Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH:6]1[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]([CH3:22])([CH3:21])[CH2:7]1)=[O:4].[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=2[CH3:44])[N:34]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([OH:51])=[CH:47][C:46]=2[OH:52])[N:32]=1>>[CH3:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[C:31]1[N:36]=[C:35]([C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][C:38]=2[CH3:44])[N:34]=[C:33]([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH2:2][C:3]([O:5][CH:6]3[CH2:11][C:10]([CH3:13])([CH3:12])[N:9]([O:14][CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:8]([CH3:22])([CH3:21])[CH2:7]3)=[O:4])=[CH:47][C:46]=2[OH:52])[N:32]=1
Reactant: CC1(C)CC(OC(=O)CCl)CC(C)(C)N1OC1CCCCC1
Reactant: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(O)cc3O)n2)c(C)c1
Product: Cc1ccc(-c2nc(-c3ccc(C)cc3C)nc(-c3ccc(OCC(=O)OC4CC(C)(C)N(OC5CCCCC5)C(C)(C)C4)cc3O)n2)c(C)c1
Yield: 54 %

Procedure:
The title compound, a yellow solid with mp 105°-109° C., is prepared in 54% yield from 1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl chloroacetate and 2,4-bis(2,4-dimethylphenyl)-6-(2,4-dihydroxyphenyl)-s-triazine according to the procedure of Example 8B.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=O)[O:17]C.Cl>O1CCCC1>[CH3:14][O:15][C:16](=[O:17])[NH:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[N:3]=1
Reactant: COC(=O)OC
Reactant: COc1nc(N)nc(OC)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)Nc1nc(OC)nc(OC)n1
Reaction time: 1.25 h
Yield: 57.9 %

Procedure:
2-Amino-4,6-dimethoxy-1,3,5-triazine (55.3 g) was added portionwise to 50% sodium hydride (38.0 g) in 1000 ml dry tetrahydrofuran at ambient temperature under nitrogen. After the reaction mixture was stirred for 1.25 hours, dimethylcarbonate (50.0 g) was added dropwise. The reaction mixture was stirred 16 hours at ambient temperature under nitrogen and concentrated hydrochloric acid (68 ml) was slowly added followed by 100 ml tetrahydrofuran. Insoluble material was removed via filtration and discarded. The filtrate was dried and the solvent removed under reduced pressure to give a solid which upon crystallization from ethanol afforded 43.9 g of the title compound, m.p. 118°-122° C.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:48])/[CH:7]=[CH:8]/[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]([O:38][Si](C(C)(C)C)(C)C)[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([CH3:46])[CH:26]=3)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:47])=[CH:12][CH:13]=1)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.S(=O)(=O)(O)[O-].[K+]>CO.O1CCCC1.C(OCC)(=O)C>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[O:10][C:9](/[CH:8]=[CH:7]/[C:6]([OH:48])=[O:5])=[CH:13][CH:12]=2)=[C:15]([CH3:47])[CH:16]=1)([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]([OH:38])[C:34]([CH3:36])([CH3:37])[CH3:35])=[C:27]([CH3:46])[CH:26]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: CCOC(=O)/C=C/c1ccc(-c2ccc(C(CC)(CC)c3ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c3)cc2C)o1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(/C=C/C(=O)O)o2)c(C)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
A 1 N potassium hydroxide aqueous solution (2 mL) was added to a solution of (E)-3-{5-[4-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2-methyl-phenyl]-furan-2-yl}-acrylic acid ethyl ester (Example 5-(1); 42 mg, 0.065 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) at room temperature, and the mixture was stirred at 60° C. for two hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and a saturated aqueous potassium bisulfate solution were added to the residue. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (0.2 mL). A 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2 mL, 2 mmol) was added at room temperature, and the mixture was stirred at 65° C. for one hour. A potassium bisulfate aqueous solution and ethyl acetate were added to the reaction mixture to separate the layers. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/2) to give the title compound (21.2 mg, 65%).
Reaction SMILES: BrCCCC=C.Cl[CH2:8][CH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16].ClCCCC(O)CCCC=C.ClCCCC(OC(=O)C)CCCC=C.C(OC([CH:50]([C:65](=[O:67])[CH3:66])[CH2:51][CH2:52][CH2:53][C:54]1[CH:64]=[CH:63][C:57]([C:58]([O:60]CC)=[O:59])=[CH:56][CH:55]=1)=O)(C)(C)C.C(C(C(OC(C)(C)C)=O)(CCCC(OC(=O)C)CCCC=C)CCCC1C=CC(C(OCC)=O)=CC=1)(=O)C.C(C(CCCC(OC(=O)C)CCCC=C)CCCC1C=CC(C(OCC)=O)=CC=1)(=O)C>>[C:65]([CH:50]([CH2:8][CH2:9][CH2:10][CH:11]([OH:17])[CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:51][CH2:52][CH2:53][C:54]1[CH:64]=[CH:63][C:57]([C:58]([OH:60])=[O:59])=[CH:56][CH:55]=1)(=[O:67])[CH3:66]
Reactant: CCOC(=O)c1ccc(CCCC(C(C)=O)C(=O)OC(C)(C)C)cc1
Reactant: C=CCCCC(=O)CCCCl
Agent: C=CCCCBr
Agent: C=CCCCC(CCCC(CCCc1ccc(C(=O)OCC)cc1)(C(C)=O)C(=O)OC(C)(C)C)OC(C)=O
Agent: C=CCCCC(CCCC(CCCc1ccc(C(=O)OCC)cc1)C(C)=O)OC(C)=O
Product: C=CCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O

