Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:8][CH2:9][C:10]#[N:11])[CH:5]=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)O1.C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:10]([CH2:9][O:8][C:4]1[CH:3]=[C:2]([C:20]2[CH:32]=[CH:31][C:23]3[N:24]=[C:25]([NH:27][C:28](=[O:30])[CH3:29])[S:26][C:22]=3[CH:21]=2)[CH:7]=[N:6][CH:5]=1)#[N:11]
Reactant: N#CCOc1cncc(Br)c1
Reactant: CC(=O)Nc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)Nc1nc2ccc(-c3cncc(OCC#N)c3)cc2s1
Temperature: 25 °C
Yield: 7.3 %

Procedure:
A dry 15 mL, one neck round bottom flask was charged with 2-(5-bromopyridin-3-yloxy)acetonitrile (0.162 g, 0.762 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazol-2-yl)acetamide (0.2021 g, 0.635 mmol), 5 mL THF and a stirbar. The flask was flushed with Ar for 2 minutes, and fitted with an inert atmosphere inlet. To the stirring solution was added tetrakis(triphenylphosphine)palladium (0.147 g, 0.127 mmol) followed by 2 M sodium carbonate (0.953 ml, 1.91 mmol). The slurry was refluxed overnight, and cooled to room temperature. The mixture was poured onto 15 mL water and extracted with DCM (3×20 mL). The DCM extracts were Loaded onto an unbuffered Varian Chem elute CE1010 (100 mL, PN 12198010). The tube was extracted with DCM (4×20 mL). The combined extracts were concentrated in vacuo, and the residue was taken up in 1 mL DCM. A precipitate formed, which was collected using a course glass filter fitted with a 0.22 μm syringe filter. The solid was dried at 60° C. at <1 mmHg for 1 h to afford N-(6-(5-(Cyanomethoxy)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (15 mg, 7.3%). 1H NMR (300 MHz, Pyr) δ ppm 2.36 (s, 3H) 4.98 (br. s., 1H) 5.56 (s, 2H) 7.75 (dd, J=8.40, 1.90 Hz, 1H) 7.93 (dd, J=2.81, 1.86 Hz, 1H) 8.02 (dd, J=8.44, 0.48 Hz, 1H) 8.27 (dd, J=1.90, 0.44 Hz, 1H) 8.77 (d, J=2.85 Hz, 1H) 8.93 (d, J=1.83 Hz, 1H). 13C NMR (75 MHz, Pyr) δ ppm 23.71 (s, 1 C) 55.20 (s, 1 C) 116.92 (s, 1 C) 120.84 (s, 1 C) 121.15 (s, 1 C) 122.27 (s, 1 C) 126.25 (s, 1 C) 133.18 (s, 1 C) 134.41 (s, 1 C) 137.61 (s, 1 C) 138.12 (s, 1 C) 143.50 (s, 1 C) 150.53 (s, 1 C) 154.29 (s, 1 C) 160.70 (s, 1 C) 170.19 (s, 1 C). HPLC-MS: retention time=1.34 min (93.6%@215 nm; 96.7% @254 nm; m/z=325.6, calculated for C16H12N2O4S+H+=325.1).
Reaction SMILES: [CH:1]([N:4]([CH:22]([CH3:24])[CH3:23])[CH2:5][CH2:6][C@@H:7]([C:14]1[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:15]=1[OH:21])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].CCOCC.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>>[C:30]([O:21][C:15]1[CH:16]=[CH:17][C:18]([CH3:20])=[CH:19][C:14]=1[C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH:22]([CH3:24])[CH3:23])(=[O:34])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC(=O)Cl
Reactant: Cc1ccc(O)c([C@H](CCN(C(C)C)C(C)C)c2ccccc2)c1
Solvent: CCOCC
Product: CCCC(=O)Oc1ccc(C)cc1[C@H](CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
A solution of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenol (1.0 g) in butyryl chloride (5 ml) is heated under reflux for 90 min. Ether is added, and the precipitate of 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl]-4-methylphenyl butyrate hydrochloride is filtered off; mp 116-119° C. Anal Calcd for C26H37NO2.HCl: C, 72.28; H, 8.86; Cl, 8.21; N, 3.24. Found: C, 72.25; H, 8.71; Cl, 8.17; N, 3.25. [α]D (c=1, MeOH) +20°.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[CH:8]=[C:9]([CH:11]=[CH:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[O:22]CCO)[CH:10]=1)=[O:5])[CH3:2]>FC(F)(F)C(O)=O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:26])[CH:8]=[C:9]([CH:11]=[CH:12][CH2:13][C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[OH:22])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C=CCc2cc(OC)ccc2OCCO)cn1C
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc(C=CCc2cc(OC)ccc2O)cn1C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
A solution of 1.00 g (2.79 mmol) of 2-ethoxycarbonyl-1-methyl-4-[2-(3-oxapropyloxy)-5-methoxyphenyl]propenylpyrrole in 5 ml of 1:1 aqueous trifluoroacetic acid was stirred at 0° for 1 hour, then at room temperature for 1 hour. The solution was partitioned between ether and water and the ether layer was washed with 3 portions of water. The ether extract was dried (Na2SO4), concentrated, and chromatographed on silica using 20% ethylacetatehexane to afford 0.68 g (77%) 2-ethoxycarbonyl-1-methyl-4-(2-hydroxy-5-methoxyphenyl)propenylpyrrole of a colorless glass.
Reaction SMILES: [S:1]1[C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=[CH:2]1.C(Cl)Cl.[Br:13]Br>C(O)(=O)C>[Br:13][C:2]1[S:1][C:5]2[C:6](=[O:9])[NH:7][CH2:8][C:4]=2[CH:3]=1
Reactant: O=C1NCc2ccsc21
Reactant: BrBr
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C1NCc2cc(Br)sc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 34.3 %

