Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13](=[O:16])[CH2:14]Cl)[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:12][C:13]([CH2:14][N:28]2[CH2:27][CH2:26][N:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH3:17])[CH2:30][CH2:29]2)=[O:16])[C:6]([O:10][CH3:11])=[N:7][C:8]=1[CH3:9])[CH3:2]
Reactant: CCc1cc(NC(=O)CCl)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCc1cc(NC(=O)CN2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
After N-(5-ethyl-2-methoxy-6-metylpyridine-3-yl)chloroacetamide(0.10 g, 0.43 mmol) and 1-(2-methoxyphenyl)piperazine(0.0091 g, 0.47 mmol) were dissolved into tetrahydrofuran(5 ml) and was added DBU(0.060 g, 0.43 mmol), the reaction mixtures were stirred at room temperature for 2 hours. After the product of reaction were concentrated, separated by column chromatography to obtain 0.12 g of the titled compound.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][OH:20])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CN=C1.Cl[Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35].O>CN(C)C=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH2:19][O:20][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:16][CH:17]=3)[CH:12]=[C:11]2[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1c(-c2ccccc2)cc2cc(CO)ccc21
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)[Si](OCc1ccc2c(c1)cc(-c1ccccc1)n2S(=O)(=O)c1ccccc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 1-benzenesulfonyl-5-hydroxymethyl-2-phenylindole (171 mg) in N,N-dimethylformamide (2.4 mL) were added imidazole (128 mg) and chlorotriisopropylsilane (0.150 mL) under cooling with ice, and the mixture was stirred at room temperature for 20 hours. Water was added to the reaction mixture and this resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (221 mg).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([OH:28])([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH:9]=[CH:10][CH:11]=1.C1C(=O)N([O:36][C:37]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45]([CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[S:55][CH2:54][CH:53]3[NH:56][C:57]([NH:59][CH:52]23)=[O:58])=[O:46])=O)C(=O)C1>CN(C=O)C.CO.C(Cl)(Cl)Cl>[OH:28][C:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][CH2:3][CH2:2][NH:1][C:37](=[O:36])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][NH:44][C:45](=[O:46])[CH2:47][CH2:48][CH2:49][CH2:50][CH:51]2[CH:52]3[CH:53]([NH:56][C:57](=[O:58])[NH:59]3)[CH2:54][S:55]2)[CH:7]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1
Reactant: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CCCCC1SCC2NC(=O)NC21)NCCCCCC(=O)NCCCOc1cccc(C(O)(c2ccccc2)c2ccc(C(=O)O)cc2)c1

Procedure:
A mixture of Trityl amino acid (4, 100 mg, 0.26 mM) and Biotin-X-NHS (113 mg, 0.25 mM) was stirred at room temperature in 3 mL of anhydrous DMF for overnight. After that DMF was removed under high vacuum and the residue obtained was passed through silica gel column using 50% CH3OH/CHCl3 as a solvent. Evaporation of the solvent yielded biotinylated trityl acid 5. (97.8%). Mass: 739 (M Na+), 715 (M-H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]2[CH:17]=[CH:16][NH:15][C:10]=2[N:11]=[C:12](Cl)[N:13]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])=[CH:21][CH:20]=1.C[Si](Cl)(C)C>C(O)CCC>[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]2[CH:17]=[CH:16][NH:15][C:10]=2[N:11]=[C:12]([NH:18][C:19]2[CH:20]=[CH:21][C:22]([N:25]([CH3:29])[C:26](=[O:28])[CH3:27])=[CH:23][CH:24]=2)[N:13]=1
Reactant: NCCCCCNc1nc(Cl)nc2[nH]ccc12
Reactant: CC(=O)N(C)c1ccc(N)cc1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: CC(=O)N(C)c1ccc(Nc2nc(NCCCCCN)c3cc[nH]c3n2)cc1
Temperature: 116 °C
Yield: 7.6 %

Procedure:
A mixture of N-(5-aminopentyl)-2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-amine (79 mg, 0.31 mmol), N-(4-aminophenyl)-N-methylacetamide (100 mg, 0.61 mmol) and trimethylsilyl chloride (0.150 mL, 1.19 mmol) in nBuOH (2 mL) was heated at 116° C. for 4 h. The mixture was then purified by HPLC to give the titled compound (9 mg). MS 382.2 (M+H); UV 210.8, 267.5, 305.5 nm.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].C(=O)([O-])[O-].[K+].[K+].[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O.ClCCl>[C:23]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8])([O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:24]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCCCCCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: O=C(NCCCCCCO)OCc1ccccc1
Reaction time: 8 h

