Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1>C(O)(=O)CC>[CH3:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:16])=[C:11]([N+:1]([O-:4])=[O:2])[CH:12]=[N:13]2)=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(O)ccnc2c1
Solvent: CCC(=O)O
Product: Cc1ccc2c(O)c([N+](=O)[O-])cnc2c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Nitric acid (6 mL of 70%) was slowly added to a hot (125° C. ) solution of 7-methyl-4-quinolinol (10.5 g) in propionic acid (125 mL). The reaction mixture was stirred for about 1.5 hours and then it was allowed to cool to ambient temperature. The resulting precipitate was isolated by filtration, rinsed well with ethanol and water and then dried to provide 6.9 g of 7-methyl-3-nitro-4-quinolinol as a pale yellow solid.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[CH:11]=[N:10][C:9]([C:12]2([CH3:19])[C:16](=[O:17])[NH:15][C:14](=[O:18])[NH:13]2)=[CH:8][N:7]=1)=O.[OH-].[Na+]>CO.C(OCC)(=O)C>[NH2:5][C:6]1[N:7]=[CH:8][C:9]([C:12]2([CH3:19])[NH:13][C:14](=[O:18])[NH:15][C:16]2=[O:17])=[N:10][CH:11]=1
Reactant: CC(C)(C)C(=O)Nc1cnc(C2(C)NC(=O)NC2=O)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1(c2cnc(N)cn2)NC(=O)NC1=O
Temperature: 25 °C
Yield: 101.5 %

Procedure:
A suspension of 2,2-dimethyl-N-[5-(4-methyl-2,5-dioxo-imidazolidin-4-yl)-pyrazin-2-yl]-propionamide (1.16 g, 4.0 mmol) in methanol (30 mL) was treated with a 1N aqueous sodium hydroxide solution (15 mL). The mixture was heated at 65° C. for 4 h and at 25° C. overnight. The mixture was concentrated in vacuo, and the residue was dried in vacuo overnight to give a crude solid. This solid material was suspended in a mixture of ethyl acetate and methanol (100 mL, 1:1) and gently heated. The mixture was filtered, and the filtrate was concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/9 to 3/7 methanol/ethyl acetate) afforded 5-(5-amino-pyrazin-2-yl)-5-methyl-imidazolidine-2,4-dione (841 mg, 100%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O1CCCC1.[CH3:20][C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:25][C:24]2[CH:26]=[CH:27][C:21]([CH3:20])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=2)=[O:10])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: Cc1ccc(N)cc1[N+](=O)[O-]
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
1-Chloro-4-isocyanato-2-(trifluoromethyl)benzene (9.97 g, 45.0 mmol) was stirred in a solvent of tetrahydrofuran (100 mL). The reaction solution was added with 4-methyl-3-nitroaniline (6.52 g, 42.9 mmol), followed by stirring for about 6 hours at room temperature. The reaction mixture was diluted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution and saline. The organic layer thus obtained was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated solid was added with a mixed solution of ethyl acetate/hexane (1/5), followed by stirring for 2 hours or more. The resulting solid was filtered under reduced pressure, and washed with diethyl ether. The filtered solid was dried with warm wind in an oven (40° C.) for 3 hours or more to obtain the title compound (14 g, 87%).
Reaction SMILES: [OH2:1].[OH2:2].[OH2:3].O.B(O[O-])([O-])[O-].[Na+].[Na+].[Na+].[SH:13][C:14]1[CH2:18][CH2:17][CH2:16][C:15]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C(O)(=O)C>[S:13]([C:14]1[CH2:18][CH2:17][CH2:16][C:15]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20])([OH:3])(=[O:2])=[O:1]
Reactant: O
Reactant: CCOC(=O)C1=C(S)CCC1
Agent: [Na+]
Agent: [O-]OB([O-])[O-]
Solvent: CC(=O)O
Product: CCOC(=O)C1=C(S(=O)(=O)O)CCC1
Temperature: 52.5 °C
Reaction time: 3 h
Yield: 156.4 %