Procedure:
A 250-mL single-neck round-bottomed flask equipped with a magnetic stirrer was purged with nitrogen and charged with 116e (1.87 g, 13.5 mmol), methylene chloride (10 mL), acetic acid (30 mL). The mixture was cooled to 0° C. Bromine (2.30 g, 14.8 mmol) was added dropwise. After the addition was complete, the mixture was stirred for 3 h at 0° C. and then at room temperature for 48 h. After that time, the mixture was partitioned between aqueous saturated sodium bicarbonate (100 mL) and a 20% (v/v) solution of methanol in methylene chloride (100 mL). The layers were separated, and the aqueous layer was extracted with a 20% (v/v) solution of methanol in methylene chloride (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography (silica, 0% to 10% methanol/methylene chloride) to afford a 34% yield (1.01 g) of 116f as an off-white solid: mp 96-97° C.; 1H NMR (300 MHz, CDCl3) δ 7.09 (s, 1H), 6.57 (br s, 1H), 4.37 (s, 2H); MS (ESI+) m/z 217.9 (M+H).
Reaction SMILES: [N+:1]([CH:4]([CH3:6])[CH3:5])([O-:3])=[O:2].[H-].[Na+].F[B-](F)(F)F.[Cl:14][C:15]1[CH:45]=[CH:44][CH:43]=[CH:42][C:16]=1C[N+]1C(C2C=CC=CC=2)=CC(C2C=CC=CC=2)=CC=1C1C=CC=CC=1.O.[CH3:47]O>CS(C)=O>[Cl:14][C:15]1[CH:45]=[CH:44][CH:43]=[CH:42][C:16]=1[CH2:5][C:4]([CH3:47])([N+:1]([O-:3])=[O:2])[CH3:6]
Reactant: CO
Reactant: CC(C)[N+](=O)[O-]
Reactant: Clc1ccccc1C[n+]1c(-c2ccccc2)cc(-c2ccccc2)cc1-c1ccccc1
Agent: F[B-](F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccccc1Cl)[N+](=O)[O-]
Temperature: 0 °C