Procedure:
6-Aminohexan-1-ol (11.7 g, 100 mmol) and potassium carbonate (16.58 g, 120 mmol) were dissolved in 100 mL water and 70 mL dichloromethane. Benzylchloroformate (14.27 mL, 100 mmol) was added dropwise over 30 minutes at a temperature of 25-30° C. The resulting mixture stood overnight, then the dichloromethane layer was separated, washed with water (3×200 mL), 2 N HCl (3×50 mL) and finally with water (3×100 mL), dried, and evaporated to give a white solid. The solid was recrystallized in hexane-ethylacetate (8:2) to give a solid, which was collected and dried under vacuum at room temperature. Yield: 23 g (91%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[CH:9]([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:19]I>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:16])[C:9]([CH3:19])([N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CI
Reactant: CC(C(=O)c1ccc(Cl)cc1)n1cncn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C(=O)c1ccc(Cl)cc1)n1cncn1
Reaction time: 0.17 h
Yield: 79.3 %

Procedure:
4'-Chloro-2-(1H-1,2,4-triazol-1-yl)propiophenone (2 g.) in dry tetrahydrofuran (30 ml) was added to a suspension of sodium hydride (480 mg. of a 60% dispersion in oil) in dry tetrahydrofuran (20 ml) at 0° under a nitrogen atmosphere. After stirring for 10 minutes, methyl iodide (2.28 g.) in dry tetrahydrofuran (10 ml.) was added dropwise and the reaction mixture was then stirred at 0° for 1 hour and then at room temperature overnight. The reaction mixture was then diluted with water (20 ml), extracted with ether (3×25 ml), and the combined organic extracts were washed with water and dried (MgSO4). The residue obtained after removal of the solvent was flash chromatographed on silica (150 g.) using ethyl acetate/hexane/diethylamine (50:50:3 v/v/v) for elution and the product-containing fractions on evaporation followed by crystallisation of the residue from ethyl acetate/hexane furnished the title compound, (1.68 g., 84% yield), m.p. 118°-9°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[C:25]([CH3:29])=[CH:24][C:23]=1[S:30]([NH:20][C:4]1[CH:5]=[C:6]([Cl:19])[C:7]([CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)=[C:2]([Cl:1])[CH:3]=1)(=[O:32])=[O:31]
Reactant: Nc1cc(Cl)c(Cc2ccc3ccccc3n2)c(Cl)c1
Reactant: Cc1cc(S(=O)(=O)Cl)c(Cl)cc1Cl
Solvent: c1ccncc1
Product: Cc1cc(S(=O)(=O)Nc2cc(Cl)c(Cc3ccc4ccccc4n3)c(Cl)c2)c(Cl)cc1Cl

Procedure:
2,4-Dichloro-N-(3,5-dichloro-4-quinolin-2-ylmethyl-phenyl)-5-methyl-benzenesulfonamide was synthesized (76%) from 3,5-dichloro-4-quinolin-2-ylmethyl-phenylamine (223), 2,4-dichloro-5-methylbenzenesulfonyl chloride (Maybridge) and pyridine (EM) in a similar manner as described in Examples 70-91. 1H NMR (400 MHz, DMSO-d6) δ 11.22 (br s, 1H), 8.25 (d, J=8.5 Hz, 1H), 8.15 (s, 1H), 7.91 (d, J=8.0 Hz, 1H), 7.88 (s, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.69 (t, J=7.1 Hz, 1H), 7.54 (t, J=7.5 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H), 7.21 (s, 2H), 4.48 (s, 2H), 2.39 (s, 3H). MS (EI): m/z 523 (M−H).
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([CH3:23])=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:27][C@H:28]1[CH2:32][CH2:31][CH2:30][C@@H:29]1[OH:33].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[OH:33][C@H:29]1[CH2:30][CH2:31][CH2:32][C@@H:28]1[N:27]1[CH2:21][C:14]2[C:15](=[CH:20][C:11]([CH2:10][C:9]3[CH:8]=[CH:7][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:25][CH:24]=3)=[C:12]([CH3:23])[CH:13]=2)[C:16]1=[O:17]
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C)cc1C=O
Reactant: N[C@H]1CCC[C@@H]1O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc2c(cc1Cc1ccc(-n3cccn3)cc1)C(=O)N([C@H]1CCC[C@@H]1O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-2-formyl-4-methylbenzoate (0.16 g), (1S,2S)-2-aminocyclopentanol hydrochloride (0.06 g), triethylamine (0.07 mL) and anhydrous magnesium sulfate (0.11 g) in THF (3.10 mL) was stirred at room temperature for 3 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (3.10 mL) and THF (3.10 mL), sodium triacetoxyborohydride (0.20 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (71 mg).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C([O-])=O.[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 99.7 %

