Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:21][CH3:22])=[CH:10][C:9]=2[CH3:23])=[O:4].[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1>>[CH2:21]([C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:23])[CH:10]=1)[N:7]=[C:6]([N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH3:25])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: CCc1cc(C)c2nc(Cl)c(C(=O)OC)c(-c3ccccc3)c2c1
Reactant: CC1CCCN1
Product: CCc1cc(C)c2nc(N3CCCC3C)c(C(=O)O)c(-c3ccccc3)c2c1

Procedure:
The title compound was prepared in analogy to example 54 step F from 2-chloro-6-ethyl-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 54 step E) and 2-methylpyrrolidine. Light brown solid. MS (ESI): 375.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][OH:7])([O-:3])=[O:2].[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[N+](C1C=CC=CC=1COC(CCCCCCCCN)=O)([O-])=O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6][O:7][C:19]([NH:18][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:20])([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CO
Reactant: O=C=NC1CCCCC1
Agent: NCCCCCCCCC(=O)OCc1ccccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCC1)OCc1ccccc1[N+](=O)[O-]

Procedure:
[[(2-nitrobenzyl)oxy]carbonyl]cyclohexylamine was prepared using 2-nitrobenzylalcohol, cyclohexylisocyanate, and toluene solvent in the same preparation method of [[(2-nitrobenzyl)oxy]carbonyl]octylamine as in Example 1.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][C@:10]3([CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23](F)=[N:24][CH:25]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([N:14]2[CH2:15][CH2:16][CH2:17][C@@:10]3([C:9](=[O:18])[N:8]([CH:5]4[CH2:6][CH2:7][O:2][CH2:3][CH2:4]4)[CH2:12][CH2:11]3)[CH2:13]2)=[N:24][CH:25]=1
Reactant: O=C1N(C2CCOCC2)CC[C@]12CCCNC2
Reactant: Fc1ccc(Cl)cn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1N(C2CCOCC2)CC[C@]12CCCN(c1ccc(Cl)cn1)C2
Temperature: 120 °C

Procedure:
A mixture of (5S)-2-(tetrahydro-2H-pyran-4-yl)-2,7-diazaspiro[4.5]decan-1-one hydrochloride (29.4 mg, 0.000107 mol, this compound was prepared by using procedures analogous to those described for the synthesis of example 92, steps 1-3), 5-chloro-2-fluoropyridine (17 mg, 0.000013 mol) and potassium carbonate (0.029 mL, 0.00032 mol) in N,N-dimethylformamide (0.6 mL, 0.008 mol) was heated at 120° C. for 5 h. The crude product was purified by prep-HPLC to afford the desired product. LC-MS: 350.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][NH:4][C:5]1[C:6]([NH2:29])=[N:7][C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)=[N:9][C:10]=1[NH2:11].C1N=CN([C:37](N2C=NC=C2)=[O:38])C=1.C(N(CC)CC)C>CN(C)C=O>[NH2:29][C:6]1[N:7]=[C:8]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[N:13]=2)[N:9]=[C:10]2[C:5]=1[N:4]([CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:37](=[O:38])[NH:11]2
Reactant: CC(C)(C)CNc1c(N)nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(=O)[nH]c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c21
Temperature: 100 °C
Reaction time: 8 h