Procedure:
2-Nitropropane (3.19 mL, 35.5 mmol) was added to a mixture of sodium hydride (0.85 g, 35 mmol) in methanol (15 mL) cooled to 0° C. The reaction mixture was then stirred and allowed to warm to 25° C. for 10 min. The solvent was rotary evaporated to provide a white solid. A mixture of this solid and N-(2-chlorobenzyl)-2,4,6-triphenylpyridinium tetrafluoroborate (6.14 g, 11.8 mmol) in dimethyl sulfoxide (45 mL) was stirred under nitrogen gas for 16 h. Water was then added to quench the reaction. This mixture was then extracted with diethyl ether (3×100 mL). The organic layer was washed with saturated aqueous sodium chloride, dried (anhydrous sodium sulfate), and filtered. The filtrate was stirred in strongly acidic Amberlyst 15 ion-exchange resin (1 g/mmol) for 4 h. The reaction mixture was filtered and rotary evaporated. This provided 2.35 g (93%) of 1-(2-chlorophenyl)-2-methyl-2-nitropropane.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([C:27](OC(C)(C)C)=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1.FC(F)(F)C(O)=O.[F:41][C:42]([F:53])([F:52])[O:43][C:44]1[CH:51]=[CH:50][C:47](C=O)=[CH:46][CH:45]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH3:1][C@@:2]1([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][N:24]([CH2:27][C:47]4[CH:46]=[CH:45][C:44]([O:43][C:42]([F:41])([F:52])[F:53])=[CH:51][CH:50]=4)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[O:6][C:5]2=[N:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][N:4]2[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(OC[C@@]3(C)Cn4cc([N+](=O)[O-])nc4O3)cc2)CC1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@]1(COc2ccc(N3CCN(Cc4ccc(OC(F)(F)F)cc4)CC3)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 5 h
Yield: 63.1 %

Procedure:
Tert-butyl (R)-4-[4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethoxy)phenyl]-piperazine-1-carboxylate prepared in Example 148 (4.22 g, 9.60 mmol) was dissolved in methylene chloride (10 ml). To the solution, trifluoroacetic acid (30 ml) was added followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure and added methylene chloride (10 ml) and triethylamine (10 ml). The solution was stirred at room temperature for 5 minutes and then concentrated under reduced pressure. The residue was dissolved in dichloroethane. To the solution, 4-trifluoromethoxybenzaldehyde (1.64 ml, 11.5 mmol) and sodium triacetoxyborohydride (3.05 g, 14.4 mmol) were added with cooling on ice-bath followed by stirring at room temperature overnight. To the reaction mixture, a saturated sodium hydrogencarbonate solution and methylene chloride were added, and the solution was stirred and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and then filtered. The resulting filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=200/1) and then crystallized from methylene chloride-ethyl acetate to afford (R)-2-methyl-6-nitro-2-{4-[4-(4-trifluoromethoxybenzyl)piperazin-1-yl]phenoxymethyl}-2,3-dihydroimidazo[2,1-b]oxazole (3.23 g, yield 63%) as a light yellow powder.
Reaction SMILES: C(O)C.[Na:4].[CH:5]1[CH2:9][CH:8]=[CH:7][CH:6]=1.O.[CH3:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[Na:4].[CH2:14]([CH:15]=[C:6]1[CH:5]=[CH:9][CH:8]=[CH:7]1)[CH2:13][CH:12]=[CH2:11]
Reactant: C1=CCC=C1
Reactant: CCCCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: C=CCCC=C1C=CC=C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Then a sodium solution of ethanol was prepared by combining 4.3 g of sodium with 150 mL of ethanol. The solution was cooled to 0° C. and then 30 g of the phenyl alkenyl ketone was added. Then 30 mL of cyclopentadiene was slowly added to the solution and the mixture stirred for 4 hrs. Then 100 mL of water and 100 mL of pentane were added. The ethanol-water layer was then extracted twice with pentane. The organic layer was dried over filtered silica and the solvent removed in a vacuum to yield 6-phenyl, 6-(but-3-enyl)fulvene.
Reaction SMILES: C[O:2][C:3](=[O:30])[CH:4]([CH3:29])[CH:5]([C:10]1([CH:16]([N:18]2C(=O)C3=CC=CC=C3C2=O)[CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)[C:6]([F:9])([F:8])[F:7].O.NN.[ClH:34]>C(O)C>[ClH:34].[NH2:18][CH:16]([C:10]1([CH:5]([C:6]([F:8])([F:9])[F:7])[CH:4]([CH3:29])[C:3]([OH:30])=[O:2])[S:11][CH2:12][CH2:13][CH2:14][S:15]1)[CH3:17]
Reactant: COC(=O)C(C)C(C(F)(F)F)C1(C(C)N2C(=O)c3ccccc3C2=O)SCCCS1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C(=O)O)C(C(F)(F)F)C1(C(C)N)SCCCS1

