Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=[C:4]([SH:11])[N:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCOCC1>[CH2:12]([S:11][C:4]1[N:3]=[C:2]([OH:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH3:10])[N:5]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: CCCc1cc(O)nc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCc1cc(O)nc(SCc2ccccc2)n1
Temperature: 80 °C

Procedure:
A mixture of 51.1 g (0.3 mole) of 4-hydroxy-6-n-propylpyrimidine-2-thiol, 51.3 g (0.3 mole) of benzyl bromide, 100 ml of dioxane and 500 ml of 1N aqueous sodium hydroxide solution was heated at 80° C. for four hours. After cooling, the solid was collected by filtration to provide white crystals of 2-benzylthio-4-hydroxy-6-n-propylpyrimidine, m.p. 122°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([NH2:15])=O)[CH:10]=[N:9]2)=[CH:5][CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:27])=CC=1>C(Cl)(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13](=[S:27])[NH2:15])[CH:10]=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1ccc(Cn2cc(C(N)=O)cn2)cc1
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(Cn2cc(C(N)=S)cn2)cc1
Yield: 51.2 %

Procedure:
According to Scheme 1 Step 4: A solution of 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxamide (109 mmol, 25.1 g) and Lawesson's reagent (109 mmol, 43.9 g) in CHCl3/toluene (1:1, 136 mL) was stirred at 85° C. for 12 hours. The reaction mixture was evaporated and the residue was recrystallized in EtOAc/pentane to yield 13.8 g of 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide. The mother liquors were evaporated and the crude residue was purified by flash chromatography over silica gel using DCM/EtOAc (100:0 to 70:30) to yield 1-(4-methoxybenzyl)-1H-pyrazole-4-carbothioamide (94.6 mmol, 23.4 g, 87%) as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:41])[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CC(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:41][C:33]2[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CS(=O)(=O)c1cc(O)cc(I)c1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 70 °C
Yield: 97.4 %

Procedure:
To a solution of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (3.79 g, 8.05 mmol), 3-iodo-5-methanesulfonyl-phenol (2.0 g, 6.71 mmol) in dimethylformamide (40 mL) and acetone (80 mL) was added potassium carbonate (9.25 g, 67.1 mmol). The resulting suspension was heated at 70° C. for 24 h. Then, the reaction mixture was cooled to room temperature, diluted with EtOAc and washed with 10% HCl and water. Then, the combined organic extracts were washed with brine. The organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which was purified by using an ISCO 120 g column. The desired compound was eluted with 40% EtOAc-Hexanes. The desired fractions were combined and evaporated under reduced pressure to afford 4.5 g (97%) of title compound as a colorless oil. HR-ES(+) m/e calcd for C30H41O8SI (M+Na)+ 711.1459, found 711.1465.
Reaction SMILES: [CH:1]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:15](Br)([Br:17])[Br:16].[OH-].[Na+]>[Cl-].C([N+](C(CCCCCC)C)(C(CCCCCC)C)C)(CCCCCC)C.ClCCl>[Br:16][C:15]1([Br:17])[CH:14]2[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2
Reactant: C1=CCCCCCCCCCCCC1
Reactant: BrC(Br)Br
Agent: CCCCCCC(C)[N+](C)(C(C)CCCCCC)C(C)CCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: BrC1(Br)C2CCCCCCCCCCCCC21
Yield: 100 %

Procedure:
Cyclotetradecene (40 g), bromoform (75.9 g), 50% aqueous sodium hydroxide solution (300 ml), dichloromethane (20 ml), tri-sec-octyl methylammonium chloride (1 drop) and 1 drop of a long-chain alcohol ethoxylate of the structure [C14-15 ] [OC2 ]11 --OH (Dobanol 45 + 11 EO, Shell Chemicals) were stirred together at 40° C. for 7 hours. The organic layer was separated and the volatile organic components removed under reduced pressure. The residue was dissolved in pentane and the solution was stirred with active charcoal (Norit). The solution was filtered and the pentane removed under reduced pressure to give the required product in almost 100% yield.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:23][CH:22]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7][N:6]1[C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])=[O:4].[OH-].[Li+].Cl>C1COCC1.CO>[C:40]([O:39][C:37]([N:6]1[CH:5]([C:3]([OH:4])=[O:2])[CH2:18][C:17]2[CH:16]=[C:15]3[C:10]([O:11][C@@H:12]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]5[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=5)=[CH:23][CH:22]=4)[C:13](=[O:20])[N:14]3[CH3:19])=[CH:9][C:8]=2[CH2:7]1)=[O:38])([CH3:43])([CH3:41])[CH3:42]
Reactant: COC(=O)C1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)[C@H](c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)Oc2cc3c(cc21)CC(C(=O)O)N(C(=O)OC(C)(C)C)C3
Temperature: 0 °C
Reaction time: 5 h
Yield: 98.9 %

