micron column using 60% ethanol/40% hexanes as the mobile phase at a flow rate of 1 mL/min. The major enantiomer eluted at retention time 11.21 min (99.0 area %). The minor enantiomer eluted at retention time 14.31 min (0.96 area %). The e.e. of the desired product was 98.08%.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH:18]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.O>CN(C)C=O>[C:19]1([C:25]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:3]2[N:2]=[N:1][C:5]([C:6]3[CH:7]=[CH:8][C:9]4[NH:10][C:11]5[C:16]([C:17]=4[CH:18]=3)=[CH:15][CH:14]=[CH:13][CH:12]=5)=[N:4]2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc2c(c1)[nH]c1ccc(-c3nn[nH]n3)cc12
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2nnc(-c3ccc4[nH]c5ccccc5c4c3)n2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.3 %

Procedure:
3-(2H-Tetrazol-5-yl)-9H-carbazole (example 401, 17 g, 72.26 mmol) was dissolved in N,N-dimethylformamide (150 mL). Triphenylmethyl chloride (21.153 g, 75.88 mmol) and triethylamine (20.14 mL, 14.62 g, 144.50 mmol) were added consecutively. The reaction mixture was stirred for 18 hours at room temperature, poured into water (1.5 L) and stirred for an additional 1 hour. The crude product was filtered off and dissolved in dichloromethane (500 mL). The organic phase was washed with water (2×250 mL) and dried with magnesium sulfate (1 h). Filtration followed by concentration yielded a solid which was triturated in heptanes (200 mL). Filtration furnished 3-[2-(triphenylmethyl)-2H-tetrazol-5-yl]-9H-carbazole (31.5 g) which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=S(Cl)[Cl:18].[CH:20]([N:23]([CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:25]O)([CH3:22])[CH3:21]>>[ClH:18].[C:1]1([C:7]2([C:13]([O:15][CH2:25][CH2:24][N:23]([CH:27]([CH3:29])[CH3:28])[CH:20]([CH3:22])[CH3:21])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Reactant: CC(C)N(CCO)C(C)C
Reactant: O=S(Cl)Cl
Product: CC(C)N(CCOC(=O)C1(c2ccccc2)CCCCC1)C(C)C
Product: Cl
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
1-Phenyl-cyclohexanecarboxylic acid (1 g, 4.9 mmol) was refluxed with SOCl2 (15 mL). After 0.5 h, the reaction mixture was evaporated and the residue was dissolved in toluene. 2-Diisopropylaminoethanol (1.4 g, 9.8 mmol) was added and the mixture was stirred at 80° C. for 14 h. The reaction mixture was filtered and chromatographed on silica gel using toluene-Et3N 95:5 as eluent. The yield was 1.5 g (84%); mp 119-122° C.; 1H NMR (D2O) δ 1.38 (d, 12H), 1.40 (m, 1H), 1.54 (m, 2H), 1.63-1.76 (m, 3H), 1.95 (t, 2H), 2.45 (d, 2H), 3.44 (t, 2H), 3.67 (m, 2H), 4.44 (t, 2H), 7.43 (t, 1H), 7.51 (t, 2H), 7.54 (d, 2H). Anal. (C21H33NO2.HCl) C, H, N.
Reaction SMILES: [C:1]([O:20][CH2:21][CH2:22][N:23]([C:46](=[O:54])[CH2:47][S:48][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])[CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Br:55][CH2:56][CH2:57][OH:58]>>[Br-:55].[C:1]([O:20][CH2:21][CH2:22][N:23]([CH2:24][CH2:25][O:26][C:27](=[O:45])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]/[CH:35]=[CH:36]\[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:46](=[O:54])[CH2:47][S:48][CH2:49][CH2:50][N+:51]([CH2:56][CH2:57][OH:58])([CH3:53])[CH3:52])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCBr
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CSCCN(C)C
Product: CCCCCCCC/C=C\CCCCCCCC(=O)OCCN(CCOC(=O)CCCCCCC/C=C\CCCCCCCC)C(=O)CSCC[N+](C)(C)CCO
Product: [Br-]
Temperature: 75 °C
Reaction time: 8 h

