Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:12]([OH:13])=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])=[CH:6][CH:5]=1.I[CH2:22]I.Cl>CN(C)P(N(C)C)(N(C)C)=O.O>[O:13]1[C:12]2[C:11]3[CH:10]([CH2:14][CH2:15][NH:16][C:17](=[O:20])[CH2:18][CH3:19])[CH2:9][CH2:8][C:7]=3[CH:6]=[CH:5][C:4]=2[O:3][CH2:22]1
Reactant: ICI
Reactant: CCC(=O)NCCC1CCc2ccc(O)c(O)c21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCC(=O)NCCC1CCc2ccc3c(c21)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.4 %

Procedure:
Hexamethyl phosphoramide (5 mL) was cooled with ice, to which was gradually added sodium hydride (0.28 g, 7.5 mmol.), content 65%). To this mixture was added dropwise a solution of N-[2-(6,7-dihydroxyindan-1-yl)ethyl] propionamide (0.85 g, 3.41 mmol.) in hexamethyl phosphoramide (5 mL) at room temperature over 6 minutes. At the time when the bubbling of hydrogen gas ceased, diiodomethane (1.1 g, 4.1 mmol.) was added dropwise to the reaction mixture, followed by stirring for two hours at room temperature. The reaction mixture was poured into water, which was neutralized with dilute hydrochloric acid, followed by extracting the organic matter with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution and water, which was then dried over anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The residue was purified by means of silica gel column chromatography (ethyl acetate) to afford the title compound (yield 280 mg, 31%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([C@:8]2([CH3:16])[C@@H:13]([F:14])[CH2:12][O:11][C:10]([NH2:15])=[N:9]2)[CH:7]=1.[Cl:18][C:19]1[C:20]([C:26](O)=[O:27])=[N:21][CH:22]=[C:23]([Cl:25])[CH:24]=1>>[NH2:15][C:10]1[O:11][CH2:12][C@H:13]([F:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:20]3[C:19]([Cl:18])=[CH:24][C:23]([Cl:25])=[CH:22][N:21]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:17])([CH3:16])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OC[C@@H]1F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OC[C@@H]1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.2) and 3,5-dichloro-pyridine-2-carboxylic acid (CAS 81719-53-1) following procedure I yielded the title compound as a crystalline white solid. MS (ISP): m/z=415.1 [M+H]+ and 417.1 [M+2+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CCC)CCC)CC.Cl[C:21]1[N:26]([CH3:27])[S:25](=[O:29])(=[O:28])[N:24]=[C:23]([O:30][CH3:31])[N:22]=1>ClCCCl>[CH3:27][N:26]1[S:25](=[O:29])(=[O:28])[N:24]=[C:23]([O:30][CH3:31])[N:22]=[C:21]1[O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1ccccc1
Reactant: COC1=NS(=O)(=O)N(C)C(Cl)=N1
Agent: CCCN(CCC)CCC
Solvent: ClCCCl
Product: COC1=NS(=O)(=O)N(C)C(OCCc2ccccc2)=N1
Reaction time: 0.25 h

Procedure:
22 parts of 2-phenylethanol and 26.8 parts of tri-n-propylamine were added, in the course of 10 minutes, to 31.7 parts of 5-chloro-6-methyl-3-methoxy-6H-1,2,4,6-thiatriazine-1,1-dioxide in 200 parts of 1,2-dichloroethane at from 0° to 5° C., while stirring. Stirring was continued for 15 minutes at room temperature, after which the reaction solution was washed successively with 1N hydrochloric acid, with 0.5N sodium hydroxide solution and with water, dried over magnesium sulfate and chromatographed over neutral aluminum oxide. After evaporating down under reduced pressure, 36 parts (81% of theory) of 6-methyl-3-methoxy-5-(2-phenylethoxy)-6H-1,2,4,6-thiatriazine-1,1-dioxide of melting point 74°-77° C. were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]2[N:15]=1)[CH3:2].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].COCCNS(C1C=CC=CC=1C1NC(=O)C2=C(C)N=C(CCC)N2N=1)(=O)=O>ClCCl.CO>[CH3:28][O:29][CH2:30][CH2:31][NH:32][S:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[C:5]([C:14]2[NH:19][C:18](=[O:20])[C:17]3=[C:21]([CH3:27])[N:22]=[C:23]([CH2:24][CH2:25][CH3:26])[N:16]3[N:15]=2)[CH:6]=1)(=[O:12])=[O:11]
Reactant: COCCN
Reactant: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)Cl)ccc3OCC)nn12
Agent: CCCc1nc(C)c2c(=O)[nH]c(-c3ccccc3S(=O)(=O)NCCOC)nn12
Solvent: CO
Solvent: ClCCl
Product: CCCc1nc(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)NCCOC)ccc3OCC)nn12

