Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][N:11]=1)[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH2:47])[S:46][C:42]=2[C:41]([N:48]([CH2:50][CH2:51][O:52][CH3:53])[CH3:49])=[CH:40][CH:39]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[CH3:36][O:37][C:38]1[C:43]2[N:44]=[C:45]([NH:47][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][N:11]=[C:3]([CH3:2])[CH:4]=3)[S:46][C:42]=2[C:41]([N:48]([CH2:50][CH2:51][O:52][CH3:53])[CH3:49])=[CH:40][CH:39]=1
Reactant: COCCN(C)c1ccc(OC)c2nc(N)sc12
Reactant: Cc1cc(C(=O)O)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCCN(C)c1ccc(OC)c2nc(NC(=O)c3ccnc(C)c3)sc12

Procedure:
From 2-methyl-isonicotinic acid hydrochloride, HATU and N-diethylisopropylamine in THF, then treatment with 4-methoxy-N7-(2-methoxy-ethyl)-N7-methyl-benzothiazole-2,7-diamine in dioxane and DMF. ES-MS m/e (%): 387 (M+H+, 100).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29](Cl)(=[O:31])=[O:30])([O-:22])=[O:21]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([NH:19][S:29]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N+:20]([O-:22])=[O:21])(=[O:30])=[O:31])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: Nc1ccc(OCc2ccccc2)c2cccnc12
Solvent: c1ccncc1
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(OCc2ccccc2)c2cccnc12
Yield: 88.9 %

Procedure:
In a similar fashion using route 18 general procedure 26, 5-benzyloxy-quinolin-8-ylamine 565 (336 mg, 1.34 mmol), 2-nitrobenzenesulfonyl chloride (357 mg, 1.61 mmol), and pyridine (3 ml) gave the title compound (519 mg, 89%) which was used in the next step without further purification.
Reaction SMILES: [C:1]([O:5]C)(=[O:4])[C:2]#[CH:3].[OH-].[Na+].[C:9]1([SH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>O>[C:9]1([S:15]/[CH:3]=[CH:2]\[C:1]([OH:5])=[O:4])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Sc1ccccc1
Reactant: C#CC(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)/C=C\Sc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
Methyl propiolate (3.37 ml, 40.0 mmol) was suspended in aqueous 2.5N NaOH (32.0 ml, 80 mmol), and the resulting mixture was cooled to 0° C. Thiophenol (4.12 ml, 40.0 mmol) was added drop wise under vigorous stirring, and the reaction was left at room temperature for 1 hour. The mixture was diluted with water (30 ml), and the pH was adjusted to 1 with aqueous 10% HCl. The aqueous solution was extracted with AcOEt (2×60 ml) and the combined organic layers were dried over Na2SO4 and evaporated to dryness (presence of two diastereoisomers, Z/E ratio about 90/10). The solid residue was suspended in CH3CN (20 ml) and heated to 40° C. to obtain complete dissolution. The solution was cooled to 0° C. and crystallization of the (Z) isomer was observed. The solid was collected by filtration and dried under vacuum affording (Z)-3-(phenylthio)acrylic acid (299a) (2.67 g, 14.81 mmol, 37% yield, MS/ESI+ 181.3 [MH]+).
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:16]=[C:15]([C:17]([C:19]2[C:20](Cl)=[N:21][CH:22]=[CH:23][CH:24]=2)=O)[NH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:27][NH2:28]>C(O)C>[CH2:1]([NH:8][S:9]([C:12]1[CH:16]=[C:15]([C:17]2[C:19]3[C:20](=[N:21][CH:22]=[CH:23][CH:24]=3)[NH:28][N:27]=2)[NH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc(S(=O)(=O)NCc2ccccc2)c[nH]1)c1cccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=S(=O)(NCc1ccccc1)c1c[nH]c(-c2n[nH]c3ncccc23)c1
Temperature: 80 °C