Procedure:
The synthesis of this compound is carried out as described in Example 1, except that in Step B(1) an equivalent amount of 5-bromo-1-pentene is used in place of amyl bromide. The product of Step B(1) thus becomes 1-chloro-8-nonen-4-one. Subsequent steps afford in order: Step B(2), 1-chloro-8-nonen-4-ol; Step B(3), 1-chloro-4-acetoxy-8-nonene; Step C, ethyl 4-(4-tert-butoxycarbonyl-5-oxohexyl)benzoate (unchanged from Example 1); Step D, ethyl 4-(4-acetyl-4-tert-butoxycarbonyl-8-acetoxytridec-12-en-1-yl)benzoate (by substituting 1-chloro-4-acetoxy-8-nonene for 1-chloro-4-acetoxynonane); Step E, ethyl 4-(4-acetyl-8-acetoxytridec-12-en-1-yl)benzoate; and Step F, 4-(4-acetyl-8-hydroxytridec-12-en-1-yl)benzoic acid, obtained as a viscous yellowish oil.
Reaction SMILES: [ClH:1].Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]([C:15]2[CH:27]=[CH:26][C:25]3[C:24]4[C:19](=[CH:20][C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]5[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]5)=[O:29])=[CH:22][CH:23]=4)[C:18](=[O:40])[C:17]=3[CH:16]=2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[BH4-].[Na+]>O>[OH2:12].[ClH:1].[ClH:1].[OH:40][CH:18]1[C:19]2[CH:20]=[C:21]([C:28]([O:30][CH2:31][CH2:32][CH2:33][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:29])[CH:22]=[CH:23][C:24]=2[C:25]2[C:17]1=[CH:16][C:15]([C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)=[O:14])=[CH:27][CH:26]=2
Reactant: O=C(OCCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN3CCCCC3)ccc1-2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C(OCCCN1CCCCC1)c1ccc2c(c1)C(O)c1cc(C(=O)OCCCN3CCCCC3)ccc1-2

Procedure:
A solution of 10.3 g (0.020 mole) of bis(3-piperidinopropyl)-9-oxofluorene-2,7-dicarboxylate dihydrochloride in 350 ml of warm water is cooled to room temperature and added to 3 g (0.079 mole) of NaBH4 in 15 ml of water with swirling. The resulting product is extracted 5 times with ether, and the combined ether extracts are washed with water, then with NaCl solution, and dried over anhydrous MgSO4. The mixture is filtered, the filtrate treated with ethereal HCl and most of the solvent distilled off. The residue is dissolved in 50 ml of hot ethanol, filtered through filter aid and the filtrate refrigerated. The crystallized solid is filtered off and is recrystallized twice from ethanol to give bis(3-piperidinopropyl) 9-hydroxyfluorene-2,7-dicarboxylate dihydrochloride hydrate.
Reaction SMILES: P(O)(O)(O)=O.[CH3:6][C:7]1[C:12]([OH:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][CH:17]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:18][CH2:19][CH2:20][CH3:21])[N:8]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>>[CH3:14][C:11]1[C:12]([O:13][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:7]([CH3:6])[N:8]=[C:9]([NH:15][CH2:16][CH:17]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:18][CH2:19][CH2:20][CH3:21])[N:10]=1
Reactant: CCOC(=O)Cl
Reactant: CCCCC(CNc1nc(C)c(O)c(C)n1)c1ccccc1
Agent: O=P(O)(O)O
Solvent: CCN(CC)CC
Product: CCCCC(CNc1nc(C)c(OC(=O)OCC)c(C)n1)c1ccccc1

