Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [BH4-].[Na+].[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:29][CH3:30])[C:14]1[N:19]=[C:18]([C:20]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[O:21])[CH:17]=[C:16]([CH3:28])[N:15]=1.C(Cl)(Cl)Cl.CO>C(O)C>[Br:3][C:4]1[CH:9]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[N:13]([CH2:29][CH3:30])[C:14]1[N:19]=[C:18]([CH:20]([OH:21])[C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[CH:17]=[C:16]([CH3:28])[N:15]=1
Reactant: CCN(c1nc(C)cc(C(=O)c2cccnc2)n1)c1ccc(C(C)C)cc1Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN(c1nc(C)cc(C(O)c2cccnc2)n1)c1ccc(C(C)C)cc1Br
Reaction time: 71 h
Yield: 97.1 %

Procedure:
Sodium borohydride (0.11 g, 2.8 mmol) was added to a solution of N-(2-bromo-4-(1-methylethyl)phenyl)-N-ethyl-4-(3-pyridylcarbonyl)-6-methylpyrimidinamine (0.6 g, 1.4 mmol) in ethanol (5 mL). After being stirred for 71 h, the reaction mixture was concentrated in vacuo, treated with a 1 N NaOH solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give a colorless oil. Column chromatography (chloroform:methanol::9:1) afforded the title product as an oil (600 mg, 96% yield, Rf 0.4): NMR (CDCl3, 300 MHz): 8.65-8.45 (m, 2H), 7.55 (br s, 2H), 7.3-7.1 (m, 2H), 6.25-6.15 (m, 1H), 5.7-5.5 (m, 0.5H), 5.45-5.3 (m, 0.5H), 5.15-4.95 (m, 1H), 4.3-4.1 (m, 1H), 3.9-3.7 (m, 1H), 3.0-2.85 (m, 1H), 2.45-2.2 (m, 3H), 2.3-2.2 (m, 1H), 1.35-1.2 (m, 9H); CI-HRMS: Calcd (C22H25BrN4O): 441.1290 (M+H), Found: 441.1274.
Reaction SMILES: S(OC)(OC)(=O)=O.[CH3:8][N:9]([CH3:12])[CH:10]=O.[CH2:13]([NH2:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].CNC.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:8][N:9]([CH3:12])[CH:10]=[N:21][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCN
Reactant: CN(C)C=O
Agent: CNC
Agent: [Na+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCN=CN(C)C
Temperature: 50 °C
Yield: 96.6 %

Procedure:
Dimethyl sulfate (34.7 g, 0.27 mole) was placed in a 300 ml 3-necked round bottom flask equipped with a heating mantle, magnetic stirrer, thermometer, addition funnel and calcium chloride drying tube. The reaction was stirred and warmed to 50° C. Heating was discontinued and dimethyl formamide (26 g, 0.36 mole) was added over a 10 minute period. The reaction temperature gradually rose to 85° C. The reaction was stirred an additional hour during which time the temperature fell to 45° C. The reaction was cooled and maintained between 0° and 10° C. while n-octylamine (32.3 g, 0.25 mole) in toluene (50 ml) was added over a period of 15 minutes. After the addition was complete, the addition funnel and drying tube were replaced by a dry ice/acetone condenser and gas inlet tube. The cooling bath was removed and gaseous dimethylamine (6.1 g, 0.14 mole) was added over a period of about 5 minutes. The reaction was stirred at room temperature for 1 hour. The reaction was extracted with sodium hydroxide (12.5 g, 0.31 mole) in water (50 ml), washed with brine (25 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield 44.5 g (97 %) of the title compound as a very light yellow liquid. GLC showed 99.6% of volatiles in a single peak.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([Cl:14])=[O:11]
Reactant: O=C(O)Cc1ccccc1I
Reactant: O=S(Cl)Cl
Product: O=C(Cl)Cc1ccccc1I

