Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][N:12]3[C:19]=2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:5][CH:4]=1)=O.[CH2:26]([N:28](CC)CC)[CH3:27].Cl.Cl.[CH3:35][C:36]1[CH:41]=[C:40]([C:42]2[NH:46][N:45]=[C:44]([CH:47]3[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]3)[N:43]=2)C=CN=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C1COCC1.C(Cl)(Cl)Cl>[CH3:27][C:26]1[N:28]=[C:40]([C:42]2[NH:43][C:44]([CH:47]3[CH2:48][CH2:49][N:50]([CH2:1][C:3]4[CH:8]=[CH:7][C:6]([C:9]5[N:10]=[C:11]6[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[CH:13][N:12]6[C:19]=5[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:5][CH:4]=4)[CH2:51][CH2:52]3)=[N:45][N:46]=2)[CH:41]=[CH:36][CH:35]=1
Reactant: CCN(CC)CC
Reactant: Cc1cc(-c2nc(C3CCNCC3)n[nH]2)ccn1
Reactant: N#Cc1ccn2c(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cccc(-c2nnc(C3CCN(Cc4ccc(-c5nc6cc(C#N)ccn6c5-c5ccccc5)cc4)CC3)[nH]2)n1
Reaction time: 0.08 h

Procedure:
To a solution of 0.150 g (0.464 mM) 2-(4-formylphenyl)-3-phenylimidazo[1,2-a]pyridine-7-carbonitrile in 3 mL of THF is added triethylamine (2 eq). The reaction mixture is stirred for 5 minutes. To this solution is added 2-methyl-4-[3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl]pyridine dihydrochloride (Intermediate C) (1.5 eq) followed by acetic acid (2.5 eq). The reaction mixture is stirred for 10 minutes. To this mixture is added NaBH(OAc)3 (6 eq) over a period of 40 minutes. The reaction mixture is stirred overnight. The reaction mixture is quenched with methanol and concentrated. The residue obtained is taken up in chloroform and washed with water, dried and concentrated. The crude is purified on a flash column chromatography to obtain the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C@@H:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)(Cl)=O.[CH:28]1(O)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([O:16][C:15](=[O:17])[C@@H:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)(=[O:12])=[O:11])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)[C@@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Reactant: OC1CCCC1
Solvent: O=S(Cl)Cl
Product: O=C(OC1CCCC1)[C@@H](NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 70 °C
Yield: 70 %

Procedure:
To a solution of stage 1 acid (4.32 g, 12.8 mmol) in cyclopentanol (60 ml) at 0° C. was added slowly thionyl chloride (9.3 ml, 128 mmol). The reaction mixture was stirred and heated under reflux at 70° C. for 2 hours. The excess thionyl chloride was removed by evaporation in vacuo, the reaction mixture was extracted into EtOAc and washed with saturated NaHCO3 solution and dried over Na2SO4, filtered and evaporated to dryness. Flash column chromatography purification with DCM gave the required product (3.6 g, 70% yield). LCMS purity of 100%, (molecular ion not observed).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][C:16]=2[CH:17]=[N:18][OH:19])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N+:18]([O-:19])=[CH:17][C:16]3[C:11]([CH:10]=2)=[CH:12][N:13]=[CH:14][CH:15]=3)=[CH:5][CH:4]=1
Reactant: COc1ccc(C#Cc2cnccc2C=NO)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2cc3cnccc3c[n+]2[O-])cc1
Temperature: 70 °C
Reaction time: 0.83 h
Yield: 79.5 %

Procedure:
3-(4-Methoxyphenylethynyl)-4-pyridine aldoxime (4.724 g) was dissolved in ethanol (100 ml), followed by the addition of potassium carbonate (2.768 g)/water (30 ml) solution, and the mixture was stirred at 70° C. for 50 min. After cooling as it was, the resulting insoluble matters were collected by filtration, and then washed with water and ethanol, to give the title compound as a dark green solid (3.757 g, yield; 75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12](Br)[CH:13]=[CH2:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH2:14]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:6][CH:7]=1)[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: O=C(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOc1ccc(CC(=O)O)cc1