Procedure:
(S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester (3.0 g) was dissolved in THF-methanol (4:1, 10 mL), 2 N lithium hydroxide solution (4.8 mL) was added, and the resulting reaction mixture was stirred at 0° C. for 5 h. The reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure to afford (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester (2.9 g). LC-MS (m/z) 614. The Boc group of (S)-3-[4-(3,4-Dichloro-benzyloxy)-phenyl]-1-methyl-2-oxo-1,2,3,5,7,8-hexahydro-4-oxa-1,6-diaza-anthracene-6,7-dicarboxylic acid 6-tert-butyl ester 7-methyl ester may be removed to provide the compound Intermediate C (“Intermediate C”).
Reaction SMILES: [OH-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][CH:19]([NH2:32])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[C@@H:13]([C:33]([O:35]C)=[O:34])[CH2:12]1>O1CCOCC1.CO.O>[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[S:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][CH:19]([NH2:32])[C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[CH:22][CH:21]=2)[C@@H:13]([C:33]([OH:35])=[O:34])[CH2:12]1
Reactant: COC(=O)[C@H]1CN(CCSc2cccs2)CC[C@H]1CCC(N)c1ccnc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: COc1ccc2nccc(C(N)CC[C@@H]3CCN(CCSc4cccs4)C[C@@H]3C(=O)O)c2c1
Yield: 102.9 %

Procedure:
1 cm3 of 5N aqueous sodium hydroxide solution is added with stirring, at a temperature in the region of 20° C., to a solution of 0.05 g of methyl (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 2 cm3 of dioxane and 2 cm3 of methanol, and then the combined mixture is brought to reflux and refluxed for 20 hours. The mixture is concentrated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained is dissolved in 6 cm3 of distilled water The aqueous phase is washed with 2 cm3 of methylene chloride and then evaporated to dryness. The residue is taken up in 2 cm3 of isopropanol and the insoluble material is washed with 2 cm3 of isopropanol and then dried to give 0.05 g of (3R,4R)-1-[2-(thien-2-ylthio)ethyl]-4-[3-(R,S)-amino-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylic acid, sodium salt.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][OH:11].[CH:12]1([C:16](Cl)=[O:17])[CH2:15][CH2:14][CH2:13]1.C1(C2C3C(=C(Cl)C=CC=3)CCN=2)C=CC=CC=1>>[CH:12]1([C:16]([NH:1][CH2:2][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:10][OH:11])=[O:17])[CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCC1
Reactant: NCCc1ccccc1CO
Agent: Clc1cccc2c1CCN=C2c1ccccc1
Product: O=C(NCCc1ccccc1CO)C1CCC1

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and cyclobutanecarbonyl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-cyclobutylcarbonylamino-2-(2-hydroxymethylphenyl)ethane as in oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-cyclobutylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-cyclobutylisoquinoline-5-acetic acid having a decomposition point of 202.8° to 209.8° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl.[NH:9]1[CH2:12][CH:11]([C:13]2[NH:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[N:14]=2)[CH2:10]1.Cl[C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)[N:27]=[CH:26][N:25]=1>CC(N(C)C)=O>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[NH:17][C:13]([CH:11]3[CH2:12][N:9]([C:24]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[N:27]=[CH:26][N:25]=4)[CH2:10]3)=[N:14][C:15]=2[CH:21]=1
Reactant: Clc1cc(C2CCOCC2)ncn1
Reactant: Clc1ccc2[nH]c(C3CNC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Clc1ccc2[nH]c(C3CN(c4cc(C5CCOCC5)ncn4)C3)nc2c1
Temperature: 70 °C
Yield: 46.9 %