Procedure:
A solution of 13.32 g (0.05 mol) of 2-iodophenylacetic acid in 75 ml thionyl chloride is refluxed for 2 hours, and the volatiles removed under vacuum. Toluene is added (3 times) and the solvent removed under vacuum after each addition to give 2-iodophenylacetyl chloride as a gum. To the preceding compound (0.05 mol) in a mixture of 100 ml of toluene-dichloromethane (1:1) is added 11 g (0.05 mol) of 2-iodoaniline and (0.10 mol) of diisopropylethylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][C:5]2=[O:12].[N+]([O-])([O-])=[O:14].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[Tl+3]>>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[O:8][CH2:7][CH:6]([C:5]([OH:12])=[O:14])[C:4]=2[CH:3]=1
Reactant: O=C1CCOc2ccc(Cl)cc21
Reactant: O=[N+]([O-])[O-]
Agent: [Tl+3]
Product: O=C(O)C1COc2ccc(Cl)cc21

Procedure:
The title compound was prepared from 6-chloro-4-chromanone (9.0 g, 0.049 mole) and thallium trinitrate (0.074 mole) absorbed onto K10 clay (75 g) by the method of Description 1, as a yellow solid (1.51 g, 16%).
Reaction SMILES: Cl[C:2]1[C:3]([NH:12][CH:13]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:14]O)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([N:22](CC)CC)C.O>CS(C)=O>[CH2:16]([C:13]1[N:12]=[C:3]2[C:2]([NH2:22])=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[CH:14]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CC(C)CC(CO)Nc1nc2ccccc2nc1Cl
Solvent: O
Solvent: CS(C)=O
Product: CC(C)Cc1cn2c(n1)c(N)nc1ccccc12
Reaction time: 8 h
Yield: 76.6 %

Procedure:
To a solution of the 2-(3-chloroquinoxalin-2-ylamino)-4-methylpentan-1-ol (1.90 g, 6.79 mmol) in 10 mL of DMSO was added triethyl amine (1.92 g, 19.0 mmol) and followed by sulfur trioxide pyridine complex (2.38 g, 14.9 mmol) at room temperature. The reaction mixture was stirred at that temperature overnight. And then 100 mL of water was added to reaction mixture. The resulting mixture was extracted with ethyl acetate (75 mL×2). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (1.25 g, 64%). MS: MH+=278:280=3:1
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([CH2:13][NH:14][C:15]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:14]([CH2:13][CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[C:15](=[O:16])[N:17]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: O=C(NCC1CCCCC1)NCC1CCCCC1
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)n(CC2CCCCC2)c(=O)n1CC1CCCCC1
Temperature: 80 °C
Yield: 94.2 %

Procedure:
Cyanoacetic acid (Aldrich, 21.0 g) was dissolved in acetic anhydride (260 ml). This solution was added to 1,3-bis(cyclohexylmethyl)urea (from step (a), 54.5 g) and the solution maintained at 80° C. for 2 h under nitrogen. Volatiles were removed in vacuo and the residual oil dried by evaporation of portions of 10% water-ethanol (3×400 ml). The residual solids were dissolved in ethanol (600 ml)-water(300 ml) at 80° C. with adjustment of the pH to 10 by addition of 10% aqueous sodium carbonate. The hot solution was diluted with water (75 ml) and cooled to ambient temperature. The colorless crystals which formed were filtered off, washed with water (3×500 ml) and dried at 0.5 Torr to give 6-amino-1,3-bis(cyclohexylmethyl)uracil (64.98 g, 94%), m.p. 138–141° C.; 1H-NMR (DMSO-d6) δ: 6.73 (br s, 2, NH2), 4.63 (s, 1, H-5), 3.67 (d, J=7.3 Hz, 2, NCH2), 3.57 (d, J=7.3 Hz, 2, NCH2), 1.55 and 1.09 (both m, 22, 2 cyclohexyl).
Reaction SMILES: [Fe].[Fe:2](Cl)Cl.[Fe].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14]>O.COCCOCCOC>[Fe:2].[CH3:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][O:13][CH3:14].[C:6]
Reactant: Cl[Fe]Cl
Agent: [Fe]
Solvent: O
Solvent: COCCOCCOC
Product: [C]

