Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[O:2]=[C:3]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[N:18]1[CH:23]=NC=N[CH:19]=1>C(O)C>[CH2:11]([C:10]1[C:3](=[O:2])[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[CH:23][NH:18][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(=O)CCc1ccccc1
Reactant: c1ncncn1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)c1c[nH]cc(Cc2ccccc2)c1=O
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a solution of sodium (0.5835 g, 25.4 mmol) in ethanol (18 ml) under nitrogen, was added ethyl 3-oxo-5-phenylpentanoate (5.5752 g, 25.3 mmol) in ethanol (5 ml) and 1,3,5-triazine (2.0544 g, 25.3 mmol). The mixture was heated at reflux for 1 h, then allowed to cool. The solvent was removed in vacuo, and water (15 ml) was added to the residue. The pH was brought to 4 by the addition of concd HCl (3 ml) and the mixture was left overnight. The resulting solid was collected by filtration, washed with ethanol and dried under vacuum at 60° C. to yield 4.6324 g (71%) of the title compound as a buff solid; 1H NMR (360 MHz, DMSO-d6) δ1.24 (3H, t, J 7.1 Hz), 3.64 (2H, s), 4.16 (2H, q, J 7.1 Hz), 7.15-7.28 (5H, m), 7.53 (1H, s), 8.18 (1H, s), 11.64 (1H, br s).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.[F:24][C:25]1[C:30]([CH:31]([CH3:33])[CH3:32])=[CH:29][C:28]([C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][C:35]=2[CH2:44]I)=[C:27]([O:46]C2CCCCO2)[CH:26]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C.[NH4+].[Cl-].O.CO>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[N:17]([CH2:44][C:35]3[CH:36]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:38]=[CH:39][C:34]=3[C:28]3[CH:29]=[C:30]([CH:31]([CH3:33])[CH3:32])[C:25]([F:24])=[CH:26][C:27]=3[OH:46])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CI)c(OC2CCCCO2)cc1F
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(C)c1cc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c(O)cc1F
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.9 mg, 0.0485 mmol) was added to a stirred solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one in dry DMF (1 mL) and the reaction was stirred for 30 min, A solution of 2-{[4-fluoro-2′-(iodomethyl)-5-isopropyl-4′-(trifluoromethyl)biphenyl-2-yl]oxy}tetrahydro-2H-pyran (16.9 mg, 0.324 mmol) in dry DMF (1 mL) was added by cannula and the reaction was stirred at room temperature overnight. The reaction was diluted with saturated NH4Cl (10 mL) and water (5 mL) and extracted with EtOAc (3×20 mL). The combined extracts were dried (Na2SO4) and concentrated in vacuo to give the crude product. A solution of the crude product and p-toluenesulfonic acid (0.6 mg, 0.00324 mmol) in MeOH (5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to give the crude product. This was purified by flash chromatography (Si, 12×160 mm, 0-35% EtOAc in hexanes gradient) to afford (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[4′-fluoro-2′-hydroxy-5′-isopropyl-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (20% EtOAc in hexanes). LCMS calc.=624.2; found=624.3 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.86 (s, 1H), 7.67 (m, 4H), 7.42 (d, J=7.1 Hz, 0.5H), 7.41 (d, J=7.1 Hz, 0.5H), 6.95 (d, J=7.3 Hz, 0.5H), 6.94 (d, J=7.3 Hz, 0.5H), 6.70 (d, J=5.6 Hz, 0.5H), 6.68 (d, J=5.6 Hz, 0.5H), 5.66 (d, J=8.0 Hz, 0.5H), 5.36 (d, J=8.1 Hz, 0.5H), 4.93 (d, J=15.8 Hz, 0.5H), 4.88 (d, J=15.8 Hz, 0.5H), 4.18 (d, J=15.8 Hz, 0.5H), 4.00 (d, J=15.8 Hz, 0.5H), 3.87-3.83 (m, 0.5H), 3.77-3.71 (m, 0.5H), 3.22-3.14 (m, 1H), 1.77 (br s, 1H), 1.27-1.17 (m, 6H), 0.57 (d, J=6.5 Hz, 1.5H), 0.45 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])=[CH:11][CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.O1CCOCC1.C(O)(=O)C.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([NH:18][CH2:19][C@H:20]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:21]([O:23][CH3:24])=[O:22])(=[O:17])=[O:16])=[CH:13][CH:14]=1
Reactant: COC(=O)[C@H](CNS(=O)(=O)c1ccc(OCc2ccccc2)cc1)N1CCCCC1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CNS(=O)(=O)c1ccc(O)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 100.9 %

