Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na:1].C(O[C:5](=O)[CH2:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[CH2:16](Br)[CH:17]=C.[OH-].[K+]>C(O)C.O>[Na:1].[C:8]1([C:7]([CH2:6][CH2:5][CH:16]=[CH2:17])=[O:14])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: C=CCBr
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCC(=O)c1ccccc1
Yield: 98 %

Procedure:
A sodium solution of alcohol was prepared by dissolving 33 g of sodium in 1000 mL of ethanol. To the warm solution, 260 mL of benzoyl-acetic acid-ethylester was added and then 130 mL of allyl bromide was slowly dropped into the solution. The mixture was refluxed for 4 hrs. and then the solid removed in a vacuum. The resulting solid was then combined in an aqueous solution of potassium hydroxide prepared by combining 145 g of potassium hydroxide with 500 mL of water. This mixture was heated under reflux for 4 hrs. The mixture was then neutralized and extracted three times with 150 mL of diethylether. The organic layer was separated, washed twice with water, and dried. The solvent was removed in a vacuum to produce a 98 percent yield of phenyl-(but-3-enyl) ketone.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[Li]CCCC.FC(F)(F)S(O[Si:20]([CH3:23])([CH3:22])[CH3:21])(=O)=O>C1COCC1.CCCCCC.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Si:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: Brc1ccccc1Br
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1ccccc1Br
Reaction time: 0 h
Yield: 69 %

Procedure:
A microsystem composed of three T-shaped micromixers (M1, M2 and M3) and two microtube reactors (R1 and R2) was used. The whole microsystem was dipped in a cooling bath (−78° C.). A solution of o-dibromobenzene (0.27 M) in THF (flow rate: 6 mL/min, 1.62 mmol/min) and a solution of n-BuLi (1.5 M) in n-hexane (flow rate: 1.2 mL/min, 1.8 mmol/min) were introduced to the first T-shaped mixer M1 (inner diameter: 250 μm) by using syringe pumps. The resulting solution was passed through the tube reactor R1 and was mixed with trimethylsilyl trifluoromethanesulfonate (Me3SiOTf) (0.65 M) in Et2O (flow rate: 3 mL/min, 1.95 mmol/min) in the second T-shaped mixer M2 (inner diameter: 500 μm). The resulting solution was passed through the tube reactor R2 and was introduced to the third T-shaped mixer M3 (inner diameter: 500 μm), where the solution was quenched with methanol (neat, flow rate=3.0 mmol/min). The residence time of the tube reactor R1 (inner diameter: 500 μm, length=50 cm) was 0.82 second. The residence time of the tube reactor R2 (inner diameter: 1,000 μm, length=100 cm) was 4.62 second. After finishing the reaction, an aliquot of the product solution was taken (15 sec) and was analyzed by GC (column, CBP1; 0.25 mm×25 m; initial oven temperature, 50° C.; rate of temperature increase, 10° C./min). As a result, 2-bromophenyltrimethylsilane (GC retention time: 15.9 min) was obtained in 69% yield. 1H NMR (400 MHz, CDCl3) δ: 0.39 (s, 9H), 7.18 (dt, J=8.0, 2.0 Hz, 1H), 7.26 (dt, J=8.0, 2.0 Hz, 1H), 7.42 (dd, J=7.6, 1.6 Hz, 1H), 7.51 (dd, J=7.6, 1.6 Hz, 1H) 13C NMR (100 MHz, CDCl3) δ: −0.4, 126.2, 130.4, 130.5, 132.6, 135.9, 141.0. HRMS (EI) m/z: calcd. for C9H13BrSi 227.9970, found 227.9967.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].C[Si]([N:20]=[C:21]=[S:22])(C)C.CN(C)C=O>CN(C)C(=O)C>[NH2:20][C:21]([NH:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8])=[S:22]
Reactant: C[Si](C)(C)N=C=S
Reactant: NC(=O)c1cc(-c2ccccc2)sc1N
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Product: NC(=O)c1cc(-c2ccccc2)sc1NC(N)=S
Yield: 35.3 %