Procedure:
In a manner similar to that of Example 1, the title compound was prepared from 4.71 g (12 mmol) of 4,6-dimethyl-5-hydroxy-2-phenylhexylaminopyrimidine phosphate salt, triethylamine (16.52 ml, 120 mmol) and ethyl chloroformate (1.7 ml, 18 mmol) to afford 3.8 g of product, mp: 44°-45° C. Mass spectrum m/e=371. NMR (CDCl3) delta: 7.34-7.16 (m, 5H): 5.00 (bs, 1H); 4.36 (q, 6, 3 Hz, 2H): 3.40 (q, 6, 3 Hz, 2H): 2.65, (t, 3 Hz, 2H); 1.74-1.36) (m, 11H). IR (CHCl3): 1761, 1583 cm-1. Anal. Calc'd for C21H29N3O3 : C, 67.90 H, 7.87; N, 11.31. Found: C, 67.95; H, 7.85; N, 11.14.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>[Cu].[Cu]I.CN(C=O)C>[N:15]1([C:2]2[S:10][C:9]3[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=3[CH:3]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CN1c2cc(-n3ccnc3)sc2C(=O)NC1(C)C
Temperature: 140 °C
Reaction time: 4 h
Yield: 42.7 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), imidazole (68.1 mg, 1.00 mmol), copper (powder) (6.35 mg, 0.10 mmol) and water (2 mL) was refluxed for 1 h. The mixture was concentrated under reduced pressure. DMF (2 mL), cesium carbonate (326 mg, 1.00 mmol), imidazole (408 mg, 6.00 mmol) and copper(I) iodide (19.1 mg, 0.10 mmol) were added to the residue, and the mixture was purged with argon. Then, the mixture was stirred at 140° C. for 4 h. Then, the mixture was poured into saturated aqueous NaHCO3 (100 mL) and extracted with EtOAc/THF (2:1, 100 mL×2), and the extract was dried over MgSO4, filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (silica gel, EtOAc to 80:20 EtOAc/MeOH) to give a solid (56 mg). The solid was triturated with EtOAc/hexane, collected by filtration and washed with water to afford the title compound (10.4 mg, 7.9%) as a pale yellow solid:
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][CH2:4][C:5](=O)[CH3:6].[CH2:9]([NH2:15])[CH2:10][O:11][CH2:12][CH2:13][OH:14]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][N:15]1[C:2]([CH3:1])=[CH:3][CH:4]=[C:5]1[CH3:6]
Reactant: NCCOCCO
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)n1CCOCCO
Yield: 90.2 %

Procedure:
A solution of 0.95 moles of 2,5-hexanedione, 0.95 mole of diglycolamine, and 1.4 g of p-toluenesulfonic acid in 400 ml of toluene was refluxed in a flask fitted with a Dean-Stark trap. After removal of the required amount of water, distillation yielded 157 g of N-(hydroxyethoxyethyl)-2,5-dimethylpyrrole with b.p.=110° C. at 13 mm.
Reaction SMILES: C[Si](C)(C)[O:3][CH2:4][CH2:5][O:6][Si](C)(C)C.[CH3:13][C:14]([CH3:23])([CH2:19][N+:20]([O-:22])=[O:21])[CH2:15][C:16](=O)[CH3:17]>ClCCl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[CH3:13][C:14]([CH3:23])([CH2:19][N+:20]([O-:22])=[O:21])[CH2:15][C:16]1([CH3:17])[O:6][CH2:5][CH2:4][O:3]1
Reactant: CC(=O)CC(C)(C)C[N+](=O)[O-]
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C[N+](=O)[O-])CC1(C)OCCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.2 %