Procedure:
By the same method, starting with 1.23 g (3 mmol) of 4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 680 mg (9 mmol) of 2-methoxyethylamine, 900 mg (67%) of N-(2-methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-benzenesulphonamide are obtained. Rf=0.25 (dichloromethane/methanol=95:5)
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[O:20][N:19]=[C:18]([CH3:21])[CH:17]=1.[OH-].[K+]>C(#N)C>[CH3:21][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)[O:20][N:19]=1
Reactant: Cc1cc(CCCCCBr)on1
Reactant: O=Cc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(C=O)cc2)on1
Yield: 67 %

Procedure:
A solution of 7.2 g of 4-hydroxybenzaldehyde, 14.6 g of 5-(5-bromopentyl)-3-methylisoxazole, 4 g of potassium hydroxide in 100 ml of acetonitrile was heated at reflux for 1.5 hours. The reaction mixture was cooled and filtered, the solvent removed, and the residue recrystallized from isopropyl acetate-hexane to give 10.8 g of 4-[5-(3-methyl-5-isoxazolyl)pentyloxy]benzaldehyde as a pale yellow powder.
Reaction SMILES: [C:1]([C:4]1([CH2:14][S:15][C:16]([CH3:19])(C)C)[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2].S.C(OC(=O)C)(=[O:23])C>FC(F)(F)C(O)=O.C(OCC)C>[C:1]([C:4]1([CH2:14][S:15][C:16](=[O:23])[CH3:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5]1)([OH:3])=[O:2]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)SCC1(C(=O)O)CCc2ccccc2C1
Agent: S
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC(=O)SCC1(C(=O)O)CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
Dissolve 2-carboxy-2-(t-butyl)thiomethyl-1,2,3,4-tetrahydronaphthalene (5.36 g, 20.0 mmol) in trifluoroacetic acid (40 mL) and add mercuric acetate (6.36 g, 20.0 mmol). Stir at ambient temperature under an atmosphere of argon for 4.5 hours, then treat with gaseous hydrogen sulfide. Remove the resulting black solid by filtration and dilute the filtrate to 100 mL with methylene chloride. Wash with water, then with brine and dry (MgSO4). Evaporate the solvent in vacuo to a residue. Mix the residue with sulfuric acid (0.3 mL of 10% solution in acetic acid) and add acetic anhydride (2.04 g, 20.0 mmol). Stir the mixture for 2 hours under an atmosphere of argon at ambient temperature, then dilute with 100 mL ethyl ether. Wash with water, brine then dry (MgSO4). Concentrate the filtrate in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14].[N:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1>COCCOC.C([O-])([O-])=O.[Na+].[Na+]>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([C:19]2[CH:20]=[CH:21][N:16]=[CH:17][CH:18]=2)[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:14]
Reactant: COC(=O)c1cc(Br)cc([N+](=O)[O-])c1N
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1cc(-c2ccncc2)cc([N+](=O)[O-])c1N
Temperature: 90 °C
Yield: 50.8 %

Procedure:
A solution of 1.0 g (3.6 mmol) of 2-amino-5-bromo-3-nitro-benzoic acid methyl ester, 0.9 g (7.2 mmol) of pyridine-4-boronic acid, 0.42 g (0.36 mmol) of (tetrakistriphenyl phosphine) palladium (0) in 50 mL of DME and 8.4 mL of 2 N Na2CO3 was degassed with nitrogen for 20 min and then heated at 90° C. for 12 h. The reaction mixture was cooled to r.t., extracted with ethyl acetate (100 mL), washed with water, brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography using 8:2 hexane and ethyl acetate to afford 0.5 g (50%) of the 2-Amino-3-nitro-5-pyridin-4-yl-benzoic acid methyl ester as a solid. LCMS: 273 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([O:19]C)=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc2oc(-c3ccc(C)cc3)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1ccc(-c2nc3cc(C(=O)O)ccc3o2)cc1