Procedure:
Sodium peroxyborate tetrahydrate (10.6 g) was admixed with acetic acid (57 ml) and heated to 50 to 55° C. and then a solution of ethyl 2-mercapto-1-cyclopentene-1-carboxylate (3.9 g, synthesized in accordance with Tetrahedron, Vol.30, p.3753 (1974)) in acetic acid (7 ml) was added dropwise over 2 hours. The mixture was stirred at 50 to 55° C. for 3 hours and then at 80 to 85° C. for 5 hours and concentrated under reduced pressure. The residue was combined with acetonitrile (100 ml) and stirred at room temperature for 12 hours and the resultant insolubles were filtered off. The insolubles were washed with acetonitrile (10 ml) and the filtrate and the washing were combined and concentrated under reduced pressure, and the resultant residue was dissolved in acetonitrile (70 ml) and stirred at room temperature for 2 hours. The resultant insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The residue was combined with diisopropyl ether (20 ml) and the pellet which precipitated was isolated by a filtration to obtain ethyl 2-sulfo-1-cyclopentene-1-carboxylate as a white powder (7.8 g) containing inorganic substances. This (1.0 g) was dissolved in thionyl chloride (3 ml) and then stirred at 80 to 90° C. for 15 hours. The mixture was evaporated under reduced pressure to dryness and the residue was dissolved in ethyl acetate (50 ml). The resultant aqueous solution was washed successively with water (50 ml) and saturated brine (50 ml) and then dried over anhydrous sodium sulfate. The solvent was evaporated off to obtain a residue, which was purified by flash chromatography on silica gel column (eluent: ethyl acetate/hexane=1/5) to yield ethyl 2-chlorosulfonyl-1-cyclopentene-1-carboxylate (153.7 mg) as a yellow oil.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH:17]=[N:16]1.O>CN(C)C=O>[CH2:1]([O:24][C:20]1[CH:19]=[C:18]2[C:23](=[CH:22][CH:21]=1)[NH:15][N:16]=[CH:17]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COc2ccc3[nH]ncc3c2)cc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 37.7 %

Procedure:
Benzyl bromide (0.089 ml, 0.745 mmol) and potassium carbonate (103 mg, 0.745 mmol) were added to a solution of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (2 ml), and the resulting mixture was heated to 40° C. After 2 hours, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-(benzyloxy)-1H-indazole (63 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.CO>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[C:11]([CH2:26][CH3:27])=[N:12][CH:13]=[CH:14][C:15]=2[C:16]2[CH:24]=[CH:23][C:19]([C:20]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:21])=[C:18]([F:25])[CH:17]=2)=[CH:4][CH:3]=1
Reactant: C1CNCCN1
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(N)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nccc(-c2ccc(C(=O)N3CCNCC3)c(F)c2)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.28 mmol) 4-[3-(6-Amino-pyridin-3-ylethynyl)-2-ethyl-pyridin-4-yl]-2-fluoro-benzoic acid (A-38) using 29 mg (0.33 mmoL) piperazine, 116 mg (0.30 mmol) HATU and 81 μL DIPEA in 1 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/MeOH-gradient. Yield: 8 mg (6%).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])=[CH:8][C:7]=1[CH3:34].[OH-:36].[Na+].Cl>O1CCCC1.C(OCC)(=O)C>[CH3:34][C:7]1[CH:8]=[C:9]([O:12][CH2:13][CH:14]([C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[N:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[CH:24][CH:23]=3)[S:19][C:20]=2[CH3:21])[CH3:15])[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:35])=[O:2].[C:9]([O:12][CH2:13][CH3:14])(=[O:36])[CH3:8]
Reactant: [OH-]
Reactant: COC(=O)CCc1ccc(OCC(C)c2nc(-c3ccc(-c4ncccn4)cc3)sc2C)cc1C
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1cc(OCC(C)c2nc(-c3ccc(-c4ncccn4)cc3)sc2C)ccc1CCC(=O)O
Temperature: 25 °C