Procedure:
p-Hydroxyphenylacetic acid (5.0 g) is dissolved in 30 ml of dimethyl formamide, 10 ml of allyl bromide and 10 g of anhydrous potassium carbonate are added thereto, and the mixture is heated at 70°-80° C. for six hours with stirring. The reaction solution is diluted with 300 ml of water, extracted with ether, the resulting extract is dissolved in 100 ml of methanol, and the mixture is heated to reflux for one hour with 30 ml of 15% aqueous solution of potassium carbonate. The reaction solution is then concentrated in vacuo, 100 ml of water is added thereto, the mixture is washed with ether, acidified with hydrochloric acid, and extracted with ether to give 5.0 g of p-allyloxyphenylacetic acid, melting point: 61°-62° C.
Reaction SMILES: N(OC(C)(C)C)=O.[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:36]=[C:37](N)[S:38][CH:39]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(OCC)(=O)C.O>O1CCCC1>[C:8]([O:12][C:13]([CH2:15][O:16][N:17]=[C:18]([C:35]1[N:36]=[CH:37][S:38][CH:39]=1)[C:19]([O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[O:20])=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1csc(N)n1
Agent: CC(C)(C)ON=O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CON=C(C(=O)OC(c1ccccc1)c1ccccc1)c1cscn1
Yield: 45.5 %

Procedure:
A solution of t-butyl nitrite (1.7 g) in tetrahydrofuran (10 ml) was dropwise added to a solution of benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetate (syn isomer) (5 g) in tetrahydrofuran (50 ml) at 50° to 53° C. under stirring and the mixture was stirred at the same temperature at 25 minutes. The reaction mixture was poured into a mixture of ethyl acetate and water and the organic layer was separated. The organic layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was subjected to column chlomatography on silica gel. The elution was carried out with a mixture of benzene and ethyl acetate (19:1) and the eluates containing the object compound were evaporated to give benzhydryl 2-t-butoxycarbonylmethoxyimino-2-(4-thiazolyl)acetate (syn isomer) (2.2 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([OH:23])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)CC)C.CO>C(Cl)Cl>[Si:1]([O:8][CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[C:16]([N:19]2[CH2:22][CH:21]([O:23][S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20]2)[S:17][CH:18]=1)=[O:13])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(O)C2)n1
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCNC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
To a solution of 1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-hydroxyazetidine (531.1 mg, 1.49 mmol) (obtained as described in Reference Example 33(4)) in methylene chloride (26.6 ml) were added methanesulfonyl chloride (0.3 ml, 3.9 mmol) and triethylamine (0.52 ml, 3.7 mmol) in an ice bath, and the mixture was stirred in the ice bath for 2 hours. After checking the completion of the reaction, methanol was added to the reaction mixture and the resulting mixture was stirred for 30 minutes. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using toluene:ethyl acetate (1:1) as the eluant to afford 1-{4-[2-(t-butyldimethylsilyloxy)ethylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (647.1 mg, yield 100%) as a pale yellow solid.
Reaction SMILES: C([Mg]Cl)(C)(C)C.CO[C:9](=[O:34])[CH2:10][C@H:11]([O:23][C:24](=[O:33])[CH:25](Br)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C1COCC1.C([Mg]Cl)(C)(C)C.C1COCC1>C(OCC)(=O)C>[CH2:26]([C:25]1[C:24](=[O:33])[O:23][C@H:11]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:10][C:9]=1[OH:34])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCCCCCC[C@H](CC(=O)OC)OC(=O)C(Br)CCCCCC
Agent: CC(C)(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCC[C@@H]1CC(O)=C(CCCCCC)C(=O)O1
Temperature: 0 °C
Yield: 78.5 %

