Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:38])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH:37]=[CH:36][C:26]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])=[O:28])=[CH:25][CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:5]1([C:45](=[O:58])[NH:46][CH2:47][CH2:48][C:49](=[O:57])[O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH2:4][CH2:3]2.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH:42]([C@H:39]1[C@@H:6]2[C@@H:7]3[C@@:2]([CH3:1])([CH2:3][CH2:4][C@@:5]2([C:45](=[O:58])[NH:46][CH2:47][CH2:48][C:49](=[O:57])[O:50][CH2:51][CH2:52][Si:53]([CH3:54])([CH3:55])[CH3:56])[CH2:41][CH2:40]1)[C@@:19]1([CH3:20])[C@@H:10]([C@:11]2([CH3:38])[C@@H:16]([CH2:17][CH2:18]1)[C:15]([CH3:21])([CH3:22])[C@@H:14]([C:23]1[CH:37]=[CH:36][C:26]([C:27]([O:29][CH2:30][CH2:31][Si:32]([CH3:33])([CH3:34])[CH3:35])=[O:28])=[CH:25][CH:24]=1)[CH2:13][CH2:12]2)[CH2:9][CH2:8]3)([CH3:44])[CH3:43]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)[C@@H]1CC[C@]2(C(=O)NCCC(=O)OCC[Si](C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](c6ccc(C(=O)OCC[Si](C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2-(trimethylsilyl)ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (15 mg, 0.018 mmol) was dissolved in a mixture of ethyl acetate and methanol (2 ml, 1:1) and treated with palladium (10% in carbon, 1 mg, 9.40 mmol) and a balloon with hydrogen. The mixture was stirred at rt for 3 h. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and filtered through a fine pad of celite. The solvent was removed in vacuo and the crude was purified in silica gel to afford 2-(trimethylsilyl)ethyl 4-((1S,3aS,5aR,5bR,7aS,11aS,11bR,13aR,13bR)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-3a-(3-oxo-3-(2-(trimethylsilyl)ethoxy)propylcarbamoyl)icosahydro-1H-cyclopenta[a]chrysen-9-yl) (12 mg, 80%) as a clear oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.92 (d, J=8.28 Hz, 2H), 7.23 (d, J=8.53 Hz, 2H), 6.22 (t, J=6.15 Hz, 1H), 4.50-4.36 (m, 2H), 4.24-4.16 (m, 2H), 3.51 (td, J=11.48, 6.40 Hz, 2H), 2.59-2.49 (m, 2H), 2.40 (dd, J=12.92, 2.89 Hz, 2H), 2.35-2.24 (m, 1H), 2.18-2.04 (m, 1H), 2.03-1.95 (m, 1H), 1.89-0.91 (m, 26H), 0.99 (s, 3H), 0.96 (s, 6H), 0.88 (d, J=7.03 Hz, 3H), 0.77 (d, J=7.03 Hz, 3H), 0.76 (s, 3H), 0.70 (s, 3H), 0.09 (s, 9H), 0.06 (s, 9H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:32]([F:35])([F:34])[F:33])([C:28]([F:31])([F:30])[F:29])[OH:27])[CH2:10]1.[CH:36]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37]1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N:20]3[CH2:21][CH2:22][N:23]([S:39]([CH:36]4[CH2:38][CH2:37]4)(=[O:41])=[O:40])[CH2:24][CH2:25]3)[CH:15]=2)[N:12]=[C:11]([C:26]([C:28]([F:31])([F:30])[F:29])([C:32]([F:33])([F:35])[F:34])[OH:27])[CH2:10]1
Reactant: O=S(=O)(Cl)C1CC1
Reactant: OC(C1=NN(c2cccc(N3CCNCC3)c2)C(c2ccccc2Cl)C1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(C1CC1)N1CCN(c2cccc(N3N=C(C(O)(C(F)(F)F)C(F)(F)F)CC3c3ccccc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.6 %