Procedure:
A solution of 2-amino-5-phenyl-3-thiophenecarboxamide (1.09 g, 5 mmol) and trimethylsilyl isothiocyanate (0.85 ml, 6 mmol) in N,N-dimethylacetamide was stirred at 75° C. for 7 days. N,N-Dimethylformamide was added until solution. The solvent was removed and the resulting slurry was chromatographed on silica gel eluting with isohexane followed by methylene chloride and diethyl ether to give the product as a yellow solid (0.49 g, 35%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].Cl.[NH2:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=2)[O:17][C:16]1([CH3:29])[CH3:28]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([NH:14][CH:15]1[C:24](=[O:25])[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=2)[O:17][C:16]1([CH3:29])[CH3:28])=[O:8]
Reactant: COc1ccc2c(c1)OC(C)(C)C(N)C2=O
Reactant: COc1ccc(Cl)cc1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)OC(C)(C)C(NC(=O)c1cc(Cl)ccc1OC)C2=O
Temperature: 27 °C
Reaction time: 3 h

Procedure:
28.7 g (0.14 mol) of 5-chloro-2-methoxybenzoyl chloride were introduced into a solution of 33.5 g (0.13 mol) of 3-amino-2,2-dimethyl-7-methoxy-4-chromanone hydrochloride in 150 ml of pyridine at 10° C. After the mixture had been stirred at about 27° C. for three hours, it was introduced into ice/water and extracted twice with methylene chloride. The combined methylene chloride extracts were washed twice with 2N hydrochloric acid and with water and then dried and evaporated, and the residue was recrystallized from ethanol/DMF. The 3-(5-chloro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-4-chromanone had a melting point of 174° C.
Reaction SMILES: CN([CH:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]([C:24](=[O:41])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[CH3:39])=[CH:27][CH:26]=2)[CH2:16][CH2:15][CH2:14]1)CCCOC1CCCCO1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>C(O)C>[CH3:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH2:13][CH2:14][CH2:15][CH2:16]2)=[O:41])=[CH:26][CH:27]=1)=[O:40]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(N(C)CCCOC3CCCCO3)c3ccccc32)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCCc3ccccc32)cc1
Temperature: 60 °C
Yield: 68.3 %

Procedure:
To a solution of 5-(N-methyl-N-[3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)propyl]amino)-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.55 g) in ethanol (10 ml) is added pyridinium p-toluenesulfonate (0.03 g) and the mixture is heated at 60° C. overnight. After the mixture is refluxed for more 2 hours, water and pyridinium p-toluenesulfonate (0.03 g) are added thereto. The mixture is refluxed for 4 hours. The reaction solution is concentrated and to the resulting residue is added dichloromethane. The mixture is basified with aqueous sodium hydrogen carbonate solution and extracted three times with dichloromethane. The extract is washed with saturated saline solution and dried over magnesium sulfate. The solvent is distilled off and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=30 :1) to give 5-IN-methyl-N-(3-hydroxypropyl)amino]-1-[4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzazepine (0.26 g) as colorless amorphous.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)=[C:21]([O:24][CH3:25])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:49][C:50]2[CH:55]=[CH:54][C:53]([N:56]3[CH2:61][CH2:60][O:59][CH2:58][CH2:57]3)=[CH:52][CH:51]=2)=CC=1)([O-])=O>>[N:56]1([C:53]2[CH:52]=[CH:51][C:50]([NH:49][C:6]([N:8]3[CH2:13][CH2:12][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([O:26][CH2:27][CH2:28][CH2:29][N:30]6[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]6)=[C:21]([O:24][CH3:25])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:10][CH2:9]3)=[O:7])=[CH:55][CH:54]=2)[CH2:57][CH2:58][O:59][CH2:60][CH2:61]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2c(C3CCN(C(=O)OC(C)(C)C)CC3)ncnc2cc1OCCCN1CCN(C)CC1
Agent: Cl
Product: COc1cc2c(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)ncnc2cc1OCCCN1CCN(C)CC1

