Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2].[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13]Br>>[Cl:9][C:10]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:11]=1[CH2:12][CH2:13][CH:1]([C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1)[CH3:2]
Reactant: Clc1ccc(CCBr)c(Cl)c1
Reactant: CCc1ccncc1
Product: CC(CCc1ccc(Cl)cc1Cl)c1ccncc1
Yield: 25.6 %

Procedure:
1.0 g (9.35 mmol) of 4-ethylpyridine and 2.37 g (9.35 mmol) of 2,4-dichlorophenethyl bromide were reacted in the same manner as in Example 1. The reaction product was purified to obtain 0.67 g of the desired compound (yield: 25.6%). The resulting compound was identified as 1-(2,4-dichlorophenyl)-3-(4-pyridyl)-butane (hereinafter referred to as compound 9) by the following analytical results.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=3[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:28][CH3:29].[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[N:30]1([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([O:16][C:17]4[CH:22]=[C:21]([CH3:23])[C:20]([CH3:24])=[CH:19][C:18]=4[C:25](=[O:27])[CH3:26])=[CH:11][CH:12]=[N:13]3)=[CH:8][C:7]=2[O:28][CH3:29])[CH:34]=[CH:33][N:32]=[CH:31]1
Reactant: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCCl
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)cc3C(C)=O)ccnc2cc1OCCCn1ccnc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
1-{2-[7-(3-Chloro-propoxy)-6-methoxy-quinolin-4-yloxy]-4,5-dimethyl-phenyl}-ethanone (compound 318) (77 mg), imidazole (38 mg), and potassium carbonate (131 mg) were suspended in N,N-dimethylformamide (2 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (52 mg, 61%).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][CH2:13][OH:14].[OH-].[Na+].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br>O.CCOCC>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:14][CH2:13][CH2:12][CH2:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=1
Reactant: BrCCCCCCBr
Reactant: OCCCc1ccc2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: BrCCCCCCOCCCc1ccc2ccccc2n1

Procedure:
2-Quinolinepropanol (0.92 g), 50% aqueous sodium hydroxide (5 ml), 1,6-dibromohexane (5 ml) and TAB (57 mg) were vigorously stirred at 21° for 6 h. The mixture was diluted with water (25 ml) and ether (100 ml) and the organic phase dried and evaporated in vacuo. The residue was purified by FCC with hexane eluant to remove 1,6-dibromohexane. Elution with ether afforded the title compound as a yellow oil (0.88 g), t.l.c. ether Rf 0.51.
Reaction SMILES: [CH2:1]([N:4]([CH2:14][CH:15]=[CH2:16])[CH2:5][C:6]([C:8]1[S:9][C:10]([F:13])=[CH:11][CH:12]=1)=O)[CH:2]=[CH2:3].N1C=CC=CC=1.Cl.[NH2:24][OH:25]>C(O)C>[F:13][C:10]1[S:9][C:8]([C:6](=[N:24][OH:25])[CH2:5][N:4]([CH2:14][CH:15]=[CH2:16])[CH2:1][CH:2]=[CH2:3])=[CH:12][CH:11]=1
Reactant: C=CCN(CC=C)CC(=O)c1ccc(F)s1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: C=CCN(CC=C)CC(=NO)c1ccc(F)s1
Temperature: 70 °C
Yield: 98.7 %

Procedure:
To a stirred solution of 2-(diallylamino)-1-(5-fluoro-2-thienyl)ethanone (4.051 g, 16.93 mmol) in ethanol (34 mL) under nitrogen is added pyridine (4.8 mL, 59.2 mmol) and hydroxylamine hydrochloride (2.94 g, 42.3 mmol). The mixture is heated to 70° C. for 4 hours. The mixture is allowed to cool and then concentrated under reduced pressure. The residue is diluted with ethyl acetate (100 mL) and water (50 mL). The phases are separated and the aqueous phase extracted with ethyl acetate (50 mL). The combined organic extracts are dried over sodium sulfate, filtered, and concentrated to give the title compound (4.25 g, 99%) (approximately a 1.4:1 mixture of oxime isomers by 1H-NMR (CDCl3). ES/MS (m/e): 255 (M+H).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>ClCCl>[CH2:21]([O:20][C:18]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]1)=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)C1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 8 h
Yield: 95 %