Procedure:
A mixture of cesium carbonate (0.83 g, 2.56 mmol), 2-(azetidin-3-yl)-5-chloro-1H-benzo[d]imidazole dihydrochloride (as described in Preparation 5) (0.18 gg, 0.64 mmol), and 4-chloro-6-(tetrahydro-2H-pyran-4-yl)pyrimidine (0.13 g, 0.64 mmol) in DMA (1 mL) was heated to 70° C. for 18 h, then cooled to RT. The resulting suspension was partitioned between ethyl acetate and water, the layers were separated, and the organic layer was washed with water twice, brine once, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give 5-chloro-2-(1-(6-(tetrahydro-2H-pyran-4-yl)pyrimidin-4-yl)azetidin-3-yl)-1H-benzo[d]imidazole (0.11 g, 0.30 mmol, 47% yield) as a white solid. [M+1] 370. IC50 (uM) 1.283.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:15]([NH2:17])=[O:16])[C:7]2[O:13][CH2:12][CH2:11][CH2:10][S:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl>CCO>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([C:15]([NH2:17])=[O:16])[C:7]2[O:13][CH2:12][CH2:11][CH2:10][S:9][C:8]=2[CH:14]=1)[CH3:2]
Reactant: CC(=O)c1cc2c(c(C(N)=O)c1)OCCCS2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(O)c1cc2c(c(C(N)=O)c1)OCCCS2
Reaction time: 0.08 h

Procedure:
To 2-acetyl-7,8-dihydro-6H-5-oxa-9-thia-benzocycloheptene-4-carboxylic acid amide (0.40 g, 1.59 mmol) suspended in EtOH (10 mL) was added NaBH4 (0.060 g, 1.59 mmol). The mixture was stirred for 5 min, made acidic with 1 N HCl, and the EtOH removed in vacuuo. The aqueous was extracted with EtOAc. The combined extracts were washed with water, dried over magnesium sulfate and concentrated to a foam (0.35 g, 87%). MS [M+H]+ 252.
Reaction SMILES: [C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:20]([O-])=O)=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>P(OCC)(OCC)(OCC)=O>[C:1]1([N:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:8]2[CH:13]=[CH:12][C:11]3[C:14]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:20][C:10]=3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(N(c2ccccc2)c2ccccc2)cc1
Solvent: CCOP(=O)(OCC)OCC
Product: c1ccc(N(c2ccccc2)c2ccc3c(c2)[nH]c2ccccc23)cc1
Temperature: 160 °C
Reaction time: 8 h
Yield: 87.7 %

Procedure:
1.5 g of 2-(4-diphenylaminophenyl)nitrobenzene and 20 ml of triethyl phosphate were heated and stirred at 160° C. for 8 hours. After triethyl phosphate was distilled off under reduced pressure, 10 ml of methanol was added, followed by filtration. The resulting solid was vacuum-dried to obtain 1.2 g of 2-diphenylaminocarbazole.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:15]1([N:21]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[NH:23][S:22]2(=[O:31])=[O:30])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Br:32][CH2:33][CH2:34]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:32][CH2:33][CH2:34][N:23]1[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[N:21]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[S:22]1(=[O:30])=[O:31]
Reactant: OCCBr
Reactant: O=S1(=O)Nc2ccccc2N1c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S1(=O)N(CCBr)c2ccccc2N1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
Diisopropyl azodicarboxylate (0.47 mL, 2.4 mmol, 1.2 equiv.) was added dropwise to a solution of 1-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide (prepared in an analogous manner as described in general procedure I, 493 mg, 2.00 mmol), 2-bromoethanol (275 mg, 2.20 mmol, 1.1 equiv.) and triphenylphosphine (630 mg, 2.40 mmol, 1.2 equiv.) in dry THF (10 mL) at 0° C. under nitrogen. The solution was stirred overnight while warming to room temperature. Solvent was removed and the oil residue was pre-adsorbed onto Florisil and purified via Isco flash column chromatography (40-g redisep silica gel column, 0-30% ethyl acetate/hexane) to give 706 mg (86%) of 1-(2-bromoethyl)-3-phenyl-1,3-dihydro-2,1,3-benzothiadiazole 2,2-dioxide as a viscous, colorless liquid. HRMS: calculated for C14H13BrN2O2S+Na+, 374.9773; found (ESI, [M+H]+), 374.9780.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)[CH3:2].C(O[CH:16](OCC)[N:17]([CH3:19])[CH3:18])C>>[CH2:1]([O:3][C:4](=[O:12])[C:5]([C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[CH:16][N:17]([CH3:19])[CH3:18])[CH3:2]
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1cccnc1