Procedure:
A mixture of 5-(2-chloro-pyridine-3-carbonyl)-1H-pyrrole-3-sulfonic acid benzylamide (100 mg), hydrazine hydrate (excess) in ethanol (10 mL) was heated at 80° C. for 48 hours. The reaction was concentrated, mixed with water, the precipitate was filtered off, the filtrate was washed with dilute HCl, water, dried and concentrated to give the titled compound as a light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[CH:3][CH:4]=1
Reactant: CN1CCNCC1
Reactant: Clc1ccc(Br)cn1
Product: CN1CCN(c2ccc(Cl)nc2)CC1

Procedure:
The title compound was prepared from 5-bromo-2-chloropyridine and 1-methylpiperazine according to Method BG and was isolated as a brown oil (27%). LCMS (ES+) 212.0 (M+H)+, RT 1.97 minutes (70% purity) (Method 2).
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[OH:9][CH:10]1[CH2:15][O:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[O:12][CH2:11]1.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1(C)C(C)=CC=CC=1>[CH2:23]([O:9][CH:10]1[CH2:11][O:12][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=2)[O:14][CH2:15]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cccc(C2OCC(O)CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Product: Cc1cccc(C2OCC(OCc3ccccc3)CO2)c1
Reaction time: 1 h
Yield: 91.9 %

Procedure:
A slurry of sodium hydride (2.1 g. 0.08 mole in 100 ml of xylene and 100 ml of benzene was stirred at ambient temperature while 5-hydroxy-2-(3-methylphenyl)-1,3-dioxane (15.9 g, 0.08 mole) was added dropwise during 1 hour. Stirring was continued for one hour and to the mixture was added benzyl chloride (10.4 g, 0.08 mole) during 0.5 hour. This mixture was heated under reflux for 22 hours, cooled, filtered and the filtrate washed with water (2 × 250 ml). The washed solution was dried over magnesium sulfate and concentrated under reduced pressure to give 20.9 g of oil which distilled at 2 × 10-4 mm. to give three fractions distilling respectively at 102°-133° C (cut 1); 133°-141° C (cut 2); and 141° C (cut 3). Analysis of the various cuts indicated that cut 3 was essentially pure cis-5 -benzyloxy-2-(3-methylphenyl)-1,3-dioxane, 2.1 g, m.p. 68°-70° C and this cut was used in further studies.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][CH2:13][C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[CH3:18])(=O)C.[Na]>CO>[CH3:11][C:10]1[CH:9]=[C:8]([O:12][CH2:13][C:14]([F:15])([F:16])[F:17])[CH:7]=[C:6]([CH3:18])[C:5]=1[OH:4]
Reactant: CC(=O)Oc1c(C)cc(OCC(F)(F)F)cc1C
Agent: [Na]
Solvent: CO
Product: Cc1cc(OCC(F)(F)F)cc(C)c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The 2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenyl acetate (733 mg, 2.80 mmol) in methanol (10 mL) was treated with sodium metal and stirred at room temperature overnight. The solvent was removed and the residue partitioned between ethyl acetate and water. The organic layer was washed twice with brine and dried. The solvent was removed to give 2,6-dimethyl-4-(2,2,2-trifluoroethoxy)phenol.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH:4](Cl)[CH:5]=O.[NH2:9][C:10]([NH2:12])=[S:11].C>O>[CH3:1][O:2][C:3]([C:4]1[S:11][C:10]([NH2:12])=[N:9][CH:5]=1)=[O:8]
Reactant: NC(N)=S
Reactant: COC(=O)C(Cl)C=O
Agent: C
Solvent: O
Product: COC(=O)c1cnc(N)s1
Temperature: 25 °C
Yield: 44.2 %

