Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C(O)C.[BH4-].[Na+].[OH-].[Na+]>O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 8.6 %

Procedure:
2-{3-[4-(4-Nitrophenyl)-1-piperazinyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (30 g), stannous chloride dihydrate (74.8 g) and ethanol (500 cc) are heated for one hour at 60° C. under a current of argon. Then sodium borohydride (1.3 g) is added over one hour in small portions. Stirring is continued for one hour at 60° C., then for 15 hours at a temperature of about 20° C. The mixture is poured into water and ice (500 cc) then alkalinized with 4N caustic soda to pH 9. The organic phase is extracted with diethyl ether (4×200 cc), absorbed in charcoal 3S (3 g), dried on anhydrous magnesium sulphate, filtered and concentrated to dryness under reduced pressure (200 mm Hg; 2.7 kPa). The residue obtained in purified by recrystallization, first from boiling 1-propanol (250 cc), then twice from boiling ethanol (20 cc). 2-{3 -[4-(4-Aminophenyl)-1-piperazinyl] propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (2.4 g) is thus obtained, m.p. 113° C.
Reaction SMILES: BrC(CC1NC=NC=1)C(O)=O.SC[CH:14]([NH2:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:23](=[O:26])([O-])[O-:24].[Na+].[Na+].SCCN>>[NH2:22][C@H:14]([C:23]([OH:24])=[O:26])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(CS)Cc1ccccc1
Reactant: O=C([O-])[O-]
Agent: NCCS
Agent: O=C(O)C(Br)Cc1cnc[nH]1
Agent: [Na+]
Product: N[C@@H](Cc1ccccc1)C(=O)O

Procedure:
This product is prepared from α-bromo-β-(5-imidazolyl) propionic acid and 2-mercapto-1-benzyl-ethylamine by reaction in the presence of sodium carbonate utilizing the procedure described for the analogous reaction involving 2-mercaptoethylamine as described in Example 1.
Reaction SMILES: [C:1]1([P:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH3:25].[NH4+].[Cl-]>C1COCC1>[C:18]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]3[C:17]=2[NH:16][CH:15]([CH3:25])[CH:14]=[CH:13]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [Li]C
Reactant: c1ccc(P(c2ccccc2)c2cccc3cccnc23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1C=Cc2cccc(P(c3ccccc3)c3ccccc3)c2N1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 8-diphenylphoshinoquinoline (1) (10 g, 31.95 mmol) in dry THF (150 mL) under nitrogen was added MeLi (39.9 mL, 1.6 M in diethyl ether, 1 mmol) at −78° C. and the solution was stirred at 0° C. for 10 minutes. The solution was cooled down to −78° C., saturated aqueous NH4Cl solution (100 mL) was added and the mixture was warmed to room temperature. Products were extracted with EtOAc, washed with water and saturated aqueous NaCl, dried (MgSO4) and evaporated to give 2 as a yellow oil, which solidified on standing (10.5 g, quantitative). 1H NMR (400.13 MHz, CDCl3) δ 7.4-7.25 (m, 10H, Ph-H), 6.86 (dd, 1H, J=7.2, 1.2, C5—H), 6.63 (ddd, 1H, J=7.6, 6.0, 1.6 Hz, C7—H), 6.49 (t, 1H, J=7.6 Hz, C6—H), 6.29 (d, 1H, J=9.6 Hz, C4—H), 5.54 (ddd, 1H, J=10.0, 4.0, 2.0 Hz, C3—H), 4.71 (d, 1H, J=7.6 Hz, N1—H), 4.35 (m, 1H, C2—H), 1.15 (d, 3H, J=6.4 Hz, C1′—CH3) ppm; 13C NMR (100.61 MHz, CDCl3) δ 147.0 (d, J=18.2 Hz), 135.5 (d, J=13.1 Hz), 135.4 (d, J=12.1 Hz), 134.2 (d, J=5.1 Hz), 133.4 (d, J=18.2 Hz), 133.3 (d, J=18.2 Hz), 128.5 (d, J=11.1 Hz), 128.4 (d, J=12.1 Hz), 128.0, 117.0, 116.1, 48.2, 24.2 ppm; 31P NMR (161.97 MHz, CDCl3) δ −23.2 ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]=[C:6](SC)[C:5]12[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl.[CH2:19]([O:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CO>[CH2:19]([O:26][N:27]=[C:6]1[C:5]2([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=2)[NH:7]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NOCc1ccccc1
Reactant: CSC1=Nc2ccc(Br)cc2C12CCCCC2
Agent: Cl
Solvent: CO
Product: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Temperature: 45 °C