Procedure:
In a nitrogen atmosphere under normal pressure, 2,4-di-tert-butylphenyl methanesulfonate (500 g, 1.76 mols), lithium formate (183 g, 3.52 mols) and methanol (3000 g) were mixed at 25° C., and with stirring, 10 mass % Pd/carbon (50 mass % water-containing product) (100 g) (as metal palladium; 1 mass % relative to 2,4-di-tert-butylphenyl methanesulfonate) as supported by a carbon carrier having a specific surface area of 780 m2/g (by BET method) was put into it. With stirring, the reaction liquid was reacted at the same temperature for 4 hours. Water (100 mL) was added to the reaction liquid and Pd-carbon was separated through filtration, then heptane (500 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (334 g, yield 100% by mass).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[F:12]
Reactant: C1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)c(F)c1
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Br)c(F)c1)N1CCCC1
Yield: 95.6 %

Procedure:
According to general procedure C, 4-Bromo-3-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and pyrrolidine (0.30 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 1-[(4-bromo-3-fluorophenyl)sulfonyl]pyrrolidine (0.43 g, 96%) was provided after purification. HRMS: calcd for C10H11BrFNO2S, 306.96779; found (EI, M+.), 306.968. HPLC purity 100.0% at 210-370 nm, 10.3 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:17])[NH:9][NH:10][C:11]2=[O:16])=[O:4].C(#[N:20])C>[OH-].[NH4+].O>[NH2:20][CH2:2][C:3]([NH:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[C:8](=[O:17])[NH:9][NH:10][C:11]2=[O:16])=[O:4]
Reactant: CC#N
Reactant: O=C(CCl)Nc1cccc2c(=O)[nH][nH]c(=O)c12
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: NCC(=O)Nc1cccc2c(=O)[nH][nH]c(=O)c12
Temperature: 25 °C
Reaction time: 192 h

Procedure:
2-Chloro-N-(1,4-dioxo-1,2,3,4-tetrahydrophthalazine-5-yl)acetamide (300 mg; 1.182 mmol) was suspended in ammonium hydroxide (7 ml) and stirred slowly in a vial at 4 C for 8 days (30%). The reaction mixture was transferred into a flask and hot water (25 ml) was added to the reaction mixture, filtered, and the filtrate was collected. The initial pH (12) of the filtrate was adjusted to 5.38 by slow addition of acetic acid to obtain the intermediate. The beige colored solid was filtered, rinse with water (10 ml), washed with methanol (50 mL), and finally with ether (50 ml), and then dried under reduced pressure. The residue was suspended in hydrazine (30% in water, 22 ml) and heated to dissolve the precipitates. The contents were allowed to cool to RT, pH was adjusted to 4.8, and precipitates were obtained upon cooling. The resultant precipitates were filtered, washed with water, methanol (cold), ether, and then dried under reduced pressure to obtain 2. 1H NMR (300 MHz, DMSO-d6) δ: 8.86 (d, 1H), 7.85 (t, 1H), 7.60 (d, 1H), 3.33 (s, 2H), 2.16 (s, 3H, Methyl for Acetic Acid); ESMS: Calcd for C10H10N4O3: 234.0, Found, 235.0; HPLC: Purity was further analyzed on a C-18 column (Vydac) employing a mobile phase eluent gradient of 10-90% acetonitrile in water containing 0.1% TFA over 30 minutes with a flow rate of 1 mL/min, Rt=13.2 min.
Reaction SMILES: [N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3OS(C(F)(F)F)(=O)=O)=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1B(O)O.[F-].[Cs+]>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[N:1]1([CH2:8][CH2:9][O:10][C:11]2[CH:38]=[CH:37][C:14]([C:15]([C:17]3[C:26]4[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=4)[CH:20]=[CH:19][C:18]=3[C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=3[F:39])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reactant: OB(O)c1ccccc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCCC4)cc3)c(-c3ccccc3F)ccc2c1
Yield: 72.5 %