Procedure:
Triethylamine (8.1 mL, 58 mmol) was added to a solution of piperidine-4-carboxylic acid (5 g, 40 mmol) and benzyl chloroformate (7.9 g, 46 mmol) in dichloromethane (100 mL) in an ice-water bath. After being stirred overnight, the solution was washed with concentrated HCl and brine, dried over Na2SO4 and concentrated. Chromatography on silica gel gave the title compound (10 g) as an oil. MS (M+H) 264.2.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[N:16]([C:24]([O:26]C(C)(C)C)=[O:25])[S:17]([CH2:20]CCC)(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[CH2:35](OC1C=CC=CC=1N(C(OC(C)(C)C)=O)S(CCCC)(=O)=O)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[N:16]([C:24]([O:26][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:25])[S:17]([CH3:20])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCS(=O)(=O)N(C(=O)OC(C)(C)C)c1cc(O)ccc1OCc1ccccc1
Reactant: CCCCS(=O)(=O)N(C(=O)OC(C)(C)C)c1ccccc1OCc1ccccc1
Solvent: CC(=O)O
Product: CS(=O)(=O)N(C(=O)OCc1ccccc1)c1cc(O)ccc1OCc1ccccc1

Procedure:
By carrying out the operation as described in preparation 13c but using the product from the preceding stage instead of the product from preparation 13b, the title compound is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][CH:3]=1.[NH2:14][NH2:15]>C(O)C>[NH:14]([C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:5]2=[CH:4][CH:3]=1)[NH2:15]
Reactant: NN
Reactant: Clc1ccc2c(n1)CCCCCC2
Solvent: CCO
Product: NNc1ccc2c(n1)CCCCCC2
Temperature: 150 °C

Procedure:
2-chloro-5,6,7,8,9,10-hexahydrocycloocta[b]pyridine was treated with ethanol (20 mL) and anhydrous hydrazine (5 mL) in a sealed tube at 150° C. bath temperature for 7 h. Initial experiments showed that the addition did not proceed in boiling ethanol at atmospheric pressure. HPLC showed that the addition was incomplete, so the reaction mixture was heated at 150° C. for a further 7 h. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel, eluting with 95% dichloromethane and 5% of a 2M solution of ammonia in methanol; 1H NMR (CDCl3, 300 MHz) 7.19 (d, 1H), 6.51 (d, 1H), 5.85 (br s, 1H), 3.77 (br s, 2H), 2.79 (m, 2H), 2.63 (m, 2H), 1.73 (m, 2H), 1.62 (m, 2H), 1.36 (m, 4H) ppm; 13C NMR (CDCl3, 75 MHz) 156.87, 158.54, 138.81, 126.67, 104.58, 34.72, 32.67, 31.45, 30.85, 26.41, 26.37; MS (ES) 192 (M+H).
Reaction SMILES: COP([CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])(OC)=O.[H-].[Na+].[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25][CH:26]=O)=[C:20]([CH3:28])[CH:19]=1.C([O-])(O)=O.[Na+]>C1COCC1>[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[C:21]([CH2:25]/[CH:26]=[CH:7]/[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[C:20]([CH3:28])[CH:19]=1
Reactant: Cc1cc(Br)cc(C)c1CC=O
Reactant: COP(=O)(CC(=O)OC(C)(C)C)OC
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Br)cc(C)c1C/C=C/C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
tert-Butyl 2-(dimethoxyphosphoryl)acetate (2.5 mL, 12.7 mmol) was added dropwise to a suspension of NaH (490 mg, 12.7 mmol, 60% dispersion in oil) in THF (60 mL) at 0° C. After stirring for 30 min at ambient temperature a solution of 53A (2.6 g, 11.4 mmol) in THF (10 mL) and stirred for 1 h at ambient temperature. The reaction mixture was poured into 50 mL saturated NaHCO3/400 mL water and extracted with diethyl ether. The combined organics were dried over Na2SO4 and concentrated in vacuo. The crude solid was purified by flash chromatography (0% to 50% EtOAc in hexanes) to yield 53B (2.35 g, 63%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.44 (s, 9 H) 2.22 (s, 6 H) 3.43 (dd, J=5.56, 1.77 Hz, 2 H) 5.43 (dt, J=15.54, 2.02, 1.89 Hz, 1 H) 6.92 (dt, J=15.66, 5.56 Hz, 1 H) 7.17 (s, 2 H).
Reaction SMILES: [OH:1][C@@H:2]1[O:10][C@@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4].[CH3:13]O>>[O:1]([CH3:13])[CH:2]1[O:10][C@@H:9]([CH2:11][OH:12])[C@H:7]([OH:8])[C@@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: OC[C@@H]1O[C@@H](O)[C@@H](O)[C@H](O)[C@H]1O
Reactant: CO
Product: COC1O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C

