Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:41][O:42][C:43](=[O:55])[C:44]1[CH:49]=[C:48]([OH:50])[CH:47]=[C:46]([O:51][CH2:52][O:53][CH3:54])[CH:45]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OC(=O)C)C>[CH3:41][O:42][C:43](=[O:55])[C:44]1[CH:45]=[C:46]([O:51][CH2:52][O:53][CH3:54])[CH:47]=[C:48]([O:50][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=2)[CH:49]=1
Reactant: COCOc1cc(O)cc(C(=O)OC)c1
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COCOc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)c1
Temperature: 130 °C
Reaction time: 6 h
Yield: 71.1 %

Procedure:
After adding 33.4 g (142 mmol) of 4-methanesulfonyl-bromobenzene, 2.67 g (11.9 mmol) of palladium acetate, 5.31 g (17.8 mmol) of 2-(di-tert-butylphosphino)biphenyl and 50.3 g (237 mmol) of potassium phosphate to a solution of 25.0 g (119 mmol) of 5-hydroxy-3-methoxymethoxybenzoic acid methyl ester in toluene (375 ml), the reactor was sealed and the mixture was subsequently stirred at 130° C. for 6 hours. Acetic acid ethyl ester was added to the reaction mixture, which was then filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:acetic acid ethyl ester=2:1) to obtain 31.0 g of 3-(4-methanesulfonyl-phenoxy)-5-methoxymethoxy-benzoic acid methyl ester (yield: 69%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([OH:12])=[CH:7][C:6]=1[OH:13])[CH3:2].Cl.Cl[CH2:17][C:18]1[CH:19]=[C:20]([CH:33]=[CH:34][CH:35]=1)[O:21][CH2:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1.C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[OH:13][C:6]1[CH:7]=[C:8]([O:12][CH2:17][C:18]2[CH:35]=[CH:34][CH:33]=[C:20]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH:19]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:4]([O:3][CH2:1][CH3:2])=[O:14]
Reactant: CCOC(=O)c1c(C)cc(O)cc1O
Reactant: ClCc1cccc(OCc2ccc3ccccc3n2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: CCOC(=O)c1c(C)cc(OCc2cccc(OCc3ccc4ccccc4n3)c2)cc1O

Procedure:
2,4-Dihydroxy-6-methyl-benzoic acid ethyl ester (315 mg, 1.6 mmol) is combined with 2-(3-chloromethyl-phenoxymethyl)-quinoline hydrochloride (0.51 g, 1.6 mmol, example 49), tetrabutylammonium iodide (55 mg, 0.15 mmol) and potassium carbonate (0.48 g, 3.5 mmol) in acetone (9 mL). The reaction is heated at reflux 48 h. The reaction is partitioned between ethyl acetate and saturated ammonium chloride. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated to yield the crude product. This material is purified by column chromatography (silica, 3% ether in dichloromethane) to the title compound; m.p. 127–128° C., MS (ESI) 444 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:31])([F:30])[F:29])[C:21]=2[N:20]=1)[CH:2]=[CH2:3]>CO.[Pd]>[CH2:1]([O:4][C@@H:5]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH2:7][C@H:6]1[NH:16][C:17](=[O:32])[CH2:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[C:27]([C:28]([F:29])([F:31])[F:30])[C:21]=2[N:20]=1)[CH2:2][CH3:3]
Reactant: C=CCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)Cc1nc2c(C(F)(F)F)cccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: CCCO[C@@H]1CN(C2CCOCC2)C[C@H]1NC(=O)Cc1nc2c(C(F)(F)F)cccc2[nH]1

Procedure:
To a solution of rel-N-[(3R,4R)-4-(allyloxy)-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide in methanol was added Pd/C and the reaction was exposed to 1 atm H2 overnight. The reaction mixture was filtered and concentrated to afford rel-N-[(3R,4R)-4-propoxy-1-(tetrahydro-2H-pyran-4-yl)pyrrolidin-3-yl]-2-[4-(trifluoromethyl)-1H-benzimidazol-2-yl]acetamide as a white solid. 1H-NMR (CDCl3) δ: 0.87 (t, 3H), 1.48-1.58 (m, 4H), 1.74 (m, 2H), 1.89 (m, 2H), 2.24-2.35 (m, 2H), 2.73 (m, 2H), 3.31-3.40 (m, 4H), 3.56 (m, 1H), 3.73 (m, 1H), 3.92-3.98 (m, 2H), 3.92 (s, 2H), 4.28 (m, 1H), 7.14 (b, 1H), 7.30 (t, J=7.9 Hz, 1H), 7.49 (d, J=7.3 Hz, 1H). MS m/z: 455 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.C([O:10][C:11](=[O:17])[CH2:12][C:13](=O)[CH2:14]Br)C>CO>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:13]([CH2:12][C:11]([OH:17])=[O:10])=[CH:14][N:4]2[N:3]=1
Reactant: CCOC(=O)CC(=O)CBr
Reactant: Cc1nnc(N)s1
Solvent: CO
Product: Cc1nn2cc(CC(=O)O)nc2s1
Temperature: 80 °C