Procedure:
In a sealed system, (Z)-((2-((2-(dimethylamino)ethyl)thio)acetyl)azanediyl)bis(ethane-2,1-diyl) dioleate (540 mg, 0.693 mmol) was combined with 2-bromoethanol (319 uL, 4.50) was added. The reaction vessel was flushed with inert gas and then sealed. Reaction was heated to 75° C. and allowed to stir overnight. Next day, cooled and concentrated in vacuo. Purification by silica gel chromatography with DCM/MeOH gradient yielded 2-((2-(bis(2-(oleoyloxy)ethyl)amino)-2-oxoethyl)thio)-N-(2-hydroxyethyl)-N,N-dimethylethanaminium bromide (324 mg).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:20].C([N:23]([CH2:26][CH3:27])[CH2:24][CH3:25])C.[CH2:28]1[CH2:32][O:31][CH2:30][CH2:29]1>>[CH:19]([C@H:25]1[C@@H:24]2[C@@H:26]([NH:23]2)[CH:27]=[C:29]([C:30]([O:31][CH3:32])=[O:20])[CH2:28]1)=[CH2:14].[CH:17]1[CH:16]=[CH:15][C:14]([P:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:19][CH:18]=1
Reactant: CCN(CC)CC
Reactant: C1CCOC1
Reactant: O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@@H]2N[C@H]12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Triphenylphosphine can be slowly added to a solution of Example 13I in THF. The reaction mixture can be stirred for 2 hours at room temperature, then water and triethylamine are added. The reaction mixture can be stirred for an additional 10 hours, then the reaction mixture can be concentrated. The concentrate can be chromatographed to afford the desired product with Ph3P as a contaminant.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:15][S:16][CH:17]([C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)[CH3:18].C[O-].[Na+]>ClCCl.O.CO>[CH3:15][S:16][C:17]([C:19]1[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[N:24]=1)([C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4])[CH3:18]
Reactant: Nc1ccccc1Cl
Reactant: COc1cc(OC)nc(C(C)SC)n1
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)nc(C(C)(SC)c2cccc(Cl)c2N)n1
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-Chloroaniline 7 g (32.7 mmol) was dissolved in dichloromethane 100 ml and the solution was cooled to −65° C. To the solution a solution of t-butyl hypochlorite 3.55 g (32.7 mmol) in dichloromethane 10 ml was added dropwise and the solution was stirred at the same temperature for 10 minutes. Then a solution of 2-(1-methylthioethyl)-4,6-dimethoxypyrimidine in dichloromethane was added thereto dropwise and the solution was stirred at the same temperature for 1 hour. After a methanol solution of sodium methoxide 12.6 g (65.3 mmol) had been added dropwise and the mixed solution had been stirred at the same temperature for 10 minutes, the reaction solution was stirred until it came to room temperature. The reaction solution was poured into water and extracted with dichloromethane. The solvent was distilled off and the residue was purified with column chromatography (hexane/ethyl acetate=5/1) to obtain 2-{1-methylthio-1-(2-amino-3-chlorophenyl)ethyl}-4,6-dimethoxypyrimidine 10.0 g (90%).
Reaction SMILES: O[CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=C2C(C(O)(O)C(=O)C2=CC=1)=O>>[Br:14][CH2:2][C@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4]
Reactant: C[C@H](CO)NC(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: O=C1c2ccccc2C(=O)C1(O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@H](CBr)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49 %

