Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(C2C=NC(N3CCN(S(C[C@H](C(C)C)C([NH:27][OH:28])=O)(=O)=O)CC3)=NC=2)=CC=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH:46]3[CH2:51][CH2:50][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:62])[CH3:61])[C:57](O)=[O:58])(=[O:54])=[O:53])[CH2:48][CH2:47]3)=[N:43][CH:44]=2)=[CH:35][CH:34]=1>>[F:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]2[CH:40]=[CH:41][C:42]([O:45][CH:46]3[CH2:51][CH2:50][N:49]([S:52]([CH2:55][C@H:56]([CH:60]([CH3:61])[CH3:62])[C:57]([NH:27][OH:28])=[O:58])(=[O:54])=[O:53])[CH2:48][CH2:47]3)=[N:43][CH:44]=2)=[CH:37][CH:38]=1
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCN(c2ncc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Reactant: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)O
Product: CC(C)[C@@H](CS(=O)(=O)N1CCC(Oc2ccc(-c3ccc(F)cc3)cn2)CC1)C(=O)NO
Yield: 53 %

Procedure:
Prepared according to the method for the preparation of 2-(R)-{4-[5-(4-fluorophenyl)pyrimidin-2-yl]piperazine-1-sulfonylmethyl}-N-hydroxy-3-methyl-butyramide, from 2-(R)-{4-[5-(4-fluorophenyl)pyridin-2-yloxy]piperidine-1-sulfonyl-methyl}-3-methylbutyric acid (0.19 g), to give the title compound as a white solid (0.10 g, 53%)
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].O.[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH2:19](O)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>C1C=CC=CC=1.O>[C:8]1([CH3:18])[CH:9]=[CH:10][C:11]([S:14]([OH:17])(=[O:15])=[O:16])=[CH:12][CH:13]=1.[CH2:32]([O:5][C:4](=[O:6])[C@H:2]([CH3:3])[NH2:1])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCCCCCCCCCCCCCO
Reactant: C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCCCOC(=O)[C@H](C)N
Reaction time: 11 h
Yield: 95 %

Procedure:
4.46 g (0.05 mole) of L-alanine was used, 11.4 g (0.06 mole) of p-toluenesulfonic acid hydrate was used, and 11.79 g (0.055 mole) of myristyl alcohol was used as an alcohol. After 200 ml of benzene was added thereto as a solvent, these materials were stirred and mixed well. The resulting mixture was heated at the reflux temperature of benzene to carry out the esterification reaction. In this case, water was formed with the progress of the esterification reaction and released in the form of an azeotropic mixture with benzene, which was continuously removed from the reaction system. Thus, the reaction was completed in about 7-15 hours. Then, the reaction mixture was concentrated under reduced pressure to remove the benzene used as solvent. After the addition of ether and petroleum ether, the precipitated crystals were collected by filtration. These crude crystals were recrystallized from acetone, ether, petroleum ether and the like to obtain 21.74 g (95% yield) of L-alanine myristyl ester p-toluenesulfonate. An infrared absorption spectrum of the L-alanine myristyl ester p-toluenesulfonate thus obtained is shown in FIG. 3. In this figure, the peak 5 indicates the absorption of light by a parasubstituted phenyl group, the peaks 6 and 7 by the ester linkage, the peak 8 by sulfonic acid, the peaks 9 and 10 by a primary amine salt, and the peak 11 by the C=O stretching vibration originating from the ester linkage.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([NH:6][CH2:7][C:8]([F:11])([F:10])[F:9])=[C:4]([CH3:14])[CH:3]=1.C([O:17][CH:18]=[C:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21])C>>[F:1][C:2]1[CH:13]=[C:12]2[C:5](=[C:4]([CH3:14])[CH:3]=1)[N:6]([CH2:7][C:8]([F:9])([F:10])[F:11])[CH:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]2=[O:17]
Reactant: Cc1cc(F)ccc1NCC(F)(F)F
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cn(CC(F)(F)F)c2c(C)cc(F)cc2c1=O
Temperature: 0 °C
Yield: 42.8 %

Procedure:
A mixture of 66.1 g of 4-fluoro-2-methyl-N-(2,2,2-trifluoroethyl)aniline and 75.0 g of diethyl ethoxymethylenemalonate was heated at 160° for 20 hours. Eight hundred grams of polyphosphoric acid (ca. 400 ml) was added and the resulting mixture heated at 105°-115° for 20 minutes. The hot reaction mass was poured onto 1 kg of cracked ice to hydrolyze the polyphosphoric acid; the resulting solid was filtered and recrystallized from acetonitrile to yield 45.2 g of 6-fluoro-1,4-dihydro-8-methyl-4-oxo-1-(2,2,2-trifluoroethyl)-3-quinolinecarboxylic acid, ethyl ester, m.p. 154°-158°.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1)[CH3:2].[NH4+:32].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl>[NH2:32][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tert-butyl 2-{2-[2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate (16.06 g, 37.3 mmol) in 75 mL of CH2Cl2 was treated with 75 mL of concentrated NH4OH solution. The mixture was chilled in an ice water bath. To the rapidly stirred mixture was added solid p-toluenesulfonyl chloride (7.82 g, 41.0 mmol) over a 10 min period. The reaction mixture was then warmed to room temperature. After 30 min, the reaction was treated with 75 mL of CH2Cl2 and 75 mL of water and the layers were separated. The organic portion was then washed with 1% Na2CO3 solution (2×), water, brine, dried over Na2SO4, concentrated give 14.95 g of tert-butyl 2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethylcarbamate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[N:22](C=O)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH2:22])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(C)C=O
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: Cc1ccccc1
Product: COc1ccc(CC(N)=O)cc1OC
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
To a solution of 35.31 g (0.18 mole) of (3,4-dimethoxyphenyl)acetic acid in 345 ml of dry toluene and 34.5 ml of dry DMF at 0° C. under argon was added 16.8 ml (0.19 mole) of freshly distilled oxalyl chloride over 40 minutes. The reaction was stirred an additional 35 minutes at 0° C. and then at room temperature for 17 hours. The reaction mixture was again cooled to 0° C. and gaseous ammonia slowly bubbled through it for 1 hour. The reaction mixture was warmed to room temperature and stirred for 4 hours after which the solid was filtered off and partitioned between chloroform and water. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo giving 20.84 g of the title compound as an off-white solid, mp 142°-144° C.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].Cl.C(N(CC)C(C)C)(C)C>ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 98.5 %

Procedure:
To a stirred solution of 11.64 g of Boc-D-Cha-OH in 100 mL of dichloromethane at 0° C. was added 6.36 g of HOBt and 9.72 g of DCC. After 20 minutes a solution of 10.35 g of H-Pro-OBzl.HCl in 40 mL of dichloromethane adjusted with N,N-diisopropyl ethylamine to pH 8 was added. After 16 h the reaction mixture was filtered and the filtrate was washed successively with water, 0.1 N hydrochloric acid, water, aqueous 5% sodium hydrogencarbonate and brine. All aqueous washes were extracted twice with ethyl acetate, all organic extracts combined, dried over sodium sulfate and concentrated. To the residue was added a mixture of ethyl acetate/heptanes=1/1 (v/v), the resulting suspension filtered and the filtrate purified by chromatography on silica gel (eluent: ethyl acetate/heptanes=1/1 v/v) to yield 19.34 g of Boc-D-Cha-Pro-OBzl.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:5]=[C:6]([Cl:18])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH2:17])[CH:10]=1.[F:27][C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1.O>N1C=CC=CC=1>[Cl:18][C:6]1[CH:5]=[C:4]([N:19]2[C:24](=[O:25])[NH:23][C:22](=[O:26])[CH:21]=[N:20]2)[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([NH:17][S:34]([C:31]2[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=2)(=[O:36])=[O:35])[CH:10]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1N