Procedure:
A solution of 4.9 g (11 mmol) of methyl(S)-3-(4-benzyloxybenzenesulfonylamino)-2-piperidin-1-yl-propanoate (prepared as described in 1.5) in 80 ml of ethyl acetate, 30 ml of dioxane and 0.5 ml of glacial acetic acid is degassed under nitrogen for 15 min and then a suspension of 490 mg (10% by weight) of palladium on carbon at 10% in 3 ml of dioxane is added. The reaction medium is then placed under a hydrogen atmosphere and stirred at ambient temperature for 5 h. After filtration through celite, the filtrate is concentrated under vacuum. The residue is taken up in ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. 3.8 g (97%) of methyl (S)-3-(4-hydroxybenzenesulfonylamino)-2-piperidin-1-ylpropanoate are obtained in the form of a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:17])C=1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:17])=[C:4]([CH3:8])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(Br)ccn1
Solvent: ClCCl
Product: Cc1cc(Br)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-bromo-2-methylpyridine (5 g, 29 mmol) in DCM (20 mL) is cooled to 0° C. and m-CPBA (7.55 g, 43.87 mmol, 1.5 equiv.) is added portionwise over 30 min. The ice bath is then removed and the mixture is allowed to stir at room temperature for 3 hours. The resulting solution is diluted with sodium bicarbonate (sat. aq.) and extracted with DCM. The organic layers are combined, washed with sodium bicarbonate (sat. aq.), dried over Na2SO4, and concentrated under vacuum to afford the title compound as a pale orange oil which is without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7].C[Si](C)(C)Cl.C(N(CC)CC)C.[O:20]1CCOC[CH2:21]1>>[CH:21]([N:1]1[CH2:6][CH2:5][CH2:4][NH:3][C:2]1=[O:7])=[O:20]
Reactant: O=C1NCCCN1
Reactant: C1COCCO1
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Product: O=CN1CCCNC1=O
Reaction time: 72 h

Procedure:
The mixture of 10 parts by weight of 1,3-diaza-cyclohexane-2-one, 49 parts by weight of trimethylchlorosilane, 25 parts by weight of triethylamine and 150 parts by volume of dioxane were boiled for 3 days with stirring and exclusion of moisture, then filtered, evaporated to 50 parts by volume in vacuo and stirred overnight with 11.5 parts by volume of formic acid-acetic acid anhydride. The mixture was evaporated to dryness in vacuo, and the residue was recrystallized from ethanol/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([OH:20])=[C:5]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:11][CH:10]=2)[N:6]=[N:7][CH:8]=1.[H-].[Na+].Br[CH2:24][C:25]1[CH:26]=[C:27]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:28]=[CH:29][CH:30]=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:27]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:28]=[CH:29][CH:30]=[C:25]([CH2:24][N:7]2[CH:8]=[C:3]([O:2][CH3:1])[C:4](=[O:20])[C:5]([C:9]3[N:13]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[N:12]=[CH:11][CH:10]=3)=[N:6]2)[CH:26]=1
Reactant: COc1cnnc(-c2ccnn2-c2ccccc2)c1O
Reactant: BrCc1cccc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cn(Cc2cccc(-c3ccccc3)c2)nc(-c2ccnn2-c2ccccc2)c1=O
Reaction time: 0.33 h
Yield: 49.7 %

Procedure:
5-Methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4-ol (0.0478 g) was dissolved in DMF (3.6 mL), NaH (0.0078 g, 60%, in oil) and tetrabutylammoniumiodide (0.0131 g) were added at 0° C., and the mixture was stirred at the same temperature for 20 min. To the reaction mixture was added 3-(bromomethyl)biphenyl (0.0462 g) at 0° C., and the mixture was stirred at room temperature for 2.5 days. The reaction mixture was diluted with water, extracted with ethyl acetate, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography (ethyl acetate/hexane→methanol/ethyl acetate) to give the title compound (0.0385 g).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14]C)=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:21]([F:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=2[F:24])=[N:4][CH:3]=1.[CH3:25]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C(OCC)(=O)C.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>[CH3:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([C:16]2[C:17]([F:24])=[CH:18][C:19]([F:23])=[CH:20][C:21]=2[F:22])=[N:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(Br)cnc(-c3c(F)cc(F)cc3F)c2c1
Reactant: CB1OB(C)OB(C)O1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1cnc(-c2c(F)cc(F)cc2F)c2cc(C(=O)O)ccc12
Temperature: 100 °C
Reaction time: 4 h
Yield: 74.1 %