Procedure:
The 5-(2-chloro-phenyl)-1-[3-(piperazin-1-yl)-phenyl]-3-[di-(trifluoromethyl)-hydroxy-methyl]-4,5-dihydro-1H-pyrazole hydrochloride (30.0 mg, 0.055 mmol) in the form of a yellow liquid, cyclopropanesulfonyl chloride (9.3 mg, 0.066 mmol), and triethylamine (31.0 uL, 0.221 mmol) were added to dichloromethane (1.0 mL). The reaction mixture was stirred at room temperature for 16 hours, washed with distilled water and brine, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to give 15.0 mg of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[C:8]([OH:10])=O)[CH3:2].[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:6]=[C:7]([C:8]([N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:10])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cc(C(=O)O)ccc1OCC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)c1cc(C(=O)N2CCCCC2)ccc1OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of 4-ethoxy isopthalic acid 3-ethyl ester (600 mg, 2.5 mmol) in 10 mL of acetonitrile was added piperidine (429 mg, 5.0 mmol). The resulting mixture was cooled to 0° C. To this solution was added HBTU (1.4 g, 3.78 mmol, in 5 mL of acetonitrile) followed by N,N-diisopropylethylamine (2.2 mL, 12.6 mmol). The reaction was allowed to stir overnight at room temperature. The reaction mixture was concentrated in vacuo. The residue was diluted with 10% potassium carbonate and extracted with methylene chloride. The organic extract was concentrated and purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 632 mg (2.07 mmol, 82%) of pure 2-ethoxy-5-(piperidine-1-carbonyl)-benzoic acid ethyl ester. LC-MS: 306.3 [(M+H)+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[N:12]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][C:9]([OH:11])=[O:10])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C1CCNC1
Reactant: O=C(O)Cc1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: O=C(O)Cc1ccccc1N1CCCC1
Temperature: 90 °C

Procedure:
A mixture of 2-(2-bromophenyl)acetic acid (10.7 g), pyrrolidine (20 cc) and copper acetate (1.66 g) is heated for 2 hours, with stirring, at 90° C.; after returning to ambient temperature, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a silica gel column (0.2-0.063 mm, diameter 5 cm, height 55 cm), eluting with 1,2-dichloroethane (1,000 cc) and then with mixtures of 1,2-dichloroethane and methanol [(proportions by volume): 1,000 cc (98/2), 2,000 cc (97/3), 1,000 cc (96/4) and 1,000 cc (95/5)] and collecting 250 cc fractions. Fractions 21 to 29 are combined and concentrated to dryness under reduced pressure (2.7 kPa). 2-[2-(1-Pyrrolidinyl)phenyl]acetic acid (2 g) is obtained in the form of an orange oil.
Reaction SMILES: [CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16](O)=[O:17])=[C:12]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.Cl.[CH3:41][NH:42][O:43][CH3:44]>ClCCl>[CH:1]1([C:4]2[C:13](/[CH:14]=[CH:15]/[C:16]([N:42]([O:43][CH3:44])[CH3:41])=[O:17])=[C:12]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:2][CH2:3]1
Reactant: CNOC
Reactant: O=C(O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Agent: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)/C=C/c1c(C2CC2)nc2ccccc2c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2.83 h

Procedure:
To a solution of (E)-3-[2-Cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-acrylic acid (2.0 g, 6.0 mmol) in dichloromethane (25 ml) at −5° C. is added triethylamine (0.668 g, 6.6 mmol).and pivaloyl chloride (0.725 g, 6.0 mmol). After stirring at 0° C. for 170 min, N,O-dimethyl-hydroxylamine hydrochloride (0.59 g, 6.0 mmol) and triethylamine (1.22 g, 12.0 mmol) are added. After stirring in an ice bath for 90 min, and at room temperature for 30 min, more N,O-dimethylhydroxylamine hydrochloride (0.177 g, 1.8 mmol) is added and the reaction is stirred at room temperature for 17 h. After quenching with 0.2M citrate buffer pH5 (25 ml), the organic phase is separated and washed with 0.2M citrate buffer pH5 (25 ml), 0.2M phosphate buffer pH7 (25 ml) and water (25 ml). The water phases are extracted with dichloromethane (2×20 ml). Combined organic phases are dried over magnesium sulphate, evaporated, and the crude product chromatographed on silica gel (hexane/ethyl acetate 2:1) to afford (E)-3-[2-cyclopropyl-4-(4-fluoro-phenyl)-quinolin-3-yl]-N-methoxy-N-methyl-acrylamide (7). MS (ES): [M+H]+ 377, Mp. 155-156° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)[NH:48]C1(C2C=CC(C3C(=O)C4C(=C(Br)C=CC=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.O=C1CNCCN1>>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([N:29]5[CH2:30][CH2:31][NH:48][C:33](=[O:32])[CH2:34]5)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCOCC5)cccc4c3=O)cc2)CCC1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)CCC1
Agent: O=C1CNCCN1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(N5CCNC(=O)C5)cccc4c3=O)cc2)CCC1
Yield: 64 %