Procedure:
Catalysts containing 3% iron were prepared generally in accordance with the method described in Example 50. A particulate carbon support (10 g) having a Langmuir surface area of approximately 1500 m2/g described in Example 50 was added to a 1 liter flask containing deionized water (400 ml) to form a slurry. Iron chloride (FeCl3.H2O) (1.497 g) (available from Aldrich Chemical Co., Milwaukee, Wis.) was introduced to 60 ml of a 50/50 (v/v) mixture of diglyme (diethylene glycol dimethyl ether) (also available from Aldrich Chemical Co., Milwaukee, Wis.) and deionized water in a 100 ml beaker. The iron-diglyme mixture was added to the carbon slurry incrementally over the course of approximately 30 minutes (i.e., at a rate of approximately 2 ml/minute) to produce an iron-diglyme-carbon mixture. The pH of the carbon slurry was maintained at from about 4.0 and about 4.4 during addition of the iron-diglyme mixture to the carbon slurry by co-addition of sodium hydroxide solution (Aldrich Chemical Co., Milwaukee, Wis.). The iron-diglyme-carbon mixture was stirred using a mechanical stirring rod operating at 50% of output (Model IKA-Werke RW16 Basic) for approximately 30 minutes; the pH of the mixture was monitored using the pH meter and maintained at approximately 4.4 by dropwise addition of 0.1 wt. % sodium hydroxide. The mixture was then heated under a nitrogen blanket to approximately 70° C. at a rate of approximately 2° C. per minute while maintaining the pH at approximately 4.4 by dropwise addition of 0.1 wt. % sodium hydroxide. Upon reaching approximately 70° C., the pH of the mixture was raised by addition of a 0.1 wt. % sodium hydroxide solution according to the following pH profile: 10 minutes at pH of approximately 5.0, 20 minutes at pH of approximately 5.5, followed by continued stirring at pH of 6.0 until the pH became relatively constant. The resulting mixture was filtered and washed with a plentiful amount of deionized water and the wet cake was dried for approximately 16 hours in a vacuum oven at 120° C. to provide a catalyst precursor. Iron-containing catalyst precursor (5 g) was charged into the Hastelloy C tube reactor and heat treated as described above regarding preparation of the cobalt-containing catalysts. A catalyst containing 3% iron was also prepared using this method using polyglyme in place of diglyme. (Entries 1 and 2 in Table 31)
Reaction SMILES: F[C:2]1[C:3](/[C:12](/I)=[CH:13]/[C:14](=O)[C:15]2[NH:16][CH:17]=[CH:18][CH:19]=2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C.O>[NH:16]1[CH:17]=[CH:18][CH:19]=[C:15]1[C:14]1[C:5]2[C:6](=[O:11])[NH:7][C:8]3=[CH:9][CH:10]=[CH:2][C:3]([C:4]=23)=[CH:12][CH:13]=1
Reactant: O=C1Cc2c(ccc(F)c2/C(I)=C/C(=O)c2ccc[nH]2)N1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Nc2cccc3ccc(-c4ccc[nH]4)c1c23
Temperature: 110 °C
Reaction time: 2.5 h