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)cc1NS(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2-[3,5-dichloro-4-(3-amino-4-methoxy-phenoxy)-phenyl]-2H-[1,2,4]triazine-3,5-dione (100 mg) in pyridine (1 mL) was added 4-fluorobenzenesulfonyl chloride (59 mg) and the resulting solution was allowed to stir at room temperature for 1 h. The reaction solution was poured over water, extracted with ethyl acetate, the organic layer washed with 1N hydrochloric acid, water, brine, dried (Na2SO4), concentrated in vacuo and flash chromatographed on silica gel (40% aceton/hexanes) to afford the title compound of Step B as a light-yellow colored solid, 115 mg. m.p. 90-96° C., MS Calc.:553.4; Found:550.9.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[CH3:18]>CC(C)=O>[CH2:17]([O:19][C:20](=[O:28])[C:21]1[CH:26]=[CH:25][C:24]([O:27][C:6]2[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:23][CH:22]=1)[CH3:18]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)c1ccc(Oc2nc(Cl)ncc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of Compound 1a (2.0 g; 10.31 mmol) and 0.5N NaHCO3 (20 mL; 10 mmol) in acetone (60 mL) was added a solution of 4-hydroxy-benzoic acid ethyl ester (1.71 g; 10.29 mmol) in acetone (20 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 1 h. The reaction mixture was concentrated under reduced pressure. The resultant residue was extracted with EtOAc (2×20 mL). The organic layer was washed with brine and dried over MgSO4 and concentrated. The crude product was purified by normal phase chromatography (SiO2) to give Compound 16a. 1H NMR (300 MHz, CDCl3): δ 9.20 (s, 1H), 8.20 (d, 2H), 7.25 (d, 2H), 4.45 (q, 2H), 1.4 (t, 3H); MS: m/z 324.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:31][CH2:32][CH2:33][OH:34].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[OH:34][CH2:33][CH2:32][NH:31][C:14]([C:13]1[CH:12]=[CH:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:18][CH:17]=1)=[O:16]
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)cc1
Reactant: NCCO
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(C(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
2.06 g (8.21 mmol) of 4-[(tert-butoxycarbonylamino)methyl]benzoic acid suspended in 40 mL of methylene chloride was mixed with 1.63 g (10.1 mmol) of 1,1′-carbonyldiimidazole at room temperature and stirred at room temperature for 1.5 hours. The reaction solution was further stirred with 1.8 mL (30 mmol) of 2-aminoethanol overnight, and after addition of 40 mL of saturated aqueous sodium hydrogen carbonate, 20 mL of water and 200 mL of methylene chloride, was allowed to separate. The organic layer was washed with 80 mL of 1 M hydrochloric acid, with 40 mL of saturated aqueous sodium hydrogen carbonate and with 20 mL of saturated aqueous sodium chloride twice, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain the desired product (2.30 g, yield 95%).
Reaction SMILES: C(=O)(O)O.[NH2:5][C:6]([NH2:8])=[NH:7].C[O-].[Na+].[Cl:12][C:13]1[CH:35]=[CH:34][C:16]2[C:17](=O)[C:18](=[CH:29]N(C)C)[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]=2[CH:14]=1>CO.O>[NH2:7][C:6]1[N:8]=[CH:29][C:18]2[CH2:19][N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C:15]3[CH:14]=[C:13]([Cl:12])[CH:35]=[CH:34][C:16]=3[C:17]=2[N:5]=1
Reactant: CN(C)C=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2C1=O
Reactant: N=C(N)N
Agent: C[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In two equal portions 14.4 g (80 mmole) of guanidine carbonate and 20 ml (82 mmole) of 4.12 M methanol solution of sodium methoxide was added over 90 min to a solution of 3.6 g (10 mmole) of 8-chloro-1-(2-chlorophenyl)-3,4-dihydro-4-[(dimethylamino)methylene]-5H-2-benzazepine-5-one in 100 ml of methanol. The mixture was diluted with water and extracted with methylene chloride. The methylene chloride solution was dried over anhydrous sodium sulfate and concentrated at reduced pressure to give a yellow oil. Crystallization of the oil with methylene chloride gave a white solid, mp 240°-241° C. Recrystallization from a mixture of ether and methylene chloride gave colorless needles, mp 240°-241° C.