Procedure:
The title compound was prepared from 4-{6-Methoxy-7-[3-(4-methyl-piperazin-1-yl)-propoxy]-quinazolin-4-yl}-piperidine-1-carboxylic acid tert-butyl ester, prepared in the previous step, and (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 66a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 7.34 (s, 1H), 7.28 (m, 2H), 7.25 (s, 1H), 6.88 (m, 2H), 6.34 (s, 1H), 4.27 (m, 4H), 4.05 (s, 3H), 3.86 (m, 4H), 3.59 (tt, 1H), 3.16 (td, 2H), 3.11 (m, 4H), 2.57 (m, 2H), 2.65-2.34 (br, 8H), 2.30 (s, 3H), 2.21-2.08 (m, 4H), 2.03-1.95 (m, 2H). LC/MS (ESI): calcd mass 603.4, found 604.4 (MH)+.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][OH:16])([O-:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[Cl-].[Na+]>CN(C)C=O>[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15][O:16][C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1)([O-:11])=[O:10]
Reactant: CSc1nsc(Cl)n1
Reactant: O=[N+]([O-])c1cccc(CO)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nsc(OCc2cccc([N+](=O)[O-])c2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Into 4 ml of N,N-dimethylformamide were dissolved 334 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 3-nitrobenzyl alcohol, 331 mg of potassium carbonate was added thereto under, and the reaction mixture was stirred for 4 hours at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 320 mg of 5-(3-nitrobenzyloxy)-3-methylthio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (26)).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[C:7]1([N:13]=[C:14]=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1C=CC=CC=1>[C:7]1([NH:13][C:14]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)NN
Reactant: O=C=Nc1ccccc1
Solvent: c1ccccc1
Product: COC(=O)NNC(=O)Nc1ccccc1
Reaction time: 0.75 h
Yield: 98.7 %

Procedure:
A solution of methyl carbazate (91.9 g, 1.02 moles) in 450 ml of benzene was added dropwise with stirring during 45 min. to phenyl isocyanate (122 g, 1.02 moles); a temperature rise to near 80° C. was observed. After addition of the ester solution the mixture was heated under reflux, with stirring, for 45 min. Stirring was continued at ambient temperature for 15 hr. Removal of volatiles under reduced pressure gave 210.6 g (99%) of product ester, as long prisms, m.p. 154°-155°. Recrystallization from isopropyl alcohol/ethanol (4/1) gave a polymorph as chunky crystals, m.p. 166°-168°.
Reaction SMILES: [N+:1]([C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:18])[CH3:17])=[CH:6][CH:5]=1)([O-])=O>CCOC(C)=O.[Pd]>[NH2:1][C:4]1[CH:20]=[CH:19][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[NH:15][C:16](=[O:18])[CH3:17])=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1ccccc1Cc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccccc1Cc1ccc(N)cc1
Reaction time: 5 h
Yield: 99.1 %