Procedure:
A solution containing 16.0 g. (0.06 mole) of methyl 2-(4-methylphenyl)-5-benzoxazolecarboxylate (1a), 4.0 g. (0.1 mole) of sodium hydroxide, and 50 ml. of water in 275 ml. of ethanol was stirred at 25° for 16 hours. The reaction mixture was poured into 1 l. of water. Acidification gave a white precipitate which was filtered, washed with water, and when air-dried amounted to 14.44 g. (95%) of 2-(4-methylphenyl)-5-benzoxazolecarboxylic acid (1b). The ir and nmr spectra were consistent with the proposed structure.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[O:20]1[C:24]2([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[O:20]1[C:24]2([CH2:29][CH2:28][N:27]([S:16]([C:14]3[S:15][C:11]([C:7]4[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=4[CH3:10])=[CH:12][CH:13]=3)(=[O:18])=[O:17])[CH2:26][CH2:25]2)[O:23][CH2:22][CH2:21]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCC4(CC3)OCCO4)s2)s1
Reaction time: 1 h
Yield: 37 %

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step 1 of example 9 (200 mg; 0.59 mmol; 1 eq.), is dissolved in DCM (10 ml). 1,4-Dioxa-8-azaspiro[4.5]decane (170.0 mg; 1.19 mmol; 2 eq.) and DIEA (460.4 mg; 3.56 mmol; 6 eq.) are added. After one hour, the solvents are evaporated. The crude product is purified by preparative HPLC, affording Compound (18) as yellow solid (96 mg; 37%). 1H NMR (DMSO-d6) δ 1.66-1.78 (m, 4H), 2.15 (s, 3H), 2.45 (s, 3H), 3-3.15 (m, 4H), 3.83 (s, 4H), 7.31 (d, J=3.8 Hz, 1H), 7.61 (d, J=3.8 Hz, 1H), 12.15 (br s, 1H). M−(ESI): 444.25; M+(ESI): 442.23. HPLC, Rt: 3.39 min (purity: 99.6%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18](F)=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:22]([N:25]([CH:29]([CH3:31])[CH3:30])[CH2:26][CH2:27][NH2:28])([CH3:24])[CH3:23]>CN1C(=O)CCC1.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][S:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:28][CH2:27][CH2:26][N:25]([CH:29]([CH3:31])[CH3:30])[CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1
Reactant: CC(C)N(CCN)C(C)C
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)N(CCNc1ccc(S(=O)(=O)Oc2ccc3nc(N)sc3c2)cc1)C(C)C
Yield: 99.1 %

Procedure:
A solution of 4-fluorobenzenesulfonic acid 2-aminobenzothiazol-6-yl ester (intermediate 16) (100 mg, 0.225 mmol) and N,N-diisopropylethylenediamine (395 μl, 2.25 mmol) in 5 ml of NMP is heated at 150° C. by microwave using an “Emrys™ Optimizer” machine for 20 minutes. The crude reaction product is taken up in 50 ml of ethyl acetate and the resulting solution is washed with 5 times 50 ml of water. After separation of the phases by settling, the organic phase is dried over sodium sulfate, filtered and evaporated under reduced pressure to give 100 mg of 4-(2-diisopropylaminoethylamino)benzenesulfonic acid 2-aminobenzothiazol-6-yl ester.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.Br[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:24]([O:23][C:21]([CH2:20][O:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)/[CH:5]=[CH:6]/[C:7]1[S:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1)=[O:22])[CH3:25]
Reactant: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 25 °C
Yield: 77 %

Procedure:
To 30 ml of acetone were added 200 mg of 2-(trans-3-hydroxystyryl)benzothiazole, 0.11 ml of ethyl bromoacetate and 131 mg of potassium carbonate, and the mixture was refluxed for 4 hours. After cooled to room temperature, the mixture was extracted with ethyl ether, dried over anhydrous magnesium sulfate and then the solvent was evaporated under reduced pressure. After the crude crystals of the residue were washed with ethyl ether and n-hexane, they were dried under reduced pressure to give 207 ml (yield 77%) of the title compound.
Reaction SMILES: C[C:2]1[CH:8]=[C:7]([OH:9])[CH:6]=[CH:5][C:3]=1[OH:4].[C:10](=O)(OC1C=CC=CC=1)OC1C=CC=CC=1>>[CH3:10][O:9][C:7]1[CH:8]=[CH:2][C:3]([OH:4])=[CH:5][CH:6]=1
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Reactant: Cc1cc(O)ccc1O
Product: COc1ccc(O)cc1
Temperature: 180 °C
Reaction time: 2 h

