Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][N:34]=[CH:33][C:32]=1[C:36](O)=[O:37]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:32]4[CH:33]=[N:34][O:35][C:31]=4[CH3:30])=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1oncc1C(=O)O
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cnoc2C)c1

Procedure:
Prepared as described in Example 269 from (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 50 mg, 0.13 mmol) and 5-methylisoxazole-4-carboxylic acid (19 mg, 0.15 mmol).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:50])([CH3:49])[O:6][C@H:7]([C@@H:22]([CH3:48])/[CH:23]=[C:24](/[CH3:47])\[CH2:25][C@H:26]([CH3:46])[C@@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])[C@H:28]([CH3:37])[C@@H:29]([OH:36])[C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:8]([CH3:21])/[CH:9]=[CH:10]\[C:11]([N:13]([CH3:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:12])([CH3:4])[CH3:3].ClC(Cl)(Cl)[C:53]([N:55]=C=O)=[O:54]>C(Cl)Cl>[NH2:55][C:53]([O:36][C@@H:29]([C@@H:30]([CH3:35])/[CH:31]=[CH:32]\[CH:33]=[CH2:34])[C@@H:28]([CH3:37])[C@H:27]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:40])[CH3:41])[C@@H:26]([CH3:46])[CH2:25]/[C:24](/[CH3:47])=[CH:23]\[C@H:22]([CH3:48])[C@@H:7]([O:6][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:49])[CH3:50])[C@@H:8]([CH3:21])/[CH:9]=[CH:10]\[C:11]([N:13]([CH3:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:12])=[O:54]
Reactant: C=C/C=C\[C@H](C)[C@H](O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)N(C)c1ccccc1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: C=C/C=C\[C@H](C)[C@H](OC(N)=O)[C@@H](C)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)C/C(C)=C\[C@H](C)[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H](C)/C=C\C(=O)N(C)c1ccccc1
Temperature: 23 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a solution of (2Z,4S,5S,6S,7Z,10S,11R,12R,13S,14S,15Z)-5,11-bis[[(1,1-dimethylethyl) dimethylsilyl]oxy]-13-hydroxy-N,4,6,8,10,12,14-heptamethyl-N-phenyl-2,7,15,17-octadecatetraenamide (110 mg, 0.152 mmol, 1 eq) in CH2Cl2 (2 mL) is treated with trichloroacetyl isocyanate (43 mg, 0.228 mmol, 1.5 eq) at 23° C. (20 minutes). The solution is concentrated, and the residue dissolved in CH3OH (2 mL). To this solution is added K2CO3 (0.1 g) and the mixture is stirred at 23° C. (2 hours). The reaction mixture is concentrated and the residue dissolved in Et2O (5 mL). The organic solution is washed with H2O (1×20 mL) and brine (1×20 mL). The aqueous layer is extracted with Et2O (3×5 mL) and the combined extracts are dried (Na2SO4) and concentrated. Chromatography (SiO2, 30–50% EtOAc-hexanes gradient elution) provided the desired compound (70 mg, 60%).
Reaction SMILES: C(O)(C(F)(F)F)=O.CC(C)(S([NH:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40]([NH2:42])=[O:41])[C:28]([CH3:43])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH2:17][O:16][CH2:15]1)=O)C>C(Cl)Cl>[NH2:13][C:14]1([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=4[CH2:39][C:40]([NH2:42])=[O:41])[C:28]([CH3:43])=[CH:27][N:26]=3)=[CH:20][CH:19]=2)[CH2:15][O:16][CH2:17]1
Reactant: Cc1cnc(Nc2ccc(C3(NS(=O)C(C)(C)C)COC3)cc2)nc1CCc1ccccc1CC(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(C3(N)COC3)cc2)nc1CCc1ccccc1CC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
TFA (0.5 mL) was added to a solution of 2-(2-(2-(2-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)phenylamino)-5-methylpyrimidin-4-yl)ethyl)phenyl)acetamide (A122) (30 mg, 0.058 mmol) in DCM (3.0 mL) under a nitrogen atmosphere and the resulting mixture stirred at room temperature for 30 minutes, then at 35° C. overnight. The volatiles were evaporated under reduced pressure, keeping the temperature below 30° C. The resulting oil was purified by semi preparative HPLC, to give the title compound 31 (5.0 mg, 21%); 1H NMR (300 MHz, d4-MeOH) δ 8.24 (br s, 1H), 8.15 (s, 1H), 7.85 (d, J=8.8 Hz, 2H), 7.38 (d, J=8.8 Hz, 2H), 7.22 (m, 4H), 5.13 (d, J=7.7 Hz, 2H), 4.97 (d, J=7.7 Hz, 2H), 3.67 (s, 2H), 3.16 (m, 2H), 3.00 (m, 2H), 2.13 (s, 3H). LCMS: rt 4.72 min; m/z 418.2 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH:19]1[C:23](=[O:24])[CH2:22][CH2:21][O:20]1>>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:23]3([OH:24])[CH2:22][CH2:21][O:20][CH:19]3[CH3:18])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1OCCC1=O
Reactant: Brc1ccc2c(c1)CN(Cc1ccccc1)C2
Product: CC1OCCC1(O)c1ccc2c(c1)CN(Cc1ccccc1)C2

