Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>C(Cl)Cl>[F:23][C:24]([F:34])([F:35])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([N:4]1[CH2:5][CH2:6][CH2:7][N:1]([CH2:8][C:9]2[NH:20][C:19]3[C:21]4[C:15]([C:16](=[O:22])[NH:17][N:18]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:10]=2)[CH2:2][CH2:3]1)=[O:28]
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: O=c1[nH]nc2c3c(cccc13)N=C(CN1CCCNCC1)N2
Solvent: ClCCl
Product: O=C(c1ccccc1C(F)(F)F)N1CCCN(CC2=Nc3cccc4c(=O)[nH]nc(c34)N2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Synthesized from compound 26. To a solution of compound 26 (0.2 g, 0.6 mmol) in 5 mL of CH2Cl2 was added 1 mmol of TEA and 0.8 mmol of 2-trifluoromethyl-benzoyl chloride. The reaction was stirred overnight at room temperature. After the solvents were evaporated, the residue was purified with semi-preparative HPLC to afford a solid (15% yield). MP: 140-142° C.; MS (ES−): 469; 1H NMR (400 MHz, CDCl3): 1.92-2.10 (m, 2H), 2.91-3.10 (m, 4H), 3.36-3.44 (m, 2H), 3.64-3.74 (m, 2H), 3.93 (m, 2H), 7.38 (m, 1H), 7.57 (m, 3H), 7.79 (m, 2H), 7.93 (m, 1H). Anal. Calcd. for C23H21F3N6O2.0.9HCl: C, 54.89; H, 4.39; N, 16.70; Found: C, 54.93; H, 4.43; N, 16.34.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:14])=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2.[OH-].[K+].CO.Cl[CH2:20][CH:21]([CH3:35])[CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][CH2:24]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([O:14][CH2:20][CH:21]([CH3:35])[CH2:22][N:23]2[CH2:24][CH2:25][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:27][CH2:28]2)=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[NH:8][C:7](=[O:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2c(O)c(Cl)cc(Cl)c2N1
Reactant: CC(CCl)CN1CCC(c2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(COc1c(Cl)cc(Cl)c2c1CCC(=O)N2)CN1CCC(c2ccccc2)CC1
Yield: 35 %

Procedure:
2.4 Grams of 6,8-dichloro-5-hydroxy-3,4-dihydrocarbostyril and 0.8 g of granular potassium hydroxide were mixed with 60 ml of methanol and concentrated under a reduced pressure to dryness. To the residue thus obtained was added 60 ml of dimethylformamide and mixed well, then 5 g of 1-chloro-2-methyl-3-(4-phenylpiperidyl)propane and heated at 70°-80° C. for 8 hours under stirring condition. The reaction mixture was concentrated under a reduced pressure to dryness, then 60 ml of 5% sodium hydrogencarbonate aqueous solution was added thereto and extracted with chloroform. The chloroform layer was washed with water and dried, then the chloroform was removed by distillation and thus obtained residue was purified by silica-gel column chromatography and recrystallized from ligroin to obtain 1.6 g (yield: 35%) of 6,8-dichloro-5-[2-methyl-3-(4-phenyl-1-piperidyl)propoxy]-3,4-dihydrocarbostyril as in the form of colorless needle-like crystals. Melting point 125°-126° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O>C(O)CCCCC>[OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:9][CH2:10][CH2:2][CH2:3][CH2:7][CH3:8])=[O:5]
Reactant: O=C(O)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Solvent: CCCCCCO
Product: CCCCCCOC(=O)c1ccc(O)cc1O
Temperature: 60 °C

Procedure:
2,4-Dihydroxybenzoic acid (5 g) is added to 20 mL of n-hexanol. Concentrated sulfuric acid (5 mL) is added dropwise. The reaction mixture is heated at 60° C. for 6 days. Hexanol is removed under reduced pressure. The residue is recrystallized from methanol/water mixture. The crystals are collected, washed with cold methanol and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][N:3]=1.[OH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][N:13]2[CH2:14][CH2:15][C@@H:11]([OH:10])[CH2:12]2)=[CH:6][CH:7]=1
Reactant: ClCc1ccc(Cl)nc1
Reactant: O[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@@H]1CCN(Cc2ccc(Cl)nc2)C1
Temperature: 80 °C
Yield: 76.9 %

