Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].Cl[S:21]([OH:24])(=[O:23])=[O:22].Cl.C[O-].[Na+:28]>C(Cl)(Cl)Cl>[S:21]([O-:24])([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:23])=[O:22].[Na+:28]
Reactant: O=S(=O)(O)Cl
Reactant: CCCCCCCCCCC(C)CCCCCCO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCC(C)CCCCCCOS(=O)(=O)[O-]
Temperature: 27.5 °C
Reaction time: 1 h

Procedure:
Into a dried 1 L 3 neck round bottom flask fitted with a nitrogen inlet, dropping funnel, thermometer, mechanical stirring and nitrogen outlet is added chloroform (300 ml) and 7-Methylheptadecanol (102 g, 0.378 mol), prepared as an intermediate in Example III. Chlorosulfonic acid (46.7 g, 0.40 mol) is slowly added to the stirred mixture while maintaining 25-30° C. temperature with a ice bath. Once HCl evolution has stopped (1 hr.) slowly add sodium methoxide (25% in methanol) while keeping temperature at 25-30° C. until an aliquot at 5% concentration in water maintains a pH of 10.5. To the mixture is added hot methanol (45° C.,1 L) to dissolve the branched sulfate followed immediately by vacuum filtration to remove the inorganic salt precipitate and repeated a second time. The filtrate is then cooled to 5° C. at which time 1 L of ethyl ether is added and let stand for 1 hour. The precipitate is collected by vacuum filtration. The product is dried in a vacuum oven at 50° C. for 3 hrs. to obtain a white solid (89 g, 88% active by cat SO3 titration). HNMR of the final product (in deuterium oxide) indicates a CH2 --OSO3 -- triplet at the 3.8 ppm resonance, CH2 --CH2 --OSO3 -- multiplet at the 1.5 ppm resonance, CH2 of the alkyl chain at the 0.9-1.3 ppm resonance and CH--CH3 branch point overlapping the R--CH2CH3 terminal methyl group at the 0.8 ppm resonance. Mass spectrometry data shows a molecular ion peak with a mass of 349.1 corresponding to the 7-methylheptadecyl sulfate ion. Also shown is the methyl branch at the 7 position due to the loss of 29 mass units at that position.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:7])([CH3:6])[C:4]#[N:5].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>ClCCl.N1C=CC=CC=1.C(OCC)C>[CH3:18][C:8]1[CH:13]=[CH:12][C:11]([S:14]([O:1][CH2:2][C:3]([C:4]#[N:5])([CH3:7])[CH3:6])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C#N)CO
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC(C)(C)C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-hydroxy-2,2-dimethylpropanenitrile (0.5 g) in dichloromethane (8 mL) and pyridine (1.5 mL) is added at 0° C. p-toluene-sulfonylchloride (1.0 g) in portions. The mixture is stirred for 12 hours at room temperature, diluted with diethylether and washed with 1 M aqueous HCl solution and brine. After drying (MgSO4) the solvent is evaporated and the residue is chromatographed on silica gel (petrole ether/ethyl acetate 90:10→50:50) to give the title compound. Yield: 770 mg; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.Cl[C:22]([O:24][CH2:25][CH2:26][CH3:27])=[O:23].C(N(CC)CC)C>CCO>[CH2:25]([O:24][C:22](=[O:23])[NH:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:19]#[N:20])=[CH:7][N:8]2[C:11]2[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1)[CH2:26][CH3:27]
Reactant: COc1ccc(-n2cc(C#N)c3ccc(N)cc32)cc1
Reactant: CCCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCOC(=O)Nc1ccc2c(C#N)cn(-c3ccc(OC)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Amino-1-(4-methoxyphenyl)-1H-indole-3-carbonitrile (30 mg, 0.12 mmol), is suspended in EtOH (300 μL). Propyl chloroformate (168 μL, 1.5 mmol) is added, and this mixture is stirred at room temperature overnight. The addition of triethylamine (300 μL), followed by another hour of stirring at room temperature, completes the reaction. This reaction mixture is loaded directly onto a silica column, and is eluted with CH2Cl2. Another silica column (3/2, ether/hexanes) is needed to fully purify the product, [3-cyano-1-(4-methoxy-phenyl)-1H-indol-6-yl]-carbamic acid propyl ester (19 mg, 45%), as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23](OCC)=[O:24])=[C:4]([CH3:22])[N:5]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].C([Al+]CC(C)C)C(C)C.C[N+]1([O-])CCOCC1>C1(C)C=CC=CC=1.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[Cl:1][C:2]1[C:3]([CH:23]=[O:24])=[C:4]([CH3:22])[N:5]([S:13]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[C:6]=1[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1c(Cl)c(-c2ccccc2)n(S(=O)(=O)c2ccccc2)c1C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: Cc1ccccc1
Product: Cc1c(C=O)c(Cl)c(-c2ccccc2)n1S(=O)(=O)c1ccccc1
Yield: 55.4 %