Procedure:
A mixture of 5-methyl-[1,3,4]thiadiazol-2-ylamine (300 mg, 2.6 mmol), 4-bromo-3-oxo-butyric acid ethyl ester (908 mg, 2.6 mmol) and 5 mL of MeOH was combined in a sealed tube and was heated to 80° C. for 3 hours. The reaction was cooled and the MeOH was removed in vacuo. The residue was dissolved in dichloromethane and the organic solution was washed with saturated aqueous NaHCO3 solution (2×). The organic solution was dried over sodium sulfate, filtered and concentrated. The crude product was purified by Combiflash (Teledyne ISCO, Lincoln, Nebr.) chromatography using 0-100% EtOAc/heptanes. Both the desired product and (2-methyl-imidazo[2,1-b][1,3,4]thiadiazol-6-ylyacetic acid methyl ester (formed by trans esterification with solvent MeOH) were obtained with a total mass of 333 mg (54%). The crude mixture was used directly in the next step
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[N:21])[CH:15]=2)[C@@H:11]([NH2:13])[CH3:12])=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.Cl[C:32]1[CH:37]=[CH:36][C:35]([C:38](=O)[C:39]([CH3:42])([OH:41])[CH3:40])=[CH:34][CH:33]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]([C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[C:20]#[N:21])[C@@H:11]([NH:13][CH:38]([C:35]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)[C:39]([OH:41])([CH3:42])[CH3:40])[CH3:12])=[CH:5][CH:4]=1
Reactant: C[C@H](N)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reactant: CC(C)(O)C(=O)c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(c1ccccc1)C(C)(C)O)[C@@H](Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Reaction time: 0.08 h

Procedure:
To a solution of 100 mg (0.31 mmol) of 3-(4-chlorophenyl)-2(S)-(3-cyanophenyl)-1(S)-methyl-propylamine hydrochloride in 2 mL of CH2Cl2, 54 μL (0.31 mmol) of diisopropylethylamine and 62 mg (0.31 mmol) of 1-(4-chlorophenyl)-2-methyl-2-hydroxy-propan-1-one were added. After 5 min, 99 mg (0.47 mmol) of sodium triacetoxyborohydride was added and stirred for 3 hr. The reaction was quenched with water and the layers were separated. The organic layer was dried and concentrated. The residue was purified on a prep TLC plate using 30% EtOAc/hexane as an eluant to isolate two products. The higher Rf band gave 3-(1(S)-(4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer A) and the lower Rf band gave 3-(1(S)-4-chlorobenzyl)-2(S)-((2-hydroxy-2-methyl-1-phenylpropyl)amino)propyl)benzonitrile (diastereomer B). Diastereomer A, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min). Diastereomer B, LC-MS: m/e=467 (M+1), 469 (M+3) (3.28 min).
Reaction SMILES: I[Si](C)(C)C.C(OC([N:13]1[C@H:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][S:15][CH:14]1[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=O)(C)(C)C.O>C(Cl)(Cl)Cl>[CH2:25]([CH:14]1[NH:13][C@H:17]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][S:15]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1CSC(Cc2ccccc2)N1C(=O)OC(C)(C)C
Agent: C[Si](C)(C)I
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)[C@@H]1CSC(Cc2ccccc2)N1
Reaction time: 1 h
Yield: 111.3 %