Procedure:
A stirred solution of 1,2-bis(trimethylsilyloxy)ethane (26.5 g, 128 mmol) in dichloromethane (50 mL) was cooled in a dry ice/isopropanol bath, and trimethylsilyl trifluoromethanesulfonate (2.2 g, 1.0 mmol) was added, followed by the dichloromethane solution of 4,4-dimethyl-5-nitropentan-2-one (50 mL, 19.0 g, 119 mmol) from the previous step. After 30 minutes, the cooling bath was removed and the solution was allowed to warm to room temperature. The solution was filtered through a plug of potassium carbonate and concentrated under reduced pressure to provide 2-(2,2-dimethyl-3-nitropropyl)-2-methyl-[1,3]dioxolane (23.5 g) as a dark oil that was used directly in the next step without further purification.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:22]1([NH:28]N)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[CH:10]=[CH:11][C:12](=[O:13])[C:7]([C:5]3[N:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:2]=[CH:3][CH:4]=3)=[N:8]2)=[CH:15][CH:16]=1
Reactant: NNc1ccccc1
Reactant: Cc1ccc(-n2ccc(=O)c(C(=O)C=CN(C)C)n2)cc1
Solvent: CO
Product: Cc1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 7.2 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-(4-methylphenyl)pyridazin-4(1H)-one (crude, 600 mg, 2.12 mmol) in 20 mL of methanol was added phenylhydrazine (916 mg, 8.48 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 1-(4-methylphenyl)-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (50 mg, 7% for two steps) as a yellow solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[CH2:12][CH2:11][NH:10][C:8]3=[CH:9][C:4]=2[N:3]=[C:2]1[SH:13].[OH-].[Na+].[ClH:16].[Cl:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>O>[ClH:17].[ClH:16].[ClH:17].[N:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][S:13][C:2]1[NH:1][C:5]2[CH:6]=[C:7]3[CH2:12][CH2:11][NH:10][C:8]3=[CH:9][C:4]=2[N:3]=1
Reactant: ClCc1ccccn1
Reactant: Sc1nc2cc3c(cc2[nH]1)CCN3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: c1ccc(CSc2nc3cc4c(cc3[nH]2)CCN4)nc1
Reaction time: 0.5 h
Yield: 55.8 %

Procedure:
To 2.5 g of 1,5,6,7-tetrahydropyrrolo-(2,3-f)benzimidazole-2-thiol, suspended in 40 ml of alcohol, were added dropwise while stirring 1.2 g of sodium hydroxide in 20 ml of water and, after 30 minutes, there were added 2.4 g of 2-chloromethyl-pyridine hyrochloride. The mixture was left to boil at reflux overnight, then evaporated and the residue was taken up in methylene chloride. The solution obtained was washed with 100 ml of 3N sodium hydroxide and three times with 100 ml of water, dried over sodium sulfate and evaporated in vacuo. The crude product, dissolved in methanol, was treated with 30 ml of hydrochloric acid in ethyl acetate and the precipitated crystals were removed by filtration under suction. There were obtained 1.6 g (31.3% of theory) of 1,5,6,7-tetrahydro-2-[(2-pyridylmethyl)thio]pyrrolo(2,3-f)benzimidazole trihydrochloride of melting point 207°-209° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11](OC)=[O:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+].O>C1COCC1>[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][OH:12])[CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2c(c1)NCCC2
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc2c(c1)NCCC2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a cooled (0° C.) solution 1 g (5.23 mmol) of methyl 1,2,3,4-tetrahydroquinoline-7-carboxylate in THF (10 ml) was added 20.92 ml, (20.92 mmol) of a solution of DIBAL-H in THF. The reaction mixture was stirred for 2 hr at 0° C. Additional DIBAL-H in THF (15.69 ml, 15.69 mmol) was added. The reaction mixture was allowed to warm to 20° C. and stirring was continued for 16 hr. The reaction mixture was treated with 30 mL of 10% aqueous sodium potassium tartrate and stirred for 1 h. Water was added and the mixture was extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure to give (1,2,3,4-tetrahydroquinolin-7-yl)methanol. HPLC (Method H) Rt=2.74 min; MS (Method A) [M+H]+=164.1
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[S:10][C:11]2[CH2:12][CH2:13][O:14][C:15]3[CH:22]=[C:21]([C:23](O)=[O:24])[CH:20]=[CH:19][C:16]=3[C:17]=2[N:18]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[NH2:32][C:33]1[CH:37]=[CH:36][O:35][N:34]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl.CN(C=O)C>[O:35]1[CH:36]=[CH:37][C:33]([NH:32][C:23]([C:21]2[CH:20]=[CH:19][C:16]3[C:17]4[N:18]=[C:9]([C:5]5[N:4]([CH:1]([CH3:3])[CH3:2])[CH:8]=[N:7][N:6]=5)[S:10][C:11]=4[CH2:12][CH2:13][O:14][C:15]=3[CH:22]=2)=[O:24])=[N:34]1
Reactant: Nc1ccon1
Reactant: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C(=O)O)ccc1-2
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)n1cnnc1-c1nc2c(s1)CCOc1cc(C(=O)Nc3ccon3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.3 %

