Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20].[C:21](OCC)(=O)[CH3:22]>CN(C=O)C.O>[CH2:21]([O:10][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([S:1][CH2:19][CH3:20])=[CH:7][CH:6]=1)[CH3:22]
Reactant: CCI
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(SCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 36 %

Procedure:
To a solution of 2-(4-mercaptophenyl)acetic acid (32 g, crude, 0.19 mol) in dry DMF (300 mL) was added potassium carbonate (105 g, 0.76 mol) and iodoethane (118 g, 0.76 mol). The reaction mixture was stirred at rt overnight. Ethyl acetate (800 mL) and water (600 mL) were added to the mixture. After partitioning, the aqueous layer was extracted with ethyl acetate (3×500 mL). The combined organic layers were washed with brine (2×800 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluting with 30:1 petroleum ether:ethyl acetate) to give ethyl2-(4-(ethylthio)phenyl)acetate (15.3 g, 36%) as a yellow oil. LC-MS tR=0.881 min in 5-95AB—1.5 min chromatography (Welch Xtimate C18, 2.1*30 mm, 3 um), MS (ESI) m/z 224.8 [M+H]+. 1H NMR (CDCl3 300 MHz): δ 7.02 (d, J=8.1 Hz, 2H), 6.94 (d, J=8.1 Hz, 2H), 3.89 (q, J=7.2 Hz, 2H), 3.31 (s, 2H), 2.67 (q, J=7.5 Hz, 2H), 1.07-0.97 (m, 6H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:33])=[O:11])[CH2:5][CH2:4]1)(=[O:36])[CH3:35]
Reactant: Cc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C)ccc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methylphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f29) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[Cl:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28]([Cl:37])[C:29]=1[C:30](=O)[C:31]([O:33]CC)=O.CC(O)=O>COCCO>[Cl:37][C:28]1[CH:27]=[N:26][CH:25]=[C:24]([Cl:23])[C:29]=1[C:30]1[C:31](=[O:33])[N:21]([CH3:22])[C:3]2[N:4]=[C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:20][CH2:19][O:18][CH2:17][CH2:16]4)=[CH:11][CH:10]=3)[N:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)C(=O)c1c(Cl)cncc1Cl
Reactant: CNc1nc(Nc2ccc(N3CCOCC3)cc2)ncc1N
Solvent: CC(=O)O
Solvent: COCCO
Product: Cn1c(=O)c(-c2c(Cl)cncc2Cl)nc2cnc(Nc3ccc(N4CCOCC4)cc3)nc21
Yield: 17.5 %

Procedure:
A mixture of 0.30 g (1 mmol) of 5-amino-4-(methylamino)-2-[[4-(morpholin-4-yl)phenyl]amino]pyrimidine, 0.37 g (1.5 mmol) of ethyl 2-(3,5-dichloropyridin-4-yl)-2-oxoacetate, and 0.3 mL HOAc in 15 mL 2-methoxyethanol as heated under reflux for 16 hours, and worked up as above in 2. Chromatography on alumina, eluting with CH2Cl2/EtOAc (4:1), gives 85 mg (18%) of the title compound (Compound 12 in Tables 1 and 2): mp (MeOH) 243–245° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:27])[C:5]2[C:10]([CH2:11][NH:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]4[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)=[CH:9][NH:8][C:6]=2[N:7]=1.NC1NC(=O)C2C(CNC3C=CC(C(O)=O)=CC=3)=CNC=2N=1.C(N(CC1C2C(=O)NC(N[C:77](=[O:85])[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])=NC=2NC=1)CC1C=CC=CC=1)C1C=CC=CC=1.C(C1C=CC(N)=CC=1)C1C=CC(N)=CC=1>>[NH2:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][C:16]2[CH:15]=[CH:14][C:13]([NH:12][CH2:11][C:10]3[C:5]4[C:4](=[O:27])[NH:3][C:2]([NH:1][C:77](=[O:85])[CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH2:83][CH3:84])=[N:7][C:6]=4[NH:8][CH:9]=3)=[CH:18][CH:17]=2)=[CH:21][CH:22]=1
Reactant: CCCCCCCC(=O)Nc1nc2[nH]cc(CN(Cc3ccccc3)Cc3ccccc3)c2c(=O)[nH]1
Reactant: Nc1ccc(Cc2ccc(NCc3c[nH]c4nc(N)[nH]c(=O)c34)cc2)cc1
Agent: Nc1ccc(Cc2ccc(N)cc2)cc1
Agent: Nc1nc2[nH]cc(CNc3ccc(C(=O)O)cc3)c2c(=O)[nH]1
Product: CCCCCCCC(=O)Nc1nc2[nH]cc(CNc3ccc(Cc4ccc(N)cc4)cc3)c2c(=O)[nH]1