Procedure:
447 mg (0.94 mmol) of the compound from example 64A were initially charged in dimethylformamide (5 ml), then 758 mg (4.68 mmol) of N,N-carbonyldiimidazole and 1.57 ml (11.23 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. The reaction mixture was purified directly by means of preparative HPLC (eluent: methanol/water with 0.1% formic acid gradient). This gave 163 mg (39% of theory) of the title compound in solid form.
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:32])[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][N:20]3C(OC(C)(C)C)=O)[CH2:11][CH2:10]2)[CH2:5][CH2:4]1>C(OCC)(=O)C.C(OCC)C>[ClH:1].[ClH:1].[ClH:1].[CH3:2][N:3]1[CH2:4][CH2:5][CH:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15](=[O:32])[CH2:16][O:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]3)[CH2:11][CH2:10]2)[CH2:7][CH2:8]1
Reactant: CN1CCC(N2CCN(C(=O)COCC3CCCCN3C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CN1CCC(N2CCN(C(=O)COCC3CCCCN3)CC2)CC1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
Hydrogen chloride (26.0 ml, 52.10 mmol, 2 M solution in diethyl ether) was added at room temperature to a solution of tert-butyl 2-((2-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)-2-oxoethoxy)methyl)piperidine-1-carboxylate (4.57 g, 10.42 mmol) in a mixture of ethyl acetate (15 ml) and diethyl ether (50 ml). The reaction mixture was stirred for 2 h at 45° C. Then the resulting white solid was filtered off and dried.
Reaction SMILES: [CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:14]=O)[CH:9]=[C:10]([CH:13]=1)[CH:11]=O)[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29].[BH4-].[Na+].[OH-].[Na+]>CCOC(C)=O.CO>[CH2:1]([CH:3]([CH2:16][CH3:17])[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:14][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:9]=[C:10]([CH2:11][NH:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH:13]=1)[CH3:2]
Reactant: CCC(CC)COc1cc(C=O)cc(C=O)c1
Reactant: CC(C)CNCCCNCCCN
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(CC)COc1cc(CNCCCNCCCNCC(C)C)cc(CNCCCNCCCNCC(C)C)c1
Reaction time: 24 h

Procedure:
5-(2-Ethylbutoxyl)isophthalaldehyde (0.20 g, 0.88 mmol) and MeOH (15 mL) were added to a round-bottom flask. To the solution was added N1-(3-aminopropyl)-N3-isobutylpropane-1,3-diamine (0.33 g, 1.76 mmol) and the reaction mixture was stirred for 24 h. Sodium borohydride (0.13 g, 3.52 mmol) was added and the reaction mixture stirred for 1 h. The reaction mixture was concentrated under reduced pressure to afford a white solid. Aqueous NaOH (10%, 50 mL) and EtOAc (50 mL) were added and the reaction mixture stirred for 1 h. The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The organic layers were combined, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product a clear oil.
Reaction SMILES: [C:1]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[NH:2][NH2:3].[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>C(O)C>[N:19]1[CH:24]=[CH:23][C:22]([CH:25]=[N:3][NH:2][C:1]([O:5][CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:4])=[CH:21][CH:20]=1
Reactant: O=Cc1ccncc1
Reactant: NNC(=O)OC(c1ccccc1)c1ccccc1
Solvent: CCO
Product: O=C(NN=Cc1ccncc1)OC(c1ccccc1)c1ccccc1
Yield: 78.6 %