Procedure:
5′-Bromo-2′-(methylthio)spiro[cyclohexane-1,3′-[3H ]indole] (9.0 g, 28.98 mmol) and O-benzylhydroxylamine hydrochloride (13.8 g, 86.9 .mmol) were combined in methanol (150 mL) and heated to 45° C. for 6 hours. Methanol was evaporated in vacuo. Ethyl acetate was added to the residue and this mixture was washed with ammonium chloride solution. Ethyl acetate was dried over magnesium sulfate, ethyl acetate collected evaporated in vacuo and the residue was flash chromatographed on alumina 90 (9:1Hexane/EtOAc) to the desired product (6.5 g, 60%).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]([CH2:6][C:7]1[O:15][C:10]2[CH2:11][NH:12][CH2:13][CH2:14][C:9]=2[CH:8]=1)[CH3:5].[C:16]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](O)=[O:28])(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:5][N:4]([CH3:3])[CH2:6][C:7]1[O:15][C:10]2[CH2:11][N:12]([C:27](=[O:28])[C:26]3[CH:30]=[CH:31][CH:32]=[C:24]([C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:25]=3)[CH2:13][CH2:14][C:9]=2[CH:8]=1
Reactant: CN(C)Cc1cc2c(o1)CNCC2
Reactant: O=C(O)c1cccc(C(=O)c2ccccc2)c1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)Cc1cc2c(o1)CN(C(=O)c1cccc(C(=O)c3ccccc3)c1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.228 g (0.900 mmol) of the above N,N-dimethyl-(4,5,6,7-tetrahydrofuro[2,3-c]pyridin-2-ylmethyl)amine dihydrochloride, 0.26 g (1.1 mmol) of 3-benzoylbenzoic acid and 0.53 ml (3.8 mmol) of triethylamine in 30 ml of dichloromethane, 0.23 g (1.43 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel chromatography (chloroform to chloroform/methanol=50/1) to yield the desired product.
Reaction SMILES: [F-:1].[K+].C1N2CCOCCOCCN(CCOCCOCC2)CCOCCOC1.Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37][CH2:38][CH2:39][CH:40]1[O:44][CH2:43][CH2:42][O:41]1>C(#N)C>[F:1][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37][CH2:38][CH2:39][CH:40]1[O:44][CH2:43][CH2:42][O:41]1
Reactant: [F-]
Reactant: ClCc1ccccc1SCCC1OCCO1
Agent: C1COCCN2CCOCCOCCN(CCO1)CCOCCOCC2
Agent: [K+]
Solvent: CC#N
Product: FCc1ccccc1SCCC1OCCO1
Reaction time: 8 h