Procedure:
C tert-Butyl (2RS,4R)-2-benzyl-4-thiazolidinecarboxalate may be prepared in the following 11.8 cm3 of iodotrimethyl-silane are introduced slowly at a temperature in the region of 25° C. into a solution of 30.5 g of tert-butyl (4R)-3-tert-butoxycarbonyl-2-benzyl-4-thiazolidine-carboxylate (isomer A) in 250 cm3 of chloroform. The reaction mixture is stirred for 1 hour, and 10 cm3 of water are then added. The organic phase is separated and the aqueous phase is extracted with twice 20 cm3 of methylene chloride. The combined organic phases are washed with 100 cm3 of water and with 100 cm3 of saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure at 40° C. 25.0 g of tert-butyl (2RS,4R)-2-benzyl-4-thiazolidinecarboxylate are thereby obtained in the form of a yellow oil, which is used in the subsequent syntheses without further treatment.
Reaction SMILES: [C:1]([C:4]1[C:5](Cl)=[C:6]2[CH:12]=[N:11][N:10]([CH2:13][CH3:14])[C:7]2=[N:8][CH:9]=1)(=[O:3])[CH3:2].Cl.[NH2:17]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)(=O)C>[CH2:13]([N:10]1[C:7]2[N:8]=[CH:9][C:4]3[C:5](=[N:17][O:3][C:1]=3[CH3:2])[C:6]=2[CH:12]=[N:11]1)[CH3:14]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(C)=O)cnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CCn1ncc2c3noc(C)c3cnc21

Procedure:
5-Acetyl-4-chloro-1-ethyl-1H-pyrazolo[3,4-b]pyridine (4.60 g) was refluxed for 2 hours in 450 ml of glacial acetic acid containing 15 g of hydroxylamine hydrochloride and 1.0 g of p-toluenesulfonic acid monohydrate. At the end of this time the reaction volume was reduced to ca. 200 ml under reduced pressure and then it was poured into 800 ml of water. The amorphous precipitate was filtered off and purified over 230-400 mesh silica gel (5% ethyl acetate/dichloromethane). The appropriate fractions were combined and evaporated and the resultant crystalline product was washed with pentane to give 1.75 g, mp 181°-182° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][CH:43]=1)[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1.C(N(CC)CC)C>CN(C)C=O.O1CCCC1>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:23]=[C:22]([NH:21][C:7]([C:5]5[N:4]([CH2:10][C:11]([F:14])([F:13])[F:12])[N:3]=[C:2]([CH3:1])[CH:6]=5)=[O:9])[CH:43]=[CH:42][CH:41]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: Cc1cc(C(=O)O)n(CC(F)(F)F)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)n(CC(F)(F)F)n1
Yield: 87.1 %

Procedure:
Using 3-methyl-1-(2,2,2-trifluoroethyl)-1H-pyrazole-5-carboxylic acid (175 mg, 0.84 mmol), N,N-dimethylformamide (1 drop), oxalyl chloride (91 μL, 1.01 mmol), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (200 mg, 0.646 mmol), triethylamine (196 mg, 1.94 mmol) and tetrahydrofuran (15 mL) as starting materials and in the same manner as in Example 109, the title compound (281 mg, 87%) was obtained as a white powder.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH:6]1[O:8][CH2:7]1)([CH3:3])[CH3:2].[H-].[Na+].[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][SH:23]>O1CCCC1>[CH2:22]([S:23][CH2:7][CH:6]([OH:8])[CH2:5][O:4][CH:1]([CH3:2])[CH3:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11]
Reactant: CCCCCCCCCCCCS
Reactant: CC(C)OCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCSCC(O)COC(C)C
Temperature: 60 °C

Procedure:
2,3-Epoxypropyl isopropyl ether (1.16 g.) in several ml. of dry tetrahydrofuran is added to a stirred suspension formed by the addition of 50 mg. of sodium hydride (56% dispersion in mineral oil) to 2.2 g. 8. of n-dodecylthiol in 50 ml. tetrahydrofuran. The mixture is then stirred at 60° C. After approximately 4 hours the solvent is removed from the reaction mixture and 20 ml. of water is added to the residue. The resultant aqueous mixture is extracted with ether and the ether extracts washed with water, dried over magnesium sulfate and evaporated to yield 1-(n-dodecylthio)-3-isopropoxy-2-propanol.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[C:7]([O:11][C:12](=[O:46])[N:13]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:14][CH2:15][NH:16][S:17]([C:20]1[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][C:26]=2[CH:27]=[CH:28][CH:29]=1)(=[O:19])=[O:18])([CH3:10])([CH3:9])[CH3:8].CI>CN(C=O)C.CCOC(C)=O>[C:7]([O:11][C:12](=[O:46])[N:13]([CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH2:39][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:14][CH2:15][N:16]([S:17]([C:20]1[C:21]2[CH:22]=[CH:23][N:24]=[CH:25][C:26]=2[CH:27]=[CH:28][CH:29]=1)(=[O:19])=[O:18])[CH3:1])([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N(CCNS(=O)(=O)c1cccc2cnccc12)CCOc1ccccc1Cc1ccccc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCN(CCOc1ccccc1Cc1ccccc1)C(=O)OC(C)(C)C)S(=O)(=O)c1cccc2cnccc12
Yield: 75.3 %