Procedure:
To a solution of 2-chloro-5-(chloromethyl)pyridine (1.0 g, 6.3 mmole) in 10 mL of dry acetonitrile is added 1.05 mL (12.6 mmol) of (R)-3-hydroxy-pyrrolidine followed by 858 mg (6.2 mmol) of potassium carbonate. The reaction is heated at 80° C. for 2 h. After cooling, the reaction mixture is quenched with 20 mL of water, extracted three-times with methylene chloride, and dried over sodium sulfate. Concentration of the solvent provided an oil which was purified by silica gel chromatography to provide 1.03 g (77% yield) of (R)-1-(6-Chloro-pyridin-3-ylmethyl)-pyrrolidin-3-ol. Diagnostic C13 NMR (100 MHz, CDCl3) 35.1, 52.5, 56.7, 63.0, 71.4, 124.2, 133.4, 139.6, 149.9, 150.4; MS 213.2 (M+H).
Reaction SMILES: Cl.C(C1C=C2C(=CC=1)[CH:15]=[C:14]([C:19](N)=[NH:20])[CH:13]=C2)CCCCCC.Cl.[CH2:23]([O:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C:39]([NH2:41])=[NH:40])[CH:33]=[CH:32]2)[CH2:24][CH2:25][CH2:26][CH3:27]>>[CH2:23]([O:28][C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]3[N:41]=[CH:15][C:14]([C:19]#[N:20])=[CH:13][N:40]=3)[CH:35]=2)[CH:30]=1)[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCc1ccc2cc(C(=N)N)ccc2c1
Reactant: CCCCCOc1ccc2cc(C(=N)N)ccc2c1
Agent: Cl
Product: CCCCCOc1ccc2cc(-c3ncc(C#N)cn3)ccc2c1

Procedure:
Operations were carried out as in Example 9 except that 6-heptyl-2-naphthalenecarboxamidine hydrochloride as a raw material was replaced by 6-pentyloxy-2-naphthalenecarboxamidine hydrochloride to produce 2-pentyloxy-6-(5-cyano-2-pyrimidinyl)naphthalene. This product exhibited a liquid crystalline phase, and its crystalline-nematic phase transition point (C-N point) was 134.8°-135.5° C. and its N-I point was 190.9°-191.1° C.
Reaction SMILES: [C:1]([NH:4][C@@H:5]1[C@@H:10]([NH:11][C:12]([NH:21]C(OC(C)(C)C)=O)=[N:13]C(OC(C)(C)C)=O)[CH2:9][C:8]([P:29]([O:34]CC)(=[O:33])[O:30][CH2:31][CH3:32])=[CH:7][C@H:6]1[O:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])(=[O:3])[CH3:2].C([O-])(=O)C.[Na+]>C(O)C>[NH4+:4].[C:1]([NH:4][C@@H:5]1[C@@H:10]([NH:11][C:12]([NH2:21])=[NH:13])[CH2:9][C:8]([P:29]([O:30][CH2:31][CH3:32])(=[O:33])[O-:34])=[CH:7][C@H:6]1[O:37][CH:38]([CH2:41][CH3:42])[CH2:39][CH3:40])(=[O:3])[CH3:2]
Reactant: CCOP(=O)(OCC)C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](NC(=NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOP(=O)([O-])C1=C[C@@H](OC(CC)CC)[C@H](NC(C)=O)[C@@H](NC(=N)N)C1
Product: [NH4+]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of diethyl ester 12b (2.73 g, 4 mmol) in ethanol (60 mL) was treated with sodium ethanoate in ethanol (6 mmol, 6 mL of 1 M solution) under a nitrogen atmosphere. The mixture was stirred for 18 h at room temperature, and then acidified with Amberlite IR-120 (H+-form). The heterogeneous solution was stirred at 40° C. for 3 h, filtered and concentrated in vacuo. The residual oil was taken up in water (15 mL) and subjected to lyophilization. The residual colorless solids were washed with cold acetone (20 mL×3), dissolved in aqueous NH4HCO3 (15 mL of 0.1 M solution), stirred for 1 h at room temperature, and then lyophilization to afford ammonium salt 13c of Tamiphosphor guanidine monoester (1.22 g, 75%) as white solids.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[C:10]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=1[CH:12]=[O:13].[OH-].[Na+]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:11]=2[CH:12]=[O:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=Cc1cc([N+](=O)[O-])ccc1Oc1ccc(F)cc1
Temperature: 25 °C

