Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:44])[NH:10][C:11]1[CH:12]=[C:13]([C:17]2[N:26]=[C:25]([NH:27][C:28]3[CH:29]=[C:30]4[C:34](=[CH:35][CH:36]=3)[N:33](C(OC(C)(C)C)=O)[N:32]=[CH:31]4)[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:33]1[C:34]2[C:30](=[CH:29][C:28]([NH:27][C:25]3[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=[C:17]([C:13]4[CH:12]=[C:11]([NH:10][C:9]([NH:8][CH2:1][C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=5)=[O:44])[CH:16]=[CH:15][CH:14]=4)[N:26]=3)=[CH:36][CH:35]=2)[CH:31]=[N:32]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)NCc5ccccc5)c4)nc4ccccc34)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccccc1)Nc1cccc(-c2nc(Nc3ccc4[nH]ncc4c3)c3ccccc3n2)c1

Procedure:
To tert-butyl 5-(2-(3-(3-benzylureido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (30 mg, 0.051 mmol) was added a solution of 1:1 TFA:CH2Cl2 (2 mL) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and left under high vacuum for several hours. The crude product was triturated with ethyl ether to afford 1-(3-(4-(1H-indazol-5-ylamino)quinazolin-2-yl)phenyl)-3-benzylurea. (25 mg, 100%)
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH:15]=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([Mg]Br)=[CH2:18]>>[OH:16][CH:15]([CH:12]1[CH2:13][CH2:14][N:9]([C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:10][CH2:11]1)[CH:17]=[CH2:18]
Reactant: C=C[Mg]Br
Reactant: O=CC1CCN(C(=O)c2ccccc2)CC1
Product: C=CC(O)C1CCN(C(=O)c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.8 %

Procedure:
To a solution of 500 mg of 1-benzoyl-piperidine-4-carboxaldehyde (step C) in 10 ml TBF at −78° C., was added 2.99 mmol of vinyl magnesium bromide. The solution was warmed to 0° C. and stirred for 1 hour. The reaction was quenched with 15 mL of aq. NH4Cl and extracted with 3×20 ml Et2O and the combined organic layers were dried over MgSO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography with 2:1 hexane:EtOAc followed by 1:1 hexane:EtOAc followed by hexane:EtOAc:MeOH, 50:50:5 to give 411 mg of the title compound. 1H NMR (500 MHz) 1.31 (m, 2H), 1.74 (m, 5H), 2.69 (m, 1H), 2.92 (m, 1H), 4.80 (m, 1H), 3.68 (m, 1H), 5.22 (dd, 2H), 5.84 (m, 1H), 7.43 (m, 5H).
Reaction SMILES: P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[CH:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:18][C@@H:19]2[O:24][C@H:23]([CH2:25][OH:26])[C@H:22]([OH:27])[C@H:21]([OH:28])[C@H:20]2[OH:29])=[CH:11][CH:10]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:9]1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[C:12]([O:18][CH:19]2[O:24][CH:23]([CH2:25][OH:26])[CH:22]([OH:27])[CH:21]([OH:28])[CH:20]2[OH:29])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1ccccc1O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccccc1OC1OC(CO)C(O)C(O)C1O

Procedure:
The assay used is based on that of Lederberg (J. Bacteriol. 1950, 60, 381), using an assay mixture comprising 2.8 ml of 50 mM sodium phosphate, pH 7.0, and 0.1 ml of 68 mM ONPG. 0.1 ml aliquots of both purified enzyme and toluene-treated cell suspension, and 10 mg. amounts in 2.9 ml of buffer of freeze dried immobilised whole cell preparation are used for the assays. Assays are carried out at incubation temperature of 65° C. and after the appropriate time interval the reactions are halted by addition of 3 ml aliquots of 0.5 M sodium bicarbonate to each reaction mixture and immediate cooling in an ice bath. The absorbance of the resultant solutions is measured at 410 nm using a Perkin-Elmer 124 double beam spectrophotometer. In the case of whole cell suspensions the assay tubes are centrifuged and in the case of the immobilised cells the mixtures are filtered, to remove cells and polyacrylamide gel respectively prior to measurement of the absorbance.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([S:13][C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[C:16](Cl)(=[O:18])[CH3:17]>C1C=CC=CC=1>[C:16]([N:6]1[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:15][C:14]=2[S:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)(=[O:18])[CH3:17]
Reactant: Fc1ccc2c(c1)Sc1ccccc1N2
Reactant: CC(=O)Cl
Solvent: c1ccccc1
Product: CC(=O)N1c2ccccc2Sc2cc(F)ccc21
Yield: 86.1 %