Procedure:
The synthesis of 2-amino-5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24 follows the same steps as the synthesis of 4-[(2-amino-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-5-ylmethyl)-amino]-benzoic acid 21, except that octanoic acid{5-[(dibenzylamino)-methyl]-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl}-amide 18 is reacted with 4,4′-methylene dianiline 22 to form octanoic acid (5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 23. Octanoic acid (5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-4-oxo-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide 23 is then reacted with 5M KOH to form 2-amino-5-{[4-(4-amino-benzyl)-phenylamino]-methyl}-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one 24.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:7][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:5][C:4]([CH3:23])([CH3:22])[NH:3]1.[CH2:25]1[O:33][CH:26]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CN(C)C=O>C(Cl)Cl>[CH3:22][C:4]1([CH3:23])[CH2:5][CH:6]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][C:15]([C:18]([O:20][CH2:25][CH:26]([OH:33])[C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[O:19])=[CH:16][CH:17]=[C:10]3[C:9]2=[O:21])[CH2:7][C:2]([CH3:24])([CH3:1])[NH:3]1
Reactant: c1ccc(C2CO2)cc1
Reactant: CC1(C)CC(N2C(=O)c3ccc(C(=O)O)cc3C2=O)CC(C)(C)N1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC1(C)CC(N2C(=O)c3ccc(C(=O)OCC(O)c4ccccc4)cc3C2=O)CC(C)(C)N1