Procedure:
Following the procedure of {1-[4-(8-morpholin-4-yl-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, {1-[4-(8-bromo-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester was reacted with 2-oxopiperazine to give the title compound as a white solid (35 mg, 64%). LCMS (Method G): RT=3.45 min, [M+H]+=566.
Reaction SMILES: C([O:3][C:4](=[O:29])[CH2:5][C:6](=[O:28])[C:7](=[O:27])[CH:8]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)C.[OH-].[Li+]>O1CCOCC1.O>[O:28]=[C:6]([C:7](=[O:27])[CH:8]([NH:16][C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][C:4]([OH:29])=[O:3]
Reactant: CCOC(=O)CC(=O)C(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CC(=O)C(=O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Reaction time: 3 h

Procedure:
To a solution of 3,4-dioxo-5-[((phenylmethoxy)carbonyl)amino]-6-phenylhexanoic acid ethyl ester (400 mg, 1.0 mmol) in dioxane/H2O (10:1), lithium hydroxide (72 mg, 3.0 mmol) is added. The mixture is stirred for 3 h, the solvents are removed in vacuo and the crude product is used without purification.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13]([O:20][CH2:21][CH3:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:23])(=O)C.C(O)C.[OH-].[Na+]>O>[CH2:21]([O:20][C:13](=[C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[NH:4][C:5]1=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH3:22]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccccc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=C1C(=O)Nc2ccccc21)c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.15 g (20 mmol) of 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-2-indolinone are suspended in a little ethanol. 10 ml of 4N sodium hydroxide solution are added and the mixture is stirred for 1.5 hours at ambient temperature. After the addition of 100 ml of water the precipitate is suction filtered, washed with water and a little ether and dried at 80° C.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:13])[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1cc(Br)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-caboxylate (1.5 g, 6.5 mmol) and potassium carbonate (0.99 g, 7.15 mmol) in DMF (25 mL) was stirred at room temperature for 15 min followed by the addition of methyl iodide (0.42 mL, 6.83 mmol). The resulting suspension was stirred at room temperature for 17 h. The mixture was partitioned between ethylacetate and water. The organic phase was separated and the aqueous phase was extracted with ethylacetate. The organic extracts were combined, washed with brine, dried over MgSO4 and concentrated to afford the title compound as a light yellow solid. MS m/z: 246(M+1).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:23]3[C:18](=[CH:19][C:20]([Cl:24])=[CH:21][CH:22]=3)[CH2:17][CH2:16][C:15]2=[O:25])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[Cl:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[N:14]([CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[C:15](=[O:25])[CH2:16][CH2:17]2
Reactant: CC(C)(C)OC(=O)N1CCC(N2C(=O)CCc3cc(Cl)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCc2cc(Cl)ccc2N1C1CCNCC1
Yield: 149.7 %

Procedure:
4-(6-Chloro-2-oxo-3,4-dihydro-2H-quinolin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 3.28 mmol) was set stirring in 1:1 TFA/CH2Cl2. After 45 min the mixture was evaporated and the golden oil brought up in Et2O. A solid formed and was filtered, washed with Et2O and air dried to give 1.3 g (93%) of a white solid. MS (electrospray): exact mass calculated for C13H17ClN2O, 264.10. m/z found, 265.1 [M++H].
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH:15]=[CH2:16])(=[O:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:25]1C=CC=C1CC(O)=O.[CH3:34][CH2:35][O:36]CC>>[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH:15]=[CH2:16])(=[O:13])=[O:14])([CH3:4])([CH3:2])[CH3:3].[C:1]([O:5][C:6](=[O:17])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[S:12]([CH2:15][CH2:16][S:25][C:35](=[O:36])[CH3:34])(=[O:13])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOCC
Reactant: O=C(O)Cc1cccs1
Agent: C=CS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)SCCS(=O)(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
N-(Vinylsulfonyl)-L-proline t-butyl ester (5.0 g, 0.0192 mole), triethylamine (2.8 ml, 0.02 mole) and thiolacetic acid (1.43 ml, 0.02 mole) are mixed in 100 ml of ether and allowed to stand overnight. The mixture is washed with 5% potassium bisulfate solution, saturated sodium bicarbonate solution and brine, then evaporated in vacuo to a yellow oil. The procedure is repeated using half of the above quantities of triethylamine and thiolacetic acid. Workup as in part (a) affords the crude product, N-[[2-(acetylthio)ethyl]sulfonyl]-L-proline t-butyl ester, which is filtered through a short silical gel column and crystallized from ether/hexane, m.p. 46°-50° (2.9 g, 45%).
Reaction SMILES: [C:1]([NH:9][C:10]1([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl.[CH3:34][NH:35][O:36][CH3:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([C:10]2([NH:9][C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH:12]([C:14](=[O:16])[N:35]([O:36][CH3:37])[CH3:34])[CH2:11]2)=[CH:18][CH:19]=1
Reactant: O=C(NC1(c2ccc(Cl)cc2)CC(C(=O)O)C1)c1ccccc1
Reactant: CNOC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CC(NC(=O)c2ccccc2)(c2ccc(Cl)cc2)C1
Reaction time: 8 h
Yield: 86.1 %