Procedure:
Prepared in analogy to Example A62(b) from 2-benzyl-5-bromo-2,3-dihydro-1H-isoindole (Example A62(a)) and 2-methyltetrahydrofuran-3-one. Brown oil. MS (m/e): 310.4 ([M+H]+, 100%).
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl[CH2:7][C:8]1[C@H:9]2[CH2:14][CH:11]([CH2:12][CH:13]=1)[C:10]2([CH3:16])[CH3:15].[O:17]=[C:18]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[NH:21][CH2:20][C@H:19]1[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]>CO>[O:17]=[C:18]1[NH:24][C:23]2[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=2[N:21]([CH2:7][C:8]2[C@H:9]3[CH2:14][CH:11]([CH2:12][CH:13]=2)[C:10]3([CH3:16])[CH3:15])[CH2:20][C@H:19]1[NH:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CNc2ccccc2NC1=O
Reactant: CC1(C)C2CC=C(CCl)[C@H]1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1CN(CC2=CCC3C[C@H]2C3(C)C)c2ccccc2NC1=O
Yield: 61.6 %

Procedure:
Sodium bicarbonate (2.02 g) and (1s)-10-chloro-2-pinene (4.1 g) were added to a solution of (R)-2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.22 g) in anhydrous methanol (40 ml), and the mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, water (200 ml) was added, and extracted with ethyl acetate (200 ml) twice. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography(n-hexane:ethyl acetate=4:1), to thereby obtain 2.03 g of the titled compound.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:22])[CH:6]([C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])C(OCC)=O)[CH3:3].O>C(O)C>[CH2:2]([O:4][C:5](=[O:22])[CH2:6][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20])[CH3:3]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(Br)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 76 %

Procedure:
To a stirred solution of concentrated HCl (18.00 mL) diluted to 72.00 mL with 95% Ethanol was added 2-(4-bromo-2-nitro-phenyl)-malonic acid diethyl ester (2.50 g, 6.94 mmol). The resulting mixture was then heated at reflux under N2 for 4 h. The reaction mixture was allowed to cool to ambient temperature and poured into H2O (250 mL). This aqueous mixture was then extracted with 2×150 mL of Diethyl ether. The Et2O layer was extracted with H2O and 5% NaHCO3 washed with brine, dried (MgSO4), and filtered. Evaporation of the filtrate in vacuo gave the intermediate title compound as a yellow liquid (1.52 g, 76%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: COc1cccc(C2CCCN2)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: COc1cccc(C2CCCN2S(=O)(=O)c2ccc(Cl)cc2)c1