Procedure:
Powdered K2CO3 (50.4 mg, 0.365 mmol) is added to a stirred solution of [2-(2-benzyl-phenoxy)-ethyl]-[2-(isoquinoline-5-sulfonylamino)-ethyl]-carbamic acid tert-butyl ester (82.0 mg, 0.146 mmol) and CH3I (18.2 μL, 0.292 mmol) in anhydrous DMF (1 mL) at ambient temperature under nitrogen. The resultant solution is stirred for 2 hours. The mixture is diluted with EtOAc (10 mL), washed with water (5 mL×3), dried over MgSO4, filtered and concentrated. The crude product is chromatographed on silica (gradient 0-5% CH3OH in CH2Cl2) to give 65 mg (0.11 mmol, 77% yield) of the title compound as a gum. ESIMS: m/z 576 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=3)=[O:15])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[F:24][C:25]([Si](C)(C)C)([F:27])[F:26].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>C1COCC1>[N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14]([C:16]3[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=3)([OH:15])[C:25]([F:27])([F:26])[F:24])=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(/C=C/c1ccc(-n2cncn2)cc1)(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 24.1 %

Procedure:
To a solution of (E)-3-(4-(1H-1,2,4-triazol-1-yl)phenyl)-1-(3,5-dichlorophenyl)prop-2-en-1-one (1 g, 3 mmol) in THF (150 mL) was added trifluoromethyltrimethylsilane (0.517 g, 3.644 mmol) and tetra-n-butylammonium fluoride (TBAF) (1.0 M, 1 mL) at 0° C. The reaction was slowly warmed to RT and allowed to stir for 2 h. The reaction was then cooled to 0° C. and 5 M HCl solution was added and the reaction was stirred for an additional 4 h at RT. The reaction was extracted with DCM and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2; 25% EtOAc/hexanes) to afford the title compound as an off-white solid (0.3 g, 25%).
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[N:14][N:15]2[CH:19]=[N:18][NH:17][C:16]2=[O:20])[CH:8]=1>N1C=CC=CC=1>[CH3:1][N:2]([CH3:6])[C:3]([N:17]1[C:16](=[O:20])[N:15]([N:14]=[CH:13][C:9]2[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=2)[CH:19]=[N:18]1)=[O:4]
Reactant: O=c1[nH]ncn1N=Cc1cccnc1
Reactant: CN(C)C(=O)Cl
Solvent: c1ccncc1
Product: CN(C)C(=O)n1ncn(N=Cc2cccnc2)c1=O
Reaction time: 14 h

Procedure:
3.2 g of dimethylcarbamoyl chloride are added to a suspension of 3.8 g of 4-(pyridin-3-yl-methyleneamino)-1,2,4-triazol-3-one in 50 ml of pyridine. The resulting solution is stirred for 14 hours at 20° and then concentrated by evaporation. Water is added to the residue. The crystals that have precipitated are filtered off with suction and dried under a high vacuum. 3.6 g of crystals of the title compound having a melting point of 181-182° are obtained.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[C:14]([F:21])[CH:15]=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[F:21][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:13]=1[N:12]([CH3:22])[CH:11]=[C:10]([OH:9])[C:19]2=[O:20]
Reactant: Cn1cc(OC(=O)c2ccccc2)c(=O)c2cccc(F)c21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: Cn1cc(O)c(=O)c2cccc(F)c21
Reaction time: 24 h

Procedure:
A mixture of 8-fluoro-1-methyl-4-oxo-1 ,4-dihydro-quinol-3-yl benzoate (10 g), piperidine (3.18 g) and dichloromethane (200 ml) was stirred for 24 hours, a further portion of piperidine (1.7 ml) was added and the stirring continued for a further 24 hours. The solvent was removed by distillation and the residue was triturated with diethyl ether (300 ml). The resultant solid was extracted with aqueous sodium hydroxide (0.1 M, 100 ml) and the extract was neutralised with hydrochloric acid (5M, 2 ml). The resultant precipitate was collected by filtration to give the novel compound 8-fluoro-3-hydroxy-1 -methyl-4-quinolone, m.p. 248°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: CCO
Reactant: O=C(O)c1c[nH]c2ccc(Cl)cc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1c[nH]c2ccc(Cl)cc12