Procedure:
A solution of 3-benzamido-3-(4-chlorophenyl)cyclobutanecarboxylic acid (1.16 g, 3.52 mmol), diisopropylethylamine (1.57 mL, 9.14 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.446 g, 4.572 mmol) in dichloromethane (45 mL) was treated with HATU (1.61 g, 4.22 mmol). After stirring overnight, the solution was diluted with dichloromethane (50 mL), washed successively with 1 M HCl (3×), 5% aqueous NaHCO3 and saturated aqueous sodium chloride. The organic phase dried over MgSO4, filtered and concentrated to give a colorless gum. Crystallization from diethyl ether gave the subject compound as a white crystalline solid (1.13 g 86%). 1H NMR (CDCl3, 600 MHz) δ 7.79 (d, J=7.5 Hz, 2H), 7.49-7.52 (m, 3H), 7.42-7.45 (m, 2H), 7.35 (d, J=8.5 Hz, 2H), 7.08 (bs, 1H), 3.68 (s, 3H), 3.43-3.47 (m, 1H), 3.22 (s, 3H), 2.98-3.01 (m, 2H), 2.87-2.91 (m, 2H). ESI MS found for C20H21ClN2O3 m/z [395.4/397.3 (M+NO, 373.3/375.3 (M+1), 371.3/373.3 (M−1)].
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([OH:23])([C:19]([F:22])([F:21])[F:20])[C:15]([F:18])([F:17])[F:16])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2].[C:25](Cl)(=[O:27])[CH3:26]>>[CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:23][C:25](=[O:27])[CH3:26])([C:19]([F:22])([F:20])[F:21])[C:15]([F:16])([F:17])[F:18])[CH:10]=2)[NH:5][C:4]1=[O:24])[CH3:2]
Reactant: CCn1c(=O)[nH]c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2c1=O
Reactant: CC(=O)Cl
Product: CCn1c(=O)[nH]c2ccc(C(OC(C)=O)(C(F)(F)F)C(F)(F)F)cc2c1=O

Procedure:
Reaction of the compounds of formula I wherein Z is hydroxy with the appropriate acid chloride affords the corresponding alkanoyloxy derivative. For instance, reaction of 3-ethyl-6-(hexafluoro-2-hydroxy-2-propyl)quinazoline-2,4-dione with acetyl chloride yields 3-ethyl-6-(2-acetoxyhexafluoro-2-propyl)quinazoline-2,4-dione.
Reaction SMILES: [N:1]1[N:5]2[C:6](O)=[CH:7][CH:8]=[N:9][C:4]2=[N:3][CH:2]=1.P(Cl)(Cl)([Cl:13])=O.[OH-].[Na+]>>[Cl:13][C:6]1[N:5]2[N:1]=[CH:2][N:3]=[C:4]2[N:9]=[CH:8][CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ccnc2ncnn12
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccnc2ncnn12
Temperature: 0 °C