Procedure:
448 G. of 4-fluoro-phenol and 742 g. of 2-chloro-5-nitro-benzaldehyde are added to a solution of 184 g. of sodium hydroxide in 7.4 liters of water. The mixture is then left to cool to room temperature. The precipitate is removed by filtration, washed carefully with water, and there is obtained 2-(4-fluoro-phenoxy)-5-nitro-benzaldehyde, having a melting point of 125°-126° C.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:9][CH2:10]Cl)[CH2:6][CH2:7]Cl.[CH2:12]([O:14][CH2:15][CH2:16][OH:17])[CH3:13]>>[CH2:4]([N:5]([CH2:9][CH2:10][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13])[CH2:6][CH2:7][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13])[CH2:3][O:17][CH2:16][CH2:15][O:14][CH2:12][CH3:13]
Reactant: ClCCN(CCCl)CCCl
Reactant: CCOCCO
Agent: Cl
Product: CCOCCOCCN(CCOCCOCC)CCOCCOCC
Yield: 68 %

Procedure:
51.6 g (i.e., 0.215 mol) of tris-(2-chloroethyl)-amine hydrochloride were added to the above mixture (a). The mixture was subsequently heated at the reflux temperature of the 2-ethoxyethanol for 12 hours and the solvent was then distilled under reduced pressure. The excess sodium 2-ethoxyethanolate was neutralized by adding 12 cm3 of aqueous HCl (10 N) thereto. The sodium chloride was filtered off and the solution was distilled. The tris-(3,6-dioxaoctyl)-amine distilled between 200° C. and 210° C. under a pressure of 1 mm Hg. The yield was 68%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[C:10]1[N:11]([CH2:24][CH2:25][OH:26])[CH:12]=[C:13]([C:15]2[N:16]([CH:21]([CH3:23])[CH3:22])[N:17]=[C:18]([CH3:20])[N:19]=2)[N:14]=1.[H-].[Na+].O>CN(C=O)C>[CH:21]([N:16]1[C:15]([C:13]2[N:14]=[C:10]3[N:11]([CH2:24][CH2:25][O:26][C:2]4[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=43)[CH:12]=2)=[N:19][C:18]([CH3:20])=[N:17]1)([CH3:23])[CH3:22]
Reactant: COc1cc(Cl)c(-c2nc(-c3nc(C)nn3C(C)C)cn2CCO)cn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cn1)-c1nc(-c3nc(C)nn3C(C)C)cn1CCO2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.2 %

Procedure:
A solution of 2-[2-(4-chloro-6-methoxy-pyridin-3-yl)-4-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-imidazol-1-yl]-ethanol (2.25 g, 5.97 mmol) in DMF (30 mL) was cooled to 0° C. and treated with sodium hydride (239 mg, 5.97 mmol), the reaction mixture stirred at 0° C. for 30 min then allowed to warm to RT and stirred for 2 h. The reaction mixture was re-cooled to 0° C. and treated with water (400 mL), the precipitated product filtered off and washed with water then dried in vacuo to give the title compound as a white solid (1.02 g, 50%). LCMS RT=2.68 min, [M+H]+=341. 1H NMR 400 MHz (DMSO-d) δ: 9.15 (1 H, s), 7.87 (1 H, s), 6.42 (1 H, s), 5.84 (1 H, m), 4.57-4.56 (4 H, m), 3.89 (3 H, s), 2.25 (3 H, s), 1.46 (6 H, d, J=6.60 Hz).
Reaction SMILES: I.[F:2][C:3]1[CH:8]=[C:7]([N:9]2[CH:13]=[N:12][C:11]([CH3:14])=[N:10]2)[C:6]([O:15][CH3:16])=[CH:5][C:4]=1[NH:17][C:18](SC)=[NH:19].[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)[C:28](O)=O.[NH2:38][NH2:39]>>[Cl:22][CH2:23][CH2:24][CH2:25][CH2:26][CH:27]([C:28]1[NH:39][N:38]=[C:18]([NH:17][C:4]2[CH:5]=[C:6]([O:15][CH3:16])[C:7]([N:9]3[CH:13]=[N:12][C:11]([CH3:14])=[N:10]3)=[CH:8][C:3]=2[F:2])[N:19]=1)[C:31]1[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=1
Reactant: NN
Reactant: O=C(O)C(CCCCCl)c1ccc(F)cc1
Reactant: COc1cc(NC(=N)SC)c(F)cc1-n1cnc(C)n1
Agent: I
Product: COc1cc(Nc2n[nH]c(C(CCCCCl)c3ccc(F)cc3)n2)c(F)cc1-n1cnc(C)n1
Yield: 12.2 %