Procedure:
Potassium fluoride (3.5 mg, 0.060 mmol) and kryptofix 222 (22.5 mg, 0.060 mmol) were dissolved in acetonitrile (1 ml) and added to 2-[2-(2-chloromethyl-phenylsulfanyl)-ethyl]-[1,3]dioxolane (7.7 mg, 0.030 mmol) in acetonitrile (1 ml). The reaction mixture was heated to 70 degrees for 30 minutes. The crude product was purified by reverse phase preparative chromatography (Vydac 218TP1022 column; solvents A=water/0.1% TFA and B=CH3CN/0.1% TFA; gradient 40-80% B over 40 min; flow 10 ml/minute; detection at 254 nm). The fractions were left in the fridge overnight and to the acetonitrile phase was added diethyl ether, dried (Na2SO4) and evaporated under reduced pressure. (Analytical HPLC: Vydac 218TP54 column; solvents: A=water/0.1% TFA and B=CH3CN/0.1% TFA; gradient 40-80% B over 20 min; flow 1.0 ml/minute; retention time 9.200 minutes detected at 214 and 254 nm). Structure verified by NMR.
Reaction SMILES: Cl[C:2]1[C:3]([N+:16]([O-])=O)=[C:4]2[O:15][CH2:14][CH2:13][O:12][C:5]2=[C:6]([C:9](=[O:11])[CH3:10])[C:7]=1Cl>[Pd].[OH-].[Na+].C(O)C>[NH2:16][C:3]1[CH:2]=[CH:7][C:6]([C:9](=[O:11])[CH3:10])=[C:5]2[O:12][CH2:13][CH2:14][O:15][C:4]=12
Reactant: CC(=O)c1c(Cl)c(Cl)c([N+](=O)[O-])c2c1OCCO2
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(=O)c1ccc(N)c2c1OCCO2
Reaction time: 7 h
Yield: 66.1 %

Procedure:
A mixture of 5',6'-dichloro-2',3'-ethylenedioxy-4'-nitroacetophenone (2 g, 7.63 mmol) and 10% palladium on carbon (800 mg) in 17 mL of 15% sodium hydroxide and 160 mL of ethanol hydrogenated at 57 psi for 7 hours. The mixture was filtered and concentrated by rotary evaporation and the residue was stirred into water. Drying gave 4'-amino-2',3'-ethylenedioxyacetophenone (970 mg, 5.04 mmol), m.p. 135°-136° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:13]([O:21][C@H:22]1[C@@H:27]2[O:28]C(C)(C)[O:30][C@@H:26]2[CH:25]=[C:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:23]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CO>[C:13]([O:21][C@H:22]1[C@H:27]([OH:28])[C@H:26]([OH:30])[CH:25]=[C:24]([C:33]([O:35][CH3:36])=[O:34])[CH2:23]1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC(=O)C1=C[C@H]2OC(C)(C)O[C@H]2[C@H](OC(=O)c2ccccc2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)C1=C[C@@H](O)[C@@H](O)[C@H](OC(=O)c2ccccc2)C1
Reaction time: 8 h
Yield: 54 %

Procedure:
Para-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) was added to a room temperature solution of Example 13D in methanol (50 mL). After stirring overnight, the reaction mixture was concentrated and the concentrate was purified by flash chromatography using ethyl acetate to afford 0.90 g (54%) of the desired product as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH:31]C(OC(C)(C)C)=O)=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:42]=[CH:41][C:5]2[NH:6][C:7]([C@@H:9]([NH:15][C:16](=[O:40])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH2:28][CH2:27][C@H:26]4[CH2:30][NH2:31])=[O:24])=[C:19]([Cl:39])[CH:18]=3)[CH2:10][CH2:11][S:12]([CH3:14])=[O:13])=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfinylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O3S (536.48); mass spectrum: (M+H)+=536/538/540 (chlorine isotope).
Reaction SMILES: [OH2:1].[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:15](=[O:16])[N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C:13]([CH3:25])([CH3:24])[CH2:12]2)=[CH:7][CH:6]=1>C1COCC1.CO.O>[C:20]([O:19][C:17]([NH:14][C:13]([CH3:25])([CH3:24])[CH2:12][CH:11]([C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1)[C:15]([OH:1])=[O:16])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1C(=O)C(c2ccc(Cl)cc2)CC1(C)C
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(CC(C(=O)O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Lithium hydroxide hydrate (6.44 ml, 232 mmol) was added to a stirred solution of tert-butyl 4-(4-chlorophenyl)-2,2-dimethyl-5-oxopyrrolidine-1-carboxylate (7.5 g, 23.2 mmol) in THF/MeOH/H2O (30 mL/30 mL/30 mL) at room temperature. The mixture was stirred at room temperature overnight and concentrated in vacuo. The residue was taken up into water (200 mL), washed with EtOAc (100 mL), acidified with concentrated HCl and extracted into EtOAc (2×200 mL). The product was dried over Na2SO4 and concentrated in vacuo. Residual HCl was removed by evaporating from toluene to give 4-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)-4-methylpentanoic acid (5.0 g, 63.2% yield) as a white solid. LCMS (APCI+) [M-Boc+H]+ 242.0; Rt: 2.8 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[C:11]([CH2:13][C:14]([OH:16])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:32]O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[C:11]([CH2:13][C:14]([O:16][CH3:32])=[O:15])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C(O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1cccc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)oc1Oc1cccc([N+](=O)[O-])c1

