Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O1CCCC1.[CH3:14][S:15][C:16]1[N:21]=[CH:20][C:19]2=[CH:22][CH:23]=[C:24]([CH:25]=[O:26])[N:18]2[N:17]=1>C(OCC)(=O)C>[CH3:14][S:15][C:16]1[N:21]=[CH:20][C:19]2=[CH:22][CH:23]=[C:24]([CH:25]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[OH:26])[N:18]2[N:17]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CSc1ncc2ccc(C=O)n2n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ncc2ccc(C(O)c3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.00 M of Phenylmagnesium bromide in Tetrahydrofuran (1.552 mL, 1.552 mmol) was added to a solution of 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (250.0 mg, 1.294 mmol) in Tetrahydrofuran (8.0 mL, 99 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature with stirring for 3 hours. The mixture was then diluted with ethyl acetate and quenched with saturated ammonium chloride. The resulting mixture was washed with water and the organic layer was extracted, dried over sodium sulfate and reduced. The resulting oil was then purified via Isco flash column chromatography (hexanes/ethyl acetate) to afford 340 mg of (2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl-methanol. 1H NMR (400 MHz, DMSO, d6) δ 8.90 (s, 1H), 7.43 (m, 2H), 7.32 (m, 2H), 6.93 (m, 1H), 6.88 (m, 1H), 6.24 (m, 1H), 6.14 (m, 1H), 3.29 (s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7](=O)[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[S:23]1[CH:27]=[C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=2)[N:25]=[N:24]1.C(N(CC)CC)C>CO>[CH3:1][O:2][C:3]([C:5]1[N:33]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26]3[N:25]=[N:24][S:23][CH:27]=3)=[CH:35][CH:34]=2)[C:7](=[O:6])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: NCc1ccc(-c2csnn2)cc1
Reactant: COC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(-c2csnn2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15 %

Procedure:
To a solution of 6-bromo-1-oxo-4-phenyl-1H-isochromen-3-carboxylic acid methyl ester (359 mg) in methanol (20 ml) were added 4-[1,2,3]thiadiazol-4-ylbenzylamine (956 mg) and triethylamine (1.4 ml) and the mixture was stirred at room temperature for 72 hrs. The solvent was evaporated under reduced pressure, and the residue was partitioned between 1N hydrochloric acid and ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure, 4N hydrochloric acid ethyl acetate solution (5 ml) was added to the obtained residue, and the mixture was stirred at room temperature for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/1→1/1) to give the title compound (80 mg, 15%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]#[N:27])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1.C(=O)([O-])[O-:29].[K+].[K+].CS(C)=O>CO>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23]5([C:26]([NH2:27])=[O:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:15]=3)[CH:10]=[CH:11][N:12]=2)[CH:4]=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C#N)CC5)cc4)nc23)cn1
Agent: [K+]
Solvent: CO
Solvent: CS(C)=O
Product: Cn1cc(-c2nccn3nc(Nc4ccc(C5(C(N)=O)CC5)cc4)nc23)cn1
Reaction time: 5 h