Procedure:
The title compound, white solid, m.p. 95° C. and MS: m/e=351 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(3-methoxy-phenyl)-pyrrolidine and 4-chloro-benzenesulfonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]([CH3:15])[C:11]([SH:14])=[N:12][N:13]=2)[CH:6]=[CH:5][N:4]=1.I[CH3:17]>[OH-].[Na+].C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]2[N:10]([CH3:15])[C:11]([S:14][CH3:17])=[N:12][N:13]=2)[CH:6]=[CH:5][N:4]=1
Reactant: COc1cc(-c2nnc(S)n2C)ccn1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(-c2nnc(SC)n2C)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
The title compound of example 24.1 (21.30 g, 95.83 mmol) was set stirring in 1 M sodium hydroxide in a cold water bath. Iodomethane (21.76 g, 153.3 mmol) in ethanol (63 mL) was added to the reaction. As the reaction progressed, solid began to precipitate out. The reaction was allowed to stir at RT for 12 hours. The reaction mixture was extracted with dichloromethane and the organic extracts were washed with brine, dried and concentrated to afford the title compound as a white solid (22 g, 97%).
Reaction SMILES: [CH2:1]([O:5][CH2:6][C@@H:7]([OH:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C1(C)C=CC=CC=1>N1C=CC=CC=1>[CH2:1]([O:5][CH2:6][C@@H:7]([O:9][S:16]([C:13]1[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=1)(=[O:18])=[O:17])[CH3:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC[C@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCOC[C@H](C)OS(=O)(=O)c1ccc(C)cc1
Yield: 162.5 %

Procedure:
A mixture of this (S)-1-butyloxy-2-hydroxypropane (47.6 g, 0.36 mol) with anhydrous pyridine (300 g) was cooled with ice, followed by dropwise adding thereto a solution of p-toluenesulfonyl chloride (75.8 g, 0.20 mol) in pyridine (70 ml) at 0° C., agitating the mixture at room temperature for 3 hours, adding toluene (800 ml), agitating the mixture, several times washing the resulting organic layer with water, drying it over anhydrous magnesium sulfate and distilling off toluene to obtain (S)-1-butyloxy-2-(p-toluenesulfonyloxy)propane (93.1 g). A solution of 4-hydroxy-4'-octyloxybiphenyl (10 g, 0.017 mol) in THF (20 ml) was dropwise added to a mixture of sodium hydride (0.85 g, 0.035 mol) with THF (10 ml), followed by further dropwise adding a solution of the above (S)-1-butyloxy-2-(p-toluenesulfonyloxy)-propane (5.7 g, 0.02 mol) in DMF (10 ml), agitating the mixture at 60° C. for 4 hours, allowing it to cool down, adding toluene, agitating the mixture, washing with 6N-HCl, then with 2N-NaOH aqueous solution and further with water, drying over anhydrous magnesium sulfate, distilling off toluene and recrystallizing the residue from ethanol (100 ml) to obtain (R)-4-(2'-butyloxy-1'-methyl)ethyloxy-4'-octyloxybiphenyl (8.2 g) (m.p. 39.6° C.).
Reaction SMILES: [NH3:1].[CH:2]1([C:8](Cl)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1>C(Cl)(Cl)Cl>[CH:2]1([C:8]([NH2:1])=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: N
Solvent: ClC(Cl)Cl
Product: NC(=O)C1CCCCC1
Yield: 46.1 %

Procedure:
Aqueous ammonia was added to solution of cyclohexanecarbonyl chloride (500 mg, 3.41 mmol) in CHCl3 (10 ml). After completion of reaction, the reaction mixture was diluted with CHCl3 (2×30 ml). The organic layer was washed with saturated sodium bicarbonate solution, brine and dried over anhydrous sodium sulfate. The organic layer was concentrated under vacuum, crude compound was washed with hexane (2×8 ml) and dried to afford 200 mg (46.1%) of cyclohexanecarboxamide.
Reaction SMILES: I[CH2:2][CH3:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([O:28]C)=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH3:33])(=[O:32])=[O:31].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:2]([O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:26]([OH:28])=[O:27])=[C:10]([CH3:25])[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=3)=[N:12]2)=[CH:7][C:6]=1[S:30]([CH3:33])(=[O:32])=[O:31])[CH3:3]
Reactant: CCI
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(O)c(S(C)(=O)=O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc2nc(-c3cccc(C(F)(F)F)c3)c(C)c(C(=O)O)c2cc1S(C)(=O)=O
Reaction time: 8 h
Yield: 91 %