Procedure:
To a solution of 1.0 g of 2-p-chlorophenyl-5-m-nitrophenoxy-4-oxazoleacetic acid in 20 ml of methanol was added 0.02 ml of concentrated sulfuric acid. The mixture was refluxed under heating for 45 minutes on a mantle heater. After the completion of reaction, the solvent was distilled off under reduced pressure. To the residue were added ice-cold water and potassium carbonate, and the mixture was extracted with ethyl acetate. After the organic layer was concentrated, recrystallization of the residue from a mixture of n-hexane and ethyl acetate gave 0.97 g of the title compound, melting at 97°-99° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].C(O)C>[F:29][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C@H:9]2[CH2:10][NH:11][CH2:12][CH2:13][NH:8]2)[CH:28]=[CH:27][CH:26]=1
Reactant: Fc1cccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Fc1cccc(CC[C@H]2CNCCN2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Combine (S)-1,4-dibenzyl-2-(2-(3-fluoro-phenyl)-ethyl)-piperazine (1.96 g, 5.04 mmol), ammonium formate (1.59 g, 25.18 mmol), 5% Pd/C (243.3 mg), and ethanol (50 mL). Stir and heat the mixture at reflux. After 4 hours 30 minutes, cool to ambient temperature and remove the catalyst by vacuum filtration through celite. Reduce the filtrate to residue and purify it on silica gel using dichloromethane/2N ammonia in methanol (80:20) to give the title compound as a white solid: mp 95–99° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis for C12H17FN2: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 69.13; H, 8.40; N, 13.28.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]=1)[CH3:2].[C:19]([CH2:24]C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20].O1CCC[CH2:46]1>>[CH2:22]([O:21][C:19](=[O:20])[CH:24]=[C:10]([C:9]1[C:4]([NH:3][CH2:1][CH3:2])=[N:5][C:6]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:8]=1)[CH3:46])[CH3:23]
Reactant: C1CCOC1
Reactant: CCNc1nc(Nc2ccccc2)ncc1C=O
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCNc1nc(Nc2ccccc2)ncc1C(C)=CC(=O)OCC
Yield: 65 %

Procedure:
To a room temperature solution of 4-ethylamino-2-phenylamino-pyrimidine-5-carboxaldehyde (200 mg, 0.83 mmol) in 10 mL of tetrahydrofuran was added (carbethoxyethylidene)triphenylphosphorane (360 mg, 1.0 mmol). The reaction mixture was heated at reflux overnight, cooled, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 1:1 ethyl acetate:hexane. The fractions containing product were concentrated, and 1:2 ethyl acetate:hexane was added to the residue. The resultant solid was collected by filtration to provide 176 mg (65%) of 3-(4-ethylamino-2-phenylamino-pyrimidin-5-yl)-but-2-enoic acid ethyl ester, mp 148-150° C.
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].[C:8]12([CH2:18]S(O)(=O)=O)[C:15]([CH3:17])(C)[CH:12]([CH2:13][CH2:14]1)[CH2:11][C:9]2=O.C(=O)([O-])[O-].[Na+].[Na+].[CH3:29][N:30]([CH3:33])C=O>>[CH3:4][C:3]1([CH3:5])[O:6][CH:7]([C:17]#[C:15][C:12]2[CH:11]=[CH:9][C:8]([CH2:18][C:29]3[C:14]4[C:8](=[CH:9][CH:11]=[CH:12][CH:13]=4)[CH:15]=[CH:33][N:30]=3)=[CH:14][CH:13]=2)[CH2:1][O:2]1
Reactant: COC(C)(C)OC
Reactant: CN(C)C=O
Reactant: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC1(C)OCC(C#Cc2ccc(Cc3nccc4ccccc34)cc2)O1
Temperature: 75 °C
Reaction time: 9 h