Procedure:
Using ethyl 4-chloro-2-methyl-5-phenyl-1-(phenylsulfonyl)-1H-pyrrole-3-carboxylate (610 mg), a 1.5 mol/L solution (6.0 mL) of diisobutylaluminum hydride in toluene, tetra-n-propylammonium perruthenate (53 mg), N-methylmorpholine N-oxide (195 mg) and molecular sieves 4A powder (300 mg), a procedure as in Reference Example 49 was performed to give the title compound as a pale-yellow solid (yield 301 mg, 55%).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[Cl:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([Cl:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:1]1=[O:2]
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2ccccc2)n1
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Temperature: 25 °C
Reaction time: 72 h
Yield: 100 %

Procedure:
A stirred solution, cooled in ice, of 0.25 ml (0.48 ml) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution of 100 mg (0.26 mmol) of 5-(2,6-dichlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine and 0.1 ml (0.7 mmol) of triethylamine in 10 ml of tetrahydrofuran. The mixture was stirred at room temperature for 3 days. 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution were added, the phases were separated and the organic phase was dried over magnesium sulfate, filtered and evaporated to give 110 mg (100%) of 3-(2,6-dichlorophenyl)-7-methylthio-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13]2)(=O)=O)=CC=1.[C-:27]#[N:28].[Na+]>CS(C)=O.[Cl-].[Na+].O>[C:27]([CH:12]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])[CH2:13]1)#[N:28]
Reactant: [C-]#N
Reactant: Cc1ccc(S(=O)(=O)OC2CCN(C(=O)OCc3ccccc3)C2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CC1CCN(C(=O)OCc2ccccc2)C1
Temperature: 80 °C
Yield: 83 %

Procedure:
To a solution of 13.4 g (35.7 mmol) of benzyl 3-(p-methylbenzenesulfonyloxy)pyrrolidine-1-carboxylate in 49 mL of DMSO were added 2.58 g (50.6 mmol) of finely powdered sodium cyanide. The reaction mixture was heated at 80° C. for 3.5 hours and then cooled to room temperature. The crude was diluted with 100 mL of brine and extracted with diethyl ether (5×250 mL). The extracts were combined, washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel with 60% ethyl acetate/hexanes to give 6.8 g (83%) of benzyl 3-cyanopyrrolidine-1-carboxylate as a clear oil. Rf=0.46 in 100% ethyl acetate; Mass Spectrum (FD+): M+=230; IR (CHCl3, cm-1): 882, 912, 986, 1030, 1119, 1169, 1292, 1347, 1362, 1424, 1451, 1468, 1486, 1498, 1702, 2891, 2962, 3021; UV (C2H5OH) λmax =206 (ε=9299), 258 (ε=214); Anal. Calcd. for C13 H14N2O2 : C,67.81; H,6.13; N,12.17; Found: C, 67.58; H. 6.26; N, 12.43; 1H NMR (300 MHz, CDC13) δ2.25-2.31 (m, 2H); 3.11 (t, J=6.5 Hz, 1H); 3.48-3.75 (m, 3H); 5.15 (s, 2H); 7.37 (s, 5H).
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.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br.CCOC(C)=O.O>CN(C=O)C.CCN(C(C)C)C(C)C>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][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]
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: BrCc1ccccc1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Br)n(C)c1=O
Temperature: 65 °C
Reaction time: 2 h