Procedure:
Iodoethane (1.10 mL, 13.65 mL) was slowly added to a mixture of methyl 7-hydroxy-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (3.0 g, 6.83 mmol) and Cs2CO3 (6.67 g, 20.48 mmol) in N,N-dimethylformamide (30 mL) at room temperature. The reaction mixture was stirred overnight, quenched with saturated NH4Cl, and extracted with methylene chloride (three times). The combined organic extracts were washed with brine (two times), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 120 g silica, 0-20% ethyl acetate/methylene chloride) to afford 7-(ethyloxy)-3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (2.92 g, 91% yield). 1H NMR (400 MHz, DMSO-d6) δ8.25 (s, 1H), 7.98-8.06 (m, 2H), 7.92 (d, J=8.03 Hz, 1H), 7.76-7.83 (m, 2H), 4.40 (q, J=6.94 Hz, 2H), 4.09 (s, 3H), 2.37 (s, 3H), 1.47 (t, J=6.90 Hz, 3H); MS (m/z) 468.1 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[NH2:21][C@@H:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[C:23]([CH3:26])([OH:25])[CH3:24]>>[CH:28]1([CH2:27][C@H:22]([NH:21][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:23]([OH:25])([CH3:26])[CH3:24])[CH2:30][CH2:29]1
Reactant: CC(C)(O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)(O)[C@H](CC1CC1)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and (S)-3-amino-4-cyclopropyl-2-methyl-butan-2-ol as starting materials, MS (EI): m/e=410.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20](N)[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1.S(=O)(=O)(O)[OH:26].[OH-].[NH4+]>O>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:21]=[C:20]([OH:26])[N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[F:17])[C:4]=2[CH:3]=1
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2
Reactant: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: Oc1ncc2c(n1)-c1ccc(Cl)cc1C(c1ccccc1F)=NC2

Procedure:
A solution of 1.2 g (0.00354 mol) of 9-chloro-7-(2-fluorophenyl)-2-amino-5H-pyrimido[5,4-d][2]benzazepine in 20 ml of concentration sulfuric acid and 20 ml of water was refluxed for 12 hr, and then cooled. After the addition of ice, the reaction mixture was basified with ammonium hydroxide and extracted with 100 ml of dichloromethane. The solids were collected by filtration and recrystallized from dichloromethane/methanol to give the end product as white prisms, mp 297°-299° dec. The dichloromethane extract was dried, evaporated and the residue crystallized from dichloromethane/methanol to give additional product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([O:21]C)=[O:20])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)CCC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
To a solution of 2.62 g (5.6 mmol) of methyl 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoate. in 14 mL dioxane is added 11.6 mL of 1N NaOH (11.6 mmol) and the mixture is heated at 60° for 2 hours. The solvent is evaporated and the residue dissolved in water. The pH of the aqueous solution is adjusted to 5.0 using 2N aqueous HCl. The resulting mixture is extracted with methylene chloride (3×20 mL). The combined organic extract is dried (MgSO4), filtered and subjected to evaporation to give an oil. Crystallization from ether yields 8-(p-chlorophenylsulfonamido)-4-[3-(3-pyridyl)propyl]-octanoic acid, m.p. 114-116°.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C([O-])([O-])=O.[K+].[K+].[CH2:34]([O:36][C:37](=[O:40])[CH2:38]Br)[CH3:35]>CC(C)=O>[CH3:1][C:2]1[C:3]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:4]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:38][C:37]([O:36][CH2:34][CH3:35])=[O:40])=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2
Reactant: CCOC(=O)CBr
Reactant: COc1ccc2c(Oc3ccc(O)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Temperature: 25 °C
Yield: 95 %