Procedure:
A solution of N-[2-(4-nitrobenzyl)phenyl]acetamide (6.80 g, 25.2 mmol) in EtOAc (700 mL) was treated with Pd (10% on C, 0.53 g, 0.5 mmol). The mixture was stirred under a H2 atmosphere for 5 h. The reaction mixture was filtered through Celite, before being concentrated to yield N-[2-(4-aminobenzyl)phenyl]acetamide (6.00 g, 99%): δH ((CD3)2SO)=2.00 (s, 3H), 3.75 (s, 2H), 4.80 (s, 2H), 6.45 (d, 2H), 6.80 (d, 2H), 7.00–7.15 (m, 3H), 7.35 (d, 1H), 9.20 (s, 1H). A PhMe (75 mL) suspension of this aniline (5.00 g, 20.8 mmol) was treated with a solution of CF3COCH2CO2Et (3.83 g, 20.8 mmol) in PhMe (50 mL), before being heated under reflux for 1.5 h. The PhMe was evaporated off under reduced pressure, then the residue was dissolved in EtOAc (400 mL), before being washed with 0.2 M HCl (50 mL) & brine (50 mL). After drying (MgSO4), the EtOAc solution was filtered & concentrated to give a foam that was dissolved in H2SO4 (40 mL). The mixture was heated at 90° C. for 1.5 h, before being cooled & poured onto crushed ice. H2O was added to adjust the volume to 400 mL, then the off-white precipitate produced was collected by filtration & air-dried. The precipitate was treated with AcOH (8 mL) & 12 M HCl (40 mL), & the resulting suspension was heated under reflux. The solid gradually dissolved & heating was stopped after 4 h. The cooled reaction mixture was poured onto crushed ice (50 g), then H2O (200 mL) was added. The aqueous phase was basicified with solid NaOH, then the mixture was extracted with EtOAc (200 mL). The EtOAc layer was dried (MgSO4), filtered, & concentrated to provide the title compound (3.01 g, 45%): δH ((CD3)2SO)=3.85 (s, 2H), 4.85 (s, 2H), 6.50 (t, 1H), 6.60 (d, 1H), 6.85 (d, 1H), 6.90–7.00 (m, 2H), 7.35 (d, 1H), 7.50 (d, 1H), 7.55 (s, 1H); m/z (ES+)=360.3
Reaction SMILES: [Cl:1][C:2]([Cl:14])([Cl:13])[CH2:3][O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]=[CH:9][CH2:8]1)=[O:6].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[O:23]1[CH:10]2[CH:9]1[CH2:8][N:7]([C:5]([O:4][CH2:3][C:2]([Cl:1])([Cl:13])[Cl:14])=[O:6])[CH2:12][CH2:11]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC=CCC1
Solvent: ClCCl
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC2OC2C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
100 g (0.38 mol) of 1-(β,β,β-trichloroethoxycarbonyl)-1,2,5,6-tetrahydropyridine are dissolved in 1,200 ml of methylene chloride and the solution is treated with 157 g (0.77 mol) of 85% strength m-chloroperbenzoic acid in portions. The slightly exothermic reaction is kept at room temperature by means of a water bath. After the addition has ended (which takes about 2 hours), the reaction mixture, in which a white suspension forms, is stirred for a further 15 hours at room temperature. The m-chlorobenzoic acid which has precipitated is filtered off and the filtrate is washed with a saturated aqueous solution of sodium carbonate, then with aqueous iron-II sulphate solution, then with 0.1 N sodium hydroxide solution and finally with water, dried over sodium sulphate and evaporated under a water pump vacuum. The oil which remains is dissolved in 100 ml of benzene and the solution is filtered through a layer of silica gel. Elution with a benzene/ethyl acetate mixture (1:1) and evaporation of the solvent gives pure 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-piperidine in the form of a slightly orange coloured oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2OC(=O)[S:12][N:11]=2)=[CH:4][CH:3]=1.[S:16]([C:26]#[N:27])([C:19]1[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=1)(=[O:18])=[O:17].CCCCC>ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]2[N:27]=[C:26]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[S:12][N:11]=2)=[CH:6][CH:7]=1
Reactant: O=c1oc(CCc2ccc(Cl)cc2)ns1
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Solvent: Clc1ccccc1Cl
Solvent: CCCCC
Product: Cc1ccc(S(=O)(=O)c2nc(CCc3ccc(Cl)cc3)ns2)cc1
Yield: 64.7 %