Procedure:
In a 500 mL 3-necked round bottom flask fitted with a Claisen head with N2 inlet, a West condenser, a thermocouple-J-KEM controller and an addition funnel was added a solution of tert-butylmagnesium chloride (341 mL of a 1.0 M solution, 341 mmole, 3 equiv.) at about 60° C. Methyl-(R)-3-(2′-bromo-1′-oxooctyloxy)tetradecanoate (52.6.0 g, 113.5 mmole, 1 equiv.) (“bromodiester”) and 25 mL of dry THF were added to an addition funnel. The bromodiester mixture was slowly added to the t-BuMgCl/THF mixture at reflux over about one hour. The reaction mixture was sampled at 1 and 2 hours at about 60° C. (resulting in 90 and 91% area normalized gas chromatography (AN GC) analysis, respectively). After 2 hours the resulting reaction mixture was cooled and concentrated on a roto-evaporator to about ⅓ to about ½ the original volume. The resulting syrupy mixture was taken up in about 250 mL of toluene (or an ether, such as methyl tert-butyl ether and the like; a hydrocarbon, such as hexane, heptane, and the like; or mixtures thereof) and added to a mixture containing 250 mL of toluene, 75 mL of 10% HCl in a 1 L jacketed flask keeping the quenched solution below 30° C. The aqueous layer was removed. The organic layer washed one time with 50 mL of 1.0 N HCl solution. The aqueous layer was removed, the organic layer washed one time with 50 mL of water, dried over magnesium sulfate, filtered and concentrated. This resulted in a gel-like solid residue. The residue was dissolved in 250 mL of ethyl acetate at 40° C. The ethyl acetate was removed on the roto-evaporator. The resulting crude off-white solid (42.4 g) was slurried up in about 100 mL of hexane and cooled to 0° C., filtered and rinsed with 50 mL of cold hexane followed by another 25 mL of cold hexane. The isolated white solids were air dried under vacuum for about 1 to 2 hours resulting in 31.4 g of (6R)-3-hexyl-5,6-dihydro-4-hydroxy-6-undecyl-pyran-2-one (78.4% yield).
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][NH:14][C:13]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=3)=[N:12]2)=[CH:7][CH:6]=1.N1C=CC=CC=1.[CH3:37][S:38]([Cl:41])(=[O:40])=[O:39].[C:42]([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[ClH:41].[CH3:42][N:14]1[C:13]([CH2:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][S:38]([CH3:37])(=[O:40])=[O:39])=[CH:28][CH:29]=2)=[N:12][CH:11]([C:8]2[CH:7]=[CH:6][C:5]([O:4][CH3:3])=[CH:10][CH:9]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH2:15]1
Reactant: O=C([O-])[O-]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2N=C(CCc3ccc(N)cc3)NCc3ccccc32)cc1
Agent: Cl
Agent: [K+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2N=C(CCc3ccc(NS(C)(=O)=O)cc3)N(C)Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an ice-cooled solution of the amine of Example 384 (b) (3.33 g, 7.3 mmol) in CH2Cl2 (35 mL) was added pyridine (17 mL), followed by methanesulfonyl chloride (0.84 mL) in CH2Cl2 (10 mL). The mixture was warmed to room temperature, stirred for 1.5 hours, and poured into saturated K2CO3 (50 mL). The organic layer was separated and the precipitate which formed over 2 hours was collected by filtration. The solid was converted into the fumarate salt, which was purified by column chromatography on neutral alumina eluting with 5-6% methanol in CH2Cl2. The purified salt was then converted back into the free base and then into the hydrochloride salt to afford 1.224 g of 4,5-dihydro-4-methyl-1-(4-methoxyphenyl)-3-[2-(4-methylsulfonylaminophenyl)ethyl]-1H-2,4-benzodiazepine hydrochloride as a light yellow powder, m.p. 149° C. (dec.).
Reaction SMILES: [CH2:1]([Li])CCC.[F:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[F:15].CI>CCCCCC.O1CCCC1>[F:6][C:7]1[C:8]([F:15])=[CH:9][C:10]([F:14])=[C:11]([F:13])[C:12]=1[CH3:1]
Reactant: Fc1cc(F)c(F)cc1F
Reactant: [Li]CCCC
Solvent: CI
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(F)c(F)cc(F)c1F
Temperature: -60 °C
Reaction time: 2 h