Reaction SMILES: [BH4-].[Na+].CO.[O:5]=[C:6]([CH:21]([CH3:31])[CH2:22][O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:7][C:8]([O:10][CH2:11]C1C=CC([N+]([O-])=O)=CC=1)=[O:9]>C(OCC)(=O)C>[O:5]=[C:6]([CH:21]([CH3:31])[CH2:22][O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH2:7][C:8]([O:10][CH3:11])=[O:9]
Reactant: CC(COCc1ccccc1)C(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)CC(=O)C(C)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium borohydride (1.89 g; 50 mmole) was added to methanol (20 ml), and the solution was heated under reflux for 10 minutes and then allowed to cool to room temperature. p-Nitrobenzyl 3-oxo-5-benzyloxy-4-methylpentanoate (3.7 g; 10 mmole) was dropwise added thereto, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and washed with dilute hydrochloric acid and an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After removal of the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give methyl 3-oxo-5-benzyloxy-4-methylpentanoate.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:17])[CH2:13][CH2:14][C:15]#[CH:16]>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>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:16]#[C:15][CH2:14][CH2:13][CH2:12][OH:17])=[CH:3][CH:4]=1
Reactant: C#CCCCO
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: OCCCC#Cc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 1 a], 1-iodo-4-trifluoromethyl-benzene was reacted with 4-pentyn-1-ol in the presence of Pd(PPh3)4 and cuprous iodide to give the title compound as yellow oil.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[O:9]=[C:10]1[C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:15][CH2:14][C:13]2[CH:25]=[CH:26][CH:27]=[CH:28][C:12]=2[NH:11]1>CCOC(C)=O>[Br:1][C:26]1[CH:27]=[CH:28][C:12]2[NH:11][C:10](=[O:9])[C@@H:16]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:23])[CH3:21])[CH2:15][CH2:14][C:13]=2[CH:25]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccccc2NC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2cc(Br)ccc2NC1=O
Yield: 103.9 %

Procedure:
23.5 g of N-bromosuccinimide (136 mmol) are introduced, at AT, as 4 portions over 3 days, into a 2 l three-necked flask, with stirring and under an argon atmosphere, containing 1.5 l of EtOAc and 8.47 g of 2a (103.0 mmol). The medium is left stirring for an additional overnight period, and washed with 500 ml of HCl (0.5N), 500 ml of a saturated aqueous solution of NaHCO3 and 500 ml of water. The organic phase is dried over MgSO4, filtered and then evaporated to dryness. 38 g of brown foam are obtained. The product is purified by chromatography on a silica cartridge (600 g), elution being carried out with heptane/EtOAc (70/30). 20.46 g of expected product 10a (white solid) are recovered.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)[CH:3]=[N:2]1.[C:12]1(B(O)O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[C:20]1([N:1]2[CH:5]=[C:4]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)[CH:3]=[N:2]2)[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(-c2cn[nH]c2)nc1
Reactant: OB(O)c1cccc2ccccc12
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: c1ccc(-c2cnn(-c3cccc4ccccc34)c2)nc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 2-(1H-pyrazol-4-yl)pyridine (292 mg, 2 mmol), 1-napthaleneboronic acid (690 mg, 4 mmol), Cu(OAc)2 (547 mg, 3 mmol) and pyridine (0.32 mL, 4 mmol) in dichloromethane (4 mL) was added 0.5 g of 4 Å molecular sieves. The resulting reaction mixture was stirred at ambient temperature under atmospheric conditions for 48 h, whereupon it was filtered through Celite, washing with dichloromethane. The reaction mixture was concentrated on to silica gel in vacuo and purified by liquid chromatography onto silica gel eluting with EtOAc:hex (2:8 to 3:7) to afford 2-[1-(1-naphthyl)-1H-pyrazol-4-yl]pyridine as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.63-8.65 (1H, m), 8.39 (1H, s), 8.34 (1H, s), 7.94-7.99 (3H, m), 7.73 (1H, ddd), 7.53-7.64 (5H, m), 7.18 (1H, m). MS (ESI) 272 (M+H)+