Procedure:
A solution of 1.1 g of the product of Example 5 in 20 ml of ethanol is treated with hydrazine hydrate (2 ml) for 2 hours at reflux. The ethanol is evaporated and the residue treated with 1 N NaOH then extracted with ether. The ether solution is dried and concentrated leaving a residue thatis taken up in 20 ml of ethanol and 10 ml of 6 N HCl and heated at reflux for 1 hour. The solvents are evaporated to give the title compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1.[C:19](OC(=O)C)(=[O:21])[CH3:20].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O>[C:19]([O:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]3)[CH2:4][CH2:3]1)(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: O=c1ccc2cc(N3CCC(O)CC3)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)OC1CCN(c2ccc3[nH]c(=O)ccc3c2)CC1
Temperature: 100 °C

Procedure:
A mixture of 6-(4-hydroxypiperidino)carbostyril (0.25 g), acetic anhydride (0.4 g) and dry pyridine (4 mL) was heated at 100° C. for 3 hours. The reaction mixture was cooled and water (about 35 mL) and sodium bicarbonate (0.6 g) were added. The mixture was chilled in ice and stirred. The resulting white solid was removed by filtration, washed with water and dried to give 6-(4-acetoxypiperidino)-2(1H)-quinolinone. 1/4 hydrate (0.3 g); m.p. 245°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=1)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:13]=[C:14]([Cl:27])[C:16]1[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][N:17]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(OC(F)(F)F)cc2Cl)nc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CS(=O)(=O)c1ccc(C(Cl)=Nc2ccc(OC(F)(F)F)cc2Cl)nc1

Procedure:
5-Methanesulfonyl-pyridine-2-carboxylic acid (2-chloro-4-trifluoromethoxy-phenyl)-amide 7 (1.1 g, 2.79 mmol) in benzene (20 mL) was added to PCl5 (1.26 g, 6.0 mmol) and the mixture was heated to reflux overnight. The solvent was removed and the residue was further dried under high vacuum. Crude N-(2-chloro-4-trifluoromethoxyphenyl)-5-(methylsulfonyl)picolinimidoyl chloride was obtained as a yellow solid (1.60 g). The N-(2-chlor-4-trifluoromethoxyophenyl)-5-(methylsulfonyl)picolinimidoyl chloride was dissolved into anhydrous THF (30 mL) and the reaction was cooled down to 0° C. and hydrazine monohydrate (9.0 mL) was added. The reaction was kept at 0° C. for 10 min and warmed to ambient temperature in 0.5 h. The solvent was removed and the residue was purified by column chromatography (eluting with hexane and ethyl acetate 1:1) to give N′-(2-chloro-4-trifluoromethoxyphenyl)-5-(methylsulfonyl)picolinimidohydrazide 8 as a yellow solid. Yield: 0.56 g, 50%.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[N:16]=[CH:15][N:14]=[C:10]3[N:11]=[CH:12][NH:13][C:9]=23)[O:4][CH:5]=1.Br[CH2:18][CH2:19][Cl:20].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:6]([NH:7][C:8]1[N:16]=[CH:15][N:14]=[C:10]2[C:9]=1[N:13]=[CH:12][N:11]2[CH2:18][CH2:19][Cl:20])[C:3]1[O:4][CH:5]=[CH:1][CH:2]=1
Reactant: c1coc(CNc2ncnc3nc[nH]c23)c1
Reactant: ClCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: ClCCn1cnc2c(NCc3ccco3)ncnc21
Yield: 80 %