Procedure:
A mixture of α-L-glucopyranose (5.4 g.), methanol (30 ml.) and cation-exchange resin [(2 g., Dowex® 50W-X8 (H+), 50-100 mesh, previously prepared by treatment with methanol] was stirred magnetically at reflux temperature for 24 hours in a 50-ml. round-bottomed flask. The solution, which gave a negative test, was then cooled and filtered. The resin was washed several times with methanol and the filtrate and washings were evaporated at reduced pressure to a syrup (5.63 g., 96%) containing no L-glucose (paper chromatography, n-butanol/ethanol water v/v 40:11:19). A sample (1.0 g.) was dissolved in boiling methanol (2 ml.) and the mixture was allowed to slowly cool to room temperature to give crystalline methyl L-glucopyranoside. The crystals were suspended in enough ethanol to make a 10% (w/v) mixture, and this mixture was boiled to effect dissolution. On cooling of the mixture pure methyl α-L-glucopyranoside was obtained, m.p. 166.5°-168°, [α]D -156° (c 2.5, water). These values compare favourably with those for methyl α-D-glucopyranoside, m.p. 167°-169°, [α]D +157° (c 2, water).
Reaction SMILES: N#N.[Br:3][C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][N:5]=1.[Li]CCCC.CN(C)[C:18](=[O:20])[CH3:19]>CCOCC>[Br:3][C:4]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[CH:7]=[CH:6][N:5]=1
Reactant: CC(=O)N(C)C
Reactant: Brc1ccnc(Br)c1
Agent: N#N
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC(=O)c1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a suspension of commercially available 2,4-dibromo-pyridine (3.30 g, 13.9 mmol) in dry Et2O (75 mL) was treated with n-BuLi (5.85 mL of a 2.5M solution in hexanes, 14.6 mmol) at −78° C. The reaction mixture was stirred at this temperature for 30 min. N,N-Dimethyl-acetamide (2.6 mL, 27.9 mmol) was then added and the mixture allowed to warm to rt over a period of 1 h and stirred at this temperature for 30 min. The reaction was quenched by the addition of sat. aq. NH4Cl (50 mL). The layers were separated and the aq. layer extracted with Et2O (2×50 mL). The combined org. extracts were dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification of the residue by FC (20:1 to 5:1 hept-EA) gave the title compound as a white solid. TLC:rf (1:1 hept-EA)=0.41. LC-MS-conditions 02: tR=0.81 min; [M+H]+=200.61.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[S:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl.C(=O)(O)[O-].[Na+]>[O:3]=[CH:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:13]2[S:17][C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:15][CH:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(OCC(OCC)OCC)c2)s1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1ccc(-c2cccc(OCC=O)c2)s1
Temperature: 0 °C
Reaction time: 6 h

Procedure:
Ethyl 5-(3-{[2,2-bis(ethyloxy)ethyl]oxy}phenyl)-2-thiophenecarboxylate (Intermediate KK-2-3) (1.41 g, 3.87 mmol) was dissolved in 20 ml of chloroform and cooled to 0° C. 5 ml of 50% aqueous trifluoroacetic acid solution was added. The mixture was stirred for 15 h at room temperature and 6 h at 65° C., cooled, diluted with chloroform and neutralized with saturated sodium bicarbonate solution. The organic layer was separated, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography (10 to 50% ethyl acetate in hexanes) to afford the title compound as a white crystalline solid.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12]CC)=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[CH3:15][NH:16][C:17]([NH:19][CH3:20])=[O:18].C(=O)(O)[O-].[Na+]>Cl.C(O)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:1]2[N:19]([CH3:20])[C:17](=[O:18])[N:16]([CH3:15])[C:10](=[O:12])[CH:9]=2)[CH:3]=1
Reactant: CNC(=O)NC
Reactant: CCOC(=O)CC(=O)c1cccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cn1c(-c2cccnc2)cc(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 35.2 %