Procedure:
A mixture of (Z)-5-fluoro-4-[1-iodo-3-oxo-3-(1H-pyrrol-2-yl)-propenyl]-1,3-dihydro-indol-2-one (from Example 8 above) (250 mg, 0.504 mmol) and 3-R-hydroxy pyrrolidine (Aldrich, 870 mg, 9.99 mmol) in DMF (5 mL) was treated with NaH (Aldrich, 120 mg, 5.04 mmol). The mixture was stirred at approximately 110° C. for 2.5 hours and then at room temperature overnight. The reaction mixture was poured in a mixture of ethyl acetate and water. The aqueous layer was extracted a few more times with ethyl acetate and the combined organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, with 0-100% ethyl acetate in hexanes and then 0-100% THF in ethyl acetate) to give 6-fluoro-5-[(R)-3-hydroxy-pyrrolidin-1-yl)]-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow-green solid. (Yield 6 mg, 5%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.C([Mg]Cl)(C)C.[CH3:12][N:13]([CH3:26])[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[C:17](N(OC)C)=[O:18].Cl>C1COCC1>[CH3:12][N:13]([CH3:26])[C:14]1[CH:15]=[C:16]([C:17]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[O:18])[CH:23]=[CH:24][CH:25]=1
Reactant: Cn1cnnn1
Reactant: CON(C)C(=O)c1cccc(N(C)C)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)c2nnnn2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a stirred solution of 1-methyl-1H-tetrazole (4.54 g, 54 mmol) in anhydrous THF (200 mL), cooled to 0° C. with a brine/ice bath, was added dropwise a solution of isopropylmagnesium chloride (2 M in THF, 27 mL, 54 mmol). After the addition was over, the resulting cloudy suspension was stirred for 15 min at 0° C. A solution of 3-(dimethylamino)-N-methoxy-N-methylbenzamide (9.37 g, 45 mmol) in THF (80 mL) was then added dropwise while keeping the internal temperature below 5° C. The reaction mixture was then allowed to warm up and stirred at room temperature for 1 h. A mixture of ice-cold water (50 mL) and aq. HCl (1 M, 55 mL) was added to the reaction mixture, the layers were separated, the water phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried. Purification on silica gel followed by recrystallization from diethyl ether afforded [3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methanone as a bright yellow solid [3.06 g, yield 25%; HPLC/MS m/z=232 (M+H); logP(HCOOH)=2.21].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12]/[C:11](=[C:19]3/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/3=[O:24])/[CH:10]=2)=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35](Cl)=[O:36])[CH2:31][CH2:30]1>C1COCC1>[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([C:35]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8][C:9]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[NH:12]/[C:11](=[C:19]4/[C:20]([CH2:25][CH2:26][CH3:27])=[N:21][NH:22][C:23]/4=[O:24])/[CH:10]=3)=[CH:6][CH:7]=2)=[O:36])[CH2:31][CH2:30]1
Reactant: CN1CCC(C(=O)Cl)CC1
Reactant: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1
Solvent: C1CCOC1
Product: CCCC1=NNC(=O)/C1=C1/C=C(Sc2ccc(NC(=O)C3CCN(C)CC3)cc2)c2ccccc2N1

Procedure:
The title compound was synthesized using (Z)-4-(4-(4-aminophenylthio)quinolin-2(1H)-ylidene)-3-propyl-1H-pyrazol-5(4H)-one and 1-methylpiperidine-4-carbonyl chloride in THF according to the procedure described in the synthesis of Example 26. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (t, J=7.33 Hz, 3H) 1.32 (dq, J=14.84, 7.35 Hz, 2H) 1.79-1.90 (m, 2H) 2.02-2.05 (m, 2H) 2.16-2.18 (m, 2H) 2.58-2.69 (m, 2H) 2.79-2.84 (m, 3H) 2.94-3.06 (m, 2H) 6.73 (s, 1H) 7.57 (t, J=7.45 Hz, 1H) 7.69 (d, J=8.59 Hz, 2H) 7.79-7.91 (m, 4H) 8.09 (d, J=8.08 Hz, 1H) 9.28 (s, 1H) 10.45 (s, 1H); ESI-MS: m/z calc'd for C28H31N5O2S 501.64. found 502.1 (M+H)+.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].C[O-].[Na+].[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH:26]([C:31](=O)[CH2:32][CH2:33][CH2:34][CH3:35])[C:27](OC)=[O:28])=[CH:21][CH:20]=1)#[N:12]>CO.O1CCOCC1>[CH2:32]([C:31]1[N:6]=[C:4]([CH:3]([CH3:7])[CH3:2])[NH:5][C:27](=[O:28])[C:26]=1[CH2:25][C:22]1[CH:21]=[CH:20][C:19]([C:14]2[C:13]([C:11]#[N:12])=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:24][CH:23]=1)[CH2:33][CH2:34][CH3:35]
Reactant: CC(C)C(=N)N
Reactant: CCCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CCCCc1nc(C(C)C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Yield: 62.8 %