Procedure:
108 grams of 3-fluorophenothiazine were dissolved in 1 liter of dry benzene. 75 grams of acetyl chloride were then added and the mixture heated under reflux for 4 hours, whereupon the mixture was evaporated. The residue was recrystallized from ethanol and 111 grams of 10-acetyl-3-fluorophenothiazine were obtained. MP: 125° Centigrade. The 111 grams of 10-acetyl-3-fluorophenothiazine were heated under reflux for 2 hours with 160 grams of anhydrous aluminium chloride in 800 milliliters of carbon disulphide. The mixture was cooled, and 70 grams of acetyl chloride were added slowly, whereupon the mixture was heated under reflux for 4 hours. The mixture was poured onto crushed ice and extracted with ether. The ether phase was evaporated, the residue dissolved in a mixture of 2 liters of ethanol and 50 milliliters of 50% sodium hydroxide solution and heated for 5 minutes on a steam bath. Thereby 2-acetyl-7-fluorophenothiazine crystallized out as white crystals which melt at 210° Centigrade. Yield: 80 grams.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]([P:18](Cl)(Cl)=[O:19])([CH3:17])[CH3:16]>>[CH:15]([P:18]1(=[O:19])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH2:1][N:8]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:17])[CH3:16]
Reactant: CC(C)P(=O)(Cl)Cl
Reactant: c1ccc(CNc2ccccc2)cc1
Product: CC(C)P1(=O)c2ccccc2CN1c1ccccc1
Yield: 11 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and isopropyl phosphonic dichloride. The reaction of the dilithio compound and the isopropyl phosphonic dichloride was conducted at -65° C. to yield 1-isopropyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (1.8 g, 11% yield) as a white solid having a melting point of 145°-147° C. and the following analysis:
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:42](OC)[O:43]C)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=O>O>[CH2:1]([S:8][CH:9]([CH:42]=[O:43])[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][CH2:24][CH2:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:18][C:17]=2[N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)(=[O:34])=[O:33])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)C(CNC(=O)c1cc2cc(OCCCS(C)(=O)=O)cc(N(C)S(=O)(=O)c3ccccn3)c2[nH]1)SCc1ccccc1
Solvent: CC(C)=O
Solvent: O
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of N-[2-(benzylthio)-3,3-dimethoxypropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (1.5 g), Amberlyst (registered trade mark) 15 ion exchange resin (0.35 g), acetone (30 mL) and water (0.15 mL) was stirred at room temperature for 18 hr. Amberlyst (registered trade mark) 15 ion exchange resin was filtered off, and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (1.4 g, yield: 100%) as a pale-yellow amorphous solid. MS: 645 (MH+).
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3]O.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:23]2)=CC=1>C1(C)C=CC=CC=1>[NH2:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][SH:23]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(C(C)(N)CO)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C(C)(N)CS)cc1
Temperature: 25 °C