Procedure:
To a mixture of ethyl nicotinoylacetate (2.30 g) and N,N'-dimethylurea (1.05 g) were added conc. hydrochloric acid (a few drops) and ethanol (1 ml) and the mixture was stirred at 110°-115° C. for 4 hours under reduced pressure (30 mmHg). After being cooled to ambient temperature, the solution was adjusted to pH 7.0 with an aqueous solution of sodium bicarbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated to give 6-(3-pyridyl)-1,3-dimethyl-2,4(1H,3H)-pyrimidinedione (0.91 g).
Reaction SMILES: [C:1]([O:4][C@H:5]([C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:6][CH2:7][C@H:8]1[C:11](=[O:12])[N:10]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[CH:15][CH:14]=2)[C@@H:9]1[C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)(=[O:3])[CH3:2].[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:34]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C@@H:9]2[C@@H:8]([CH2:7][CH2:6][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)[C:11](=[O:12])[N:10]2[C:13]2[CH:14]=[CH:15][C:16]([I:19])=[CH:17][CH:18]=2)=[CH:21][CH:22]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)O[C@@H](CC[C@H]1C(=O)N(c2ccc(I)cc2)[C@@H]1c1ccc(O)cc1)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc([C@@H]2[C@@H](CC[C@H](OC(C)=O)c3ccc(F)cc3)C(=O)N2c2ccc(I)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (1S)-1-(4-fluorophenyl)-3-[(2S,3R)-2-(4-hydroxyphenyl)-1-(4-iodophenyl)-4-oxoazetidin-3-yl]propyl acetate (1-7a) (2 g, 3.58 mmol) (prepared according to Burnett, D. S.; Caplen, M. A.; Domalski, M. S.; Browne, M. E.; Davis, H. R. Jr.; Clader, J. W. Bioorg. Med. Chem. Lett. (2002), 12, 311) in CH2Cl2 (25 mL) under nitrogen atmosphere was added acetic anhydride (0.4 mL, 4.30 mmol), triethylamine (0.75 mL, 5.38 mmol) and DMAP. The reaction mixture was stirred at RT for 1 hr and the solvent removed under vacuum. The residue was purified by MPLC (silica column) with stepwise gradient elution; (0-100% EtOAc/hexanes as eluent) to afford the title compound (i-8). m/z (ES) (M-OAc)+. 1HNMR (500 MHz, CDCl3) δ: 7.57 (d, J=8.6, 1H) 7.38-7.26 (m, 5H), 7.22 (br d, J=7.1 H, 2H), 7.14 (d, J=8.5 Hz, 1H), 7.08-7.02 (m, 3H), 5.74 (t, J=6.7 Hz, 1H), 4.62 (d, J=2.3 Hz, 1H), 3.10 (dt, J=2.3, 7.8 Hz, 1H), 2.34 (s, 3H), 2.08 (s, 3H), 2.09-2.03 (m, 2H), 1.94-1.86 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][CH:23]=1)[CH2:6][CH2:7][NH:8][C:9](=[O:20])[CH2:10][CH2:11][NH:12]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:12][CH2:11][CH2:10][C:9]([NH:8][CH2:7][CH2:6][C:5]1[CH:21]=[CH:22][CH:23]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:20]
Reactant: COc1cccc(CCNC(=O)CCNC(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(CCNC(=O)CCN)c1
Temperature: 0 °C

Procedure:
tert-butyl (3-((3-methoxyphenethyl)amino)-3-oxopropyl)carbamate was dissolved in dichloromethane (0.5 mL) then the solution was cooled to 0° C. in an ice bath. Trifluoroacetic acid (300 μL) was added then the solution was allowed to warm slowly to room temperature with stirring. Upon completion of the reaction the solvent is removed under reduced pressure to give crude product which is used without further purification.
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: O=C([O-])O
Reactant: Clc1ccnc2cc(N=C(c3ccccc3)c3ccccc3)cnc12
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1cnc2c(O)ccnc2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
8-chloro-1,5-naphtpyridin-3-amine. 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: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=3)=[CH:15][C:14]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].Cl>C(O)C>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([N:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:27])=[O:26])=[CH:23][CH:24]=3)=[CH:15][C:14]=2[C:30]2[NH:34][N:33]=[N:32][N:31]=2)[C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(N(C(N)=O)c3cccc(C(F)(F)F)c3)c(-c3nnn[nH]3)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)N(c1cccc(C(F)(F)F)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1-c1nnn[nH]1
Temperature: 25 °C
Yield: 90.1 %

Procedure:
To a suspension of 3-trifluoromethylphenyl-4-(4-ethoxycarbonylphenyl) -2-(5-tetrazolyl)phenyl urea (4.5 g, 9 mmol) in 96% ethanol was added sodium hydroxide (4 N, 25 mL). The reaction was heated to reflux for 30 min, then cooled to room temperature and acidified with hydrochloric acid. The precipitate was filtered off to give 3.8 g of the desired material. M.p. 300° C. (dec.).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:9][NH:10]CC1C=CC=CC=1)[CH2:2][CH2:3][CH3:4]>COCCO.[Pd]>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:18]=[C:19]([S:28](=[O:31])(=[O:30])[NH2:29])[C:20]=1[O:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[CH2:9][NH2:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(CNCc2ccccc2)cc(S(N)(=O)=O)c1Oc1ccccc1
Agent: [Pd]
Solvent: COCCO
Product: CCCCNc1cc(CN)cc(S(N)(=O)=O)c1Oc1ccccc1