Procedure:
Methyl 2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (0.485 g, 1.642 mmol, from preparation B) and 6-chloro-2-(4-fluorophenyl)hexanoic acid (0.442 g, 1.806 mmol, from preparation AE) were coupled and then reacted with hydrazine (0.206 mL, 6.56 mmol) using a procedure analogous to Step A of Example 13. The crude products were purified using silica gel chromatography (0-95% ethyl acetate/chloroform) to afford 5-(5-chloro-1-(4-fluorophenyl)pentyl)-N-(2-fluoro-5-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine (97 mg, 0.20 mmol, 12% yield). LC-MS (M+H)+ 488.2.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[C:9]([CH3:11])[N:10]=1)=[O:5])C.[OH-].[Na+]>O.C1COCC1>[CH3:11][C:9]1[N:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1nc(C)c(-c2cccc3ccccc23)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(C(=O)O)sc1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-methyl-5-naphthalen-1-yl-thiazole-2-carboxylic acid ethyl ester (30 mg, 0.10 mmol) in water (1 ml) and THF (1 ml) is added sodium hydroxide (0.2 mL, 1M, 0.20 mmol). The reaction mixture is stirred at rt for 1 hr, and then extracted with ethyl ether (30 mL). The aqueous layer is acidified to pH<7.0 by phosphate buffer and then extracted with EtOAc (2×50 mL). The combined organic layers are washed with brine, dried over MgSO4, and then concentrated. The crude product is used in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([OH:24])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13].[CH2:26](OCC)C.[N+](=C)=[N-].C(OC(C)C)(C)C>C(OCC)(=O)C.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:23]=[C:22]([O:24][CH3:26])[C:21]([F:25])=[CH:20][C:11]=1[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:13]
Reactant: CCOCC
Reactant: CCOC(=O)CC(=O)c1cc(F)c(O)nc1Nc1ccc(F)cc1F
Agent: C=[N+]=[N-]
Solvent: CC(C)OC(C)C
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)c1cc(F)c(OC)nc1Nc1ccc(F)cc1F
Yield: 77 %

Procedure:
In 2 ml of ethyl acetate was dissolved 100 mg of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-hydroxynicotinoyl]acetate, and a diethyl ether solution containing 15 mg of diazomethane was added thereto with ice-cooling, after which the resulting mixture was subjected to reaction at room temperature for 30 minutes. Subsequently, acetic acid was added to the reaction mixture until foaming was not caused in the reaction mixture. The solvent was then removed by distillation under reduced pressure and to the crystalline material thus obtained was added 2 ml of diisopropyl ether, after which crystals were collected by filtration to obtain 80 mg (yield 77.0%) of ethyl 2-[2-(2,4-difluorophenylamino)-5-fluoro-6-methoxynicotinoyl]acetate. The physical properties of this compound were identical with those of the compound obtained in Example 18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.Cl.[N:19]1([CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[CH:29][CH:28]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1.[CH3:36][OH:37]>C(Cl)Cl>[C:31]([OH:33])(=[O:32])[C:36]([OH:2])=[O:37].[C:31]([OH:33])(=[O:32])[C:36]([OH:2])=[O:37].[N:19]1([CH2:24][CH2:25][CH2:1][O:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[S:13][C:12]4[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=4[C:10]=3[C:31]([C:30]3[CH:29]=[CH:28][C:27]([O:26][CH2:25][CH2:24][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[CH:35][CH:34]=3)=[O:33])=[CH:5][CH:4]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1ccc(-c2cc3ccccc3s2)cc1
Reactant: CO
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: O=C(O)C(=O)O
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(OCCCN3CCCC3)cc2)sc2ccccc12
Yield: 59 %