Procedure:
A solution of 1 mmol of 2-amino-2-(4-methoxyphenyl)propan-1-ol (Example 3k) and 0.5 mmol of 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) [19172-47-5] in 10 ml of toluene is heated to reflux for 2 hours. The reaction mixture is cooled to room temperature and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: [CH2:1]1[CH2:22][O:21][C:20]2[C:3](=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH:6]([C:14]([O-])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1.[BH4-].[Na+]>C(O)C.C(OCC)(=O)C>[CH2:1]1[CH2:22][O:21][C:20]2[C:3](=[C:4]([CH:17]=[CH:18][CH:19]=2)[CH2:5][CH:6]([CH2:14][OH:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[O:2]1
Reactant: CC(C)(C)OC(=O)C(Cc1cccc2c1OCCO2)C(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(C)(C)OC(=O)C(CO)Cc1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
761 mg of tert-butyl (2,3-ethylenedioxybenzyl)malonate was dissolved in 20 ml of ethanol. Then, 0.57 g of sodium borohydride was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with 150 ml of ethyl acetate and washed with 100 ml of water and then with 100 ml of a saturated sodium chloride aqueous solution. The organic layer was dried over anhydrous magnesium sulfate, then concentrated under reduced pressure and purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1) to obtain 241 mg (yield: 36%) of the desired product as syrup.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1>O1CCOCC1.C(O)C.[Ni]>[OH:1][C:2]1[C:3]([OH:22])=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=c1c(-c2ccc([N+](=O)[O-])cc2)coc2cc(O)c(O)cc12
Agent: [Ni]
Solvent: C1COCCO1
Solvent: CCO
Product: Nc1ccc(-c2coc3cc(O)c(O)cc3c2=O)cc1
Reaction time: 18 h

Procedure:
6,7-Dihydroxy-3-(4-nitrophenyl)-4H-1-benzopyran-4-one [cp. J. Inst. Chem. (Calcutta) 43, 234 (1971)] (1 g) is dissolved in 250 ml of a mixture of dioxan and ethanol 1:1. Raney nickel (0.45 g) is added and the mixture is hydrogenated for 18 h at room temperature, then filtered. The solution is evaporated under vacuum to about one third of its original volume until a precipitate occurs which is filtered and crystallized in dioxan to give 6,7-dihydroxy-3-(4-aminophenyl)-4H-1-benzopyran-4-one, m.p. 305°-306°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[BH4-].[Na+].S(=O)(=O)(O)O.C1C=CC=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8]([CH:7]=[CH:6][CH2:5]2)=[CH:9][CH:10]=1
Reactant: O=C1CCc2cc(Br)ccc21
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: Brc1ccc2c(c1)CC=C2

Procedure:
Reduction of 5-bromo-1-indanone E1 with sodium borohydride in MeOH followed by dehydration of the resulting alcohol with sulfuric acid in refluxing benzene at about 80° C. affords 6-bromo-1H-indene E2 (CAS# 33065-61-1; see, Young J R, Huang S X, Walsh T F, Wyvratt M J, Yang Y T, Yudkovitz J B, Cui J, Mount G R, Ren R N, Wu T-J, Shen X, Lyons K A, Mao A-H, Carlin J R, Karanam B V, Vincent S H, Cheng K and Goulet M T, Bioorg. Med. Chem. Lett. 2002, 12 (5), 827-832).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH2:15].[S:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[C:30]1[O:34][C:33](=[O:35])[C:32]2([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)[N:31]=1>C1(C)C=CC=CC=1>[CH3:11][O:12][C:13](=[O:20])[C@H:14]([CH2:16][CH2:17][S:18][CH3:19])[NH:15][C:33]([C:32]1([NH:31][C:30]([C:22]2[S:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)=[O:35]
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Reaction time: 8 h
Yield: 86.4 %

Procedure:
679 mg (5.3 mmol) of diisopropylethylamine was added to a suspension of 419 mg (2 mmol) of L-methionine methyl ester hydrochloride and 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 10 ml of toluene, and the mixture was refluxed under heating overnight. After the solvent was distilled off under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with a 10% aqueous potassium hydrogensulfate solution and saturated brine and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diethyl ether was added thereto, and the mixture was stirred overnight. The precipitated solid was collected by filtration and dried under reduced pressure to obtain 678 mg (86%) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][C@@H:9]1[CH2:24][O:25][C:26]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:49]=[N+:50]=[N-:51].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:49]=[N+:50]=[N-:51])[CH2:10][C@@H:9]1[CH2:24][O:25][C:26]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=1)[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(C(OC[C@H]2C[C@@H](OS(=O)(=O)c3ccc(C)cc3)CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(OC[C@H]2C[C@H](N=[N+]=[N-])CN2C(=O)OC(C)(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 80 °C
Yield: 92 %