Procedure:
A solution of (R)-tert-butyl 1-hydroxypropan-2-ylcarbamate (100 mg, 571 μmol) and carbon tetrabromide (303 mg, 913 μmol) was cooled on an ice bath. Triphenylphosphine (299 mg, 1141 μmol) was added and the reaction was stirred for 10 min. The reaction was then allowed to warm to r.t. and stirred for 18 hours. After this time, a TLC suggested that the reaction was complete (silica, 50% EtOAc/Hexanes, Ninhydrin stain). The solvent was removed and the product purified by column chromatography (0,5,10,15,20% EtOAc/Hexanes) to yield (R)-tert-butyl 1-bromopropan-2-ylcarbamate (67.1 mg, 0.28 mmol, 49.3%) as a colorless oil that turned solid upon standing. LCMS 238.1 (M+H); 1H NMR (400 MHz, MeOH-d4) δ ppm 1.23 (d, J=6.57 Hz, 3 H), 1.46 (s, 9 H), 3.44 (dd, J=5.56, 1.77 Hz, 2 H), 3.71-3.92 (m, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:38]=[CH:37][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:17](=[N:18][CH:19]=[N:20][C:21]=4[NH2:23])[N:16]([C@H:24]4[CH2:29][CH2:28][C@@H:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[N:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[CH2:39]([N:46]=[C:47]=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>N1C=CC=CC=1>[C:6]([OH:48])(=[O:7])[CH3:37].[NH2:23][C:21]1[N:20]=[CH:19][N:18]=[C:17]2[N:16]([C@H:24]3[CH2:29][CH2:28][C@@H:27]([N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH2:26][CH2:25]3)[N:15]=[C:14]([C:11]3[CH:12]=[CH:13][C:8]([O:7][C:6]4[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:47]([NH:46][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=5)=[O:48])=[CH:38][CH:37]=4)=[CH:9][CH:10]=3)[C:22]=12
Reactant: O=C=NCc1ccccc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CN)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Solvent: c1ccncc1
Product: CC(=O)O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(Oc5ccc(CNC(=O)NCc6ccccc6)cc5)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Yield: 54 %

Procedure:
Cis-3-{4-[4-(aminomethyl)phenoxy]phenyl}-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.051 g, 0.0001 mol) was dissolved in anhydrous pyridine (1 mL), benzyl isocyanate (0.013 g, 0.0001 mol) was added and the resulting solution was stirred at ambient temperature for twenty hours. The solvent was removed under reduced pressure and the resulting residue purified by preparative HPLC (Hypersil C 18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield cis-N-[4-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenoxy)benzyl]-N′-benzylurea acetate (0.019 g, 0.000027 mol) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:16][CH3:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:19]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=1.C(=O)(O)[O-].[K+].O>C(#N)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH2:16][CH3:17])[C:19]2[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CCNCC1CCN(Cc2ccccc2)CC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(CC1CCN(Cc2ccccc2)CC1)c1ncccc1[N+](=O)[O-]

Procedure:
1-Benzyl-4-[(N-ethylamino)methyl]piperidine (EXAMPLE 261, 5.68 g) and 2-chloro-3-nitropyridine (3.87 g) are dissolved in 96 ml of acetonitrile and 4.05 g of solid potassium bicarbonate is added. The reaction is refluxed for 20 hr, cooled to 20°-25°, poured into water and extracted with ethyl acetate. The organic extracts are dried (sodium sulfate), and concentrated under reduced pressure. Purification by flash column chromatography (15% ethyl acetate/hexane to 80% ethyl acetate/hexane) gives the title compound, HRMS calcd. for C20H26N4O2 =354.2056, found=354.2045.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].Cl.[N+]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=[O:14]>>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:14])=[O:4].[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([C:19]1[CH:20]=[CH:21][C:16]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:17][CH:18]=1)=[O:4]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: CCC(C)C(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCC(C)C(=O)O
Product: CCC(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Yield: 54 %