Procedure:
By essentially following the procedure detailed in Example 1, Part C, the title compound was prepared from 2-(4-methoxyphenyl)benzo[b]thiophene (Example 3, Part A) and 4-[2-(1-pyrrolidinyl)ethoxy]benzoic acid hydrochloride in 59% yield as an oil following radial chromatography (SiO2; gradient of 2-5% MeOH in CH2Cl2).
Reaction SMILES: [OH:1][C:2]1(S)[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=[CH:4][NH:3]1.ClCC(O)=[O:17].[OH-].[Na+]>O>[OH:17][C:4]1[N:3]=[C:2]([OH:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][O:11][CH3:12])[N:5]=1
Reactant: COCCCC1=CC(O)(S)NC=N1
Reactant: O=C(O)CCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCCc1cc(O)nc(O)n1
Temperature: 120 °C
Yield: 52.9 %

Procedure:
A suspension of 4-hydroxy-4-mercapto-6-(3-methoxypropyl)pyrimidine (Method 84) (3.9 g, 19.5 mmol) and chloroacetic acid (1.89 g, 19.9 mmol) in water (20 ml) was heated at 120° C. for 24 hours. The mixture was allowed to cool, adjusted to pH7 with sodium hydroxide solution and extracted with EtOAc. The extracts were combined, dried (Na2SO4) and the solvent removed by evaporation to give the title compound (1.9 g, 55%) as a solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[CH2:25]Br>C1(C)C=CC=CC=1>[CH2:1]([N:8]1[CH2:25][C:19]2[C:18](=[CH:23][CH:22]=[C:21]([F:24])[CH:20]=2)[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)c(CBr)c1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Fc1ccc2c(c1)CN(Cc1ccccc1)C2

Procedure:
A solution of benzylamine (64.3 ml) and triethylamine (164 ml) in toluene (1 L) was added to 1,2-bis(bromomethyl)-4-fluorobenzene (164.1 g) (J. Org. Chem., 1988, 53, 1775-9). This mixture was heated to reflux for 4 h under argon. The reaction mixture was then filtered and the solid was washed with toluene (3×150 ml). The filtrate was evaporated in vacuo and the residue dissolved in dichloromethane (1 L). This solution was washed successively with a saturated solution of potassium carbonate (1 L) and water (0.5 L). The organic extract was dried (MgSO4), concentrated to a volume of 0.5 L and cooled in ice. The unwanted precipitate was filtered off and the filtrate evaporated to a residue which was purified by chromatography over silica gel eluting with a gradient of dichloromethane/ethyl acetate to give the title compound (D7) as an oil (49.3 g). MS electrospray (+ion) 228 (MH+). 1H NMR δ (CDCl3): 7.24-7.42 (5H, m), 7.07-7.12 (1H, m), 6.82-6.89 (2H, m), 3.89 (6H, br, s).
Reaction SMILES: [CH2:1]([C@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]1[C@H:41]2[C@H:37]([O:38][CH2:39][CH2:40]2)[O:36][CH2:35]1)[C@H:9]([OH:30])[CH2:10][N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pd]>[NH2:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([N:11]([O:24][CH:25]([CH2:28][CH3:29])[CH2:26][CH3:27])[CH2:10][C@@H:9]([OH:30])[C@@H:8]([NH:31][C:32](=[O:42])[O:33][C@@H:34]2[C@H:41]3[C@H:37]([O:38][CH2:39][CH2:40]3)[O:36][CH2:35]2)[CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCC(CC)ON(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Reaction time: 16 h
Yield: 71 %