Procedure:
A mixture of 2.4 g of 2-chloro-3-oxo-propionic acid methyl ester (8-2), water 20 ml and 1.75 g of thiourea was refluxed for 2 hours. The mixture was cooled to room temperature and 0.25 g of norit was added and filtered. A solution of 2.5N sodium hydroxide was added to the filtrate until neutral pH. The filtration yielded 1.23 g (44%) of 2-aminothiazole-5-carboxylic acid methyl ester (8-3).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][CH:5]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([N:6]1[CH:5]=[C:4]([Br:3])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]1=[O:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]cc(Br)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(Br)cn1Cc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.656 g, 16.4 mmol) was carefully added to a solution of 4-bromoisoquinolin-1(2H)-one (3.5 g, 15.6 mmol) in anhydrous DMF (60 mL) cooled to 0° C. The reaction was stirred at 0° C. for 30 min, then benzyl bromide (8.02 g, 46.9 mmol) was added slowly. The reaction was allowed to warm to rt and stirred for 17 h. After that time the reaction was diluted with water (200 mL) and extracted with ethyl acetate (3×200 mL). The organic phase was washed with water, brine, dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10 hexanes/ethyl acetate to 75:25 hexanes/ethyl acetate) to give 2-benzyl-4-bromoisoquinolin-1(2H)-one (4.55 g, 93%) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J=7.4 Hz, 1H), 7.79-7.84 (m, 1H), 7.71-7.79 (m, 1H), 7.53-7.60 (m, 1H), 7.29-7.38 (m, 6H), 5.21 (s, 2H); ESI MS m/z 314 [M+H]+ and 316 [M+H]+.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9]>CC(C)=O>[Br-:6].[CH2:11]([O:10][C:8](=[O:9])[CH2:7][S+:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH3:12]
Reactant: CCOC(=O)CBr
Reactant: C1CCSC1
Solvent: CC(C)=O
Product: CCOC(=O)C[S+]1CCCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
Tetrahydrothiophene (10 g, 113 mmol) and ethyl bromoacetate (13 mL, 113 mmol) were taken in acetone (50 mL) and stirred at room temperature for 3 days. The precipitate was filtered, washed with acetone and air dried to get 1-(2-ethoxy-2-oxoethyl)tetrahydro-1H-thiophenium bromide (23 g, yield 82%), which was carried through without further purification.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[CH:12]=[CH:11][N:10]=[C:9]([S:13][CH3:14])[N:8]=1)=O.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(O)C>[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:5]2[N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][N:10]=1.[CH3:14][S:13][C:9]1[N:8]=[C:7]([C:5]2[CH:4]=[CH:3][N:22]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:23]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NNc1ccccc1
Reactant: CSc1nccc(C(=O)/C=C/N(C)C)n1
Solvent: CC(=O)O
Solvent: CCO
Product: CSc1nccc(-c2ccn(-c3ccccc3)n2)n1
Product: CSc1nccc(-c2ccnn2-c2ccccc2)n1

Procedure:
A solution of (2E)-3-(dimethylamino)-1-[2-(methylthio)pyrimidin-4-yl]prop-2-en-1-one (1-4, 3.60 g, 16.1 mmol, 1 equiv), phenylhydrazine (1.58 mL, 16.1 mmol, 1.00 equiv) and acetic acid (90 uL, 1.6 mmol, 0.10 equiv) in ethanol (100 mL) was heated at reflux for 20 hours. The reaction mixture was concentrated and the residue purified by flash column chromatography (hexanes initially, grading to 40% ethyl acetate in hexanes) to give 2-(methylthio)-4-(1-phenyl-1H-pyrazol-5-yl)pyrimidine (1-5) and 2-(methylthio)-4-(1-phenyl-1H-pyrazol-3-yl)pyrimidine (1-6) as white solids. 1H NMR 1–5 (300 MHz, CDCl3) δ 8.44 (d, 1H, J=5.2 Hz), 7.77 (d, 1H, J=1.8 Hz), 7.50–7.30 (m, 5H), 6.95 (d, 1H, J=1.8 Hz), 6.92 (d, 1H, J=5.2 Hz), 2.08 (s, 3H); 1H NMR 1–6 (300 MHz, CDCl3) δ 8.60 (d, 1H, J=4.9 Hz), 8.02 (d, 1H), J=1.8 Hz), 6.92 (d, 1H, J=4.9 Hz), 7.68 (br d, 2H, j=7.8 Hz), 7.52 (br t, 2H, J=7.5 Hz), 7.37 (m, 1H), 7.23 (d, 1H, J=1.8 Hz), 2.68 (s, 3H).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=2)[N:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([S:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5])[CH:20]=[CH:19]2
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: OCc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: OCc1ccccc1Sc1ccc2cc(Cl)ccc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 9.8 %