Procedure:
A solution of n-butyllithium in hexane (1.6 M, 62.5 ml) was added dropwise to a well stirred solution of 1,2,4,5-tetrafluorobenzene (15.0 g) in dry tetrahydrofuran (150 ml) maintained at a temperature of -60° C. under an atmosphere of dry argon. When the addition was complete the mixture was stirred at -45° C. for 2 hours and then methyl iodide (14.2 g) was added dropwise whilst the temperature was kept at -45° C. After a period of 30 minutes the mixture was allowed to warm to the ambient temperature, poured into distilled water and the mixture extracted with diethyl ether (2×50 ml), and the extracts dried over anhydrous magnesium sulphate. After filtering the solution was concentrated by evaporation of the solvents at atmospheric pressure. The residual oil was distilled and the fraction boiling in the range 115°-122° C. at atmospheric pressure (6.2 g) collected, identified by n.m.r. and gas chromatographic analysis as consisting of ca. 95% of the required 2,3,5,6-tetrafluorotoluene and ca. 5% of 2,3,5,6-tetrafluoro-1,4-xylene.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:10])([CH3:9])[C:5](OC)=[O:6].[C:11](#[N:13])[CH3:12]>O1CCCC1.O>[C:4]([C:5]([CH2:12][C:11]#[N:13])=[O:6])([CH3:10])([CH3:9])[CH3:3]
Reactant: COC(=O)C(C)(C)C
Reactant: CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)CC#N
Temperature: 25 °C
Yield: 56 %

Procedure:
A suspension of 9.6 g of sodium hydride in 300 ml of tetrahydrofuran was stirred at 60° C. while a mixture of 23.2 g of methyl trimethylacetate and 8.2 g of acetonitrile was added in one portion. The reaction mixture was heated at reflux for five hours, and then cooled to room temperature and concentrated by evaporation of the solvent under reduced pressure. The product thus formed was dissolved in water and washed with dichloromethane. The aqueous layer was made acidic with 1N hydrochloric acid, and the acidic solution was extracted with fresh dichloromethane. The organic extracts were combined, washed with water, dried, and the solvent was removed by evaporation to give 14.0 g of cyanomethyl tert.-butyl ketone.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[CH:11][C:10]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].O>CC(O)=O.Br.[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-]>[OH:2][C:3]1[C:12]([OH:13])=[CH:11][C:10]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(S(=O)(=O)c2ccc(C)cc2)cc(OC)c1OC
Agent: Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)c2cc(O)c(O)c(C(=O)O)c2)cc1
Temperature: 140 °C
Reaction time: 20 h