Procedure:
Into a 125 ml reaction flask equipped with a magnetic stirrer, thermometer, condenser and nitrogen atmosphere were placed the HALS of Example 1 (5.0 g, 0.015 mol), styrene oxide (1.6 g, 0.013 mol), ADOGEN® (Ashland Chemical Co.) (0.15 g) and 60 ml of dimethylformamide. The reaction was refluxed for 5 hours then cooled. The mixture was transferred to a separatory funnel with 100 ml methylene chloride and washed with 200 ml of 2.5% sodium hydroxide. Additional methylene chloride, 100 ml, was added and the solution extracted with two 100 ml portions of 5% sodium hydroxide and then 100 ml water. The organic solution was then dried with anhydrous magnesium sulfate and the solvent stripped using aspirator and high vacuum systems. The solid residue (2.9 g) was recrystallized from aqueous ethanol, then recrystallized again from methyl t-butyl ether/hexanes. After high vacuum removal of residual solvent, the product weighed 0.6 g and melted at 144°-146° C. The infrared spectrum (in chloroform) showed a broad carbonyl absorption at 1710 cm-1 (imide and ester). The structure of this material was further confirmed using proton NMR spectroscopy.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH:25]C(=O)OC(C)(C)C)[CH2:13]2)=[CH:8][CH:7]=1.O1C=CN=C1C1C=CC(N2CCCC2CN[C@@H]2CCCC[C@H]2NC(=O)OC(C)(C)C)=CC=1.FC(F)(F)C(O)=O>C(Cl)Cl>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C@@H:19]3[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]3[NH2:25])[CH2:13]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Agent: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@H]1NCC1CCCN1c1ccc(-c2ncco2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H]1CCCC[C@H]1NC1CCCN(c2ccc(-c3ncco3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (1R,2R)-2-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-ylamino)cyclohexylcarbamate (32 mg, 0.073 mmol) and tert-butyl (1R,2R)-2-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methylamino)cyclohexylcarbamate (134.0 mg, 0.304 mmol) in CH2Cl2 (1.5 mL) was added trifluoroacetic acid (1.5 mL, 19.47 mmol). The reaction was stirred at rt for 1 h. After this time, LC/MS showed no SM remained and the desired product formed. The reaction was concentrated, and the resulting residue was reconcentrated from CH2Cl2 (2×5 mL). The residue was dried under high vacuum for 1 h to afford the desired product (1R,2R)—N1-(1-(4-(oxazol-2-yl)phenyl)piperidin-3-yl)cyclohexane-1,2-diamine bis-trifluoroacetate (41 mg, 0.072 mmol, 99% yield) and (1R,2S)—N1-((1-(4-(oxazol-2-yl)phenyl)pyrrolidin-2-yl)methyl)cyclohexane-1,2-diamine bis-trifluoroacetate (32 mg, 0.053 mmol, 100% yield) as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>CN(C=O)C.ClCCl.[Na+].[Cl-]>[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:8]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][CH:11]=2)=[O:10])[CH2:25][CH2:24]1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN1CCNCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(C(=O)c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 3.5 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A mixture of 2.0 g of 4-nitrobenzoic acid (11.97 mmol), 10.42 mL of diisopropylethylamine (59.84 mmol) and 1.46 mL of 1-methylpiperazine (13.16 mmol) in 40 mL of DMF is cooled to 2-5°C. on an ice bath. 11.53 g (35.9 mmol) of O-benzotriazolyltetramethylisouronium tetrafluoroborate (TBTU, CAS No.=125700-67-6) are then added portionwise and the mixture is stirred at temperature overnight. The reaction mixture is diluted with dichloromethane and saturated aqueous NaCl solution. After separation of the phases by settling, the aqueous phase is extracted with dichloromethane. The organic phases are combined, dried over Na2SO4, filtered and concentrated under vacuum. The oily residue containing insoluble material is drained by suction and then rinsed with dichloromethane and a small amount of methanol. 1.67 g of the expected product are obtained in the form of a pale pink solid, which is used as obtained without further purification. Yield=56%.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl:11][C:12]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:13]=1[O:14][CH2:15][C@@H:16]1[CH2:20][CH2:19][CH2:18][NH:17]1.C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[C:3]([C:4]([N:17]2[CH2:18][CH2:19][CH2:20][C@H:16]2[CH2:15][O:14][C:13]2[C:21]([Cl:26])=[CH:22][C:23]([Cl:25])=[CH:24][C:12]=2[Cl:11])=[O:5])=[CH:7][CH:8]=[CH:9][N:10]=1
Reactant: Clc1cc(Cl)c(OC[C@@H]2CCCN2)c(Cl)c1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1cccnc1Cl)N1CCC[C@H]1COc1c(Cl)cc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.9 %