Procedure:
10.90 g (45.1 mmol) of 5-[2-(4-chlorophenyl)ethyl]-1,3,4-oxathiazol-2-one and 8.58 g (47.4 mmol) of tosyl cyanide are stirred in 11 ml of 1,2-dichlorobenzene at 160° C. for 1 h. Subsequently, the reaction mixture is cooled and treated with 10 ml of pentane, and the precipitate is filtered off and dried under vacuum. 11.06 g of product are obtained (99.9% purity, 64.7% yield, log P (pH 2.3)=4.62).
Reaction SMILES: C([O:8][CH:9]1[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:11]([CH2:21][O:22][C:23]2[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][C:24]=2[O:34][CH3:35])[CH2:10]1)C1C=CC=CC=1>CCO.[Pd]>[C:17]([O:16][C:14]([N:12]1[CH2:13][CH:9]([OH:8])[CH2:10][CH:11]1[CH2:21][O:22][C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][C:24]=1[O:34][CH3:35])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)c1ccc(OCC2CC(OCc3ccccc3)CN2C(=O)OC(C)(C)C)c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(OCC2CC(O)CN2C(=O)OC(C)(C)C)c(OC)c1
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A stirred mixture of ethyl 4-[4-benzyloxy-1-(tert-butoxycarbonyl)-2-pyrrolidinyl]methoxy-3-methoxybenzoate (1.189 g, 2.449 mmol) and 5% Pd—C (240 mg) in EtOH (10 mL) was hydrogenated overnight at room temp. The mixture was filtered to remove the catalyst and the filtrate was concentrated in vacuo to give ethyl 4-[1-(tert-butoxycarbonyl)-4-hydroxy-2-pyrrolidinyl]methoxy-3-methoxybenzoate (735.3 mg, 76%) as a pale yellow oil. To a stirred cold (minus 78° C.) solution of DAST (0.491 mL, 3.718 mmol) in CH2Cl2 (7.4 mL) was added dropwise a solution of this compound in CH2Cl2 (2 mL), and the resulting mixture was stirred overnight. The mixture was quenched with water and extracted with CHCl3. The extract was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (3:1, v/v) as eluent to afford 418.7 mg (57%) ethyl 4-[1-(tert-butoxycarbonyl)-4-fluoro-2-pyrrolidinyl]methoxy-3-methoxybenzoate as an oil. 1H-NMR (400 MHz, CDCl3) δ 1.39 (t, J=7.3 Hz, 3H), 1.49 (s, 9H), 2.16 (br m, 1H), 2.58 (dd, J=15.6, 19.0 Hz, 1H), 3.60–3.75 (m, 2H), 3.91 (s, 3H), 3.97 (t, J=9.3 Hz, 1), 4.35 (q, J=7.3 Hz, 2H), 4.33–4.53 (m, 2H), 5.25 (d, J=52.7 Hz, 1H), 7.04 (dd, J=7.8, 56.2 Hz, 1H), 7.55 (s, 1H), 7.65 (br s, 1H); MS (FAB) m/z 398 (M++1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[CH:12]=[CH:13][C:14](=S)[NH:15][N:16]=2)[CH:10]=1)(=[O:3])[CH3:2].O.[NH2:29][NH2:30]>C(O)C>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:18][CH2:19][CH:20]([OH:27])[CH2:21][NH:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:9]([C:11]2[N:16]=[N:15][C:14]([NH:29][NH2:30])=[CH:13][CH:12]=2)[CH:10]=1)(=[O:3])[CH3:2]
Reactant: NN
Reactant: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(=S)[nH]n2)c1
Solvent: CCO
Solvent: O
Product: CC(=O)Nc1ccc(OCC(O)CNC(C)(C)C)c(-c2ccc(NN)nn2)c1

Procedure:
Reaction of 6-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-3(2H)-pyridazinethione with hydrazine hydrate in boiling ethanol followed by evaporation of the reaction mixture under reduced pressure gave the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:12][CH2:11]1)[CH:5]=O.[CH:22]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:24])[CH3:23]>>[CH:22]([N:25]1[CH2:30][CH2:29][N:28]([CH2:5][C:4]2[CH:7]=[CH:8][C:9]([N:10]3[CH2:15][CH2:14][CH:13]([CH2:16][N:17]4[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)=[C:2]([CH3:1])[CH:3]=2)[CH2:27][CH2:26]1)([CH3:24])[CH3:23]
Reactant: CC(C)N1CCNCC1
Reactant: Cc1cc(C=O)ccc1N1CCC(CN2CCCC2)CC1
Product: Cc1cc(CN2CCN(C(C)C)CC2)ccc1N1CCC(CN2CCCC2)CC1

Procedure:
Prepared from the product of Example 66 and 1-isopropylpiperazine.
Reaction SMILES: OC1C=CC(C(=O)C)=CC=1.[C:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21](O)[CH3:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12].OS([O-])(=O)=O.[K+]>>[C:11]([O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]=[CH2:22])=[CH:17][CH:16]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)Oc1ccc(C(C)O)cc1
Agent: CC(=O)c1ccc(O)cc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Product: C=Cc1ccc(OC(C)=O)cc1