Procedure:
(2R,4R)-1-(tert-Butyloxycarbonyl)-2-(4,4'-Dimethoxytrityl)oxymethyl-4-[(p-toluenesulfonyl)oxy]pyrrolidine 39 (5.1 g, 7.58 mmol) was dissolved in dimethylformamide (50 ml) and diluted with water (5 ml ). To this stirred solution was added sodium azide (0.65 g, 10 mmol) and heated at 80° C. for 8 h. It was cooled and evaporated to dryness. The residue was partitioned between CH2Cl2 (200 ml) and water (100 ml), and extracted in CH2Cl2. The organic extract was washed with brine (50 ml), dried over Na2SO4 and evaporated to dryness. The crude product was purified by flash chromatography over silica gel using hexane→EtOAc as the eluent. The pure fractions were pooled together and evaporated to give 3.8 g (92%) of a clear oil. 1HNMR (CDCl3): 1.45 (s, 9H, Boc), 1.90 (dd, 1H), 2.34 (m, 1H), 3.40-3.62 (m, 3H), 3.74 (s, 6H, 2.0CH3), 4.00 (m, 2H), 4.28 (bs, 1H), 4.44 (m, 1H), 6.82 (d, 4H, Ph), and 7.26-7.80 (m, 9H, Ph).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:27]=[CH:26][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[O:28]1[CH2:30][C@H:29]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:35][CH:34]=1>C(Cl)(Cl)Cl.CO>[CH2:18]([NH:17][C:15]([N:12]1[CH2:13][CH2:14][CH:9]([NH:8][C:7]2[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:30][C@H:29]([OH:28])[CH2:31][O:32][C:33]3[CH:34]=[CH:35][C:36]([NH:39][S:40]([CH3:43])(=[O:42])=[O:41])=[CH:37][CH:38]=3)=[CH:27][CH:26]=2)[CH2:10][CH2:11]1)=[O:16])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCN)cc2)CC1
Reactant: CS(=O)(=O)Nc1ccc(OC[C@@H]2CO2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(NS(C)(=O)=O)cc3)cc2)CC1
Yield: 12.1 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-octyl-1-piperidinecarboxamide (0.245 g, 0.58 mmol) was reacted with N-{4-[(2S)oxiranylmethoxy]phenyl}methanesulfonamide (0.13 g, 0.53 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.04 g, 0.064 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14])[CH:6]=1
Reactant: COC(=O)Cc1cccc(O)c1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCOc1cccc(CC(=O)OC)c1
Yield: 79.6 %