Procedure:
1-{4-[8-(1-Methyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyrazin-2-ylamino]-phenyl}-cyclopropanecarbonitrile is dissolved in methanol before potassiumcarbonate (5 eq.), DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) are added. The mixture is stirred for 5 h and monitored via LCMS MS. DMSO (3.5 eq) and hydrogeneperoxide (30% solution, 5.eq) ares added and the mixture iss stirred at rt for 16 h. The mixture is concentrated and the crude material purified via column chromatographie. LCMS purity (Method D): 100%, Rt: 1.70 min, observed [M+H]=375.1;
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11](=[O:12])[CH2:10][S:9][C:8]1=S.[N:14]1([C:20]2[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.CCN(CC)CC>C1COCC1.[Hg](Cl)Cl>[N:14]1([C:20]2[CH:21]=[CH:22][C:23]([N:24]=[C:8]3[N:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11](=[O:12])[CH2:10][S:9]3)=[CH:25][CH:26]=2)[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C1CSC(=S)N1c1ccccn1
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CSC(=Nc2ccc(N3CCOCC3)cc2)N1c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
3-(2-pyridyl)-2-thioxo-thiazolidin-4-one (1.1 g, 5.3 mmol, 1.0 equiv), prepared as described in J. Chem. Soc. (1956) 1644, was dissolved in 30 ml THF and charged with 4-morpholin-4-yl aniline (0.94 g, 5.28 mmol, 1.0 equiv) and Et3N (1.47 ml, 10.6 mmol, 2.0 equiv). Mercury (II) chloride (1.4 g, 5.28 mmol, 1.0 equiv) was added in one portion as a solid, and the heterogeneous mixture was stirred at ambient temperature overnight. The reaction mixture was filtered through Celite, and the filtrate was partitioned between EtOAc and saturated NH4Cl. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. Flash chromatography (40% to 100% EtOAc in hexanes, silica) afforded 0.83 g (44%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 8.70 (m, 1H), 7.90 (m, 1H), 7.37–7.44 (m, 2H), 3.99 (s, 2H), 3.84 (m, 4H), 3.11 (m, 4H); MS (ESI) m/z=355.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[C:13]2[N:14]([CH:18]=[CH:19][N:20]=2)[CH:15]=[CH:16][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[N:20]1[CH:19]=[CH:18][N:14]2[CH:15]=[CH:16][CH:17]=[C:12]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[C:13]=12
Reactant: Brc1cccn2ccnc12
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Oc1ccc(-c2cccn3ccnc23)cc1
Yield: 75 %

Procedure:
A mixture of 4-hydroxyphenylboronic acid (0.77 g), 8-bromoimidazo[1,2-a]pyridine (1.1 g), tetrakis(triphenylphosphine)palladium(0) (0.19 g), sodium carbonate (2.1 g), DME (30 ml) and water (6 ml) was heated under reflux overnight under an argon atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) and recrystallized from ethyl acetate to give the title compound (0.88 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([OH:17])=O)[CH:6]=[CH:5]2.ClC1C(Cl)=CC(C(O)=O)=C(C=O)C=1.C([O:37][C:38](=[O:56])[CH2:39][C@H:40]([NH2:55])[CH:41]([OH:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[C:8](=[O:13])[N:7]([C@@H:14]([CH2:18][CH3:19])[C:15]([NH:55][C@H:40]([C:41](=[O:54])[CH2:42][O:43][C:44]1[C:49]([F:50])=[C:48]([F:51])[CH:47]=[C:46]([F:52])[C:45]=1[F:53])[CH2:39][C:38]([OH:56])=[O:37])=[O:17])[CH:6]=[CH:5]2
Reactant: CC[C@@H](C(=O)O)n1ccc2cc(Cl)c(Cl)cc2c1=O
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Agent: O=Cc1cc(Cl)c(Cl)cc1C(=O)O
Product: CC[C@@H](C(=O)N[C@@H](CC(=O)O)C(=O)COc1c(F)c(F)cc(F)c1F)n1ccc2cc(Cl)c(Cl)cc2c1=O

Procedure:
This compound was prepared using (S)-2-(6,7-dichloro-1-oxo-1H-isoquinolin-2-yl)-butyric acid (synthesized from 4,5-dichloro-2-formyl-benzoic acid [prepared as described in methods Q-S] using procedures similar to those described in methods A-E) and (3S)-3-amino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (prepared as described in methods N-P) using procedures similar to those described in methods F, G and E. The title compound was isolated as a white solid (94% last step). IR (solid) 1784.5, 1734.7, 1650.1, 1610.2, 1585.4, 1515.7, 1490.8, 1426.0, 1216.9, 1172.1, 1092.5, 933.1 cm−1; 1H NMR (400 MHz, d6-DMSO) δ 0.80 (3H, t), 1.90-1.98 (1H, m), 2.04-2.12 (1H, m), 2.55-2.79 (2H, m), 4.56-4.71 (1H, m), 5.08-5.41 (3H, m), 6.67 (1H, d), 7.56-7.59 (2H, m), 8.07 (1H, brd s), 8.25 (1H, d), 8.85-8.95 (1H, 2×d), 12.73 (1H, brd s) ppm; 19F NMR (376 MHz, d6-DMSO) (proton decoupled) δ −140.93, −140.95, −140.99, −141.01, −141.04, −141.07, −141.10, −156.76, −156.79, −156.82, −156.85, −156.89, −156.91; MS ES (+): 577.14 (M+H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10]O.N1C=CC=CC=1>CCOCC>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(CO)cc(OC)c1
Solvent: c1ccncc1
Solvent: CCOCC
Product: COc1cc(CCl)cc(OC)c1
Reaction time: 3 h
Yield: 86.5 %