Procedure:
p-Hydroxyacetophenone was converted to 1-(p-acetoxyphenyl)ethanol and then dehydrated using liquid phase dehydration in the presence of potassium acid sulfate to produce p-acetoxystyrene, according to the method of Corson et al (J. Org. Chem., 1958 23, 544). p-Acetoxystyrene (1.6 g) was added to a stirred solution of potassium hydroxide (1.4 g) in water (14 ml) at 5 degrees Centigrade. Stirring was continued at 0-5 degrees Centigrade for 2 h. The mixture was then washed with ether, and the aqueous phase neutralised with saturated sodium hydrogen carbonate solution. The product was extracted into dichloromethane, the solution was dried over anhydrous calcium chloride and the solvent removed, to yield a cloudy oil (0.7 g) which solidified on standing to a waxy solid.
Reaction SMILES: [OH:1][CH:2]([CH2:30][O:31]C)[CH2:3][N:4]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:13]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:12]=3[C:11]=2[C:10]2[CH:9]=[C:8]([O:28]C)[CH:7]=[CH:6][C:5]1=2>C(OCC)(=O)C.CCCCCC>[OH:1][CH:2]([CH2:30][OH:31])[CH2:3][N:4]1[C:16]2[CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:13]3[C:23](=[O:27])[NH:24][C:25](=[O:26])[C:12]=3[C:11]=2[C:10]2[CH:9]=[C:8]([OH:28])[CH:7]=[CH:6][C:5]1=2
Reactant: COCC(O)Cn1c2ccc(OC)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CC(O)CO
Yield: 31.6 %

Procedure:
Demethylation of alcohol (225) (96 mg, 0.22 mmol) prepared as described in example 290 employing the procedure described in example 80 was followed by chromatography on silica eluting with ethyl acetate/hexane (4:1). Crystallisation from ethyl acetate/hexane gave phenol (226) (28 mg, 31%) as an orange/yellow powder, mp 290–295° C. 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.30 (s, 1H), 8.40 (d, J=2.4 Hz, 1H), 7.79 (s, 1H), 7.63 (m, 2H), 7.55 (d, J=8.8 Hz, 1H), 7.47 (m, 3H), 7.11 (dd, J=8.8, 2.4 Hz, 1H), 5.00 (d, J=5.4 Hz, 1H), 4.86 (t, J=5.4 Hz, 1H), 4.51 (dd, J=3.8, 14.9 Hz, 1H), 4.35 (dd, J=7.5, 14.9 Hz, 1H), 3.89 (m, 1H), 3.41 (m, 2H). Found: C, 67.94; H, 4.69; N, 6.50. C23H18N2O5.1/4H2O requires: C, 67.89; H, 4.58; N, 6.88.
Reaction SMILES: [C:1]([CH:4]1[O:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:6]1[CH2:7][CH2:8][O:9][CH:4]([C:1](=[O:3])[CH3:2])[CH2:5]1
Reactant: CC(=O)C1CN(C(=O)OC(C)(C)C)CCO1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)C1CNCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.7 %

Procedure:
To a solution of tert-butyl 2-acetylmorpholine-4-carboxylate (6.9 g, 30.0 mmol) in DCM (80 mL) was added TFA (20 mL). The mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated to give 1-(morpholin-2-yl)ethanone (3.9 g, crude) for next step.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:25](=[O:26])[C:24]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]2[C:22]1=[O:31].C(N(CC)C(C)C)(C)C>CN(C=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:25](=[O:26])[C:24]4[C:23](=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:22]3=[O:31])[CH2:14][CH2:15]2)=[N:2]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCN1CCN(c2nsc3ccccc23)CC1
Temperature: 80 °C
Yield: 65.4 %

Procedure:
An 18.01 g sample of 1-(1,2-benzisothiazol-3-yl)piperazine (83.7 mmol), 29.5 g of N-(4-bromobutyl)phthalimide (104.6 mmol) and 36 mL of N,N-diisopropylethylamine (375.4 mmol) were added to 400 mL of dry DMF. The solution was heated at 80° C. for 18 hours, and the solvent was then removed in vacuo. The residue was dissolved in 500 mL of methylene chloride and was washed with saturated aqueous sodium bicarbonate. The combined aqueous layers were re-extracted with 2 portions of methylene chloride. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was crystallized from isopropanol with the addition of 4N HCl/isopropanol to give 23.03 g of the title compound as the hydrochloride, quarter hydrate, m.p. 253°-255° C.