Procedure:
Kinetin (2 g, 9.3 mmol), 1-bromo-2-chloroethane (1.3 g, 9.1 mmol) and K2CO3 (2.5 g, 24 mmol) were mixed in 100 ml dimethylsulfoxide (DMSO) for 18 h. The reaction mixture was poured onto 200 ml drift ice and then extracted in ethyl acetate and dried over Na2SO4. The ethyl acetate layer was evaporated in vacuo. The pure product of white powder character was recrystallised from methanol. Yield: 80%. 1H NMR (DMSO-d6): 4.07 (2H, t, J=5.82), 4.52 (2H, t, J=5.82), 4.70 (2H, s (br)), 6.23 (1H, d, J=2.67), 6.35 (1H, m), 7.53 (1H, d, J=2.67), 8.22 (2H, m), 8.25 (1H, s)
Reaction SMILES: [N:1]([CH2:4][C:5]([OH:7])=[O:6])=[N+:2]=[N-:3].B(F)(F)F.CCOCC.[CH:17]#[C:18][CH3:19]>C(Cl)Cl>[N:1]([CH2:4][C:5]([O:7][C:18]([CH3:19])=[CH2:17])=[O:6])=[N+:2]=[N-:3]
Reactant: C#CC
Reactant: [N-]=[N+]=NCC(=O)O
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: C=C(C)OC(=O)CN=[N+]=[N-]

Procedure:
Azidoacetic acid (5.35 g, 0.05 mole) and mercuric acetate (1.82 g, 5.7 mMoles) are added to 50 ml of methylene chloride containing 0.1 ml of boron trifluoride etherate. Propyne, which had been passed through Linde Co. Molecular Sieves 4A, is bubbled slowly through the mixture for 3 hours. Sodium bicarbonate (0.5 g) is added and the mixture is filtered through a short Florisil column. The eluent is concentrated in vacuo and the residue obtained is purified by vacuum distillation to give isopropenyl azidoacetate.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:21][CH2:20]4)=[C:10]([O:34][CH3:35])[CH:9]=2)[O:6][CH:7]=1)[CH3:2].[Li+].[OH-]>C1COCC1.O.CCO>[CH2:1]([C:3]1[N:4]=[C:5]([C:8]2[CH:33]=[CH:32][C:11]([O:12][CH2:13][CH2:14][CH2:15][O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C@H:22]([CH2:26][C:27]([OH:29])=[O:28])[CH2:21][CH2:20]4)=[C:10]([O:34][CH3:35])[CH:9]=2)[O:6][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H]1CCc2cc(OCCCOc3ccc(-c4nc(CC)co4)cc3OC)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCc1coc(-c2ccc(OCCCOc3ccc4c(c3)CC[C@H]4CC(=O)O)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
To a solution of ethyl ((1S)-5-{3-[4-(4-ethyl-1,3-oxazol-2-yl)-2-methoxyphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (52.2 mg, 0.109 mmol) (Example 173) in THF/water/EtOH (1:2:1, 4 mL) was added LiOH (5.2 mg, 0.218 mmol). The solution was stirred at rt for 3 h and concentrated under reduced pressure. The residue was diluted with water and acidified using HCl (2 N aqueous solution), resulting in precipitation of a white solid. The solid was collected by filtration and dried to give 38.0 mg (77%) of the title compound. 1H NMR (400 MHz, CD2Cl2): δ 7.82 (s, 1H), 7.66 (d, 1H), 7.47 (s, 1H), 7.07 (d, 1H), 6.98 (d, 1H), 6.79 (s, 1H), 6.70 (d, 1H), 4.28 (t, 2H), 4.19 (t, 2H), 3.94 (s, 3H), 3.51 (m, 1H), 2.91 (m, 2H), 2.75 (m, 3H), 2.50 (m, 1H), 2.40 (m, 1H), 2.30 (m, 2H), 1.79 (m, 1H), 1.34 (t, 3H); LC-MS: RT=3.31 min, (M+H)+ 452.1.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1>>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Product: COc1ccc(-c2cc(C#N)cc3c(C)c4n(c23)CCNC4=O)cc1