Procedure:
3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic acid methyl ester (698 mg, 1.43 mmol) is dissolved in tetrahydrofuran (2 mL) and 5N sodium hydroxide (2 mL) solution is added with stirring at room temperature. The reaction is heated to reflux and monitored by HPLC. Upon complete conversion, the reaction is allowed to cool to room temperature and neutralized with 5N hydrochloric acid (2 mL), diluted with ethyl acetate, and extracted. The organic layer is washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The pure 3-(2-Methyl-4-{2-[5-methyl-2-(4-pyrimidin-2-yl-phenyl)-thiazol-4-yl]-propoxy}-phenyl)-propionic acid (462 mg, 0.9755 mmol) may also be obtained by recrystalization from ethyl acetate (68% yield), MS (ES): ?? (M++1).
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Br:8][C:9]1[CH:10]=[C:11]([C:16](=O)[CH2:17][F:18])[C:12]([F:15])=[N:13][CH:14]=1.O.C(=O)(O)[O-]>CCOC(C)=O>[Br:8][C:9]1[CH:10]=[C:11](/[C:16](=[N:7]\[S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])/[CH2:17][F:18])[C:12]([F:15])=[N:13][CH:14]=1
Reactant: O=C(CF)c1cc(Br)cnc1F
Reactant: CC(C)(C)[S@](N)=O
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)[S@@](=O)/N=C(/CF)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Titan (IV)-ethoxide tech. (0.298 mL, 1.441 mmol) was added to a solution of (R)-2-methyl-2-propanesulfinamide (1.44 mmol) and 1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethanone (170 mg, 0.720 mmol) in methylene chlorice (15 mL). The reaction mixture was stirred at room temperature (light-yellow solution) for 4 h (or until complete conversion by LCMS). The reaction mixture was poured into water and saturated aqueous bicarbonate solution and EtOAc were added. The suspension was stirred vigorously for 20 min. The organic phase was separated. The aqueous phase was extracted twice with EtOAc. The organic phases were combined and filtered through a pad of celite. The filtrate was washed with brine and dried over MgSO4. The solvent was removed under reduced pressure. The residue (239 mg of a yellow oil) was purified by column chromatography (silica gel, 10-70% hexanes/EtOAc) to yield (R,E)-N-(1-(5-bromo-2-fluoropyridin-3-yl)-2-fluoroethylidene)-2-methylpropane-2-sulfinamide as a yellow oil (106 mg; 43%). MS m/z=338.9 [M+H]+. Calculated for C11H13BrFN2OS: 339.2.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][Si:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH3:4]>>[CH2:3]([O:5][SiH:6]([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH3:4]
Reactant: CCO[Si](OCC)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Product: CCO[SiH](OCC)OCC

Procedure:
The procedure in Example 1 was used with the following modifications: the metal hydride was sodium hydride [95% purity; 1.0 grams (g); 39.6 millimole (mmol)]; tetraethoxysilane (0.5 ml/h; 2.4 mmol/h); the carrier gas was argon (1 ml/min). Reaction was carried out at a fixed temperature of 250° C. Results of percent triethoxysilane produced (HSi(OEt)3) can be seen in Table 6.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3I)[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:34]([C:38]1[CH:39]=[CH:40][C:41]([O:47][CH3:48])=[C:42](B(O)O)[CH:43]=1)([CH3:37])([CH3:36])[CH3:35].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:18][C:17](=[O:19])[N:16]([CH2:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][C:29]=3[C:42]3[CH:43]=[C:38]([C:34]([CH3:35])([CH3:37])[CH3:36])[CH:39]=[CH:40][C:41]=3[O:47][CH3:48])[CH2:26][CH2:25][CH2:24]4)[C@@H:15]([CH3:31])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1C[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc2c(cc1I)CCC2
Reactant: COc1ccc(C(C)(C)C)cc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)C)cc1-c1cc2c(cc1CN1C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)C[C@@H]1C)CCC2