Procedure:
To a 1 L glass reaction vessel, methylhydroquinone (1.2 moles, 148.97 g) and diphenyl carbonate (1.29 moles, 277.63 g) were added. After heating the system to about 180° C., the system underwent Segments 1 through 5 and then skipped to Sement 11. After about 2 hours, the polymer crystallized at about 270° C. when about 90 wt % phenol had evolved. The solidified polymer could not be stranded.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([NH:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][C:15](=[O:20])[N:16]3[CH3:19])=[CH:11][CH:10]=2)=[O:7])=[C:4]([NH:23][CH2:24][CH2:25][OH:26])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>O1CCCC1>[CH3:36][S:37]([O:26][CH2:25][CH2:24][NH:23][C:4]1[CH:3]=[C:2]([Cl:1])[CH:22]=[CH:21][C:5]=1[C:6](=[O:7])[NH:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15](=[O:20])[N:16]2[CH3:19])=[CH:11][CH:10]=1)(=[O:39])=[O:38]
Reactant: CS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCO)cc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)CCc2ccc(NC(=O)c3ccc(Cl)cc3NCCOS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-Chloro-2-[(2-hydroxyethyl)amino]-N-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)benzamide was dissolved in tetrahydrofuran, diisopropylethylamine and methanesulfonyl chloride were added, followed by stirring at room temperature for 3 hours. By post-treating the reaction liquid, 2-({5-chloro-2-[(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-7-yl)carbamoyl]phenyl}amino)ethyl methanesulfonate was obtained.
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:35]1[CH:40]=[CH:39][C:38]([F:41])=[C:37]([C:42]([F:45])([F:44])[F:43])[CH:36]=1)[CH2:18][N:19]([CH:32]([CH3:34])[CH3:33])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:41][C:38]1[CH:39]=[CH:40][C:35]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH:32]([CH3:34])[CH3:33])=[CH:36][C:37]=1[C:42]([F:43])([F:44])[F:45]
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Reactant: CC(C)N(C[C@@H](N)c1ccc(F)c(C(F)(F)F)c1)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: CC(C)NC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C(F)(F)F)c1

Procedure:
Compound 52 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-fluoro-3-trifluoromethyl-phenyl)-ethyl]-N-isopropyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound as a white solid. LC/MS [437 (M+H)]; 1H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.93 (d, 1H), 8.49 (t, 3H), 7.79-7.64 (m, 2H), 7.28 (t, 1H), 6.59 (s, 1H), 5.38 (s, 1H), 3.14 (dt, 2H), 2.89-2.72 (m, 1H), 1.03 (t, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[S:6][CH:7]=1.[CH:13]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:13]([N:26]1[CH2:31][CH2:30][N:29]([CH2:2][C:3]2[N:4]=[C:5]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[S:6][CH:7]=2)[CH2:28][CH2:27]1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)N(C)c1nc(CCl)cs1
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(C)c1nc(CN2CCN(C(c3ccccc3)c3ccccc3)CC2)cs1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 31.2 %

Procedure:
A mixture of 4-chloromethyl-2-(N-methylacetamido)thiazole (2.05 g), 1-benzhydrylpiperazine (2.5 g) and potassium carbonate (1.4 g) in N,N-dimethylformamide (20 ml) was stirred at 80° C. for 1.5 hours. After the reaction mixture was poured into ice-water, the precipitated crystals were washed with water and then dried, followed by recrystallization from a mixture of ethyl acetate and n-hexane to obtain pale yellow crystals of 4-(4-benzhydrylpiperazin-1-ylmethyl)-2-(N-methylacetamido)thiazole (1.3 g), mp 140°-142° C.
Reaction SMILES: C([N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2([CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[N:3]1([C:28]([CH:25]2[CH2:26][CH2:27][C:20]3([CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH2:22][CH2:21]3)[CH2:23][CH2:24]2)=[O:30])[CH2:4][CH2:6][CH2:9][CH2:7]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)O)CC2)CC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)N3CCCC3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Ethyl-diisopropylamine (4 eq.) was added to a solution of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (commercially obtainable from Anthem, Order No. A1106) (0.35 g, 1.18 mmol, 1 eq.) in methylene chloride. The reaction mixture was cooled to 0° C. and N-ethyl-N′-3-(dimethylamino)-propyl-carbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.2 eq.) were then added. The mixture was stirred at this temperature for 15 min, before the amine (1.1 eq.) was finally added. The reaction mixture was then stirred at room temperature overnight. For working up, the reaction mixture was washed in each case 1× with 10% strength NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica; ethyl acetate/ethanol) in order to obtain the desired product. Yield: 0.23 g (56%)
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=O.C(N=CC)(C)(C)C.ClP(=O)(OCC)[O:26][CH2:27][CH3:28].C(O)(=O)C(O)=O>CCCCCC.O1CCCC1>[F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])=[CH:28][CH:27]=[O:26]
Reactant: CCOP(=O)(Cl)OCC
Reactant: O=C(c1ccccc1F)c1ccccc1F
Agent: CC=NC(C)(C)C
Agent: O=C(O)C(=O)O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=CC=C(c1ccccc1F)c1ccccc1F
Temperature: 85 °C