Procedure:
The title compound, light grey solid (34 mg, 41%), MS (ISP) m/z=332.6 [(M+H)+], mp 285° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 4-methoxy-phenylboronic acid (49.4 mg, 0.325 mmol).
Reaction SMILES: C(C1C=CC(C=O)=CC=1[N+]([O-])=O)C.C(NC(C1CCNCC1)=O)(C)(C)C.[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[C:43]([N+:49]([O-])=O)[CH:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:32]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:40][C:41]2[CH:46]=[CH:45][C:44]([CH2:47][CH3:48])=[C:43]([NH2:49])[CH:42]=2)[CH2:36][CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]
Reactant: CCc1ccc(CN2CCC(C(=O)NC(C)(C)C)CC2)cc1[N+](=O)[O-]
Agent: CC(C)(C)NC(=O)C1CCNCC1
Agent: CCc1ccc(C=O)cc1[N+](=O)[O-]
Product: CCc1ccc(CN2CCC(C(=O)NC(C)(C)C)CC2)cc1N

Procedure:
The title compound is prepared according to the reactions described for BB-5 above starting from 4-ethyl-3-nitro-benzaldehyde and piperidine-4-carboxylic acid tert-butylamide yielding after reductive amination 1-(4-ethyl-3-nitro-benzyl)-piperidine-4-carboxylic acid tert-butylamide; LC-MS A: tR=0.67 min; [M+H]+=348.18 followed by reduction with stannous chloride the title compound; LC-MS A: tR=0.53 min; [M+H]+=318.22.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])[NH:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:34]([S:46]SC(=N)N)[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45].C(OCC)(=O)C>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:46][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[C:12]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([Cl:25])=[CH:19][C:18]=2[Cl:26])=[N:11]1
Reactant: CCCCCCCCCCCCSSC(=N)N
Reactant: COc1cc(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c(Cl)cc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCCCCCCCCSC1C(=O)N(c2c(Cl)cc(Cl)cc2Cl)N=C1Nc1cc(OC)c(Cl)cc1Cl
Reaction time: 0.17 h

Procedure:
15.1 g of 1-(2,4,6-trichlorophenyl)-3-(2,4-dichloro-5-methoxyanilino)-5-pyrazolone was dissolved in 500 ml of 80% ethanol (ratio by volume of ethanol:water=4:1), and 2.5 g of potassium carbonate was added thereto. A solution prepared by dissolving 10.4 g of S-(n-dodecylthio)isothiourea hydrochloride in 100 ml of ethanol was added dropwise thereto over 10 minutes with stirring while heating on a steam bath, and the mixture was stirred for another 10 minutes. After cooled rapidly under a water stream, 300 ml of ethyl acetate was added thereto, and the mixture was washed twice with water. After drying the ethyl acetate layer with anhydrous sodium sulfate, sodium sulfate was removed and the solvent was removed by condensing under a reduced pressure. The residue was crystallized with acetonitrile. The resulting crystals were recrystallized with acetonitrile-ethyl acetate (ratio by volume: 10:1) to obtain 18 g of the coupler having a melting point of 100° to 102° C.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14][CH:15]([O:23][CH3:24])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[CH3:13][O:14][CH:15]([O:23][CH3:24])[C:16]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=1
Reactant: COC(OC)c1ccncc1O
Reactant: COC(=O)c1cccc(CO)n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(COc2cnccc2C(OC)OC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
Into a 50-mL round-bottom flask, which was purged and maintained with an inert atmosphere of nitrogen, was placed a solution of methyl 6-(hydroxymethyl)pyridine-2-carboxylate (300 mg, 1.79 mmol, 1.00 equiv) in tetrahydrofuran (15 mL). 4-(Dimethoxymethyl)pyridin-3-ol (304.2 mg, 1.80 mmol, 1.00 equiv), and triphenylphosphane (615 mg, 2.34 mmol, 1.30 equiv) was added to the reaction mixture. This was followed by the addition of DIAD (473.1 mg, 2.34 mmol, 1.30 equiv) dropwise at 0° C. The resulting solution was stirred overnight at room temperature, and then it was quenched by the addition of 10 mL of water. The resulting solution was extracted with 2×50 mL of ethyl acetate and the combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5-1:1) as eluent to yield 340 mg (60%) of methyl 6-([[4-(dimethoxymethyl)pyridin-3-yl]oxy]methyl)pyridine-2-carboxylate as a white solid.