Procedure:
2,2-Dimethoxypropane (0.36 ml), 10-camphorsulfonic acid (43 mg), and molecular sieves (4 Å) were added to a solution of the compound of Example B109 (34 mg) in dimethylformamide (2 ml), and this reaction mixture was stirred at 75° C. for 9 hours. After an saturated aqueous sodium carbonate solution was added, the reaction mixture was extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (14 mg).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([NH:16][C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[H-].[Na+].[F:25][C:26]([F:49])([F:48])[C:27]1[CH:47]=[CH:46][C:30]([CH2:31][C@H:32]2[CH2:36]OS(=O)(=O)N2C(OC(C)(C)C)=O)=[CH:29][CH:28]=1.[OH-].[Na+].[CH3:52]N(C=O)C>>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[O:15][N:14]=[C:13]([N:16]([CH2:52][C@@H:32]([CH3:36])[CH2:31][C:30]4[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:48])[F:49])=[CH:47][CH:46]=4)[C:17](=[O:22])[O:18][CH2:19][CH:20]=[CH2:21])[CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2ccc(C(F)(F)F)cc2)COS1(=O)=O
Reactant: C=CCOC(=O)Nc1cc(-c2ccc3cnccc3c2)on1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)N(C[C@@H](C)Cc1ccc(C(F)(F)F)cc1)c1cc(-c2ccc3cnccc3c2)on1
Reaction time: 0.25 h
Yield: 51 %

Procedure:
To a solution of allyl 5-(isoquinolin-6-yl)isoxazol-3-ylcarbamate (0.030 g, 0.10 mmol) in 1 mL of DMF was added sodium hydride (0.0049 g, 0.20 mmol). After 15 minutes, (S)-tert-butyl 4-(4-(trifluoromethyl)benzyl)-1,2,3-oxathiazolidine-3-carboxylate-2,2-dioxide (0.077 g, 0.20 mmol) (prepared as shown in Scheme 1) was added. The mixture was stirred for 30 minutes. The solvent was removed under reduced pressure and the residue was taken up in 5 mL of EtOAc. 5 mL of 10% aq. HCl was then added and the mixture was stirred for 1 hour. A precipitate formed during this period. 10 mL of 5% aqueous NaOH was then added to solubilize the precipitate and the biphasic mixture was partitioned in a separatory funnel. The aqueous portion was extracted three times with 5 mL of EtOAc. The combined organic extracts were washed with 5 mL of brine and dried over MgSO4. Filtration and concentration under reduced pressure, followed by flash chromatography on silica gel (10% to 50% EtOAc/hexanes) afforded the desired adduct (0.031 g, 51% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[C:5]([O:9][CH3:10])=[C:4](Br)[N:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)#[CH:13]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[Br:8][C:6]1[C:5]([O:9][CH3:10])=[C:4]([C:13]#[C:12][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=[C:2]([NH2:1])[CH:7]=1
Reactant: C#Cc1ccccc1
Reactant: COc1c(Br)cc(N)nc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1c(Br)cc(N)nc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (17 mg, 25 μmol) is added to a mixture of 2-amino-4,6-dibromo-5-methoxy-pyridine A1 (70 mg, 0.25 mmol), ethynylbenzene (55 μl, 0.50 mmol), copper(I) iodide (5 mg, 25 μmol) triethylamine (140 μl,1 mmol) and THF (1 ml) under argon atmosphere and is stirred at 50° C. for 1 h. The mixture is concentrated in vacuo and the product purified by RP HPLC. Yield: 35 mg (47%). HPLC-MS: tR=1.21 min (METHOD—1).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[O:8][CH:9]=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][N:24]4[CH:28]=[CH:27][N:26]=[CH:25]4)=[CH:16][CH:15]=3)[N:11]=2)=[CH:4][C:3]=1[CH3:29]>[Zn]>[N:24]1([CH2:23][CH2:22][CH2:21][CH2:20][C:17]2[CH:16]=[CH:15][C:14]([O:13][CH2:12][C:10]3[N:11]=[C:7]([C:5]4[S:6][CH:2]=[C:3]([CH3:29])[CH:4]=4)[O:8][CH:9]=3)=[CH:19][CH:18]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: Cc1cc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)sc1Br
Agent: [Zn]
Product: Cc1csc(-c2nc(COc3ccc(CCCCn4ccnc4)cc3)co2)c1
Yield: 89 %