Procedure:
Under argon gas atmosphere, a mixture of methyl 4-bromo-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylate (160 mg), trimethylboroxin (117 mg), tetrakis(triphenylphosphine)palladium (23 mg), 2M aqueous sodium carbonate solution (1 mL), and 1,4-dioxane (5 mL) was heated under stirring in an oil bath at 100° C. for 4 hours. The reaction mixture was returned to room temperature and diluted with ethyl acetate, and then the insoluble materials were separated by filtration through Celite. The filtrate was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain 4-methyl-1-(2,4,6-trifluorophenyl)isoquinoline-7-carboxylic acid (95 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:4].[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30](O)=[O:31])#[N:26].CCN=C=NCCCN(C)C>>[C:25]([C:27]1[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=1)[C:30]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]1[CH2:9][N:8]([CH:10]2[CH2:15][CH2:14][C:13]([OH:24])([C:16]3[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:12][CH2:11]2)[CH2:7]1)=[O:31])#[N:26]
Reactant: N#Cc1cccc(C(=O)O)c1
Reactant: COc1ccc(C2(O)CCC(N3CC(NC(=O)CN)C3)CC2)cn1
Agent: CCN=C=NCCCN(C)C
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C#N)c4)C3)CC2)cn1

Procedure:
The title compound was prepared as yellow solid from 2-amino-N-{1-[4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexyl]-azetidin-3-yl}-acetamide, as prepared in Step D of Example 16, and 3-cyanobenzoic acid (Aldrich) by EDCI coupling using the procedure described in Step C of Example 16.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.[C:9]1([S:15]([C:18]2[C:19]([S:29][CH3:30])=[N:20][N:21]3[C:26](Cl)=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[C:9]1([S:15]([C:18]2[C:19]([S:29][CH3:30])=[N:20][N:21]3[C:26]([N:6]4[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]4)=[CH:25][C:24]([CH3:28])=[N:23][C:22]=23)(=[O:17])=[O:16])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1ccccc1
Solvent: CN(C)C=O
Product: CSc1nn2c(N3C[C@@H](C)N[C@@H](C)C3)cc(C)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
0.28 g (2 mmol) of cis-2,6-dimethylpiperazine was added to a solution of 0.35 g (1 mmol) of 3-benzenesulphonyl-7-chloro-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine in 5 ml of DMF and stirred at 60° for 2 hrs. The reaction solution was cooled to RT and evaporated in a high vacuum. The residue was partitioned between 2N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2,and the combined organic phases were dried (MgSO4), filtered and evaporated. Subsequent chromatography (SiO2, CH2Cl2/MeOH 19:1) and crystallization from EtOH yielded 0.29 g (67%) of (3R,5S)-3-benzenesulphonyl-7-(3,5-dimethyl-piperazin-1-yl)-5-methyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidine as colorless crystals, m.p. 220-221°.
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:38][C:39]#[N:40]>CC(C)=O>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:38][C:39]#[N:40])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:24])[C:9]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(O)cc3)ccc21
Reactant: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc21