Procedure:
Methyl 2,3-dimethoxy-5-(toluene-4-sulfonyl)-benzoate (1.3 g, 4.036 mmol) was dissolved in 5 mL AcOH to which HBr (15 mL of a 33% solution in AcOH) and Bu4NBr (1.1 g, 3.4 mmol, 0.85 eq.) were added. The reaction mixture was stirred at 140° C. for 20 h, then H2O was slowly added and the mixture was extracted with EtOAc. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc/AcOH 3:2:0.2→1:3:0.2) to yield the desired product as an orange solid.
Reaction SMILES: C(NC1C=CN([C@@H]2O[C@H](CO)[C@@H](O)C2)C(=O)N=1)(=O)C1C=CC=CC=1.C(NC1C=CN([C@@H]2O[C@H](CO)[C@@H](OC(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)C2)C(=O)N=1)(=O)C1C=CC=CC=1.[C:72]([NH:80][C:81]1[CH:140]=[CH:139][N:84]([C@@H:85]2[O:115][C@H:89]([CH2:90][O:91][C:92]([C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)([C:101]3[CH:106]=[CH:105][C:104]([O:107][CH3:108])=[CH:103][CH:102]=3)[C:93]3[CH:98]=[CH:97][C:96]([O:99][CH3:100])=[CH:95][CH:94]=3)[C@@:87](C(C3C=CC=CC=3)(C3C=CC(OC)=CC=3)C3C=CC(OC)=CC=3)([OH:88])[CH2:86]2)[C:83](=[O:141])[N:82]=1)(=[O:79])[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1.O>C(#N)C>[C:72]([NH:80][C:81]1[CH:140]=[CH:139][N:84]([C@@H:85]2[O:115][C@H:89]([CH2:90][O:91][C:92]([C:109]3[CH:114]=[CH:113][CH:112]=[CH:111][CH:110]=3)([C:93]3[CH:98]=[CH:97][C:96]([O:99][CH3:100])=[CH:95][CH:94]=3)[C:101]3[CH:106]=[CH:105][C:104]([O:107][CH3:108])=[CH:103][CH:102]=3)[C@@H:87]([OH:88])[CH2:86]2)[C:83](=[O:141])[N:82]=1)(=[O:79])[C:73]1[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=1
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@]2(O)C(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: COc1ccc(C(O[C@H]2C[C@H](n3ccc(NC(=O)c4ccccc4)nc3=O)O[C@@H]2CO)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C(Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)c1ccccc1
Solvent: O
Solvent: CC#N
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3ccc(NC(=O)c4ccccc4)nc3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1

Procedure:
Referring to PCT Publication No. WO00/75154, the non-hydrated N4-benzoyl-5′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine (2.00 g), including N4-benzoyl-2′-deoxycytidine, N4-benzoyl-3′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine, and N4-benzoyl-3′, 5′-O-bis(4, 4′-dimethoxytrityl)-2′-deoxycytidine with rates by peak areas of 1.0%, 0.15%, and 2.2%, respectively, was dissolved in acetonitrile (2.3 mL). The solution was added dropwise to water (41 mL) with vigorous stirring and the resultant mixture was stirred for one hour. A white precipitate was recovered by filtration, was washed twice with water and was dried at 50° C. in a vacuum to yield N4-benzoyl-5′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine (1.82 g). The XRD pattern and the DSC thermogram showed neither an absorption peak nor an endothermic peak due to the crystallization, which indicates the resultant components was not crystallized. Moreover, the component contained N4-benzoyl-2′-deoxycytidine, N4-benzoyl-3′-O-(4, 4′-dimethoxytrityl)-2′-deoxycytidine, and N4-benzoyl-3′, 5′-O-bis(4, 4′-dimethoxytrityl)-2′-deoxycytidine and the respective peak areas were 0.9%, 0.13%, and 1.8%, respectively, which indicates that the above procedure had no substantial effect on the purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].O1COCO[CH2:13]1.FC(F)(F)C([O-])=O.C[NH2+]C1C=CC=CC=1.CCOCC>C1COCC1>[OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][C:5](=[CH2:13])[C:6]2=[O:11]
Reactant: O=C1CCc2c(O)cccc21
Reactant: C1OCOCO1
Agent: C[NH2+]c1ccccc1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C1Cc2c(O)cccc2C1=O