Procedure:
At a temperature of 0° C., a solution of 2-chloro-nicotinoyl chloride (0.313 g; 1.78 mmol) in dichloromethane (5 ml) was added dropwise to a stirred solution of (S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidine (0.30 g; 1.78 mmol), which was prepared as described in example P13, and triethylamine (0.50 ml; 3.56 mmol) in dichloromethane (10 ml). The ice bath was removed and reaction mixture was allowed stirring for 16 hours at ambient temperature. Dichloromethane (40 ml) was added to the mixture. The reaction mixture was washed with 2M HCl (40 ml), 1M NaOH (50 ml) and saturated NaCl (50 ml) and then dried over Na2SO4. After removal of the solvent, the residue (0.21 g in the form of an oil) was purified by flash chromatography over silica gel (eluent:cyclohexane/ethyl acetate 1:1). 0.134 g (17.9% of theory) of (2-chloro-pyridin-3-yl)-[(S)-2-(2,4,6-trichloro-phenoxymethyl)-pyrrolidin-1-yl]-methanone was obtained in form of an oil. 1H NMR (400 MHz, CDCl3): δ 1.88-1.97 (m, 1H), 2.10-2.28 (m, 2H), 2.47-2.54 (m, 1H), 3.30-3.41 (m, 2H), 4.21-4.24 (m, 1H), 4.44 (m, 1H), 4.60-4.65 (m, 1H), 7.26 (s, 2H, Ar—H), 7.30-7.34 (m, 1H, Py-H), 7.68-7.72 (m, 1H, Py-H), 8.42-8.44 (m, 1H, Py-H). MS [M+H]+ 419/421/423/425.
Reaction SMILES: C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-].[CH3:8][C:9]1[O:10][C:11](=[O:29])[CH:12]([CH2:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[CH:18]=[CH:17][C:16]=2[O:27][CH3:28])[N:13]=1>C(OC(=O)C)(=O)C>[O:29]=[C:11]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[C:22]2[O:25][CH3:26])[CH:18]=[CH:17][C:16]([O:27][CH3:28])=[C:15]3[CH2:14][CH:12]1[NH:13][C:9](=[O:10])[CH3:8].[O:29]=[C:11]1[C:23]2=[C:24]3[C:19](=[CH:20][CH:21]=[C:22]2[OH:25])[CH:18]=[CH:17][C:16]([O:27][CH3:28])=[C:15]3[CH2:14][CH:12]1[NH:13][C:9](=[O:10])[CH3:8]
Reactant: COc1ccc2ccc(OC)c(CC3N=C(C)OC3=O)c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2ccc(O)c3c2c1CC(NC(C)=O)C3=O
Product: COc1ccc2ccc(OC)c3c2c1CC(NC(C)=O)C3=O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The compound obtained in Preparation 33 (5 mmol; 1.65 g) is dissolved in 10 cm3 of acetic anhydride and the reaction medium is maintained at the reflux temperature of the solvent for 40 min. The excess anhydride is evaporated to dryness with a trolley pump in order to isolate the 2-methyl-4-[(2,7-dimethoxynaphth-1-yl)methyl]oxazolin-5-one, which is used without further purification. 30 cm3 of anhydrous CH2Cl2 and aluminum chloride (18 mmol; 2.37 g) are introduced into a three-necked flask placed under an inert atmosphere, followed by dropwise addition of 2-methyl-4-[(2,7-dimethoxynaphth-1-yl)methyl]oxazolin-5-one (6 mmol; 1.78 g) dissolved in 40 cm3 of the same solvent. The reaction medium is maintained at 60° C. for 2 h and, after cooling, is then poured onto an ice/concentrated HCl mixture and stirred for 1 h. The organic phase is recovered and the aqueous phase is extracted several times with CH2Cl2. The combined organic phases are dried over MgSO4 and then evaporated. The residue is purified by chromatography on a column of silica gel (particle size 60-200 μm); eluent: CH2Cl2 then CH2Cl2 :MeOH 99:1 v/v. N-(1-oxo-4,9-dimethoxy-2,3-dihydro-1H-phenalen-2-yl)acetamide (a) and N-(1-oxo-9-hydroxy-4-methoxy-2,3-dihydro-1H-phenalen-2-yl)acetamide (β) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1>CCOC(C)=O>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=2)[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N#CCc1cccc(N)c1
Solvent: CCOC(C)=O
Product: N#CCc1cccc(Nc2nc(Cl)ncc2Cl)c1

Procedure:
[3-(2,5-Dichloro-pyrimidin-4-ylamino)-phenyl]-acetonitrile was prepared from (3-Amino-phenyl)-acetonitrile and 2,4,5-Trichloro-pyrimidine in an analogous manner to Example 1223b. Title product was isolated as a beige solid (144 mg, 40%) after silica gel chromatography (ISCO 40 g 0-100% EtOAc in hexanes). 91% HPLC purity, MP=155-157, LCMS 279.11 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.26 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.45 (dd, J=7.8 Hz, 1H), 7.28 (d, J=8.6 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 3.82, s, 1H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH2:6]([NH:8][C@@H:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C@H:10]1[OH:20])[CH3:7].C(N(CC)CC)C.O>C(Cl)Cl>[CH2:6]([N:8]([C@@H:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C@H:10]1[OH:20])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:7]
Reactant: CCN[C@@H]1CCCc2ccccc2[C@H]1O
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCN(C(=O)CCl)[C@@H]1CCCc2ccccc2[C@H]1O
Reaction time: 0.5 h