Procedure:
Dissolve trifluoromethanesulfonic acid 1-[4-(2-azepan-1-yl-ethoxy)-benzoyl]-6-methoxynaphthalen-2-yl ester (1.68 g, 3.05 mmol) in 30 mL of acetonitrile and add 2-fluorobenzene boronic acid (0.85 g, 6.10 mmol), trans[dichlorobis(triphenylphosphine)]palladium II (0.43 g, 0.61 mmol) and sonicate briefly. Next add cesium fluoride (4.17 g, 27.45 mmol) and heat to 75° C. for 1 hour. Add Celite and filter. Concentrate the solvent under vacuum, dissolve in methanol and purify on an SCX cartridge, eluting with 2 N ammonia/methanol. Purify further on a silica gel column eluting with a 0-10% methanol/methylene chloride gradient to isolate 1.10 g of the title compound (72%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([O:10][CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH2:16]([O:15][C:13]([C:12]1[CH:18]=[N:1][C:2]2[C:7]([C:11]=1[OH:10])=[CH:6][N:5]=[CH:4][CH:3]=2)=[O:14])[CH3:17]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1ccncc1
Product: CCOC(=O)c1cnc2ccncc2c1O
Reaction time: 16 h

Procedure:
4-Aminopyridine (15.84 g) and diethyl ethoxymethylenemalonate (34.3 ml) were heated at 110° C. then allowed to stand for 16 h at room temperture. The resulting solid was collected by filtration, washed wtih diethyl ether then pentane and dried in vacuo. A sample of the resulting enamine (10.0 g) was added portionwise to refluxing Dowtherm A (400 ml ). After heating for a further 0.25 h the reaction mixture was cooled then diluted with pentane (400 ml). The precipitated solid was collected by filtration and washed wtih diethyl ether to afford the title compound as a beige solide (3.84 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1.C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.O>ClCCl>[C:31]([NH:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:11]3=[N:12][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:15]=[C:10]3[N:9]=[C:8]2[CH3:20])=[C:4]([Cl:23])[CH:3]=1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(N)cc3Cl)c2n1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(NC(=O)c4ccccc4)cc3Cl)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 80.4 %

Procedure:
To a solution of methyl 3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (3 ml) was added triethylamine (110 mg). Benzoyl chloride (134 mg) was added under ice-cooling and the mixture was stirred at room temperature for 12 hr. Water was added to the reaction mixture and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Hexane was added to the residue for crystallization, and the crystals were collected by filtration and dried under reduced pressure to give the objective compound (317 mg) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:18]3[CH:17]=[CH:16][N:15]=[C:14]([C:19]#N)[C:13]=3[N:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:21]1CCOC[CH2:22]1.Cl.C[OH:29]>>[CH3:22][O:21][C:19]([C:14]1[C:13]2[N:12]=[CH:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[C:18]=2[CH:17]=[CH:16][N:15]=1)=[O:29]
Reactant: C1COCCO1
Reactant: CO
Reactant: N#Cc1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: COC(=O)c1nccc2c1ncn2-c1ccc([N+](=O)[O-])cc1
Reaction time: 4 h
Yield: 41 %