Reaction SMILES: Cl.C([O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]2[CH:22]=[C:21]3[C:16]([C:17](=[O:31])[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19][N:20]3[CH:23]3[CH2:25][CH2:24]3)=[CH:15][C:14]=2[F:32])[CH:10]=[C:9]([CH3:33])[N:8]=1)(=O)C>C(O)C>[CH:23]1([N:20]2[C:21]3[C:16](=[CH:15][C:14]([F:32])=[C:13]([C:11]4[CH:10]=[C:9]([CH3:33])[N:8]=[C:7]([CH2:6][OH:5])[CH:12]=4)[CH:22]=3)[C:17](=[O:31])[C:18]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:19]2)[CH2:25][CH2:24]1
Reactant: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(COC(C)=O)c3)c(F)cc2c1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cn(C2CC2)c2cc(-c3cc(C)nc(CO)c3)c(F)cc2c1=O
Yield: 98.5 %

Procedure:
Ethanolic hydrogen chloride (150 ml) was added to a suspension of 7.5 g ethyl 7-[2-(acetoxymethyl)-6-methyl-4-pyridinyl]-1-cyclopropyl-6-fluoro-1,4dihydro-4-oxo-3-quinolinecarboxylate (Example 17a) in 200 ml absolute ethanol, and the mixture heated at reflux for 90 min. The reaction mixture was concentrated in vacuo to give 6.68 g ethyl 1-cyclopropyl-6-fluoro-7-[2-(hydroxymethyl)-6-methyl-4-pyridinyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylate in the form of its hydrochloride salt, m.p. 240° C.(decompn.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C([Li])CCC.[CH3:15][Si:16](Cl)([CH3:18])[CH3:17]>C(OCC)C>[CH3:15][Si:16]([CH3:18])([CH3:17])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6]
Reactant: C[Si](C)(C)Cl
Reactant: OCc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1cccc(CO)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromobenzylalcohol (9.35 g, 50 mmol) in diethyl ether (50 ml) at 0° C. was added dropwise 1.5M butyllithium (66.7 ml) and the mixture was stirred 30 min. Then trimethylsilylchloride (11.39 g, 105 mmol) in diethyl ether (50 ml) was added dropwise and the mixture was stirred at room temperature 18 hours. The reaction mixture was treated with ice water (100 ml) and the organic layer extracted, washed with water, brine, dried over MgSO4 and concentrated. The crude product was dissolved in 90% aqueous methanol (100 ml) and refluxed 1 hour. The solvents were removed and 3-trimethylsilylbenzylalcohol was purified by distillation.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:24])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[N:15]=1.Cl>O.O1CCOCC1>[CH3:23][O:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:24])=[O:5])[S:12][CH:13]=1
Reactant: COC(=O)CCCCc1nc(-c2ccccc2OC)cs1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccccc1-c1csc(CCCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
Add a solution of LiOH.H2O (2.62 g, 62.5 mmol) in water (60 mL) to a rapidly stirred solution of 5-[4-(2-methoxy-phenyl)-thiazol-2-yl]-pentanoic acid methyl ester (3.82 g, 12.5 mmol) in dioxane (120 mL), stir at room temperature. After 1 hour, acidify to pH 1 with 5N HCl solution and concentrate to remove the majority of the dioxane. Partition residue between 20% i-PrOH/CHCl3 and 1N HCl solution, separate layers. Backextract from aqueous layer with 20% i-PrOH/CHCl3 and dry combined organic layers over MgSO4, and concentrate to get 3 grams of a pink oil. Recrystallize from EtOAc to afford the title compound (2.52 g, 69%). MS (IS) 292 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH:11]1([C:17]2[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([CH:11]3[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]3)=[CH:18][CH:19]=2)=[O:7])=[CH:4][N:3]=1
Reactant: Nc1ccc(C2CCCCC2)cc1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(C2CCCCC2)cc1)c1ccc(Cl)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.2 %

Procedure:
6-Chloronicotinoyl chloride (0.24 g) was dissolved in toluene (5 mL), and the solution was cooled to 0° C. 4-Cyclohexylaniline (0.47 g) was added thereto at 0° C., and the mixture was stirred at room temperature for 1 hour. Ethyl acetate was added thereto, and the organic layer was washed with a 1 N aqueous sodium hydroxide solution and water and dried over sodium sulfate. After concentration under reduced pressure, the obtained solid was collected by filtration and washed with diethyl ether. The solid was dried under reduced pressure to obtain the title compound (0.40 g) as a white solid (yield: 95%).