Procedure:
A solution of 0.75 ml (0.022 m) of chloroacetyl chloride in 10 ml of methylene chloride was added dropwise to a solution of 2.3 g (0.0112 m) of trans-6-(N-ethylamino)-6,7,8,9-tetrahydro-5H-benzo cyclohepten-5-ol and 3.2 ml (0.023 m) of triethylamine in 90 ml of methylene chloride. The mixture was stirred 1/2 hour, water is added, and the layers are separated. The organic layer was dried over anhydrous sodium sulfate and concentrated to dryness in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]([F:27])([F:26])[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH2:21]>>[F:15][C:16]([F:26])([F:27])[O:17][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH2:20][NH:21][C:8]1[CH:7]=[CH:6][C:5]2[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: NCc1ccccc1OC(F)(F)F
Product: Nc1cccc2nc(NCc3ccccc3OC(F)(F)F)ccc12

Procedure:
The title compound, MS: m/e=334.3 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 2-(trifluoromethoxy)benzylamine.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH:16]=[O:17].[OH-:18].[Na+].Cl>C(O)C.O>[OH:18][C:13]1[CH:14]=[CH:15][S:11][C:12]=1[C:16]1[O:17][C:6]2[C:5]([C:3](=[O:4])[CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: O=Cc1cccs1
Reactant: [OH-]
Reactant: O=C(CO)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=c1cc(-c2sccc2O)oc2ccccc12
Yield: 46 %

Procedure:
A solution of 3 g (22.2 mmol) of 2-hydroxyacetophenone, 2.5 g (22.2 mmol) of 2-thiophenecarboxaldehyde and 3 g NaOH (in 15 ml of water) in 50 ml of ethanol was stirred for 12 hours before the solution was poured into 300 ml of water. The resulting mixture was neutralized with dilute HCl to yield a chalcone. The yellow precipitate obtained was filtered and dried. The product was purified by recrystallized from methylene chloride. Further oxidation of above chalcone was carried out with excess of H2O2 (30%) in ethanol under basic conditions for 12 hours. The resulting solution was poured into 300 ml water and acidified with dilute HCl. Yellow precipitate obtained was filtered and dried. Product was recrystallized from THF/hexane mixture. Yield: 46%. Quantum Yield: (1.25 relative to 3HF in methyl cyclohexane), Extinction Coefficient: εmax (M-1 cm-1)=22000. λmax (abs)=355 nm and λmax (em)=545 nm. MP=202°-203° C.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH:9]1[C:16](=[O:17])[N:15]2[CH:10]1[S:11][CH2:12][C:13]([CH3:21])=[C:14]2[C:18]([OH:20])=[O:19].Cl[C:23]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl>CN(C)C=O.C(Cl)(Cl)Cl>[C:18]([C:14]1[N:15]2[CH:10]([S:11][CH2:12][C:13]=1[CH3:21])[CH:9]([NH:8][C:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:16]2=[O:17])([OH:20])=[O:19]
Reactant: CC1=C(C(=O)O)N2C(=O)C(N)C2SC1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)O)N2C(=O)C(NC(c3ccccc3)(c3ccccc3)c3ccccc3)C2SC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.3 %