Procedure:
To 24.11 gm (0.1 mole) of benzhydryl carbazate in 200 ml of warm absolute ethanol is added 10.66 gm (0.1 mole) of 4-pyridinecarboxaldehyde in 75 ml of absolute ethanol. The mixture is refluxed 7 hr and cooled. The solvent is removed in vacuo. Recrystallization from ethanol-Skellysolve B yields 26.03 gm (78.5%) of the title compound having a melting point of 159°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.Br[CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH:28]([CH3:36])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[N:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Reactant: CC(Br)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C(C)C(=O)OC(C)(C)C)cc1NC(=O)c1cnn2cccnc12
Temperature: 75 °C
Yield: 70.4 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.7 mmol, 1 equiv), tert-butyl 2-bromopropanoate (0.54 mL, 3.2 mmol, 1.2 equiv), and cesium carbonate (1.1 g, 3.2 mmol, 1.2 equiv) in N,N-dimethylformamide (15 mL) was heated at 75° C. for 3 h. The reaction mixture was concentrated, and the resulting residue was partitioned between half-saturated aqueous sodium chloride solution (50 mL) and ethyl acetate (50 mL). The aqueous was extracted with ethyl acetate (2×50 mL). The collected organic was dried over anhydrous sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (90% ethyl acetate in heptane) provided product (0.945 g, 70%). LCMS (ESI): M+H=497.2.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:16][O:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:15][CH2:14]1.IC.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:13]1([CH2:16][O:17][CH:18]2[CH2:23][CH2:22][C:21]([CH3:1])([C:24]([OH:26])=[O:25])[CH2:20][CH2:19]2)[CH2:14][CH2:15]1
Reactant: CC(C)NC(C)C
Reactant: O=C(O)[C@H]1CC[C@H](OCC2CC2)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCC(OCC2CC2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diisopropylamine (15 mL, 105 mmol) in THF (100 mL) was cooled to 0° C. under Ar. n-Butyllithium (38 mL, 95 mmol, 2.5M in hexane) was added dropwise over 10 min. The reaction mixture was left to stir for 15 min at 0° C. A solution of 4-[(cyclopropylmethyl)oxy]cyclohexanecarboxylic acid (D43, 9.47 g, 43.0 mmol) in THF (50 mL) was added and the resulting yellow solution was heated at 50° C. for 2 h. The reaction mixture was cooled to 0° C. and iodomethane (8 mL, 128 mmol) was added dropwise, the reaction was then allowed to warm to rt and left to stir for 3 days. 10% Citric acid (200 mL) was then added and the reaction mixture was concentrated by rotary evaporation. The residual mixture was diluted with H2O and extracted with Et2O (2×). The organics were combined, dried (Na2SO4) and concentrated by rotary evaporation to give a mixture of cis and trans 4-[(cyclopropylmethyl)oxy]-1-methylcyclohexanecarboxylic acid (D44, 10.0 g, 93%) as a brown oil.
Reaction SMILES: [CH:1]1([N:7]2[C:11]([NH2:12])=[CH:10][C:9]([CH3:13])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:14]1([C:17](=O)[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]1>>[CH:1]1([N:7]2[C:11]3[N:12]=[C:17]([CH:14]4[CH2:15][CH2:16]4)[CH:18]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]=3[C:9]([CH3:13])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(N)n(C2CCCCC2)n1
Reactant: CCOC(=O)C(=O)CC(=O)C1CC1
Product: CCOC(=O)c1cc(C2CC2)nc2c1c(C)nn2C1CCCCC1

Procedure:
The title compound was prepared in the same manner as described for intermediate 37 using 1-(1-cyclohexyl)-3-methyl-1H-pyrazol-5-amine (500 mg, 2.79 mmol) and ethyl 4-cyclopropyl-2,4-dioxobutanoate (514 mg, 2.79 mmol). The final product was collected as a solid, 0.827 g (91%). LCMS E-S (M+H)=328.3 1H NMR (400 MHz, DMSO-d6) δ ppm 1.01-1.10 (m, 3 H), 1.20-1.30 (m, 1 H), 1.37 (t, J=7.07 Hz, 3 H), 1.41-1.52 (m, 2 H), 1.70 (d, 1 H), 1.79-1.98 (m, 6 H), 2.30-2.38 (m, 1 H), 2.54 (s, 3 H), 4.42 (q, J=7.07 Hz, 2 H), 4.60-4.74 (m, 1 H), 7.44 (s, 1 H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH:7]([OH:8])[CH2:6][C@H:5]([C:9]2[N:14]=[C:13]3[NH:15][N:16]=[C:17]([I:18])[C:12]3=[C:11](C)[N:10]=2)[O:4]1.[OH-].[NH4+:21]>>[NH2:21][C:11]1[N:10]=[C:9]([C@@H:5]2[O:4][C@H:3]([CH2:2][OH:1])[CH:7]([OH:8])[CH2:6]2)[N:14]=[C:13]2[NH:15][N:16]=[C:17]([I:18])[C:12]=12
Reactant: [NH4+]
Reactant: Cc1nc([C@H]2CC(O)[C@@H](CO)O2)nc2[nH]nc(I)c12
Agent: [OH-]
Product: Nc1nc([C@H]2CC(O)[C@@H](CO)O2)nc2[nH]nc(I)c12