Procedure:
A mixture of 2-mercaptobenzyl alcohol (1.78 g, 12.7 mmol), 2,6-dichloroquinoline (2.48 g, 12.5 mmol) and potassium carbonate (1.73 g, 12.5 mmol) in N,N-dimethylformamide (25 mL) was stirred at room temperature under nitrogen for 3 hours, then at 60° C. for 17 hours. The cooled reaction mixture was poured into water and extracted with ethyl acetate (x2). The combined organic layers were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash column chromatography on silica, eluting with 5-10% ethyl acetate/dichloromethane, to give {2-[(6-chloroquinolin-2-yl)thio]phenyl}methanol (0.37 g, 9%) as a colourless oil. 1H NMR (400 MHz, CDCl3) δ 7.84 (1H, d, J=8.7 Hz), 7.72-7.66 (4H, m), 7.55-7.51 (2H, m), 7.39-7.35 (1H, m), 7.19 (1H, dd, J=1.2, 8.7 Hz), 4.84 (2H, s), 3.78 (1H, s); m/z (ES+) 302, 304 [MH+].
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[C:18]([C:19]([OH:21])=[O:20])[C:8]=3[C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH2:22]([N:24](CC)[CH2:25]C)C.Cl.CNC>>[CH3:22][N:24]([CH3:25])[S:2]([C:5]1[CH:14]=[CH:13][C:12]2[NH:11][C:10](=[O:15])[C:9]3[NH:16][CH:17]=[CH:18][C:8]=3[C:7]=2[CH:6]=1)(=[O:3])=[O:4].[CH2:18]([C:19]([O-:21])=[O:20])[CH3:17]
Reactant: O=C(O)c1c[nH]c2c(=O)[nH]c3ccc(S(=O)(=O)Cl)cc3c12
Reactant: CCN(CC)CC
Agent: CNC
Agent: Cl
Product: CCC(=O)[O-]
Product: CN(C)S(=O)(=O)c1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Yield: 47 %

Procedure:
This compound is prepared according to synthesis 25, from 115 mg (0.35 mmol) of 8-chlorosulfonyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-carboxylic acid (synthesis 2), 147 μL (1.05 mmol) of triethylamine and 35 mg (0.42 mmol) of dimethylamine hydrochloride. After purification by chromatography on silica (eluent dichloromethane/methanol 95/5) then trituration in methanol, 30 mg (24%) of 8-dimethylsulfamoyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate is obtained in the form of a white solid.
Reaction SMILES: C([O:8][C:9]1[C:10](=[O:20])[N:11]([CH2:17][O:18][CH3:19])[C:12]([CH3:16])=[N:13][C:14]=1[CH3:15])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.[C].[Pd]>[OH:8][C:9]1[C:10](=[O:20])[N:11]([CH2:17][O:18][CH3:19])[C:12]([CH3:16])=[N:13][C:14]=1[CH3:15]
Reactant: COCn1c(C)nc(C)c(OCc2ccccc2)c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COCn1c(C)nc(C)c(O)c1=O
Yield: 100.1 %