Procedure:
Triethylamine (55.6 cc) is added to a suspension of 7-amino-2-carboxy-3-methyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (42.8 g) in dry N,N-dimethylformamide (250 cc), and after cooling the mixture to -20° C. a solution of chlorotriphenylmethane (55.8 g) in chloroform (250 cc) is added in the course of 2 hours. The reaction mixture is stirred for 24 hours at 25° C. and then poured into normal hydrochloric acid (400 cc). After filtration, the organic phase is separated off, concentrated to half its volume under reduced pressure (40 mm Hg) at 40° C., and taken up in ethyl acetate (400 cc). The aqueous phase is extracted with ethyl acetate (400 cc), and the combined organic phases are washed with normal hydrochloric acid (2×250 cc) and then extracted with a half-saturated sodium bicarbonate solution (4×500 cc). These combined aqueous phases are washed with ethyl acetate (300 cc), then acidified to pH 3 with 12 N hydrochloric acid and extracted with ethyl acetate (2×500 cc). The combined organic solutions are washed with a saturated sodium chloride solution (250 cc), dried over sodium sulphate and concentrated to dryness under reduced pressure (40 mm Hg) at 40° C. The residue is caused to solidify by adding isopropyl ether (250 cc). The solid is filtered off, washed with isopropyl ether (100 cc) and dried. A mixture (22.2 g) of 2-carboxy-3-methyl-8-oxo-7-tritylamino-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene (40%) and its oct-3-ene isomer (60%) is obtained in the form of a cream-coloured solid.
Reaction SMILES: C[Al](C)C.[F:5][C:6]([F:17])([F:16])[O:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][NH2:12].[Br:18][C:19]1[CH:20]=[C:21]([C:27]2[O:31][N:30]=[C:29]([C:32](OCC)=[O:33])[N:28]=2)[CH:22]=[C:23]([Br:26])[C:24]=1[OH:25].O>CCCCCC.C(Cl)(Cl)Cl>[Br:26][C:23]1[CH:22]=[C:21]([C:27]2[O:31][N:30]=[C:29]([C:32]([NH:12][CH2:11][C:10]3[CH:13]=[CH:14][CH:15]=[C:8]([O:7][C:6]([F:16])([F:17])[F:5])[CH:9]=3)=[O:33])[N:28]=2)[CH:20]=[C:19]([Br:18])[C:24]=1[OH:25]
Reactant: NCc1cccc(OC(F)(F)F)c1
Reactant: CCOC(=O)c1noc(-c2cc(Br)c(O)c(Br)c2)n1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: O
Product: O=C(NCc1cccc(OC(F)(F)F)c1)c1noc(-c2cc(Br)c(O)c(Br)c2)n1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 61.4 %

Procedure:
Trimethylaluminum (0.11 mL of a 2 N solution in hexane, 0.22 mmol) was added to a stirred solution of 3-(trifluoromethoxy)benzyl amine (42 mg, 0.22 mmol) in anhydrous chloroform (2 mL) under nitrogen and the resulting solution was stirred at room temperature for 20 minutes. Ethyl 5-(3,5-dibromo-4-hydroxyphenyl)-1,2,4-oxadiazole-3-carboxylate (78 mg, 0.2 mmol) was then added in one portion and the reaction was stirred at 50° C. for 5 h before standing at room temperature overnight. Water (2 mL) was added followed by more chloroform (3 mL), the organic phase was separated and evaporated to dryness to give a yellow oil. This was purified by preparative HPLC to give the title compound (66 mg, 62%) as a colourless solid. 1H NMR δ (ppm) (DMSO-d6): 4.58 (2 H, d, J=6.20 Hz), 7.31 (1 H, d, J=8.20 Hz), 7.39-7.47 (2 H, m), 7.53 (1 H, t, J=7.91 Hz), 8.20 (2 H, s), 10.07 (1 H, t, J=6.24 Hz). LCMS (10 cm_apci_formic) tR 4.14 min; m/z 534/536/538 [M−H]−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([F:23])[CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH3:43][C:44]1[S:48][C:47]([CH:49]([NH2:51])[CH3:50])=[N:46][CH:45]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:35]([NH:51][CH:49]([C:47]2[S:48][C:44]([CH3:43])=[CH:45][N:46]=2)[CH3:50])=[O:41])=[C:18]([F:23])[CH:17]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cnc(C(C)N)s1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4ncc(C)s4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (30 mg) was dissolved in chloroform (1 ml) and triethylamine (0.1 ml) to prepare a solution. A solution of triphosgene (35 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for one hr. Next, a solution of 1-(5-methyl-1,3-thiazol-2-yl)-1-ethylamine (35 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (13 mg, yield 29%).