Procedure:
Compound 8 (6.8 g, 17.35 mmol) was stirred in 200 mL of concentrated ammonium hydroxide (sealed container) at room temperature for 36 h. The mixture was evaporated and the residue was precipitated from acetonitrile-ether. The solid was filtered and dried: 5.36 g (82%) yield. NMR and spectral data on this compound is identical to.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10])[OH:7])([CH3:3])[CH3:2].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC.[NH4+].[Cl-]>C1COCC1.O>[CH3:16][C@@H:8]([C@@H:6]([OH:7])[C:5]([O:4][CH:1]([CH3:2])[CH3:3])=[O:15])[C:9]([O:11][CH:12]([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)OC(=O)C[C@H](O)C(=O)OC(C)C
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: CC(C)OC(=O)[C@@H](C)[C@@H](O)C(=O)OC(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To a cold (−78° C.) solution of diisopropyl-(S)-(−)-malate (4.72 mL, 22.9 mmol, 1 eq.) in anhydrous THF (8.50 mL) was added slowly a solution (1 M) of lithium bis(trimethylsilyl)amide (48.1 mL, 48.1 mmol, 2.10 eq.) in THF. The temperature was raised to 20° C. over 30 minutes, than lowered again to −78° C. Iodomethane (1.7 mL, 28 mmol, 1.20 eq.) was added and the mixture stirred at RT for 16 hours. The reaction mixture was then cooled to 0° C. and a saturated solution of NH4Cl was added. The resulting mixture was diluted with water, extracted three times with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated under reduced pressure. The residue was then purified by chromatography (SiO2, 20/80 EtOAc/c-hex) to give the product (mixture of diatereoisomers) as a colourless oil (3.77 g, 71%).
Reaction SMILES: [C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12](=[S:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25]Br)=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.[I-].[K+]>C(#N)C>[C:1]([C:5]1[CH:30]=[CH:29][C:8]([C:9]([NH:11][C:12](=[S:28])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:27])[CH2:22][CH2:23][CH2:24][CH2:25][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:16][CH:15]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCBr)cc2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCN3CCOCC3)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-pentanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide (intermediate JH140, prepared as described for tenovin 6) (80 mg, 0.16 mmol) in acetonitrile (4 mL) was added morpholine (0.4 mL) and potassium iodide (cat. amount). The reaction mixture was heated at reflux for 40 min, cooled to rt and concentrated in vacuo. The remaining residue was partitioned between 75% saturated aqueous sodium bicarbonate and CH2Cl2. The organic layer was dried with MgSO4 and concentrated in vacuo to give a crude beige solid. Purification by recrystallisation from EtOAc gave 5-morpholin-4-yl-pentanoic acid {4-[3-(4-tert-butyl-benzoyl)-thioureido]-phenyl}-amide which was converted to the hydrochloride salt by vapour diffusion. A solution of the dimethylamine in 25% CDCl3/diethyl ether was exposed to hydrogen chloride to give 1 as a white precipitate which was collected by filtration.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:28])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[S:16]([O:19][NH:20]C(=O)OC(C)(C)C)(=[O:18])=[O:17].[N:29]1[C:38]2[CH:37]=[CH:36][N:35]=[C:34]([NH2:39])[C:33]=2[CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[NH2:20][N:35]1[CH:36]=[CH:37][C:38]2[N:29]=[CH:30][CH:31]=[CH:32][C:33]=2[C:34]1=[NH2+:39].[CH3:15][C:10]1[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:28])[C:9]=1[S:16]([O-:19])(=[O:18])=[O:17]
Reactant: Nc1nccc2ncccc12
Reactant: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Nn1ccc2ncccc2c1=[NH2+]
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To trifluoroacetic acid (10 mL), stirred at 0° C., was added tert-butyl mesitylsulfonyloxycarbamate (6.50 g, 20.6 mmol), and the mixture was stirred at 0° C. for 30 min. The mixture was poured into ice-water (10 mL). A white precipitate was formed, which was filtered and collected. The white precipitate was dissolved in DCM (20 mL), and dried with Na2SO4. To the DCM solution was added 1,6-naphthyridin-5-amine (1.0 g, 6.88 mmol), and the mixture was stirred at room temperature for 4 h. The solvent was removed under reduced pressure and the residue was washed with Et2O (3×15 mL). The yellow solid obtained was used in the next step without further purification (3.30 g). ESI MS: m/z 161 [M+H]+.
Reaction SMILES: O([C:3]([CH3:6])([CH3:5])[CH3:4])[K].BrP(C)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:28]1[C:32]2([CH2:37]CC(=O)C[CH2:33]2)[O:31][CH2:30][CH2:29]1>CCOCC>[CH2:4]=[C:3]1[CH2:6][CH2:37][C:32]2([O:31][CH2:30][CH2:29][O:28]2)[CH2:33][CH2:5]1
Reactant: CC(C)(C)O[K]
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOCC
Product: C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.3 %