Procedure:
A solution of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-1-benzyl-3-{(1-ethylpropoxy)[(4-nitrophenyl)sulfonyl]amino}-2-hydroxypropylcarbamate (237 mg, 0.390 mmol) in absolute methanol (5 mL) was combined with Palladium on carbon (10 wt %, 50 mg) and reduced under a Hydrogen atmosphere over 16 hours. The reaction was filtered and evaporated in vacuo. The residue was purified on silica gel eluting with 50-60% ethyl acetate in hexane. Fractions containing the product were combined and evaporated in vacuo. The residue was triturated with water, filtered and dried under high vacuum to provide (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](1-ethylpropoxy)amino]-1-benzyl-2-hydroxypropylcarbamate (160 mg, 71%) as a white solid. H1-NMR (chloroform-D3): 0.90 (m, 6H), 1.58 (m, 7H), 2.95 (m, 5H), 3.69 (m, 2H), 3.91 (m, 4H), 4.13 (m, 1H), 4.26 (b, 2H), 4.80 (d, 1H), 5.00 (m, 1H), 5.63 (d, 1H), 6.67 (d, 2H), 7.22 (m, 5H), 7.58 (d, 2H). ). MS(ESI): 600(M+Na).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:32]=[CH:31][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28](O)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH2:66][CH2:67][CH2:68][CH2:69][OH:70]>CN(C=O)C.O>[OH:70][CH2:69][CH2:68][CH2:67][NH:66][C:28]([C:25]1[CH:24]=[C:23]([C:19]2[CH:18]=[C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=4)=[O:10])=[CH:32][CH:31]=3)[CH:22]=[CH:21][N:20]=2)[NH:27][CH:26]=1)=[O:29]
Reactant: NCCCO
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)O)c[nH]4)c3)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCO)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxylic acid (1.00 g, 2.34 mmol) in 20 ml of anhydrous DMF were added HATU (1.07 g, 2.80 mmol) and N,N-diisopropylethylamine (604 mg, 4.68 mmol). The mixture was stirred at room temperature for 10 minutes, followed by addition of 3-amino-1-propanol (263 mg, 3.51 mmol). The mixture was stirred for another 5 minutes and poured into 200 ml of water with vigorous stirring. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-hydroxypropyl)-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as white solid. Yield: 1.10 g, 97%.
Reaction SMILES: COC[O:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][C:22]4[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=4)=[N:18][C:17]=3[NH2:34])[O:13][N:12]=2)[CH:8]=[CH:9][CH:10]=1.FC(F)(F)C(O)=O.C1(C)C=CC=CC=1>O1CCOCC1>[NH2:34][C:17]1[N:18]=[C:19]([NH:21][C:22]2[CH:27]=[C:26]([O:28][CH3:29])[C:25]([O:30][CH3:31])=[C:24]([O:32][CH3:33])[CH:23]=2)[S:20][C:16]=1[C:14]1[O:13][N:12]=[C:11]([C:7]2[CH:6]=[C:5]([OH:4])[CH:10]=[CH:9][CH:8]=2)[N:15]=1
Reactant: COCOc1cccc(-c2noc(-c3sc(Nc4cc(OC)c(OC)c(OC)c4)nc3N)n2)c1
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: COc1cc(Nc2nc(N)c(-c3nc(-c4cccc(O)c4)no3)s2)cc(OC)c1OC
Temperature: 15 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
To a solution of 200 mg (0.412 mmol) of 5-[3-(3-methoxymethoxy-phenyl)-[1,2,4]oxadiazol-5-yl]-N2-(3,4,5-trimethoxy-phenyl)-thiazole-2,4-diamine (prepared in Example B(4)) in 8 mL of 50% aqueous dioxane was added trifluoroacetic acid (8 mL) with water bath cooling at 15° C. After 2 hours at room temperature, toluene was added, and the solution was concentrated in vacuo with the water bath at 22° C. With five milliliters of solvent left, the solution was poured into cold aqueous sodium bicarbonate. This solution was extracted with two portions of dichloromethane, which was subsequently washed with brine and dried over sodium sulfate. Radial silica chromatography eluting with 5-10% methanol/dichloromethane gave 3-{5-[4-amino-2-(3,4,5-trimethoxy-phenylamino)-thiazol-5-yl]-[1,2,4]oxadiazol-3-yl}-phenol (60 mg) as a pale-yellow solid.
Reaction SMILES: [OH:1][CH:2]([CH3:5])[CH:3]=[CH2:4].I[C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1.CCN(CC)CC>CC#N.CCOCC.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:1]=[C:2]([CH3:5])[CH2:3][CH2:4][C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C=CC(C)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(CCC(C)=O)cc1

Procedure:
3-Hydroxy-1-butene (Aldrich) (2.15 mL, 25 mmol), ethyl 4-iodobenzoate (5.52 g, 20 mmol), Et3N (3.5 mL, 25 mmol) and Pd(OAc)2 (19 mg, 0.08 mmol) were combined in 6 mL CH3CN, sealed in a glass pressure tube and heated at 100° for 3 h. The mixture was cooled, diluted with Et2O, washed with water, 1N NaOH, 5% KHSO4, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 10% EtOAc/hexanes) provided 21-1 as a white crystalline solid.