Procedure:
The compound 326-4 (1.42 g) was dissolved in ethyl acetate (30 ml). Palladium-carbon (700 mg) was added to the solution, and the obtained mixture was stirred in a hydrogen atmosphere for 1 hour. The reaction mixture was filtered with Celite, and the filtrate was concentrated under reduced pressure, so as to obtain the crude title compound (954 mg).
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]([CH3:21])[CH3:20])[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13](C)=[C:12]([F:17])[CH:11]=2)[CH:9]=1)([OH:3])=[O:2].C1(CN2[C:32](=[O:33])C(OC)C(=C=O)C(C3C=CC(OC)=C(F)C=3)=N2)CC1>>[C:1]([C:4]1[C:5](=[O:22])[N:6]([CH2:18][CH:19]2[CH2:20][CH2:21]2)[N:7]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:33][CH3:32])=[C:12]([F:17])[CH:11]=2)[CH:9]=1)([OH:3])=[O:2]
Reactant: COc1ccc(C2=NN(CC3CC3)C(=O)C(OC)C2=C=O)cc1F
Reactant: Cc1ccc(-c2cc(C(=O)O)c(=O)n(CC(C)C)n2)cc1F
Product: COc1ccc(-c2cc(C(=O)O)c(=O)n(CC3CC3)n2)cc1F
Yield: 98.9 %

Procedure:
Following the procedure of Example 1 (7), 2-cyclo-propylmethyl-6-(3-fluoro-4-methoxyphenyl)-4-methoxy-carbonyl-2H-pyridazin-3-one was reacted to yield the title compound as yellow crystals (yield: 98.9%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][C:23]=3[OH:31])=O)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH3:18])[C:12]([C:19]3[O:31][C:23]4[CH:24]=[C:25]([N+:28]([O-:30])=[O:29])[CH:26]=[CH:27][C:22]=4[N:21]=3)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1C(=O)Nc1ccc([N+](=O)[O-])cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1nc2ccc([N+](=O)[O-])cc2o1
Temperature: 155 °C
Reaction time: 4 h

Procedure:
To 2-((3-fluorophenyl)amino)-N-(2-hydroxy-4-nitrophenyl)-4-(propylamino)pyrimidine-5-carboxamide (E24, 11 mg) and p-toluenesulfonic acid monohydrate (15 mg), xylene (1.5 mL) was added at room temperature, and the mixture was stirred at 155° C. for 4 hours. The reaction mixture was cooled to room temperature, and then purified by silica gel column chromatography (eluent, 100 to 80% ethyl acetate in methanol). To the obtained solid matter, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with saturated aqueous sodium hydrogencarbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the obtained residue, ethyl acetate were added, and the solid matter was taken by filtration to obtain N2-(3-fluorophenyl)-5-(6-nitrobenzo[d]oxazol-2-yl)-N4-propylpyrimidine-2,4-diamine (E25) as yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:38])([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:24]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:23]=1)[C:16]([O:18]CC)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:38])([CH2:31][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:21]=[C:22]([C:24]2([C:29]#[N:30])[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:23]=1)[C:16]([OH:18])=[O:17])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(COCC(C)(Cc2ccccc2)NC(=O)OC(C)(C)C)cc(C2(C#N)CCCC2)c1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 64 h

Procedure:
A solution of ethyl 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoate (0.13 g, 0.25 mmol) and LiOH.H2O (31 mg, 0.75 mmol) in 6.5 mL THF and 2.5 mL H2O was stirred at rt overnight. Additional LiOH.H2O (25 mg, 0.60 mmol) was added and the reaction was continued for 64 h. The mixture was concentrated, diluted with H2O, made acidic with 10% citric acid solution and extracted with EtOAc. The combined organic layers were washed with brine. Drying and solvent evaporation gave 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid. 1H NMR (500 MHz, CDCl3) δ 8.09 (app d, J=1.5 Hz, 1H), 8.04 (s, 1H), 7.74 (s, 1H), 7.28-7.20 (m, 3H), 7.17 (m, 2H), 4.62 (s, 3H), 3.58 (bs, 1H), 3.48 (d, J=8.5 Hz, 1H), 3.15 (d, J=12.9 Hz, 1H), 2.95 (d, J=13.2 Hz, 1H), 2.54 (m, 2H), 2.14-1.96 (m, 6H), 1.47 (s, 9H), 1.28 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:11][C:12]1([CH3:29])[CH2:16][O:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[C:19]([O:25][CH3:26])[C:18]=2OC)=[N:13]1.O>O1CCCC1>[CH3:26][O:25][C:19]1[C:18]([CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:17]([C:14]2[O:15][CH2:16][C:12]([CH3:11])([CH3:29])[N:13]=2)[CH:22]=[CH:21][C:20]=1[O:23][CH3:24]
Reactant: COc1ccc(C2=NC(C)(C)CO2)c(OC)c1OC
Reactant: Br[Mg]CCc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2=NC(C)(C)CO2)c(CCc2ccccc2)c1OC
Reaction time: 16 h