Procedure:
A solution of 2-methylpropanimidamide hydrochloride (10 g), 28% sodium methoxide (25 mL) and methyl 2-[(2′-cyanobiphenyl-4-yl)methyl]-3-oxoheptanoate (14 g) in methanol (140 mL) and 1,4-dioxane (70 mL) was stirred overnight. The solvent was evaporated under reduced pressure, and water and 1 M hydrochloric acid were added. The precipitated solid was collected by filtration, and washed with water and diethyl ether to give the title compound (9.7 g, 62%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:14]([O:15]C2CCCCO2)=[C:13]([CH3:22])[C:12]([CH:23]=O)=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1(O2)[CH2:9][CH2:8][CH2:7]1.[Br-].[H-].[Na+].[OH2:28].[CH3:29]N(C=O)C>>[CH3:1][C:2]1[C:14]([OH:15])=[C:13]([CH3:22])[C:12]([CH:23]=[CH2:29])=[C:11]2[C:3]=1[CH2:4][CH2:5][C:6]1([O:28]2)[CH2:7][CH2:8][CH2:9]1
Reactant: O
Reactant: Cc1c(C=O)c2c(c(C)c1OC1CCCCO1)CCC1(CCC1)O2
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=Cc1c(C)c(O)c(C)c2c1OC1(CCC1)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 5,7-dimethyl-6-(tetrahydro-2H-pyran-2-yloxy)spiro[chroman-2,1′-cyclobutane]-8-carbaldehyde (1.5 g) and triphenylphosphinemethyl bromide (2.5 g) and sodium hydride (400 mg) in DMF (20 mL) was stirred at 40° C. for 5 h. After pouring it into water, it was extracted with ethyl acetate, and the organic layer was dried and evaporated. Then the residue was dissolved in MeOH with dil. HCl and it was stirred at room temperature for 30 min. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was washed, dried, and evaporated. The residue was purified by silica gel column eluting with 10% ethyl acetate in hexane, giving 507.7 mg of 5,7-dimethyl-8-vinyl-3,4-dihydrospiro[chromene-2,1′-cyclobutan]-6-ol as a light brown oil.
Reaction SMILES: [CH:1]([C:3](=[C:8]([CH3:10])[CH3:9])[CH2:4][C:5]([OH:7])=[O:6])=[O:2].CCOCC.[Cl-:16].[Li+].Cl>O>[Cl:16][C:8]([C@H:3]1[C@H:1]([OH:2])[O:6][C:5](=[O:7])[CH2:4]1)([CH3:10])[CH3:9]
Reactant: CC(C)=C(C=O)CC(=O)O
Reactant: [Cl-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CC(C)(Cl)[C@@H]1CC(=O)O[C@H]1O
Temperature: 25 °C
Reaction time: 54 h