Procedure:
(4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-[(6-iodo-2,3-dihydro-1H-inden-5-yl)methyl]-4-methyl-1,3-oxazinan-2-one (Intermediate 25; 25 mg; 0.043 mmol) was treated with (5-tert-butyl-2-methoxyphenyl)boronic acid (11.6 mg; 0.056 mmol), 1-1′-bis(di tert-butylphosphino)ferrocene palladium dichloride (2.8 mg; 0.0043 mmol), 1 N K2CO3 (1.2 mL) and THF (1.2 mL) as described in Example 38 to afford (4S,6S)-6-[3,5-bis(trifluoromethyl)phenyl]-3-{[6-(5-tert-butyl-2-methoxyphenyl)-2,3-dihydro-1H-inden-5-yl]methyl}-4-methyl-1,3-oxazinan-2-one as a clear glass. LCMS=620.1 (M+1)+. 1H NMR (CDCl3, 500 MHz, mixture of atropisomers): δ 7.84-7.82 (m, 2H), 7.75 (s, 1H), 7.36 (dd, J=8.5, 2.6 Hz, 1H), 7.31 (s, 1H), 7.22 (d, J=2.5 Hz, 1H), 7.12 (s, 1H), 6.91 (d, J=8.7 Hz, 1H), 5.22 (d, J=15.4 Hz, 1H), 5.13 (d, J=10.3 Hz, 1H), 4.22 (d, J=15.5 Hz, 1H), 3.81 (s, 3H), 3.41-3.32 (m, 1H), 2.99-2.93 (m, 4H), 2.24-2.20 (m, 1H), 2.16-2.11 (m, 2H), 1.82-1.75 (m, 1H), 1.31 (s, 9H), 1.02 (d, J=6.1 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][C:10]=1[CH3:36])([CH3:7])[CH3:6])C.[OH-].[Na+]>C1COCC1.CO>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:7])([CH3:6])[C:4]([OH:37])=[O:3])=[C:10]([CH3:36])[CH:11]=3)[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OC(C)(C)C(=O)O
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)-ethoxy]-2-methylphenoxy}-2-methylpropionic acid ethyl ester (11.8 mmol) in THF (30 mL) and methanol (60 mL) was treated with 5N aqueous NaOH (20 mL). The solution was heated at 55° C. for 1 h, cooled to ambient temperature, and concentrated in vacuo. The residue was treated with ice water (20 mL), acidified with 5N aqueous HCl (25 mL), and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (40 mL), dried (Na2SO4), and concentrated to yield the desired product. mp 122-123° C.; 1H NMR (400 MHz, CDCl3) δ 8.07 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz, 2H), 7.62 (dt, J=6.8, 1.2 Hz, 2H), 7.45 (tt, J=6.8, 1.2 Hz, 2H), 7.37 (tt, J=7.2, 2.0 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 6.71 (d, J=3.2 Hz, 1H), 6.57 (dd, J=8.8, 3.2 Hz, 1H), 4.16 (t, J=6.4 Hz, 2H), 3.82 (t, J=6.4 Hz, 2H), 2.40 (s, 3H), 2.21 (s, 3H), 1.56 (s, 6H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([N:12]=C(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:7]2.Cl.C(=O)(O)[O-:28].[Na+]>O1CCCC1>[NH2:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:28])=[CH:3][CH:4]=[N:5]2)=[N:10][CH:9]=1
Reactant: Clc1ccnc2cc(N=C(c3ccccc3)c3ccccc3)cnc12
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cnc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
A round bottom flask under nitrogen was charged with 8-chloro-N-(diphenylmethylene)-1,5-naphthyridin-3-amine (315 mg, 0.92 mmol), 2M aqueous HCl (1.42 mL, 2.84 mmol), and tetrahydrofuran (0.25M, 3.67 mL). This was stirred at RT for 30 minutes. Reaction basified with aq. sodium bicarbonate solution and product extracted with dichloromethane. This was dried over sodium sulfate and concentrated to afford orange solid; which was purified via ISCO silica gel chromatography, 40 g column, 30% (90/10/1 DCM:MeOH:NH4OH)/DCM over 40 minutes to afford 7-amino-1,5-naphthyridin-4-ol (140 mg, 95% yield) as yellow solid. MS[M+H]=180.2. Calc'd for C8H6ClN3=179.6.
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:20][OH:21])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.C(O)(=O)C>C1C=CC=CC=1>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:21][CH2:20]1)=[CH:9][C:10]([O:17][CH2:18][CH3:19])=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3
Reactant: CCOc1cc2c(cc1OCC)C(C(CO)CO)NCC2
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: CCOc1cc2c(cc1OCC)C1C(CO)COC(c3ccccc3)N1CC2
Yield: 70 %

Procedure:
10 mmoles (2.8 g) of 1-[bis(hydroxymethyl)-methyl]-6,7-diethoxy-1,2,3,4-tetrahydroisoquinoline and 11 mmoles (1.17 g) of freshly distilled benzaldehyde are refluxed in 50 ml of absolute benzene, in the presence of a catalytic amount of hydrochloric acid or acetic acid for 4 hours. The solvent is distilled off and the residual pale-yellow oil is crystallized by trituration with ether. The aimed compound is obtained in a yield of 70%.
Reaction SMILES: [CH3:1][N:2]([C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)CCC.C(O)=[O:22]>O>[CH:1]([NH:2][C:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[S:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:22]
Reactant: O=CO
Reactant: CCCN(C)c1c(-c2ccccc2)sc2ccccc12
Solvent: O
Product: O=CNc1c(-c2ccccc2)sc2ccccc12