Procedure:
8-Chlorotheophylline (10 g, 46.6 mmol) was dissolved in 250 ml of DMF and 8 ml of DIEA, and 2-bromobenzyl bromide (12.2 g, 48.9 mmol) was added. The mixture was stirred at 65° C. for 2 hours. The reaction mixture was added 20 ml of EtOAc and 250 ml of cold water. The white precipitate was collected by filtration to afford compound (10A) as white crystals.
Reaction SMILES: [C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:16](=[O:23])[CH2:17][CH2:18][CH2:19][C:20]=53)=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC=CC=1.O>ClCCl>[C:1]1([CH:7]2[N:21]3[C:22]4[C:14]([C:15]5[C:20]3=[CH:19][CH:18]=[CH:17][C:16]=5[OH:23])=[CH:13][CH:12]=[CH:11][C:10]=4[O:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCCc2c1c1cccc3c1n2C(c1ccccc1)CO3
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: Oc1cccc2c1c1cccc3c1n2C(c1ccccc1)CO3
Reaction time: 3 h
Yield: 66.6 %

Procedure:
Water is decanted from wet Raney nickel (2.5 g) and toluene is added and additional water is azeotroped off under vacuum. Toluene and decalin (4 mL) are added to the damp Raney nickel and toluene is again azeotroped off. 1-Phenyl-1,2,9,10-tetrahydro[1,4]oxazino[2,3,4-jk]carbazol-7(8H)-one (0.180 g, 0.593 mmol) is added and the mixture is heated at 180° C. (additional toluene/water azeotroping occurs). After 3 h, the mixture is cooled. Dichloromethane is added and the Raney nickel is removed by filtration. The filtrate is concentrated under vacuum until solids begin precipitating out. Hexane is added and the mixture is stored in the refrigerator overnight. The solids are then collected by filtration (wash with hexane) and chromatographed on silica gel gel (30 mL) using ethyl acetate/hexane (20/80) to give 0.119 g (66%) of 1-phenyl-1,2-dihydro[1,4]oxazino[2,3,4-jk]carbazol-7-ol.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.CN(C)C=O.[NH2:54][C:55]1[CH:64]=[CH:63][CH:62]=[C:61]2[C:56]=1[CH:57]=[CH:58][N:59]([CH2:66][C:67]([NH2:69])=[O:68])[C:60]2=[O:65]>>[NH2:69][C:67](=[O:68])[CH2:66][N:59]1[CH:58]=[CH:57][C:56]2[C:61](=[CH:62][CH:63]=[CH:64][C:55]=2[NH:54][C:9](=[O:11])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)[C:60]1=[O:65]
Reactant: O=C(O)Cc1ccc(Cl)c(C(F)(F)F)c1
Reactant: NC(=O)Cn1ccc2c(N)cccc2c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)Cn1ccc2c(NC(=O)Cc3ccc(Cl)c(C(F)(F)F)c3)cccc2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A round bottom flask was charged with 2-(4-chloro-3-(trifluoromethyl)phenyl)acetic acid (170 mg, 0.00072 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (400 mg, 0.001 mol), N,N-diisopropylethylamine (0.2 mL, 0.001 mol), N,N-dimethylformamide (2 mL, 0.03 mol) and 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)acetamide (120 mg, 0.00055 mol). The reaction was stirred for 16 h at room temperature and the solvent was removed and the residue purified by preparative HPLC (reverse phase) to yield the product as a white powder. MS m/z=437.8 (M+1). 1H NMR (400 MHz; DMSO-d6) δ 10.09 (s, 1H), 8.04 (d, J=8.07 Hz, 1H), 7.89 (bs, 1H), 7.83 (d, J=8.07 Hz, 1H), 7.73-7.70 (m, 2H), 7.63 (bs, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.42 (d, J=7.76 Hz, 1H) 7.19 (bs, 1H), 6.64 (d, J=7.70 Hz, 1H), 4.56 (s, 2H), 3.92 (s, 2H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[C:66]1([CH:72]([NH2:74])[CH3:73])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:74][CH:72]([C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)[CH3:73])=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CC(N)c1ccccc1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC(C)c2ccccc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 76.3 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.30 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.018 g (0.15 mmole) 1-phenyl-ethylamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with acetonitrile-water (gradient, 100:0-20:80) to give 0.042 g of rac-4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(1-phenyl-ethyl)-benzamide (I-37) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.[S:9](Cl)([C:12]1[CH:18]=[CH:17][C:15]([CH3:16])=[CH:14][CH:13]=1)(=[O:11])=[O:10].CCOCC>C(N(CC)CC)C>[C:15]1([CH3:16])[CH:17]=[CH:18][C:12]([S:9]([C:5]2[NH:1][N:2]=[C:3]([C:6]([NH2:8])=[O:7])[N:4]=2)(=[O:11])=[O:10])=[CH:13][CH:14]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: NC(=O)c1nc[nH]n1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)c2nc(C(N)=O)n[nH]2)cc1