Procedure:
A mixture of KO-tBu (7.4 g, 65.9 mmol) and bromo(methyl)triphenylphosphorane (21.6 g, 60.5 mmol) in ether (100 mL) was refluxed for 0.5 h. Then a solution of 1,4-dioxaspiro[4.5]decan-8-one (6.24 g, 40.0 mmol) in ether (100 mL) was added dropwise during 1.5 h. The reaction mixture was stirred for 2 h, cooled to rt, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography (EtOAc/hexane) to afford 8-methylene-1,4-dioxaspiro[4.5]decane (1.5 g) as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 4.62-4.74 (2H, m), 3.98 (4H, s), 2.30 (4H, dd, J=7.03, 6.02 Hz), 1.66-1.77 (4H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[Cl:7][C:8]1[CH:9]=[C:10]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([Cl:41])[CH:35]=2)[OH:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)O)[CH:11]=[CH:12][C:13]=1[CH3:14]>C(O)C>[Cl:7][C:8]1[CH:9]=[C:10]([B:15]([CH:17]([O:24][CH:25]([B:32]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[C:36]([Cl:41])[CH:35]=2)[O:33][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:5][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1])[CH:11]=[CH:12][C:13]=1[CH3:14]
Reactant: Cc1ccc(B(O)C(OC(B(O)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl
Reactant: CN(C)CCO
Solvent: CCO
Product: Cc1ccc(B(OCCN(C)C)C(OC(B(OCCN(C)C)c2ccc(C)c(Cl)c2)c2ccccc2)c2ccccc2)cc1Cl

Procedure:
The entitled compound (5 mg) was obtained by allowing 22 mg of N,N-dimethylethanolamine to act on 99 mg of bis(4,4′-(3-chloro-4-methylphenyl-hydroxyboryl)benzyl) ether in 0.5 mL of ethanol.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([OH:15])=O)[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[N:6][CH:7]=2.[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>O.CN(C)C=O>[CH3:1][N:2]1[C:10](=[O:11])[N:9]([CH2:12][C:13]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:15])[C:8]2[C:3]1=[N:4][C:5]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[N:6][CH:7]=2
Reactant: Nc1ccccc1
Reactant: Cn1c(=O)n(CC(=O)O)c2cnc(-c3ccccc3)nc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(=O)n(CC(=O)Nc2ccccc2)c2cnc(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.3 %