Procedure:
To a solution of (3-n-butylamino-4-phenoxy-5-sulfamyl-benzyl)benzylamine (8.8 g; prepared as described in Example 136) in 2-methoxyethanol (90 ml), palladium (10%) on carbon (4.0 g) is added and the mixture is hydrogenated. After about 5 hours the theoretical amount of hydrogen has been absorbed, and the mixture is heated on a steam-bath and filtered to remove the catalyst. The filtrate is evaporated in vacuo and the residue triturated with water to yield crude 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine. The crude amine is dissolved in formic acid (50 ml), whereafter the solution is evaporated in vacuo. The residue is recrystallized from a mixture of ethanol and 2-methoxyethanol to yield, after filtration and drying, 3-n-butylamino-4-phenoxy-5-sulfamylbenzylamine formate hemihydrate with a melting point of 224°-226° C.
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]1[C:10]([CH3:11])=[CH:9][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:7][C:6]=1[CH:18]1[CH2:20][CH2:19]1)C.[OH-].[K+]>C(O)CO.O>[CH:18]1([C:6]2[CH:7]=[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[CH:9]=[C:10]([CH3:11])[C:5]=2[C:4]([OH:21])=[O:3])[CH2:19][CH2:20]1
Reactant: CCOC(=O)c1c(C)cc(N2CCOCC2)cc1C1CC1
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1cc(N2CCOCC2)cc(C2CC2)c1C(=O)O
Temperature: 155 °C
Reaction time: 16 h
Yield: 69.9 %

Procedure:
To a stirred solution of 2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzoic acid ethyl ester (0.54 g, 1.86 mmol) in ethylene glycol (10 ml) is added solid potassium hydroxide (0.42 g, 7.47 mmol) and the mixture is stirred at 150-160° C. for 16 h. After completion of the reaction, the mixture is diluted with water (30 ml) and extracted with ethyl acetate (2×10 ml). The aqueous layer is acidified with 2M HCl to pH 3 and extracted with ethyl acetate (3×30 ml). The combined organic layers are washed with water (3×40 ml), dried over sodium sulfate and concentrated in vacuo yielding 2-cyclopropyl-6-methyl-4-morpholin-4-yl-benzoic acid (0.34 g, 1.3 mmol, 70%).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)#[N:2].C(=O)([O-])O.[Na+].Cl.[NH2:20][OH:21]>CO>[NH2:2][C:1](=[N:20][OH:21])[CH2:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(CC#N)cc1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CC(N)=NO)cc1

Procedure:
Methyl 4-(cyanomethyl)benzoate (2.0 g) was suspended in methanol (30 mL), and sodium hydrogen carbonate (0.96 g) and hydroxylamine hydrochloride (0.80 g) were added. The reaction mixture was heated under reflux for 12 hr, and the insoluble material was removed by filtration. The solvent was evaporated under reduced pressure from the obtained filtrate to give the title compound as a bister solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:16]#[C:17][C:18]2([CH3:32])[CH2:23][CH2:22][C:21]3[C:24]([CH3:31])=[C:25]([OH:30])[C:26]([CH3:29])=[C:27]([CH3:28])[C:20]=3[O:19]2)[CH:5]=[CH:6][C:7]=1[O:8]CC1C=CC=CC=1.C(O)C>[Pd].C(O)(=O)C>[OH:30][C:25]1[C:26]([CH3:29])=[C:27]([CH3:28])[C:20]2[O:19][C:18]([CH2:17][CH2:16][C:4]3[CH:3]=[C:2]([OH:1])[C:7]([OH:8])=[CH:6][CH:5]=3)([CH3:32])[CH2:23][CH2:22][C:21]=2[C:24]=1[CH3:31]
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1ccc(OCc3ccccc3)c(O)c1)O2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CCc1ccc(O)c(O)c1)O2
Yield: 62.6 %

Procedure:
A mixture of 1 g of rac-3,4-dihydro-2-{[3-hydroxy-4-(phenylmethoxy)phenyl]ethynyl}-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 0.5 g of 5% palladium on carbon. 100 ml of ethanol and 10 ml of glacial acetic acid was hydrogenated at atmospheric pressure for 4.5 hours. The catalyst was filtered off and the filtrate was evaporated. The residue was partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was dried and evaporated and the residue was crystallized from ether/hexane to give 0.5 g of colorless crystals with m.p. 167°-170°.