Procedure:
A solution of phenylethyl magnesium bromide (1M in tetrahydrofuran (40 ml) was added to a stirred solution of 4,5-dihydro 4,4-dimethyl-2-(2,3,4-trimethoxyphenyl) oxazole (5.3 g 0.02M) in dry tetrahydrofuran under a nitrogen atmosphere. The mixture was stirred at 20° for 16 hours. Water (200 ml) was added and the aqueous phase thoroughly extracted with diethyl ether (3×200 ml). The organic solution was dried over magnesium sulphate, filtered and evaporated to leave an oil which was purified by column chromatography on SiO2 eluting with ether/petroleum ether (50/50) to give a colorless oil (6.2 g); MS m/e 339.
Reaction SMILES: [CH:1]1([N:7]2[CH2:11][C@@H:10]([NH:12][CH3:13])[C@H:9]([OH:14])[CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>>[ClH:21].[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([N:12]([C@H:10]2[C@H:9]([OH:14])[CH2:8][N:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)[CH2:11]2)[CH3:13])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN[C@@H]1CN(C2CCCCC2)C[C@H]1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CN(C2CCCCC2)C[C@H]1O
Product: Cl

Procedure:
This compound was made according to the procedure of Example 11, using 10 g trans-1-cyclohexyl-4-methylamino-3-pyrrolidinol, 10 g of potassium carbonate and 8.9 g of p-chlorobenzoyl chloride in comparable quantities of solvent. The melting point of the salt was 215.0°-218° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=[O:11].[OH-].[K+].[CH3:17][C:18]1([O:21][CH2:20]1)[CH3:19].Cl>CS(C)=O.C(OCC)(=O)C.O>[OH:21][C:18]([CH3:20])([CH3:19])[CH2:17][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=[O:11]
Reactant: CC1(C)CO1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(O)Cn1c(C(=O)O)cc2ccccc21
Reaction time: 0.5 h

Procedure:
To 760 mg of ethyl 2-indole carboxylate (4 mmol) dissolved in 8 ml dimethyl sulfoxide was added 290 mg of crushed potassium hydroxide (4.4 mmol). The mixture was stirred for approximately 30 minutes. 1.8 ml of isobutylene oxide was then added and the mixture was stirred at 50 C for 65 hours. The reaction was worked up by addition of water, 1M HCl to adjust the pH to 4-5, and ethyl acetate. The layers were separated and the ethyl acetate layer was washed with brine and dried over sodium sulfate. Evaporation gave 1-(2-hydroxy-2-methyl-propyl)-1H-indole-2-carboxylic acid (840 mg) as a solid (M−H=233) that was used directly in the next step.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:21]1(=[O:31])[NH:25][C:24](=[O:26])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.[K].O>CN(C)C=O>[C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:2]([O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:25]2[C:24](=[O:26])[C:23]3=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]3[C:21]2=[O:31])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCCCCOc1ccccc1-c1ccccc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCOc1ccccc1-c1ccccc1

Procedure:
A solution of 1-(2-biphenyloxy)-6-chlorohexane 8.0 g) and potassium phtalimide (5.6 g) in dimethylformamide (100) ml) was heated at reflux temperature for 3 hours. The solution was cooled and poured into water, and the product was extracted out with ethyl acetate. The extract was dried and evaporated to afford N-[6-(biphenyloxy)hexyl]phthalimide.