Procedure:
The compound was prepared according to the procedure described in Example 84. The following reagents were used: 2,2'-difluorobenzophenone (6.0 g) diisopropylamine (28.8 mL) 1.6M n-butyl lithium in hexane (129 mL). acetaldehyde N-tert-butylimine (13.2 mL), diethyl chlorophosphonate (14.85 mL) and tetrahydrofurane (100 mL). The reaction was worked up in the usual manner, with the exception that the oxalic acid catalyzed hydrolysis was slow and it was necessary to heat the mixture to 85° C. for one hour to complete the conversion. The crude product (5.8 g), obtained as an orange oil, was crystallized from hexane to give 4.6 g of 3,3-bis(2-fluorophenyl)-2-propenal mp 75°-77° C.
Reaction SMILES: [Br-:1].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.[C:34]([C:36]1[C:37]([O:47][CH3:48])=[C:38]([O:45][CH3:46])[CH:39]=[C:40]([C:42](=[O:44])[CH3:43])[CH:41]=1)#[N:35]>O1CCCC1>[Br:1][CH2:43][C:42]([C:40]1[CH:39]=[C:38]([O:45][CH3:46])[C:37]([O:47][CH3:48])=[C:36]([CH:41]=1)[C:34]#[N:35])=[O:44]
Reactant: COc1cc(C(C)=O)cc(C#N)c1OC
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)CBr)cc(C#N)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
3.48 g or phenyltrimethylammonium bromide dibromide dissolved in 30 ml of tetrahydrofuran are added dropwise at room temperature within 45 minutes to 1.9 g of 5'-cyano-3',4'-dimethoxyacetophenone dissolved in 30 ml of tetrahydrofuran, whereupon the mixture is stirred for 30 minutes. Thereupon, the reaction mixture is poured into 120 ml or ice-water and extracted three times with 70 ml of methylene chloride. The combined methylene chloride phases are washed with 2N sulfuric acid, dried over sodium sulfate and evaporated. The residue is chromatographed on 20 g of silica gel with methylene chloride. After recrystallization from methylene chloride/hexane there is obtained 5-(bromoacetyl)-2,3-dimethoxybenzonitrile of m.p. 138°-141°.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:16](OCC)(=[O:18])[CH3:17].O>C1C=CC=CC=1>[C:16]([CH:9]1[CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10]1=[O:13])(=[O:18])[CH3:17]
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)C1CC(c2ccccc2)CCC1=O
Temperature: 40 °C
Reaction time: 3 h

Procedure:
A solution of 4-phenylcyclohexanone (10 mmol, Lancaster) in benzene (5 ml) is added dropwise to a suspension of NaH (20 mmol) in absolute ethyl acetate (20 mmol) and the reaction mixture is stirred after complete evolution of the gas for 3 h at 40° C. Then it is mixed with water, the reaction mixture is extracted three times with ether, the combined organic phases are washed with water and saturated sodium chloride solution, dried over sodium sulphate and the solvent is removed in a vacuum. After column chromatography purification on silica gel with hexane/EtOAc 15:1 a clean product is obtained. tR 2.14; MS (pos. Ion.) m/z 217.26 [M+H]+. (J. Med. Chem. 1989, 32(2), 351-357).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([OH:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClC=CCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([O:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:11])=[O:12])(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClC=CCl
Product: O=[N+]([O-])c1ccc(S(=O)(=O)OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
A mixture of p-nitrobenzenesulfonic acid (20 g), phosphorous pentoxide (50 g) and 1,2-dichloroethylene (100 ml) is heated at reflux for 4 days. The hot supernatant is decanted from the gummy residue and allowed to cool to room temperature. The resulting crystalline precipitate of p-nitrobenzenesulfonic anhydride (1.5 g) is collected, washed with anhydrous diethylether, and dried under vacuum. The gummy residue is twice more refluxed overnight with 100 ml portions of dichloroethylene and worked up as above to provide additional p-nitrobenzenesulfonic anhydride (4.0 g) m.p. 171°-172°.