Procedure:
To a cooled, stirred mixture of 3.0 g. of 1,2,4-triazole- 3-carboxamide and 5.1 g. of tosyl chloride in 125 ml. of anhydrous ether is added rapidly 2.75 g. of triethylamine. The cooling bath is removed and the mixture is stirred at room temperature for 23 hours. The heterogeneous mixture is filtered and washed successively with ether, cold water and then ether and dried in vacuo for 4.5 hours yielding a crude colorless solid. This solid is heated in about 50 ml. of acetonitrile and the hot mixture is filtered. The filtrate is concentrated to a smaller volume of about 20 ml. in vacuo. A colorless solid separates from the filtrate, which is collected and washed with acetonitrile and air dried for 10 minutes. The product is then dried overnight in vacuo, m.p. 148°-150° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH3:15])[C:12](Cl)=[O:13])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][OH:21].C(N(CC)CC)C.O>O1CCCC1>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][O:21][C:12](=[O:13])[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][CH:7]=1)[CH3:15]
Reactant: CC(C)Cc1ccc(C(C)C(=O)Cl)cc1
Reactant: OCc1cccc(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2cccc(F)c2)cc1
Yield: 78.1 %

Procedure:
To a solution of 5.4 g of 2-(4-isobutylphenyl)propionic acid chloride and 3.7 g of m-fluorobenzyl alcohol in 30 ml of tetrahydrofuran was added 3.7 g of triethylamine, dropwise under cooling, and the mixture was reacted at room temperature for 1.5 hours. After the reaction was complete, the crystals procuced were removed by filtration. The filtrate was freed of solvent by distillation to leave a residue, to which was added water. The resulting mixture was extracted with ether. The ether extract was dehydrated and freed of ether by distillation. The oily residue thus obtained was distilled in vacuo to yield 5.9 g of 2-(4-isobutylphenyl)propionic acid-m-fluorobenzyl ester as a colorless oil, boiling at 143°-144° C./0.2 mmHg. Mass spectrum: parent ion 314 m/e.
Reaction SMILES: [CH2:1]([CH:3]([NH:6][C:7]1[C:8]([N+:19]([O-:21])=[O:20])=[C:9]([C:12]([CH3:18])=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[CH2:10][OH:11])[CH2:4][CH3:5])[CH3:2].[CH3:22][N:23]=[C:24]=[O:25]>C(N(CC)CC)C.C1C=CC=CC=1>[CH3:22][NH:23][C:24](=[O:25])[O:11][CH2:10][C:9]1[C:12]([CH3:18])=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:7]([NH:6][CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:8]=1[N+:19]([O-:21])=[O:20]
Reactant: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(CO)c1[N+](=O)[O-]
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCC(CC)Nc1c([N+](=O)[O-])cc(C)c(COC(=O)NC)c1[N+](=O)[O-]
Yield: 91.6 %