Procedure:
In 10 mL of methanol, 74 mg (0.28 mmol) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile prepared in Step A was dissolved, and 2 mL of a 4N hydrogen chloride dioxane solution was added thereto, and the mixture solution was refluxed under heating with stirring for four hours. The solvent was distilled under reduced pressure, and the residue was partitioned between ethyl acetate (10 mL×2) and a sodium hydrogencarbonate aqueous solution (10 mL). The combined organic layers was washed with a saturated sodium chloride solution, dried on anhydrous sodium sulfate and then concentrated under reduced pressure. The solvent was distilled and the residue was separated by Megabond Elute Silica Gel (2 g, dichloromethane:methanol=30:1) to obtain 34 mg (41%) of 1-(4-nitrophenyl)-1H-imidazo[4,5-c]pyridine-4-carboxylic acid methyl ester as a white solid.
Reaction SMILES: [C:1]([CH:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2].[OH-].C([N+](CC)(CC)CC)C1C=CC=CC=1.[CH:32]([C:34]([CH2:36][CH3:37])=[O:35])=[CH2:33]>O1CCCC1>[C:1]([C:4]1([CH2:33][CH2:32][C:34](=[O:35])[CH2:36][CH3:37])[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)(=[O:3])[NH2:2]
Reactant: C=CC(=O)CC
Reactant: NC(=O)C1c2ccccc2-c2ccccc21
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC(=O)CCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 52.3 g. of 9-carbamoylfluorene and 10 ml. of benzyltriethylammonium hydroxide in 700 ml. of tetrahydrofuran was heated at 45° C. for thirty minutes and then cooled to 25° C. The reaction mixture was diluted by addition in one portion of 25.2 g. of ethyl vinyl ketone. The reaction mixture was stirred at 25° C. for sixteen hours and at reflux for three hours. The mixture was cooled, added to 200 g. of ice and extracted with 50% ethyl acetate-diethyl ether. The organic extract was washed with water, with 10% sodium hydroxide, dried and the solvent was removed by evaporation under reduced pressure. The solid residue was crystallized from ethyl acetate and petroleum ether to afford 42.6 g of 9-carbamoyl-9-(3-oxopentyl)fluorene. m.p. 133°-135° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:5]O)[CH2:3]O.O=S(Cl)[Cl:9].[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]=[S:23]>>[CH3:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[N:21]=[C:22]1[NH:1][CH:2]([CH2:5][Cl:9])[CH2:3][S:23]1
Reactant: NC(CO)CO
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: O=S(Cl)Cl
Product: Cc1cc([N+](=O)[O-])ccc1N=C1NC(CCl)CS1

Procedure:
2-Amino-1,3-propanediol was reacted with excess SOCl2 followed by 2-methyl-4-nitrophenyl isothiocyanate according to Method C2a to give 2-(2-methyl-4-nitrophenylimino)-4-(chloromethyl)-1,3-thiazolidine. The thiazolidine was reacted with N-methylamine according to Method D13a to give 2-(2-methyl-4-nitrophenylimino)-4-(N-methylaminomethyl)-1,3-thiazolidine, which was reacted with isobutyl bromide according to Method D2a to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-4-(N-isobutyl-N-methylaminomethyl)-1,3-thiazolidine.
Reaction SMILES: CC[O:3][C:4](/[CH:6]=[C:7](/[CH:9]=[CH:10]/[CH:11]=[C:12](/[CH:14]=[CH:15]/[C:16]1[C:17]([CH3:26])=[CH:18][C:19]([O:24][CH3:25])=[C:20]([CH3:23])[C:21]=1[CH3:22])\[CH3:13])\[CH3:8])=[O:5].[OH-].[K+].CC(C)=O.Cl>C(O)C>[CH3:26][C:17]1[C:16](/[CH:15]=[CH:14]/[C:12](/[CH3:13])=[CH:11]/[CH:10]=[CH:9]/[C:7](/[CH3:8])=[CH:6]/[C:4]([OH:5])=[O:3])=[C:21]([CH3:22])[C:20]([CH3:23])=[C:19]([O:24][CH3:25])[CH:18]=1
Reactant: CCOC(=O)/C=C(C)/C=C/C=C(C)/C=C/c1c(C)cc(OC)c(C)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1cc(C)c(/C=C/C(C)=C/C=C/C(C)=C/C(=O)O)c(C)c1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 69 %

Procedure:
Acitretin was obtained by stirring the contents of thirty 25 mg capsules of etretinate in ethyl acetate for 4 days, filtering and concentrating to dryness to give recovery of greater than 90% of the theoretical quantity of etretinate. This etretinate was then dissolved in 20 ml of ethanol, 3 ml of 4N KOH, and enough acetone to make the solution one phase. The solution was stirred at room temperature for 2 1/2 days, acidified to pH 3 with 3N HCl, and extracted with ethyl acetate. The ethyl acetate was washed with brine, dried over Na2SO4, filtered and concentrated to give a 69% yield of acitretin.