Procedure:
Then, 4.0 g of (+)-2-methylbutanoic acid chloride and 7 ml of nitrobenzene were charged into a flask and cooled to 0° C., to which was added 10.74 g (80 mmol) of aluminum chloride with stirring and further added a solution of 4.97 g (19.6 mmol) of (+) 2-methylbutanoic acid-4-biphenyl in 9 ml of nitrobenzene and then stirred at room temperature for 70 hours. Thereafter, the resulting mixture was added with 2 normal hydrochloric acid and ice and extracted with chloroform. The chloroform layer was washed with water, dried on anhydrous magnesium sulfate, and purified by a column chromatography of silica gel after the distillation off of the solvent to obtain 3.60 g (yield 54%) of oily 2-methylbutanoic acid-4-(2-methylbutanoyl) biphenyl. The NMR analytical values of this purified product were as follows.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:25])[CH3:24])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5])[CH3:3].[NH:29](C(OC(C)(C)C)=O)[C@H:30]([C:41](O)=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(O)(C(F)(F)F)=O.C(Cl)Cl>CN(C=O)C>[NH2:29][C@H:30]([C:41]([NH:1][C@H:2]([C:4]([NH:6][C@H:7]([C:18]([NH:20][C@H:21]([C:26]([NH2:28])=[O:27])[CH2:22][CH:23]([CH3:24])[CH3:25])=[O:19])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:17])[NH:13][N+:14]([O-:16])=[O:15])=[O:5])[CH3:3])=[O:42])[CH2:31][CH2:32][CH2:33][NH:34][C:35](=[NH:40])[NH:36][N+:37]([O-:39])=[O:38]
Reactant: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)N)C(N)=O
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](CCCNC(=N)N[N+](=O)[O-])NC(=O)[C@H](C)NC(=O)[C@@H](N)CCCNC(=N)N[N+](=O)[O-])C(N)=O

Procedure:
From 515 g of H-Ala-Arg(NO2)-Leu-NH2 in 2.5 l of DMF and 333 g of Boc-Arg(NO2)-OH and 500 g of BOP, 607 g (85%) of a white solid monitored by TLC and NMR are obtained by employing the operational conditions described in Example I-1, after treatment with the mixture TFA-CH2Cl2.
Reaction SMILES: [NH2:1][OH:2].CO.Cl[C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH3:23])[N:13]=[C:14]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:7]=12>C(O)C>[OH:2][NH:1][C:6]1[N:11]=[CH:10][N:9]=[C:8]2[N:12]([CH3:23])[N:13]=[C:14]([C:15]3[O:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[C:7]=12
Reactant: NO
Reactant: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(Cl)ncnc21
Solvent: CCO
Solvent: CO
Product: Cn1nc(-c2ccc([N+](=O)[O-])o2)c2c(NO)ncnc21
Reaction time: 0.5 h

Procedure:
A solution containing 0.7 grams of anhydrous hydroxylamine in 50 millilitres if methanol was added to a solution containing 1.4 grams of 4-chloro-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d]pyrimidine dissolved in 600 millilitres of ethanol, at a temperature of 30° C. and the mixture was allowed to stand for 30 minutes at room temperature. The mixture was gently heated at reflux for a further 15 minutes and cooled. The crystalline product was washed with ether and dried. Recrystallisation from dimethylformamide gave 4-hydroxyamino-1-methyl-3-(5-nitro-2-furyl)-1H-pyrazolo [3,4-d] pyrimidine, having melting point 294° C.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:16][C:15](N)=[N:14][N:13]=2)[CH2:8][CH2:7]1.[C:24]([Cu])#[N:25].O.C(Cl)Cl>CC#N>[F:23][C:2]([F:22])([F:1])[C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[O:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[S:16][C:15]([C:24]#[N:25])=[N:14][N:13]=2)[CH2:10][CH2:11]1
Reactant: N#C[Cu]
Reactant: Nc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: N#Cc1nnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Temperature: 55 °C