Procedure:
Preparation of the starting product by reduction of the 3-formamido-2-phenyl-benzo(b)thiophene which can be isolated either by drying of the intermediate product formed from preparation of the 3-amino-2-phenyl-benzo(b)thiophene from the 2-phenyl-benzo(b)thiophen-3-ol produced as an intermediate product (described following Example 14) by heating for 1 hour the 3-amino-2-phenyl-benzo(b)thiophene with the same quantity of formic acid at 98 to 100%, followed by dissolving in water and drying. In both cases, 3-formamido-2-phenyl-benzo(b)thiophene is obtained in a quantitative yield: thin colourless needles, mp 185°-186° C. (benzene). 3.0 g (11.8 mmol) of this amide and 1.08 g (28.4 mmol) of LiAlH4 in 60 milliliters of absolute dioxan are refluxed with stirring for 30 minutes. Water is added to the cooled reaction mixture to decompose the excess LiAlH4 and, after the addition of approximately 100 milliliters of CH2Cl2, it is stirred for a further 15 minutes. After centrifuging with the addition of a filtration aid the organic phase is dried over K2CO3 and evaporated. The hydrochloride of the solution of the residue is precipitated in a little chloroform by the action of hydrochloric gas: 2.6 g (80% of theory). The hydrochloride of 3-methylamino-2-phenyl(b)thiophene, colourless crystals in ethanol-ether, decomposition from 198° C. (in sealed tube). From this salt the base is released by the action of ammonia: 3-methylamino- 2-phenyl -benzo(b)thiophene, yellow rods, mp 78°-79° C. (methanol).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:15](Cl)(=[O:17])[CH3:16]>C(Cl)Cl>[C:15]([O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)(=[O:17])[CH3:16]
Reactant: Oc1cccc(F)c1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(F)c1
Temperature: 25 °C

Procedure:
A solution of 3-fluorophenol (100 g, 0.890 mol) in methylene chloride is cooled to 0° C. to 5° C., treated with pyridine (75.0 mL, 0.930 mol), stirred for several minutes, treated dropwise with acetyl chloride (66.0 mL, 0.930 mol) while maintaining the reaction mixture temperature below 17° C., stirred at ice-bath temperature for two hours, warmed to room temperature, and poured into an ice-water mixture. The organic phase is separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain the title product as a yellow oil which is identified by 1H NMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH3:10][O:11][P:12]([O:15]C)[O:13][CH3:14]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][P:12](=[O:15])([O:13][CH3:14])[O:11][CH3:10]
Reactant: Clc1ccccc1CBr
Reactant: COP(OC)OC
Product: COP(=O)(Cc1ccccc1Cl)OC

Procedure:
Following the procedure of Compound 11, 2-chlorobenzyl bromide is reacted with trimethylphosphite.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[NH2:21][NH2:22].O>CN(C=O)C.C1(C)C=CC=CC=1.C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C:14]([NH:21][NH2:22])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: NN
Reactant: COc1ccc(-c2ccc(C(=O)O)s2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc(C(=O)NN)s2)cc1
Temperature: 80 °C
Yield: 78.5 %

Procedure:
To a solution of 1.8 g (7.7 mmol) of the thienoic acid in 1 mL of dry DMF and 30 mL of toluene is added 1.1 mL (15.4 mmol) of thionyl chloride and the mixture is heated at 80° C. for 3 hours. After cooling to room temperature, the solvent and excess thionyl chloride are removed under reduced pressure. The resulting residue is dissolved in 50 mL of dry THF and is added dropwise over a period of 30 minutes into a solution of 4.8 mL (154 mmol) of anhydrous hydrazine in 100 mL of dry THF while stirring at -30° C. After stirring at room temperature for 2 hours, 100 mL of water is added to the reaction mixture. The desired product is extracted with chloroform (4×100 mL), dried over anhydrous Na2SO4 and concentrated to give 1.5 g (75%) of 5-(4-methoxyphenyl)-2-thienoylhydrazine.
Reaction SMILES: C[O-].[Na+].[CH:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22]([CH3:24])=[O:23].S([O-])([O-])(=O)=O.[Na+].[Na+]>CO.C(OCC)(=O)C>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](/[CH:24]=[CH:4]/[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:23]
Reactant: O=Cc1cccnc1
Reactant: CC(=O)c1ccc2ccccc2c1
Agent: C[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(/C=C/c1cccnc1)c1ccc2ccccc2c1
Reaction time: 30 h
Yield: 45.9 %

Procedure:
A 28% solution of sodium methoxide in MeOH (0.90 g) was added to a stirred mixture of nicotinaldehyde (9.70 g) and methyl 2-naphthyl ketone (15.26 g) in MeOH (150 ml). Sodium sulfate (10 g) was added to the mixture and the mixture was stirred for 30 hours. The mixture was diluted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was recrystallized from cold MeOH to give the titled compound (10.68 g).