Procedure:
A mixture of 3-[(1-ethylpropyl)amino]-6-methyl-2,4-dinitrobenzyl alcohol (1.0 g; 0.0033 mol), methyl isocyanate (used in excess over theory), triethylamine (1 drop) and benzene (10 ml) is refluxed for 2 hours. The precipitated solid is collected to afford 1.1 g (91.6%) title product, melting point 117°-120° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]#[N:16])=[N:13][CH:14]=1.[OH-].[Na+].OO.CC(O)=[O:34]>CCO.CS(C)=O>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:10]=[C:11]([NH:17][C:18]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:19]=2[CH:20]=[CH:21][N:22]3[CH3:27])[C:12]([C:15]([NH2:16])=[O:34])=[N:13][CH:14]=1
Reactant: CC(=O)O
Reactant: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C#N)cccc21
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cn1ccc2c(Nc3nc(N[C@@H]4CCCC[C@@H]4N)cnc3C(N)=O)cccc21
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 5-((1R,2S)-2-aminocyclohexylamino)-3-(1-methyl-1H-indol-4-ylamino)pyrazine-2-carbonitrile (18 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (9 mg). MS 380.5 (M+H); UV 221.2, 273.8, 322.5 nm; t 0.518 min.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[NH:20][C:19]([CH2:21][O:22]CC4C=CC(OC)=CC=4)=[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1.ClCCl.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([C:16]3[NH:20][C:19]([CH:21]=[O:22])=[C:18]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:17]=3)[CH:9]=[CH:10][C:11]=2[O:12][CH:13]([F:15])[F:14])[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cc(-c2ccc(OC(F)F)c(OCC3CC3)c2)[nH]c1COCc1ccc(OC)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cc(-c2ccc(OC(F)F)c(OCC3CC3)c2)[nH]c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To 10.3 g (20.6 mmol) of ethyl 5-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)-2-(4-methoxybenzyloxymethyl)-1H-pyrrol-3-carboxylate obtained in Reference example 45-(c) were added 100 ml of dichloromethane and 10 ml of water, then, 5.15 g (22.7 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone was added to the mixture under ice-cooling, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction suspension was filtered through Celite, the filtrate was successively washed with a saturated aqueous solution of sodium hydrogencarbonate, and then, with a saturated aqueous solution of sodium chloride. The organic layer after separation was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the obtained concentrate was added 100 ml of a mixed solvent (diisopropyl ether/hexane=1/1 (V/V)), and the precipitated solid was collected by filtration. The obtained solid was washed with diisopropyl ether, and dried under reduced pressure to obtain 3.98 g of the title compound as a pale yellowish solid. (Yield: 49%)
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:15][CH:14]=1.O>CN(C)C=O>[CH3:1][N:2]([CH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)CCc1ccc(OCc2ccc(CBr)cc2)cc1
Reactant: CNc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCc1ccc(OCc2ccc(CN(C)c3ccccc3)cc2)cc1
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
N-Methylaniline (57 mg, 0.53 mmol) was dissolved in N,N-dimethylformamide (5 mL), and 60% sodium hydride (21 mg, 0.53 mmol) was added under ice-cooling. The reaction mixture was stirred for 30 min., and methyl 4-[[4-(bromomethyl) phenyl]methoxy]benzenepropanoate (0.15 g, 0.41 mmol) was added. The mixture was stirred at room temperature for 3 hrs, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=18:1) to give the title compound (74 mg, yield 45%) as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:11]=O)[C:4]=2[O:3]1.O.[OH-].[Na+].[CH3:20][C:21]([CH3:23])=[O:22]>>[CH3:1][C:2]1([CH3:16])[CH2:6][C:5]2[C:7]([CH3:15])=[C:8]([CH3:14])[C:9]([CH3:13])=[C:10]([CH:11]=[CH:20][C:21](=[O:22])[CH3:23])[C:4]=2[O:3]1
Reactant: CC(C)=O
Reactant: Cc1c(C)c(C=O)c2c(c1C)CC(C)(C)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)C=Cc1c(C)c(C)c(C)c2c1OC(C)(C)C2

Procedure:
To a solution of 19.5 g of the 2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-carboxaldehyde in 65 ml of acetone was added 32 ml of water and 36 g of 1% aqueous solution of sodium hydroxide. After refluxing for 20 hours, the reaction mixture was quenched with 2N hydrochloric acid and the aqueous layer was extracted three times with 50 ml of diethyl ether. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a crude product. Final purification was carried by recrystallization to afford 17.6 g of 4-(2,3-dihydro-2,2,4,5,6-pentamethylbenzofuran-7-yl)-3-buten-2-one as a yellow plate crystal.