Procedure:
A mixture of 1.0 g (6 mmol) of 3-hydroxyphenylacetic acid methyl ester, 2.2 g (6.6 mmol) of 1-bromooctadecane and 3.7 g (27 mmol) of anhydrous potassium carbonate in 80 ml of anhydrous acetone and 15 ml of DMF was stirred at reflux for 67 hours. The solvent was removed at reduced pressure, water was added to the residue and the product was extracted with ethyl acetate. The dried extract was concentrated to a solid which was purified by chromatography on 150 g of silica gel using 10% ethyl acetate-hexane to give 2.0 g (80% yield, mp 43°-45°) of 3-(octadecyloxy) phenylacetic acid methyl ester. The mass and nmr spectra were consistent with the structure.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH2:34])([CH3:27])([CH3:26])[CH3:25]>CCO.CCOC(C)=O>[C:24]([O:28][C:29](=[O:35])[NH:30][CH2:31][CH2:32][CH2:33][NH:34][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 25 °C
Yield: 55.2 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (100 mg, 0.32 mmol) and (3-amino-propyl)-carbamic acid tert-butyl ester (67 mg, 0.39 mmol) in EtOH (8 mL) was refluxed for 16 h. After cooling to r.t., mixture was diluted with EtOAc and washed with a pH 3 aqueous solution until the washes became acidic. The organic layer was dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 80 mg of the title compound as a pale yellow solid. MS: (−) m/z 451.37 (M−1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:25][C:23]1[N:24]=[C:4]2[CH:3]=[C:2]([C:31]3[CH:32]=[CH:33][C:28]([C:27]([F:38])([F:37])[F:26])=[CH:29][CH:30]=3)[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]3[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=3)[N:5]2[CH:22]=1
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(C(F)(F)F)cc3)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 30.2 mg (48% of theory) of the product are obtained starting from 50 mg (0.13 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 31A) by coupling with 30.2 mg (0.15 mmol) of [4-(trifluoromethyl)phenyl]boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[C:12]([O:24][C:25]([F:28])([F:27])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2)(=[O:8])=[O:7].[C:29](=O)([O-])[O-].[K+].[K+].CI.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O>[CH3:29][N:9]([S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])[C:10]1[CH:11]=[C:12]([O:24][C:25]([F:27])([F:28])[F:26])[CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15]2
Reactant: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: O=C([O-])[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OC(F)(F)F)cc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A mixture of ethyl 7-[(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxylate (3.30 g), potassium carbonate (1.05 g) and N,N-dimethylformamide (50 mL) was stirred at 0° C. for 30 min. Methyl iodide (1.08 g) was added to the reaction mixture at 0° C., and the mixture was stirred at room temperature for 15 hr. Aqueous citric acid solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (9:1-3:1, volume ratio) to give the title compound (2.26 g, yield 66%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane to give colorless prism crystals. melting point 149-150° C.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][CH2:16][CH2:17]I.O>CS(C)=O>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[CH2:15][CH2:16][CH3:17]
Reactant: NCCCCNc1ccccn1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCN(CCCCN)c1ccccn1
Yield: 66.9 %

Procedure:
Sodium hydride (1.1 g) was dissolved in DMSO (20 ml) at 70°-75° C. under nitrogen. The solution was cooled and a solution of 2-(4-aminobutylamino)pyridine (6.9 g) in DMSO (20 ml) added at room temperature. N-Propyl iodide (7.81 g) in DMSO (10 ml) was added dropwise maintaining the temperature at 25°-35° C. After a further 15 min. water (200 ml) was added and the mixture was extracted with ether. The ether extract was washed with hydrochloric acid (2N) and the aqueous layer made alkaline to pH 6. After extracting with chloroform, the pH of the aqueous layer was raised to pH 14 and extracted with ether. The ether extracts were washed with 0.1N sodium hydroxide, dried (K2CO3) and the ether evaporated to give 2-[N-(4-aminobutyl)-N-propylamino]pyridine (5.79 g) as an oil which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:5]2[N:11]=[CH:10][N:9]=[C:8]([S:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[NH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[F:19][C:16]1[CH:17]=[CH:18][C:13]([S:12][C:8]2[C:6]3[N:7]=[C:2]([N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:3]=[C:4]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:5]=3[N:11]=[CH:10][N:9]=2)=[CH:14][CH:15]=1
Reactant: Fc1ccc(Sc2ncnc3c(N4CCOCC4)nc(Cl)nc23)cc1
Reactant: C1CNCCN1
Product: Fc1ccc(Sc2ncnc3c(N4CCOCC4)nc(N4CCNCC4)nc23)cc1

Procedure:
This compound was prepared analogous to Example 1 from 2-chloro-8-(4-fluorophenyl-thio)-4-morpholino-pyrimido-[5,4-d]-pyrimidine (m.p.: 213°-215° C.) and piperazine.