Procedure:
Over a period of 20 minutes a solution of 150 g (1.26 moles) of thionyl chloride in 0.65 l of ether was added to 100 g (0.59 moles) of 3,5-dimethoxybenzyl alcohol and 6.6 ml of pyridine in 1.35 l of ether. After stirring for 3 hr the solution containing the product was separated from the residual dark oil, concentrated, and the crude product was redissolved in 1 l of ether, washed with water (3×250 ml), dried (brine, magnesium sulfate), filtered, and reconcentrated to give a dark oil which was vacuum distilled: b.p. 115°-118° C. at 0.4 mm Hg. Upon standing, fractions containing the desired compound solidified to give 95.3 g (86%) of white solid, m.p. 43°-45° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:16][C:17]([CH3:22])([CH3:21])[C:18](Cl)=[O:19]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][C:10]=1[O:11][C:18](=[O:19])[C:17]([CH3:22])([CH3:21])[CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(O)c(C(C)(C)C)c1
Reactant: CC(C)(C)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(OC(=O)C(C)(C)C)c(C(C)(C)C)c1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
5.00 g of 3-t-butyl-4-hydroxyanisole was dissolved in 30 ml of dimethylformamide and the solution was added dropwise into a suspension of 1.33 g of oily sodium hydride in 30 ml of dimethylformamide at 0° C. under a nitrogen stream. After stirring for 30 minutes, 3.76 ml of trimethylacetyl chloride was added dropwise and the solution was stirred overnight and allowed to attain room temperature. After the reaction was quenched with a saturated aqueous ammonium chloride solution, the reaction solution was extracted with water and ethyl acetate. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 3%-5% ethyl acetate) to give 5.25 g of 3-t-butyl-4-trimethylacetoxyanisole as a white solid (yield 72%).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([SH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]2>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=[CH:9][C:10]([S:13][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)=[CH:11][CH:12]=1
Reactant: Sc1ccc(-c2ccccc2)cc1
Reactant: O=C1CCc2cc(OCCCCBr)ccc2N1
Product: O=C1CCc2cc(OCCCCSc3ccc(-c4ccccc4)cc3)ccc2N1

Procedure:
Prepared analogous to Example 1 from 4-phenyl-thiophenol and 6-(4-bromo-butoxy)-3,4-dihydro-carbostyril.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[NH:5]([C:7]([O:9][CH2:10][CH:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[NH2:6]>ClCCl.C([O-])(O)=O.[Na+]>[CH:13]1[C:12]2[CH:11]([CH2:10][O:9][C:7]3[O:8][C:1](=[O:2])[NH:6][N:5]=3)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]=2[CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=c1[nH]nc(OCC2c3ccccc3-c3ccccc32)o1
Reaction time: 0.25 h

Procedure:
Two equivalents of phosgene (1.89 M in toluene; 4.2 ml) are added to a solution of 995 mg of 9H-fluoren-9-yl-methyl hydrazinecarboxylate in 40 ml of dichloromethane and 40 ml of saturated aqueous NaHCO3 solution. The mixture is stirred for 15 minutes and then worked up as usual, giving 5-(9H-fluoren-9-ylmethoxy)-3H-[1,3,4]oxadiazol-2-one (“A”).
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]([O:13]C(C)(C)C)=[O:12])[CH2:8][S:7]1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]([S:4][CH2:5][C@H:6]1[CH2:10][C@H:9]([C:11]([OH:13])=[O:12])[CH2:8][S:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC[C@H]1C[C@H](C(=O)OC(C)(C)C)CS1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)SC[C@H]1C[C@H](C(=O)O)CS1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-2-acetylthiomethyl-4-tert-butoxycarbonyltetrahydrothiophene (compound No. 4-1, 130 mg) in methylene chloride (2 ml), trifluoroacetic acid (1 ml) was added and the mixture was stirred for 2 hours at room temperature. The mixture was concentrated in vacuo and the oily residue was purified by a silica gel column chromatography to give 112 mg (quantitative yield) of the titled compound (compound No. 6-1) as white powder.
Reaction SMILES: C([Sn:5]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])CCC.[Sn](Cl)(Cl)(Cl)[Cl:43]>CCCCCCC>[CH2:6]([Sn:5]([Cl:43])([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: Cl[Sn](Cl)(Cl)Cl
Reactant: CCCCCCCCCCCC[Sn](CCCC)(CCCCCCCCCCCC)CCCCCCCCCCCC
Solvent: CCCCCCC
Product: CCCCCCCCCCCC[Sn](Cl)(CCCCCCCCCCCC)CCCCCCCCCCCC
Yield: 97.1 %