Procedure:
A mixture of 8,9-dihydro-9-methyl-8-oxo-2-phenyl-7H-purin-7-acetic acid (3 g) obtained in Example 48-(2), aniline (1.3 g), BOP reagent (5.1 g), triethylamine (1.2 g) and dimethylformamide (20 ml) is stirred at room temperature for two hours. To the reaction mixture is added water, and the precipitates are collected by filtration, and washed with water to give crude 8,9-dihydro-9-methyl-8-oxo-2-phenyl-N-phenyl-7H-purin-7-acetamide (3.5 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([CH3:24])=[CH2:23]>CN(C=O)C>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][CH2:23][C:22]([CH3:24])=[CH2:21]
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1cc(C(=O)OC)ccc1OC
Temperature: 60 °C
Reaction time: 5 h

Procedure:
22 g of methyl 3-hydroxy-4-methoxybenzoate are dissolved in 200 ml of anhydrous DMF and 41 g of ground potassium carbonate and 14.7 ml of 3-chloro-2-methylpropene are then added. The mixture is stirred at 60° C. for 5 h. After cooling, the precipitate is filtered off with suction, water is added to the filtrate and it is then extracted 3 times with ethyl acetate. The residue which remains after concentrating the extracts is crystallized using petroleum ether. 21 g of the title compound of m.p. 62-63° C. are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.[CH:18]([Mg]Br)=[CH2:19]>C1COCC1.C(Cl)Cl>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:14])([CH:18]=[CH2:19])[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:15]=1
Reactant: C=C[Mg]Br
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (326 mg) in THF (10 mL)-78° C. was added vinyl magnesium bromide (2.42 mL of 1.0 M in THF) dropwise. The resulting mixture was then stirred at 0° C. for 2 hr. The resulting mixture was quenched with H2O and 1 N HCl, extracted with EtOAc, dried over Na2SO4, filtered, and concentrated to yield a residue. The residue was purified by flash chromatography with Biotage 40s+ column and elution with 10%-40% EtOAc/hexanes to yield a yellow gum. The yellow gum was dissolved in a minimal amount of CH2Cl2 and triturated with hexanes to yield the title compound as a light yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([NH:8][CH2:9][CH:10]([OH:13])[CH2:11]O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl[C:17]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])=[CH:19][C:18]=1[N+:30]([O-:32])=[O:31].[C:33](=[O:36])([O-])[O-].[K+].[K+]>C(#N)C.C(Cl)(Cl)Cl.C(O)(C)C>[N+:30]([C:18]1[CH:19]=[C:20]([S:23]([C:26]([F:29])([F:28])[F:27])(=[O:25])=[O:24])[CH:21]=[CH:22][C:17]=1[O:13][CH:10]([CH2:11][O:36][C:33]1[CH:22]=[CH:21][C:20]([S:23]([C:26]([F:29])([F:27])[F:28])(=[O:24])=[O:25])=[CH:19][C:18]=1[N+:30]([O-:32])=[O:31])[CH2:9][NH:8][C:7]1[CH:14]=[CH:15][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([O-:32])=[O:31]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)C(F)(F)F)ccc1Cl
Reactant: O=[N+]([O-])c1ccc(NCC(O)CO)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CC(C)O
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(NCC(COc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])Oc2ccc(S(=O)(=O)C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of 3-(4-nitroanilino)-1,2-propanediol (71 mg, 0.33 mmol), 1-chloro-2-nitro-4-trifluoromethanesulfonyl-benzene (135 mg, 0.47 mmol) and potasium carbonate (190 mg, 1.33 mmol) in acetonitrile (2 mL) was heated to reflux for 2 days. The reaction was diluted with chloroform/isopropanol mixture, washed with brine, dried, concentrated and column chromatographed to give the title compound (di-arylated) and 1-(4-nitro-phenylamino)-3-(2-nitro-4-trifluoromethanesulfonyl-phenoxy)-propan-2-ol (mono-arylated). 1H NMR (360 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.37 (dd, 1H), 8.30 (d, J=8.8 Hz, 2H), 7.83 (d, 1H), 7.66 (d, J=8.8 Hz, 2H), 7.50 (dd, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 4.91 (m, 1H), 4.76 (m, 2H), 4.15 (dd, 1H), 3.91 (dd, 1H).