Procedure:
In substantially the same manner as in Working Example 138, 2-(5-bromo-4-methyl-2-thienyl)-4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]oxazole was reduced by zinc powder to give 4-[4-[4-(1-imidazolyl)butyl]phenoxymethyl]-2-(4-methyl-2-thienyl)oxazole. The yield was 89%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 77-78° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[C:30](Br)[CH:31]=2)[C:28]2[C:38]5[C:24]([C:25](Br)=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[C:18](Br)=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:3])[CH3:2].[C:41]([C:45]1[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][CH:46]=1)([CH3:44])([CH3:43])[CH3:42].[C:52](=[O:55])([O-])[O-].[K+].[K+].Cl>CN1CCCC1=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]1[C:35](=[O:36])[C:32]2[C:33]3[C:34]4[C:29](=[C:30]([O:51][C:48]5[CH:47]=[CH:46][C:45]([C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:50][CH:49]=5)[CH:31]=2)[C:28]2[C:38]5[C:24]([C:25]([O:51][C:48]6[CH:47]=[CH:46][C:45]([C:41]([CH3:44])([CH3:42])[CH3:43])=[CH:50][CH:49]=6)=[CH:26][CH:27]=2)=[CH:23][CH:22]=[CH:21][C:20]=5[C:19]=4[C:18]([O:55][C:52]2[CH:49]=[CH:50][C:45]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:46][CH:47]=2)=[CH:17][C:16]=3[C:14]1=[O:15])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: O=C([O-])[O-]
Reactant: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Br)c3c4cccc5c(Br)ccc(c6c(Br)cc(c2c36)C1=O)c54
Agent: Cl
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)c1cccc(C(C)C)c1N1C(=O)c2cc(Oc3ccc(C(C)(C)C)cc3)c3c4cccc5c(Oc6ccc(C(C)(C)C)cc6)ccc(c6c(Oc7ccc(C(C)(C)C)cc7)cc(c2c36)C1=O)c54
Temperature: 120 °C
Reaction time: 6 h
Yield: 93 %

Procedure:
A mixture of 32.3 g (45 mmol) of N-(2,6-diisopropylphenyl)-1,6,9-tribromoperylene-3,4-dicarboximide (prepared in accordance with Example 1a of WO 96/22 332), 27.0 g (180 mmol) of p-tert-butylphenol, 16.6 g (120 mmol) of anhydrous, finely pulverized potassium carbonate and 1200 ml of N-methylpyrrolidone (NMP) was heated at 120° C. with stirring for 6 h. After cooling to room temperature, the reaction mixture was introduced with stirring into 4500 g of 6% strength by weight aqueous hydrochloric acid, the mixture was subsequently stirred for 2 h, and the precipitated solid was filtered off, washed to neutrality with water and dried under reduced pressure at 100° C. Filtration through a short silica gel column using methylene chloride as eluent, and removal of the solvent under reduced pressure, gave 38.9 g (93%) of the desired product in the form of reddish violet crystals having a softening point of 156° C.