Procedure:
A 500 ml four-necked flask was charged with 95.0 g of n-butyl tri-n-dodecyltin, 36.4 g of tin tetrachloride and 150 ml of n-heptane, and they were reacted at 40° to 50° C. for 1 hour. After the reaction, the reaction mixture was washed three times with 100 ml of 10% aqueous solution of hydrochloric acid to remove mono-n-butyltin trichloride. The organic layer was dried with anhydrous magnesium sulfate, and concentrated to afford 89.3 g of tri-n-dodecyltin chloride having a purity of 97.2% as an oily substance (m.p. 30° to 32° C.).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7].I[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[N:12][C:4]=1[NH2:3])[CH3:15]
Reactant: CCI
Reactant: Nc1ncccc1C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccnc1N
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.2 %

Procedure:
A 60% sodium hydride suspension in mineral oil (1.28 g, 32 mMol) was added to a stirring suspension of 2-aminonicotinic acid (4.21 g, 30 mMol) in DMF (50 mL), and the mixture was gently heated until gas evolution was observed. The suspension was stirred at room temperature for 4 hours, after which a homogeneous amber solution was observed. Iodoethane (4.75 g, 30 mMol) was added, and the mixture was allowed to stir overnight at room temperature. The solution was concentrated in-vacuo, the residue was taken up in 9:1 ethyl acetate/hexane (200 mL), washed with water (5×50 mL), and brine (50 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 25%-50% ethyl acetate/hexane, to yield 3.6 g of colorless solids as product. NMR (500 MHz, DMSO) δ 8.20 (dd, 1 H, J=5 Hz, 2 Hz), 8.06 (dd, 1H, J=8 Hz, 2 Hz), 7.16 (s, 2H), 6.63 (dd, 1H, J=8 Hz, 5 Hz), 4.28 (q, 2H, J=7 Hz), 1.30 (t, 3 H, J=7 Hz). Yield=72%.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17][C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH:10]=2)[NH:5][C:4](=[O:28])[CH:3]=1.[OH:29]O>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][S:17]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)=[O:29])[CH:10]=2)[NH:5][C:4](=[O:28])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(OCCCCSc3ccc4ccccc4n3)cc12
Reactant: OO
Product: Cc1cc(=O)[nH]c2ccc(OCCCCS(=O)c3ccc4ccccc4n3)cc12

Procedure:
Prepared analogous to Example 123 from 4-methyl-6-[4-(2-quinolyl-mercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7](O)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[NH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:33]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[CH:1]1([CH:6]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[C:22](=[O:23])[CH2:21][O:20][C:19]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[N:18]3)=[CH:12][CH:11]=2)[C:7]([NH:31][CH:32]2[CH2:37][CH2:36][CH2:35][CH:34]([CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41])[CH2:33]2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)CCC1CCCC(N)C1
Reactant: O=C(O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCC1CCCC(NC(=O)C(c2ccc(CN3N=C(c4ccccc4)OCC3=O)cc2)C2CCCC2)C1