Procedure:
5.4 g of [1,2,4]triazolo[1,5-a]pyrimidin-7-ol from the first synthesis step are introduced into 20 ml of phosphorus oxychloride with vigorous stirring. After completion, the mixture is warmed under reflux for a further 1.5 h. For work-up, the cooled batch is stirred in portions into 100 ml of ice-water and subsequently adjusted to pH 12 using conc. NaOH solution. The aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, and the solvent is removed in vacuo. The 7-chloro-[1,2,4]triazolo[1,5-a]pyrimidine obtained is employed in the following reaction without further purification; m.p. 190° [lit. 186-187° C.];
Reaction SMILES: [C@@H:1]1([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[O:12][C@H:6]([CH:7]([C:9]([OH:11])=[O:10])[OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].S(=O)(=O)(O)O.C(N([CH2:33][CH3:34])CC)C>C(O)CCCCC>[CH2:1]([O:10][C:9]([CH:7]([OH:8])[C@H:6]1[O:12][C@@H:1]([N:13]2[C:22]3[N:21]=[CH:20][N:19]=[C:17]([NH2:18])[C:16]=3[N:15]=[CH:14]2)[C@H:2]([OH:3])[C@@H:4]1[OH:5])=[O:11])[CH2:2][CH2:4][CH2:6][CH2:33][CH3:34]
Reactant: CCN(CC)CC
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(O)C(=O)O)[C@@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)C(O)[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 8 h
Yield: 48 %

Procedure:
5 g of adenosine-5'-carboxylic acid are dissolved in 200 ml of n-hexanol and 2 ml of concentrated sulfuric acid and heated to 100° C. for 3 hours. After cooling, the reaction mixture is neutralized with triethylamine and left to stand overnight, the desired n-hexyl ester and triethylamine sulfate thereby crystallizing out. After filtering off with suction, the triethylamine sulfate is washed out with water and the remaining ester is recrystallized from methanol. There are obtained 3.1 g (48% of theory) of adenosine-5'-carboxylic acid n-hexyl ester, which has a melting point of 145°-147° C.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=1)[O:21][CH:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])([O-:17])=[O:16]>C1(C)C=CC=CC=1>[CH2:1]([NH:8][C:23](=[O:24])[CH:22]([O:21][C:20]1[CH:28]=[CH:29][CH:30]=[C:18]([N+:15]([O-:17])=[O:16])[CH:19]=1)[CH2:26][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CCC(Oc1cccc([N+](=O)[O-])c1)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCC(Oc1cccc([N+](=O)[O-])c1)C(=O)NCc1ccccc1
Yield: 58.7 %

Procedure:
In 30 ml of toluene were dissolved 1.6 g (0.015 mole) of benzylamine and 1.2 g (0.015 mole) of pyridine, and thereto was added dropwise a solution of 3.1 g (0.013 mole) of 2-(3-nitrophenoxy)-butyroyl chloride in 30 ml of toluene at room temperature with stirring. Subsequently, after the same procedure as in Synthesis Example 7 was followed, the resultant crude crystals were recrystallized from ethanol to give 2.4 g of N-benzyl-2-(3-nitrophenoxy)-butyramide melting at 114°~116° C. as pale yellow needles.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]#[N:8].Cl[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C1(C)C=CC=CC=1.[NH2-].[Na+]>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:7]#[N:8]
Reactant: Clc1ccccn1
Reactant: N#CCc1cccs1
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#CC(c1ccccn1)c1cccs1
Temperature: 60 °C

Procedure:
To a well-stirred solution containing 61.5 g. of 2-thienylacetonitrile and 56.5 g. of 2-chloropyridine in 400 ml. of toluene, slowly add a stirred suspension of 40 g. of sodamide in 300 ml. of toluene keeping the reaction temperature at 60°-65° C by cooling with an ice bath. After completing the addition maintain the temperature at 60° C for 2 hrs., add 200 ml. of water to the cooled reaction mixture, decant the tarry by-products and separate the aqueous layer. Evaporate in vacuo the resulting solution and dilute the thick black residue with 300 ml. of ether. Filter the separated solid and evaporate the filtrate. The desired product is distilled off at 145°-150° C/1 ml. and is recrystallized from alcohol to yield α-(2-thienyl)-2-pyridylacetonitrile, m.p. 48°-50° C.
Reaction SMILES: [SH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].N12CCCN=C1CCCCC2>C(#N)C>[CH3:17][O:16][C:12](=[O:15])[CH2:13][CH2:14][S:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc(CS)c1
Reactant: C=CC(=O)OC
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCSCc1cccc(C(=O)O)c1
Yield: 28 %

Procedure:
To a solution of 3-(mercaptomethyl)benzoic acid (500 mg, 2.97 mmol, 1.00 equiv) in acetonitrile (10.0 mL) was added methyl acrylate (10.0 mL) and 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.0 g, 6.57 mmol, 2.00 equiv) and the resulting solution was heated to reflux overnight. The reaction was concentrated under vacuum and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (0˜1:6) to afford 220 mg (28%) of 3-((3-methoxy-3-oxopropylthio)methyl)benzoic acid as light-red oil.