Procedure:
To a solution of 4-hydroxy-1-indanone (1 g; 6.7 mmol) in THF were added, at ambient temperature and under argon, powdered 1,3,5-trioxane (1.2 g; 13.4 mmol) and N-methyl-N-phenylammonium trifluoroacetate (2.9 g; 13.4 mmol). The suspension was refluxed for 4 hours. Ether was added to the mixture and the resulting precipitate was filtered off. The organic phase was washed with water, dried over MgSO4, filtered and evaporated. The residue obtained was purified by flash chromatography on silica gel, eluting with petroleum ether/ethyl acetate (8/2) to give 4-hydroxy-2-methylene-1-indanone as a beige solid (0.76 g; 70%).
Reaction SMILES: [OH:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18].[C:26](OC(=O)C)(=[O:28])[CH3:27]>N1C=CC=CC=1>[C:26]([O:1][CH:2]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=[CH:4][C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[C@H:6]1[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])(=[O:28])[CH3:27]
Reactant: CCCCCC(O)C=C[C@@H]1CCC(=O)[C@H]1C/C=C\CCCC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCCCCC(C=C[C@@H]1CCC(=O)[C@H]1C/C=C\CCCC(=O)OC)OC(C)=O
Temperature: 0 °C

Procedure:
A solution of the compound of formula I, methyl trans,cis- 7-[2-(3-hydroxy-1-octenyl)-5-oxocyclopentyl]-5-heptenoate (5 g), described in Example 161, in 50 ml of pyridine and 50 ml of acetic anhydride is stirred at room temperature for 4 hr. The solution is diluted with ice-water and extracted with ether. The ether is washed with 10% H2SO4, water 10% Na2CO3 and water, dried (Na2SO4) and evaporated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.[CH:11]([C:13]1[CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]([OH:22])=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.C(OCC)(=O)C>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][O:22][C:16]1[CH:15]=[CH:14][C:13]([CH:11]=[O:12])=[CH:21][C:17]=1[C:18]([O:20][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1])=[O:19]
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2F)c(C(=O)OCc2ccc(F)cc2F)c1
Yield: 95.6 %

Procedure:
2,4-Difluorobenzyl bromide (0.77 mL, 6 mmol, 1 eq) was added dropwise to a stirred solution of 5-formylsalicylic acid (1 g, 6 mmol, 1 eq) and cesium carbonate (5.87 g, 18 mmol, 3 eq) in N,N-dimethylformamide (30 mL). The reaction mixture was diluted with ethyl acetate (50 mL) and the organic solution washed with water (50 mL), saturated aqueous sodium bicarbonate (2×50 mL) and brine (50 mL), then dried over sodium sulfate and evaporated in vacuo to give the product as a white powder (1.2 g, 50%). 1H NMR (CDCl3) δ9.91 (s, 1H, O═C—H), 5.37 (s, 2H, CH2Ar), 5.25 (s, 2H, CH2Ar).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2.Cl.[C:22](=[O:25])([O-])[O-:23].[K+].[K+].[CH2:28](C(Cl)(Cl)Cl)[CH:29]([CH3:31])[CH3:30]>CN(C=O)C>[CH2:28]([O:23][C:22](=[O:25])[N:2]([CH2:3][CH2:4][CH2:5][N:6]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2)[CH3:1])[CH:29]([CH3:31])[CH3:30]
Reactant: CC(C)CC(Cl)(Cl)Cl
Reactant: CNCCCN1c2ccccc2CCc2ccccc21
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)COC(=O)N(C)CCCN1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Desipramine hydrochloride (1 equivalent, 0.3 gram) was added drop wise to a stirred solution of potassium carbonate (5 equivalents, 0.68 gram) in dry DMF at 0° C. Isobutyl chloroform (1.5 equivalents, 0.18 ml) which had been dissolved in dry DMF was added drop wise to this mixture and stirred for 6 hours at room temperature. The reaction mixture was quenched with water, extracted with ethyl acetate, the organic layer separated, washed with brine solution and dried over anhydrous sodium sulfate. The dried material was concentrated and purified by column chromatography to provide a pale yellow liquid (yield: 0.18 gram) and analyzed by HPLC (purity 96.4%) The FTIR, MS and 1H NMR spectra were consistent with the assigned structure with the empirical formula of C22H28N2O2.