Procedure:
A solution of 590 mg (1.5 mmol) of cyclopentyl{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}acetic acid (enantiomer 2; Example 77A), 400 mg (1.8 mmol) of methyl 3-(3-aminocyclohexyl)propanoate hydrochloride (mixture of isomers), 1.05 ml (6.0 mmol) of N,N-diisopropylethylamine and 857 mg (2.26 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU) in 13 ml of DMF was stirred at room temperature overnight. After the reaction had ended, the reaction mixture was poured onto ice-water, whereupon the target compound precipitated in the form of white crystals. After filtration, the crystals obtained were washed three times with water and then dried overnight at 40° C. in a vacuum drying cabinet. This gave 830 mg (1.58 mol, 98% of theory) of the title compound as a mixture of diastereomers.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12](I)=[CH:11][C:10]=2[F:18])=[O:5])[CH3:2].[C:19]1([CH3:28])[C:20](B(O)O)=[CH:21][CH:22]=[CH:23][CH:24]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>CN(C=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][C:12]([C:24]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:28])=[CH:11][C:10]=2[F:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(F)cc(I)cc2c1O
Reactant: Cc1ccccc1B(O)O
Agent: [Ba+2]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cnc2c(F)cc(-c3ccccc3C)cc2c1O
Temperature: 80 °C
Yield: 47 %

Procedure:
6-Iodo-8-fluoro-4-hydroxy-3-quinolinecarboxylic acid ethyl ester (903 mg) from Example No. 5 and o-tolueneboronic acid (374 mg) are dissolved in DMF (50 mL) and at 50° C. a solution of barium hydroxide octahydrate (1.18 g) in water (5 mL) is added followed by palladium tetrakistriphenylphosphine (58 mg). The mixture is heated at 80° C. for 20 h, allowed to cool to rt, poured into water (200 mL), and extracted with ethyl acetate (3×100 mL). The organic layer is washed with brine (25 mL), dried (MgSO4), and concentrated. The solid is then triturated with MTBE, and filtered to afford 382 mg of 6-(2-methylphenyl)-8-fluoro-4-hydroxy-3-quinoline-carboxylic acid ethyl ester. The crude ester is mixed with 4-chlorobenzylamine (380 mg) and is heated to 190° C. for 1 h. The mixture is diluted with toluene (4 mL), allowed to cool to rt, poured into a mixture of 50% acetic acid (10 mL) and 1 N hydrochloric acid (25 mL), and is extracted with ethyl acetate (3×25 mL). The organic layer is dried (MgSO4) and allowed to crystallize. Recrystallization from acetic acid/water affords 166 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]#[N:4].[C:11]([CH2:19][C:20](=O)[CH3:21])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O-]CC.[Na+]>C(O)C.C1C=CC=CC=1>[NH2:4][C:3]1[C:19]([C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:20]([CH3:21])[NH:1][C:2]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N#CC(N)c1ccccc1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: CC[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCO
Solvent: c1ccccc1
Product: Cc1[nH]c(-c2ccccc2)c(N)c1C(=O)c1ccccc1
Reaction time: 12 h

Procedure:
2-Amino-2-phenyl-acetonitrile (0.04 mole) and benzoyl acetone (0.04 mole) are refluxed for four hours in 30 ml. of anhydrous benzene in the presence of 100 mg. of p-toluenesulfonic acid. After cooling the reaction mixture is filtered and the solvent is evaporated off to give an oily residue which is dissolved in an ethanol solution containing sodium ethoxide (0.041 mole) and the mixture is allowed to stand for 12 hours at the room temperature. The solid precipitate which forms is recovered by filtration.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:28]=2)[CH:26]=[O:27])O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:26]=[O:27])[CH:28]=2)[CH:9]=[CH:8][C:5]=1[C:6]#[N:7])[CH3:12]
Reactant: CC1(C)OB(c2cncc(C=O)c2)OC1(C)C
Reactant: CCOc1cc(Br)ccc1C#N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOc1cc(-c2cncc(C=O)c2)ccc1C#N
Temperature: 25 °C

Procedure:
A mixture of 4-bromo-2-ethoxybenzonitrile (1.13 g, 5.00 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinaldehyde (1.165 g, 5.00 mmol), sodium carbonate (5.00 mL, 10.00 mmol) and Pd(PPh3)4 (1.136 g, 0.125 mmol) in DME (20 mL) was heated to reflux for 6 h. After cooling to room temperature, filtration, drying over Na2SO4, concentration, a colorless solid was obtained. 1H NMR (400 MHz, CDCl3): δ 7.14 (d, J=1.5 Hz, 1H), 7.23 (dd, J=8, 1.5 Hz, 1H), 7.70 (d, J=8=Hz, 1H), 8.33 (t, J=2 Hz, 1H), 9.06 (d, J=2 Hz, 1H), 9.11 (d, J=2 Hz, 1H), 10.21 (s, 1H).