Procedure:
The desired product was prepared using a procedure similar to step 5 of example 3. Thus, 4-(3-benzyl-1-methyl-2-phenyl-1H-indol-5-yl)-phenol (0.140 g, 0.359 mmol) was reacted with K2CO3 (0.065 g, 0.467 mmol) and bromoacetonitrile (0.056 g, 0.467 mmol) in acetone (5 ml) to give the product (0.141 g, 0.329 mmol, 92%) as a glass-like solid. 1H NMR (DMSO-d6) δ 3.62 (s, 3H), 4.04 (s, 2H), 5.18 (s, 2H), 7.07-7.13 (m, 5H), 7.18 (t, J=7.5 Hz, 2H), 7.44-7.49 (m, 4H), 7.52-7.55 (m, 3H), 7.57-7.60 (m, 3H); [ESI(+)], m/z 429 (M+H)+.
Reaction SMILES: C[Si]([C:5]#[N:6])(C)C.[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N+:11]=1[O-])([CH3:9])[CH3:8].C(N(CC)C(Cl)=O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH:7]([C:10]1[N:11]=[C:12]([C:5]#[N:6])[CH:13]=[CH:14][CH:15]=1)([CH3:9])[CH3:8]
Reactant: C[Si](C)(C)C#N
Reactant: CC(C)c1cccc[n+]1[O-]
Agent: CCN(CC)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)c1cccc(C#N)n1
Reaction time: 0.08 h

Procedure:
Trimethylsilyl cyanide (1.53 mL) was added to a solution of 2-isopropylpyridine 1-oxide (example 85, step b) (1.3 g) in DCM (40 mL) and the resulting mixture was stirred for 5 min. Diethylcarbamoyl chloride (1.2 mL) was added and the mixture stirred for 3 days. An aqueous solution of potassium carbonate (10%, 40 mL) was added and the mixture stirred for 10 min. The layers were separated and the aqueous phase extracted with DCM (2×40 mL). The combined organic solutions were washed with brine (40 mL), dried over sodium sulphate, filtered and evaporated. Purification was by silica gel chromatography eluting with 3:1 isohexane:ethyl acetate. The fractions containing product were combined and evaporated to give the subtitled compound as a clear oil. Yield 1.23 g.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][NH:11][CH2:10][CH2:9][NH:8]2)[CH:2]=1.Cl[C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20][N:21]2[CH:24]2[CH2:26][CH2:25]2)=[CH:16][C:15]=1[F:31]>N1C=CC=CC=1>[CH:24]1([N:21]2[C:22]3[C:17](=[CH:16][C:15]([F:31])=[C:14]([N:11]4[CH2:10][CH2:9][NH:8][CH:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH2:12]4)[CH:23]=3)[C:18](=[O:30])[C:19]([C:27]([OH:29])=[O:28])=[CH:20]2)[CH2:25][CH2:26]1
Reactant: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Reactant: c1cncc(C2CNCCN2)c1
Solvent: c1ccncc1
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNC(c4cccnc4)C3)c(F)cc2c1=O
Temperature: 135 °C
Yield: 19.6 %

Procedure:
A mixture of 733.5 mg of 2-(3-pyridinyl)piperazine, 421.5 mg of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid and 10 ml of pyridine was heated at 135° C. for 24 hours. The solvent was removed and the residue purified by chromatography on silica gel using chloroform:methanol:triethylamine:water (9.5:0.5:0.01:0.01), giving 120 mg of the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][CH:4]=1)=O.[CH3:13][C:14]1([CH3:29])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]2[CH:19]=[C:18]([C:26](=[O:28])[CH3:27])[CH:17]=[CH:16][C:15]1=2.Cl>[OH-].[Na+].CO>[O:28]=[C:26]([C:18]1[CH:17]=[CH:16][C:15]2[C:14]([CH3:29])([CH3:13])[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[C:20]=2[CH:19]=1)[CH:27]=[CH:1][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CCC(C)(C)c2cc(C(=O)C=Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.9 %