Procedure:
To a suspension of 2-(4-isopropyl-4H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-8-carboxylic acid (226 mg, 0.63 mmol) in DCM (5 mL) at 0° C. was added DMF (4 drops, catalytic) then oxalyl chloride (115 μL, 1.32 mmol) dropwise. The reaction mixture was stirred at room temperature for 18 hours. 3-Amino-isoxazole (233 μL, 3.15 mmol) was added followed by triethylamine (176 μL, 1.26 mmol) and the reaction mixture was stirred for 4 hours. Aqueous saturated sodium bicarbonate solution was added and then ether and the mixture was filtered. The filtrate was concentrated in vacuo to remove the organics and the resulting aqueous phase was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, 0-5% MeOH in EtOAc) then trituration with EtOAc to give 140 as an off-white solid (126 mg, 47%). LCMS: RT=9.86 min, [M+H]+=423. 1H NMR δ (ppm) (DMSO-d6): 11.39 (1H, s), 8.94 (1H, s), 8.81 (1H, d, J=1.76 Hz), 8.39 (1H, d, J=8.33 Hz), 7.79 (1H, dd, J=8.34, 1.90 Hz), 7.70 (1H, d, J=1.87 Hz), 7.00 (1H, d, J=1.76 Hz), 5.51-5.41 (1H, m), 4.41-4.35 (2H, m), 3.47-3.41 (2H, m), 1.54 (6H, d, J=6.70 Hz)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH3:28])[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[C:12]3([CH2:15][CH2:14][CH2:13]3)[S:11](=[O:27])(=[O:26])[CH2:10]2)[C:5]([F:8])=[N:6][CH:7]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:39](Br)[CH:40]=[CH2:41]>C1COCC1>[CH2:41]([C@@H:10]1[C@:9]([C:4]2[C:5]([F:8])=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)([CH3:28])[N:17]=[C:16]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[C:12]2([CH2:13][CH2:14][CH2:15]2)[S:11]1(=[O:27])=[O:26])[CH:40]=[CH2:39]
Reactant: C=CCBr
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(Br)cnc2F)CS(=O)(=O)C12CCC2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1[C@@](C)(c2cc(Br)cnc2F)N=C(NC(=O)OC(C)(C)C)C2(CCC2)S1(=O)=O
Reaction time: 0.67 h
Yield: 37.2 %