Procedure:
A mixture of 1 g of 3-formyl-4-methyl-pent-3-ene-1-oic acid, 25 ml of anhydrous ether and 1 g of lithium chloride was stirred under a current of gaseous hydrogen chloride at -30° C. for 2 hours and then for 2 hours at 0° C. after which the gaseous hydrogen chloride was shut off. The mixture was stirred at room temperature for 48 hours and after 54 hours of contact, the mixture was poured into iced water. The decanted aqueous phase was extracted with benzene and the organic phase was dried and evaporated to dryness under reduced pressure. The 1.1 g of residue was chromatographed over silica gel and was eluted with a 1-1 benzene-ethyl acetate mixture to obtain 545 mg of crystalline (dl trans 4-(2-chloro-prop-2-yl)-5-hydroxy-tetrahydrofuran-2-one melting at 80° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23].[NH:24]1[C:32]2[C:27](=CC=C[CH:31]=2)[C:26]2(COC3C=C4C(=[CH:43][C:33]2=3)CCO4)C1=O.Br.BrCC1C=CC=CN=1.BrCC1CCCCO1>>[N:24]1[CH:43]=[CH:33][CH:26]=[CH:27][C:32]=1[CH2:31][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:21][CH2:20][CH2:19][CH2:18][O:17][C:16]=4[CH:22]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:23]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Agent: Br
Agent: BrCC1CCCCO1
Agent: BrCc1ccccn1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1cc3c(cc12)OCCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and 2-(bromomethyl)pyridine hydrobromide to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-(pyridin-2-ylmethyl)-3,4-dihydro-2H-spiro[furo[2,3-h][1,5]benzodioxepine-9,3′-indol]-2′(1′H)-one was obtained (90%) as a colorless solid: mp 122-123° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ8.59 (d, J=4.8 Hz, 1H), 7.71 (ddd, J=7.8, 7.5, 1.2 Hz, 1H), 7.31-7.15 (m, 4H), 7.03 (dd, J=7.5, 7.5 Hz, 1H), 6.92 (d, J=7.8 Hz, 1H), 6.61 (s, 1H), 6.42 (s, 1H), 5.24 (d, J=15.9 Hz, 1H), 5.04 (d, J=15.9 Hz, 1H), 4.98 (d, J=9.0 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.28-4.20 (m, 1H), 4.14-4.05 (m, 2H), 4.02-3.94 (m, 1H), 2.22-2.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ177.5, 156.8, 155.4, 153.1, 149.1, 146.3, 142.1, 137.7, 132.2, 129.0, 124.0, 123.7, 123.1, 123.0, 121.9, 116.2, 109.6, 103.6, 80.5, 70.87, 70.85, 58.1, 45.9, 32.2; MS (ES+) m/z 401.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15]#[N:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-:17].[NH4+]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15]([NH2:16])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: N#CCC1NCCc2ccc([N+](=O)[O-])cc21
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)CC1NCCc2ccc([N+](=O)[O-])cc21
Reaction time: 6 h
Yield: 89 %

Procedure:
To cold concentrated sulfuric acid (100 ml) was added, in a single portion, 7-nitro-1,2,3,4-tetrahydroisoquinoline-1-acetonitrile (12.6 g, 58.0 mmol). The reaction mixture was stirred for 6 h at that temperature after which time all the starting material had dissolved. The reaction mixture was poured on ice and the solution made basic with concentrated ammonium hydroxide at such a rate as to control the exotherm. The precipitated product was collected, washed with copious amounts of water, and air-dried to give the title compound as a red solid (12.1 g, 89%), m.p. 246-7° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][NH2:24])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(OCC(Cl)=O)(=O)C.N1C=CC=CC=1.[O:41]1[CH2:45][CH2:44][CH2:43][CH2:42]1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][N:24]5[CH2:45][CH2:44][CH2:43][C:42]5=[O:41])[CH:21]=4)[CH:16]=[CH:15]3)[CH2:12][CH2:13]2)=[CH:25][CH:26]=1
Reactant: C1CCOC1
Reactant: NCc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Agent: CC(=O)OCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1CCCN1Cc1ccc2ccn(C3CCN(CCc4ccc(F)cc4)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
A mixture of 1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindole (150 mg) obtained in Example 322-3), acetoxyacetyl chloride (64 mg), pyridine (3 ml) and tetrahydrofuran (5 ml) was stirred under ice cooling for 30 min. Then ice water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the resulting residue were added methanol (10 ml) and potassium carbonate (100 mg) followed by stirring for 30 min. Then ice water and ethyl acetate were added to the reaction mixtures. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/ethanol system) to give the title compound (140 mg) as white scales (yield: 80%).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]([CH3:27])[N:17]=[N:18][C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:9][CH:8]=1>O.C1COCC1.CO>[F:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]2[N:18]=[N:17][N:16]([CH3:27])[C:15]=2[CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:28])=[O:5])=[CH:8][N:9]=2)=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)nnn2C)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nnc(-c2ccc(F)cc2)c1COc1ccc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A solution of lithium hydroxide monohydrate (101 mg, 2.41 mmol) in water (3 mL) was added dropwise to a suspension of 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-nicotinic acid methyl ester (413 mg, 1.21 mmol) in THF (3 mL) and MeOH (0.6 mL). The reaction mixture was then stirred at room temperature for 1 h. The reaction mixture was then evaporated and the residue dissolved in water, acidified with HCl (1N), and the resulting precipitate filtered off to afford the title product (380 mg, 96%) as a white solid. MS: m/e=327.3 [M−H]−.