Procedure:
Methyl 4-formylbenzoate (1.28 g, 7.83 mmol) was added to a solution of 1-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound 1, 1.80 g, 7.83 mmol) in 10 mL of 1 N NaOH and 20 mL of methanol. After stirring at room temperature for 18 h, the reaction mixture was acidified with 1N HCl and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with brine (1×10 mL), dried (MgSO4) and concentrated at reduced pressure. Recrystallization (acetonitrile) gave the title compound (1.70 g, 60% yield) as a white solid:
Reaction SMILES: [OH:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+].Br[CH:44]([CH3:46])[CH3:45]>CN(C)C=O.O1CCCC1>[CH:44]([O:1][C:2]1[C:3]([CH2:4][OH:6])=[CH:8][CH:9]=[CH:10][N:11]=1)([CH3:46])[CH3:45]
Reactant: CC(C)Br
Reactant: COC(=O)c1cccnc1O
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ncccc1CO
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a solution of methyl 2-hydroxynicotinate (250 mg) in dimethylformamide (3 ml), 0.459 ml of 2-bromopropane and 676 mg of potassium carbonate were added, and the reaction solution was stirred at 50° C. for 5 hours and at 70° C. for 3 hours. The reaction solution was cooled, then a saturated aqueous ammonium chloride solution was added, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford a crude product as a colorless oil. To a solution of lithium aluminum hydride (247 mg) in tetrahydrofuran (2 ml), a solution of the crude product in tetrahydrofuran 3 ml was added under ice-cooling. The reaction solution was stirred for 2 hours under ice-cooling, followed by adding sodium sulfate decahydrate and further stirring the mixture at the same temperature for 1 hour. The reaction solution was Celite-filtered, the filtrate was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50:50)) to afford the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.ClC1C=[C:27]([C:31]2[C:35](COC3C=CC(C(O)=O)=CN=3)=C(C)O[N:32]=2)C=CC=1.C(N)(C)C>>[CH:31]([NH:32][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)([CH3:35])[CH3:27]
Reactant: Cc1onc(-c2cccc(Cl)c2)c1COc1ccc(C(=O)O)cn1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Solvent: CC(C)N
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NC(C)C)cn1
Yield: 73 %

Procedure:
As described for example 98b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (19 mg, 0.06 mmol) was converted, instead of 6-[3-(3-chloro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (16 mg, 73%) which was obtained as a white solid. MS: m/e=354.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:24][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[C@@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:21]3)[CH2:19]2)[C:13](=[O:16])[CH:14]=[CH2:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[N:39]1[CH:44]=[CH:43][N:42]=[CH:41][C:40]=1[CH:45]=[O:46].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:17][C@H:18]2[CH2:38][CH2:37][C:20]3([O:21][C@H:22]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@@H:23]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:24]3)[CH2:19]2)[C:13](=[O:16])[CH2:14][CH2:15][C:45]([C:40]2[CH:41]=[N:42][CH:43]=[CH:44][N:39]=2)=[O:46])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=Cc1cnccn1
Reactant: C=CC(=O)C(C[C@H]1CCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(C[C@H]2CCC3(C2)O[C@H](c2ccccc2)[C@@H](c2ccccc2)O3)C(=O)CCC(=O)c2cnccn2)cc1Cl
Temperature: 25 °C
Yield: 44 %

Procedure:
To a solution of 4-[3-chloro-4-(methylsulfonyl)phenyl]-5-[(2R,3R,7R)-2,3-diphenyl-1,4-dioxaspiro[4.4]non-7-yl]pent-1-en-3-one (539 mg) in ethanol (5 mL) were added pyrazine-2-carbaldehyde (126 mg), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (29.0 mg) and triethylamine (59 μL), and the mixture was stirred with heating under reflux for 1 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (284 mg, yield 44%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[C:6](Br)[C:5]([F:10])=[C:4]([C:11]2[CH:16]=[C:15]([N+:17]([O-])=O)[CH:14]=[CH:13][C:12]=2[F:20])[N:3]=1.C(N(CC)CC)C.C(O)C>ClCCl.[Pd]>[F:10][C:5]1[C:4]([C:11]2[CH:16]=[C:15]([NH2:17])[CH:14]=[CH:13][C:12]=2[F:20])=[N:3][CH:2]=[C:7]([F:8])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2nc(Br)c(F)c(Br)c2F)c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccc(F)c(-c2ncc(F)cc2F)c1

Procedure:
To 2,4-dibromo-3,5-difluoro-6-(2-fluoro-5-nitrophenyl)pyridine (1.20 g, 2.91 mmol) dissolved in dichloromethane (30 ml) was added triethylamine (3 ml) and ethanol (80 ml) followed by 10% palladium on carbon (0.536 g). The mixture was then shaken under an atmosphere of hydrogen gas at 45 psi until complete reaction was indicated by TLC (0.25 to 3.5 h). The catalyst was then removed by filtration through glass microfibre filter paper (GF/A) and the solvent stripped at reduced pressure to afford 3-(3,5-difluoropyridin-2-yl)-4-fluorophenylamine which was used subsequently without further purification: m/z (ES+) 225 (MH+).