Procedure:
To a suspension of 5-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3,4-thiadiazol-2-amine (10.0 g, 29.0 mmol) in CH3CN (150 mL) was added CuCN (5.3 g, 59.2 mmol) and t-BuONO (90%) (8 mL, 60.0 mmol) at room temperature. The reaction mixture was heated at 50-60° C. for 2 h until TLC indicated disappearance of the starting material. The reaction mixture was poured into water and CH2Cl2 was added. The solid was removed by filtration and the filtrate was extracted with CH2Cl2, dried (Na2SO4) and filtered. Solvents were removed in vacuo to afford the crude product, which was purified by column chromatography on silica gel (eluting with 5:1 petroleum ether/EtOAc) to afford the title compound. 1H NMR (400 MHz, CDCl3): δ7.61 (d, 1H), 7.50 (t, 1H), 6.93-7.06 (m, 2H), 4.86 (br s, 1H), 3.77-3.83 (m, 4H), 2.01-2.20 (m, 4H). MS: m/z 355 (MH+).
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.Cl.[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH2:26])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]>>[ClH:11].[Cl:11][C:12]1[CH:13]=[C:14]([C:19]2[O:23][C:22]([CH2:24][CH2:25][NH:26][C:7]([C:5]3[N:6]=[C:2]([CH3:1])[NH:3][CH:4]=3)=[O:9])=[CH:21][CH:20]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: NCCc1ccc(-c2ccc(Cl)c(Cl)c2)o1
Reactant: Cc1nc(C(=O)O)c[nH]1
Agent: Cl
Product: Cc1nc(C(=O)NCCc2ccc(-c3ccc(Cl)c(Cl)c3)o2)c[nH]1

Procedure:
The title compound was prepared as in Example 12 starting from 2-methyl-1H-imidazole-4-carboxylic acid and 2-[5-(3,4-dichlorophenyl)furan-2-yl]ethylamine hydrochloride. The crude product was purified by flash chromatography using CH—2Cl2/MeOH as a gradient eluent (100:0-97:3). The product was dissolved in DCM, ethyl acetate saturated with hydrogen chloride was added and the precipitated product as a hydrogen chloride salt was filtered. Recrystallization from MeOH/EtOAc. The HCl salt: 1H NMR (400 MHz, MeOH-d4): 2.62 (3H, s), 3.02 (1H, t), 3.69 (1H, t), 6.26 (1H, d), 6.76 (1H, d), 7.49 (1H, distorted d), 6.53 (1H, distorted dd), 7.71 (1H, d), 7.82 (1H, s).
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@H:13](O)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Cl:54])C(=O)C1>C(Cl)Cl>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@:14]([F:26])([CH3:25])[C@@H:13]([Cl:54])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@]1(F)[C@H](O)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[C@@]1(F)[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@@H]1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of mixture of compound 8 (1.0 g, 2.67 mmol) and PPh3 (1.4 g, 5.34 mmol) in CH2Cl2 (15 mL) was added NCS (1.07 g, 8.01 mmol) portionwise at 0° C. Then the resulting mixture was stirred at rt for 1 h and poured into a silica gel column and eluted with EtOAc-hexanes (1:4) using pressure. The collected right fractions were combined, concentrated, and co-evaporated with CH2Cl2 several times and used next step (1.0 g, 95%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:23]1[CH:24]=[CH:25][C:26]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)=[C:27]([CH:37]=1)[C:28]([NH:30][C:31]1[CH:36]=[CH:35][N:34]=[N:33][CH:32]=1)=[O:29]>COCCOC.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>[F:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][O:38][C:26]2[CH:25]=[CH:24][C:23]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)=[CH:37][C:27]=2[C:28]([NH:30][C:31]2[CH:36]=[CH:35][N:34]=[N:33][CH:32]=2)=[O:29])=[CH:45][CH:44]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(Nc1ccnnc1)c1cc(Br)ccc1OCc1ccc(F)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: COCCOC
Product: Cn1cc(-c2ccc(OCc3ccc(F)cc3)c(C(=O)Nc3ccnnc3)c2)cn1
Temperature: 120 °C

Procedure:
1-Methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.37 mmol), 1M sodium carbonate (0.75 ml, 0.75 mmol) and tetrakis(triphenylphosphine)palladium(0) (25.9 mg, 0.02 mmol) were added to a solution of 5-bromo-2-{[(4-fluorophenyl)methyl]oxy}-N-4-pyridazinylbenzamide (may be prepared as described in Example 77; 150 mg, 0.37 mmol) in 1,2-dimethoxyethane (4 ml). The reaction was heated at 120° C. for one hour. The solvent was removed in vacuo to give a residue. Purification by MDAP yielded the title compound as a white solid. 50 mg.