Procedure:
A round-bottomed flask was charged with 4-{[3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenyl]oxy}phenol (233) (0.150 g, 0.421 mmol), K2CO3 (0.116 g, 0.842 mol), acetone, and ethylbromoacetate (0.105 g, 0.632 mmol) under N2. The reaction mixture was refluxed for 5 h and cooled at room temperature. Reaction mixture was filtered and concentrated under reduced pressure to afford the crude product. The product was purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 9:1) as an eluent to give 0.177 g (95%) of the title compound (234) as a white foam. 1H NMR (400 MHz, CDCl3): δ 7.80 (d, J=9.2 Hz, 1H), 7.54 (s, 1H), 7.29-7.22 (m, 3H), 7.13-7.11 (m, 3H), 7.05 and 7.03 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.63 (d, J1=9.2 Hz, 2H), 6.50 (d, J1=9.2 m, 2H), 4.48 (s, 2H), 4.24 (q, J=3.8 Hz, 2H), 3.93 (s, 3H), 2.23 (s, 3H), 1.27 (t, J=3.00 Hz, 3H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH3:30][O:31][C:32]1[CH:40]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[C:38]([N+:45]([O-:47])=[O:46])=[CH:37][C:33]=1[C:34](O)=[O:35].[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52]>C(Cl)Cl.CO>[C:48]([OH:55])(=[O:54])/[CH:49]=[CH:50]/[C:51]([OH:53])=[O:52].[CH2:16]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][C:34](=[O:35])[C:33]2[CH:37]=[C:38]([N+:45]([O-:47])=[O:46])[C:39]([NH:41][C:42](=[O:44])[CH3:43])=[CH:40][C:32]=2[O:31][CH3:30])[CH2:25][CH2:24]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)O
Reactant: NC1CCN(Cc2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N,N'-Dicyclohexylcarbodiimide (4.12 g; 0.02 moles) and 1-benzyl-4-aminopiperidine (3.8 g; 0.02 moles) were added successively to a solution of 2-methoxy-4-acetamido-5-nitrobenzoic acid (5.1 g; 0.02 moles) in methylene chloride (125 ml). After stirring overnight at room temperature, the insoluble N,N'-dicyclohexylurea was filtered off, the solution was washed with water, dried (Na2SO4) and the solvent removed in vacuo to give a solid. It was suspended in hot methanol and treated with the stoichiometric amount of fumaric acid to give a solution from which the N-(1-benzylpiperid-4-yl)-2-methoxy-4-acetamido-5-nitrobenzamide fumarate (6.2 g) crystallized. After recrystallization from methanol this compound melted at 204°-206° C.
Reaction SMILES: [N:1]([C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][OH:17])=[C:6]([NH2:18])[N:5]=1)=[N+]=[N-]>[Pd].C(O)C>[NH2:1][C:4]1[N:12]=[C:11]2[C:7]([N:8]=[CH:9][N:10]2[CH2:13][O:14][CH2:15][CH2:16][OH:17])=[C:6]([NH2:18])[N:5]=1
Reactant: [N-]=[N+]=Nc1nc(N)c2ncn(COCCO)c2n1
Agent: [Pd]
Solvent: CCO
Product: Nc1nc(N)c2ncn(COCCO)c2n1
Reaction time: 3.5 h

Procedure:
A mixture of 2-azido-9-(2-hydroxyethoxymethyl)adenine (0.41 g) and 10% palladium on charcoal (80 mg) in ethanol (41 ml) was shaken under hydrogen at 50 psi for 3.5 hours. The catalyst as removed by filtration through a celite pad and washed thoroughly with ethanol and water. The solvent was removed by evaporation under reduced pressure giving a quantitative yield (0.37 g) of nearly pure (one spot on TLC) 2-amino-9-(2-hydroxyethoxymethyl)adenine, m.p. 183°-184° C. after recrystallization from n-propanol.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([NH2:5])=[NH:4].Cl.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17]N)=[CH:13][CH:12]=1.C(N(CC)CC)C>CO>[F:1][C:2]([F:7])([F:6])[C:3](=[N:5][NH:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=1)[NH2:4]
Reactant: N=C(N)C(F)(F)F
Reactant: COc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc(NN=C(N)C(F)(F)F)cc1
Reaction time: 6 h
Yield: 108.3 %

Procedure:
To a solution of trifluoroacetoamidine (4.24 g, 37.8 mmol) in methanol (20 mL), were added 4-methoxyphenylhydrazine hydrochloride (4.72 g, 27 mmol) and then triethylamine (3.77 mL, 27 mmol) at room temperature. The mixture was stirred for 6 hours. The solvent was removed under reduced pressure. 20 mL of water and 50 mL of ethyl acetate-tetrahydrofuran (9:1) were added to the residue and the organic layer was separated and the aqueous layer was extracted with 50 mL of ethyl acetate-tetrahydrofuran (9:1). A combined organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was removed under reduced pressure to give 2,2,2-trifluoro-N′-(4-methoxyphenyl)ethanehydrazonamide (6.82 g, 108.2% yield). The residue was used for the next reaction without purification.