Procedure:
To a suspension of 5.23 g (26.74 mmol) 5-chloro-1H-indole-3-carboxylic acid in 140 ml dry ethanol were added 10 ml concentrated sulfuric acid, and the mixture was heated with reflux for 16 h. It was concentrated under reduced pressure, and the residue was tretaed with ethanol/hexane to give the crystalline title ester, which was filtered and dried in vacuo.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:22]=[CH:21][C:20]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1.[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].CO>C(OCC)(=O)C>[C:31]([OH:36])(=[O:35])[C:32]([OH:34])=[O:33].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:26]3[CH2:27][CH2:28][CH:23]([C:20]4[CH:21]=[CH:22][C:17]([C:16]([F:15])([F:29])[F:30])=[CH:18][CH:19]=4)[CH2:24][CH2:25]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: FC(F)(F)c1ccc(C2CCNCC2)cc1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(c2ccc(C(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-trifluoromethylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 34% overall yield. FDMS m/e=419 (M+ of free base). α[D]589 =-10.15 (c=0.47, methanol).
Reaction SMILES: [CH2:1]([N:3]([C:29]([C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][N:32]=1)=O)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:39][CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:33][N:32]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCN(C(=O)c1ccc(O)cn1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCC1
Product: CCN(Cc1ccc(OCCN2CCCCC2)cn1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 46.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(5-hydroxypyridine-2-carbonyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-1-piperidin-1-ylethanone (16 mg) according to an analogous synthetic method to Example 404 described below and purified by LC-MS, the title compound (12 mg) was obtained.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:14]1)=[O:11].Br[CH2:39][CH2:40][C:41]([O:43][CH2:44][CH3:45])=[O:42].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH2:44]([O:43][C:41](=[O:42])[CH2:40][CH2:39][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([N:12]([CH2:34][CH:35]([CH3:37])[CH3:36])[C@H:13]1[CH2:18][C@@H:17]([C:19]([N:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)=[O:20])[CH2:16][N:15]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH2:14]1)=[O:11])[CH3:45]
Reactant: CC(C)CN(C(=O)c1nc2ccccc2[nH]1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCOC(=O)CCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 70 °C
Reaction time: 15 h
Yield: 73.3 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-[(1H-benzimidazol-2-ylcarbonyl) (2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (257 mg) and ethyl 3-bromopropanoate (181 mg) in N,N-dimethylacetamide (5 ml) was added cesium carbonate (489 mg), and the mixture was stirred at 70° C. for 15 hr. Ethyl 3-bromopropanoate (181 mg) was added to the reaction mixture, and the mixture was further stirred at 70° C. for 5 hr. The reaction mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (6:4) was concentrated under reduced pressure to give the object product (225 mg).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16](OC)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[O:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH2:43]([N+:45]1[C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=2[S:47][C:46]=1[CH3:54])[CH3:44].C(N(CC)CC)C>C(#N)C>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([N:8]1[C:16]([CH:54]=[C:46]2[N:45]([CH2:43][CH3:44])[C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][C:48]=3[S:47]2)=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]2)=[C:9]1[CH:19]=[CH:20][C:21]1[O:22][C:23]2[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=2[N+:25]=1[CH2:26][CH3:27])[CH3:7]
Reactant: CCn1c(C=Cc2oc3ccccc3[n+]2CC)c2ccccc2c1OC
Reactant: CC[n+]1c(C)sc2ccccc21
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCN1C(=Cc2c3ccccc3c(C=Cc3oc4ccccc4[n+]3CC)n2CC)Sc2ccccc21

Procedure:
2-[2-(2-Ethyl-3-methoxyisoindol-1-yl)vinyl]-3-ethyl-benzoxazolium perchlorate (1.0 g) and 3-ethyl-2-methylbenzothiazolium p-toluenesulfonate (0.9 g) were dissolved in acetonitrile. Triethylamine was added and the reaction mixture stirred until the absorption at 520 nm disappeared. The reaction mixture was evaporated to dryness and chromatographed on silica gel. After recrystallization of the product from methanol, the melting point was 180° C. CH3CN λ max 625 nm.