Procedure:
37.4 g (226 mmol) pyridin-3-ylacetic acid ethyl ester are heated in 100 g (679 mmol) dimethylformamide diethyl acetal overnight at 100° C. After cooling, the mixture is concentrated and the residue is pre-purified by means of flash chromatography on silica gel (mobile phase: gradient cyclohexane/ethyl acetate 1:1→ethyl acetate/ethanol 9:1). The product obtained is subjected to fine purification by vacuum distillation (1 mbar, 200° C. bath temperature).
Reaction SMILES: [CH3:1][NH2:2].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2Cl)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O>[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]2[NH:2][CH3:1])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1cnc2ccc(OCc3ccccc3)cc2c1Cl
Reactant: CN
Solvent: O
Product: CNc1c([N+](=O)[O-])cnc2ccc(OCc3ccccc3)cc12
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
Methylamine (available as a 40% solution in water, 21 mL, 0.25 mol) was added to a suspension of 6-benzyloxy-4-chloro-3-nitroquinoline (13.74 g, 43.65 mmol) in distilled water (300 mL), and the reaction was stirred at 100° C. for 1.5 hours. The reaction was allowed to cool to ambient temperature and stirred for three hours. A precipitate formed, which was isolated by filtration, washed with distilled water (3×), and recrystallized from 2-propanol (44.2 mL/g). The crystals were isolated by filtration and washed with cold hexanes (2×100 mL) to provide 11.36 g of N-(6-benzyloxy-3-nitroquinolin-4-yl)-N-methylamine as orange crystals.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([NH2:9])=[O:8])=[CH:4][C:3]=1[CH3:10].[Cl:11][CH2:12][C:13]([CH2:15]Cl)=O>>[Br:1][C:2]1[S:6][C:5]([C:7]2[O:8][CH:15]=[C:13]([CH2:12][Cl:11])[N:9]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: O=C(CCl)CCl
Reactant: Cc1cc(C(N)=O)sc1Br
Product: Cc1cc(-c2nc(CCl)co2)sc1Br
Yield: 53 %

Procedure:
In substantially the same manner as in Reference Example 47, 5-bromo-4-methyl-2-thiophenecarboxamide was allowed to react with 1,3-dichloroacetone to give 2-(5-bromo-4-methyl-2-thienyl)-4-chloromethyloxazole. The yield was 53%. Recrystallization from ethyl acetate-hexane gave clolorless prisms, mp 71-72° C.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][CH2:34][CH2:35][OH:36].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:29])([F:30])[F:31])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[O:5]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: NCCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: O=C(NCCCO)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 25.7 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-V, 30 mg, 0.070 mmol), 3-aminopropan-1-ol (7.84 mg, 0.104 mmol), 4-methylmorpholine (28.1 mg, 0.278 mmol), and HATU (34.4 mg, 0.090 mmol) were dissolved in DMF (1 mL). The mixture was stirred for 1 h and then purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.4 min) to provide (R/S)-2-hydroxy-N-(3-hydroxypropyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (12 mg, 0.018 mmol, 26.5% yield): LCMS=489.1 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ ppm 8.20 (2 H, d, J=8.35 Hz), 7.50-7.71 (7 H, m), 6.82-6.90 (1 H, m), 5.20 (1 H, s), 3.41-3.62 (4 H, m), 3.34 (3 H, s) HPLC peak RT=9.1 min (Method A).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23].OCCN>>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:17]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: NCCCCCO
Solvent: NCCO
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCCCCO

Procedure:
3-Benzyloxy-2-methyl-4-pyrone, prepared as described under Example 10, is reacted with 1-amino-5-hydroxypentane under substantially similar conditions to those described under Example 11 for reaction with 2-hydroxyethylamine to give 3-benzyloxy-1-(5'-hydroxypentyl)-2-methylpyrid-4-one. This is deprotected using the procedure described under (I) to give 3-hydroxy-1-(5'-hydroxypentyl)-2methylpyrid-4-one as white crystals, m.p. 136°-138° C.; νmax (nujol) 1625, 3350 cm-1 : δ(d6DMSO) 1.3 (m, 6H), 2.40 (s, 3H), 3.25 (t, 2H), 4.20 (t, 2H) 7.20 (d, 1H), 8.15 (d, 1H).
Reaction SMILES: [CH3:1][C:2]([C:5]1[N:10]=[CH:9][N:8]=[C:7](O)[CH:6]=1)([CH3:4])[CH3:3].C(N(CC)CC)C.P(Cl)(Cl)([Cl:21])=O>C(Cl)Cl>[Cl:21][C:7]1[CH:6]=[C:5]([C:2]([CH3:4])([CH3:3])[CH3:1])[N:10]=[CH:9][N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(O)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(Cl)ncn1

Procedure:
6-(1,1-Dimethylethyl)-4-pyrimidinol (Intermediate 9, 1.66 g, 10.91 mmol) was suspended in DCM (10 mL), treated with triethylamine (1.520 mL, 10.91 mmol), followed by phosphorus oxychloride (1.118 mL, 12.00 mmol) dropwise. An exotherm was observed. The resulting mixture was heated under reflux for 3 hours. LCMS indicates no desired product present and starting material remaining. The reaction mixture was allowed to cool to room temperature and evaporated under reduced pressure. The residue was treated with phosphorus oxychloride (5.08 mL, 54.5 mmol) and the resulting mixture was heated under reflux for 30 minutes. The reaction mixture was allowed to cool to room temperature, evaporated under reduced pressure and the residue was poured into 2M aqueous hydrochloric acid solution (10 mL). This solution was extracted with DCM (×2). The DCM layers were combined, dried under magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography (Biotage SP4) eluting with a gradient of 0-20% ethyl acetate and iso-hexane. Product containing fractions were combined and evaporated under reduced pressure to give the title compound as a colourless oil (1.17 g);
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:17][CH:18]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]#[N:25])[CH2:19]1.N.[H][H]>[Ni].CO>[NH2:25][CH2:24][CH2:23][N:20]1[CH2:21][CH2:22][CH:18]([NH:17][C:9]2[N:8]([CH2:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]=2)[CH2:19]1
Reactant: [H][H]
Reactant: N#CCN1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCN1CCC(Nc2nc3ccccc3n2Cc2ccccn2)C1
Yield: 91 %

Procedure:
A mixture of 11 parts of 3-[[1-(2-pyridinylmethyl)-1H-benzimidazol-2-yl]amino]-1-pyrrolidineacetonitrile and 320 parts of methanol, saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in 2,2'-oxybispropane while stirring. The product was filtered off and dried, yielding 10 parts (91%) of N-[1-(2-aminoethyl)-3-pyrrolidinyl]-1-(2-pyridinylmethyl)-1H-benzimidazol-2-amine; mp. 130° C. (compound 138).
Reaction SMILES: [ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[N:14][N:13](O)[C:12]=3[CH:17]=2)[CH:6]=[CH:5][N:4]=[CH:3]1.[H][H]>CO>[ClH:1].[N:2]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]3[NH:15][N:14]=[N:13][C:12]=3[CH:17]=2)[CH:6]=[CH:5][N:4]=[CH:3]1
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Reactant: [H][H]
Agent: Cl
Solvent: CO
Product: c1cn(Cc2ccc3[nH]nnc3c2)cn1
Yield: 72 %

Procedure:
A mixture of 4.3 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol monohydrochloride and 120 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of platinium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized twice from ethanol. The product was filtered off and dried, yielding 2.9 parts (72%) of 5-(1H-imidazol-1-ylmethyl)-1H-benzotriazole monohydrochloride; mp. 230.4° C. (compound 234).