Procedure:
A solution of (R)-tert-butyl (7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (5.0 g, 10.50 mmol) in THF (100 mL) was brought to −78° C. followed by the dropwise addition of potassium bis(trimethylsilyl)amide, 1 m in tetrahydrofuran (63.0 ml, 63.0 mmol). The resulting mixture was stirred at this temperature for 40 min then neat allyl bromide (2.72 ml, 31.5 mmol) was added dropwise. The mixture was kept at this temperature for 40 min. Then, it was quenched with saturated NH4Cl at −78° C. and brought to rt, and extracted with EtOAc. The combined organics were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-25% Et2O/heptane to afford a white solid as tert-butyl ((6R,7R)-6-allyl-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (2.02 g, 3.91 mmol, 37.3% yield). LC/MS (ESI+) m/z=537.8 (M+H) and tert-butyl ((6S,7R)-6-allyl-7-(5-bromo-2-fluoropyridin-3-yl)-7-methyl-5,5-dioxido-5-thia-8-azaspiro[3.5]non-8-en-9-yl)carbamate (1.06 g, 2.053 mmol, 19.56% yield). LC/MS (ESI) m/z=537.8 (M+H).
Reaction SMILES: [OH:1][C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:7][N:6]([CH3:8])[CH2:5][C:4]2[O:9][CH:10]=[CH:11][C:3]1=2.N.B(F)(F)F.[CH3:24]O>>[CH3:24][O:1][C:2]1([C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH2:7][N:6]([CH3:8])[CH2:5][C:4]2[O:9][CH:10]=[CH:11][C:3]1=2
Reactant: CO
Reactant: CN1Cc2occc2C(O)(c2ccc(Br)cc2)C1
Agent: FB(F)F
Agent: N
Product: COC1(c2ccc(Br)cc2)CN(C)Cc2occc21

Procedure:
Two grams (0.005 mol) of 4-hydroxy-4-(p-bromophenyl)-6-methyl-4,5,6,7-tetrahydro-furano[2,3-c]pyridine were heated to 50° C. for four hours in 40 ml of a boron trifluoride/methanol mixture (20% BF3), and then the mixture was poured onto ice and neutralized with ammonia. The mixture was extracted with ether, and the ether was distilled off in vacuo. The residue was purified over silica gel [cyclohexane/ethyl acetate (75:25)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=1.[BH4-].[Na+]>CO.C(O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: Nc1ccc(O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Oc1ccc(NCc2cccnc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Alternately, a solution of 4-aminophenol (1.0 equiv.) (Aldrich) in 2:1 methanol/ethanol was treated with 3-pyridinecarboxaldehyde (1.05 equiv.). The solution was allowed to stir for 1 hour. The reaction was cooled to 0° C. and treated with sodium borohydride (4.2 equiv.) in 5 portions. The cooling bath was removed and stirring continued for 20 hours. The reaction mixture was concentrated in vacuo. The residue was mixed with 1M HCl, warmed, and partitioned between ethyl acetate and 0.1M K2CO3. The pH of the aqueous phase was adjusted to pH=7 (using 1M HCl and 1M K2CO3) and the product extracted 4-6 times with ethyl acetate. The organic phases were combined, washed with brine, dried over anhydrous MgSO4, and concentrated to afford N-(4-hydroxyphenyl)pyridin-3-ylmethylamine. 1H NMR(400 MHz, DMSO-d6): d 4.18(2H, s), 5.65(1H, s), 6.41-6.53(4H, m), 7.29-7.32(1H, m), 7.70-7.72(1H, m), 8.39-8.40(2H, m), 8.53-8.54(1H, m). MS Found 201.2 [M+H]+.
Reaction SMILES: C(O[CH:5]([O:12][C:13](=[O:36])[CH2:14][C:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]([C:26](=[O:34])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)[C:16]=1[CH3:35])C1C=CC=CC=1)(=O)C.[C:37]([OH:40])(=[O:39])C>[C].[Pd]>[Cl:33][C:30]1[CH:31]=[CH:32][C:27]([C:26]([N:17]2[C:18]3[C:23](=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:15]([CH2:14][C:13]([O:12][CH2:5][C:37]([OH:40])=[O:39])=[O:36])=[C:16]2[CH3:35])=[O:34])=[CH:28][CH:29]=1
Reactant: COc1ccc2c(c1)c(CC(=O)OC(OC(C)=O)c1ccccc1)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(=O)O
Agent: [Pd]
Product: COc1ccc2c(c1)c(CC(=O)OCC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1

Procedure:
25.4 g (0.050 mol) of [1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indoleacetoxy]-benzyl acetate were dissolved in 400 ml of glacial acetic acid and hydrogenated on 2.0 g of palladium carbon at room temperature. After the absorption of hydrogen had finished (1 hour), the catalyst was filtered off, the filtrate was concentrated by evaporation under vacuum and the compound was caused to crystallise by adding petroleum ether. The compound melted at 149.5°-150.5°C (determined on the micro-Kofler bench); the yield was 19.4 g which corresponds to 93% of the theoretical yield.