Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([O:12]CC)=[O:11])[NH:5][C:4]=2[C:3]=1[N:15]([CH3:24])[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([OH:12])=[O:11])[NH:5][C:4]=2[C:3]=1[N:15]([CH3:24])[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17]
Reactant: CCOC(=O)c1cc2sc(C)c(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1sc2cc(C(=O)O)[nH]c2c1N(C)S(=O)(=O)c1cccs1
Temperature: 60 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a mixture of ethyl 2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxylate (8.39 g), tetrahydrofuran (50 mL) and ethanol (50 mL) was added 8N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated, 6N hydrochloric acid was added to the obtained residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. Crystallization from diethyl ether gave 2-methyl-3-[methyl(2-thienylsulfonyl)amino]-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (7.07 g, yield 91%) as brown crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.C([Li])CCC.[CH3:27][Si:28]([CH3:31])(Cl)Cl.CN(C)CCN(C)C.[H-].C([Al+]CC(C)C)C(C)C.CCCCCC>C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:10][C:11]([SiH:28]([CH3:31])[CH3:27])=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2ccsc2-c2ccc(OC)cc2)cc1
Reactant: C[Si](C)(Cl)Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: CN(C)CCN(C)C
Agent: [H-]
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(-c2cc([SiH](C)C)sc2-c2ccc(OC)cc2)cc1
Reaction time: 2.5 h

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)thiophene (5.92 g, 20 mmole) in 100 ml diethyl ether/20 ml toluene was treated with 1.6 M n-butyl lithium (14 ml, 1.12 equiv.) and heated at reflux for 1.5 hours. The reaction mixture was cooled to -76° and cannulated into a solution of dimethyldichlorosilane (4.6 ml, 1.9 equiv.) in 40 ml diethyl ether at -76°. After 2.5 hours, the reaction mixture was treated with a diisobutylaluminum hydride tetramethylethylenediamine complex prepared by addition of tetramethylethylenediamine (9.9 ml, 66 mmole) to 1 M diisobutylaluminum hydride in hexane (66 ml, 66 mmole). The reaction mixture was stirred 2 hours at 0°, recooled to -30° and quenched with saturated aqueous potassium-sodium tartrate.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[N:5][C:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][C:8]=1[CH:9]([CH3:11])[CH3:10])#[CH:2].[I:25]I>C([SnH](CCCC)CCCC)CCC.CCOCC.CC(N=NC(C#N)(C)C)(C#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:4]2[C:3](/[CH:1]=[CH:2]/[I:25])=[C:8]([CH:9]([CH3:11])[CH3:10])[CH:7]=[C:6]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:5]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1c(C(C)C)cc(-c2ccccc2)nc1-c1ccc(F)cc1
Reactant: II
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CCOCC
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1/C=C/I
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 49 %

Procedure:
A mixture of 3-Ethynyl-2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenylpyridine (700 mg, 2.22 mmol) (the preparation of which is described in Example 14) and AIBN (11 mg) in tri-n-butylstannyl hydride (1.40 ml) was rapidly heated to 120° C. After 5 minutes of heating, the temperature of the reaction was raised to 140° C. and approximately 12 mg of AIBN was added to the reaction mixture every 0.5 hour thereafter. After 2.5 hours, the mixture was cooled to room temperature, diluted with Et2O (20 ml) and treated with solid I2 (2.00 gm, 7.9 mmol). The dark reaction mixture was stirred for one hour, then quenched with 60 ml saturated NaHCO3 containing 4 gm Na2SO3. The layers were shaken and separated. The ethereal layer was washed with brine, dried (Na2 SO4), filtered and stripped to yield a yellow oil. The oil was chromatographed twice (Merck SiO2, 5% EtOAc in hexane (1st) then 3% EtOAc in hexane (2nd)) to (E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine as a foam which solidified (671 mg). Recrystallization of the solid from hot hexane gave 482 mg of (E)-2-(4-Fluorophenyl)-3-(2-iodoethenyl)-4-(1-methylethyl)-6-phenyl-pyridine. An additional 100 mg of 2 was obtained from the mother liquor to give a total of 582 mg (59%) product.
Reaction SMILES: [CH2:1]([N:3]([CH2:39][CH3:40])[C:4]([C:6]1[CH:38]=[CH:37][C:9]([C:10]([C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[O:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:19][CH2:18]2)=[O:11])=[CH:8][CH:7]=1)=[O:5])[CH3:2].[BH4-].[Na+].O>C(O)C>[CH2:39]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH:10]([C:12]2[CH:36]=[CH:35][CH:34]=[CH:33][C:13]=2[O:14][CH2:15][CH2:16][N:17]2[CH2:18][CH2:19][CH:20]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[NH:25][C:24]3=[O:32])[CH2:21][CH2:22]2)[OH:11])=[CH:37][CH:38]=1)=[O:5])[CH3:40]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)c2ccccc2OCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(C(O)c2ccccc2OCCN2CCC(n3c(=O)[nH]c4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.5 %

Procedure:
The 1-[2-[2-(4-diethylcarbamoylbenzoyl)phenoxy]ethyl]-4-(1,3-dihydro-2H-benzimidazol-2-on-1-yl)piperidine (39 mg) obtained in Example 23 was dissolved in ethanol (1 ml), added with sodium borohydride (1 mg) with ice cooling and stirred at room temperature for 30 minutes. The reaction mixture was added with water (5 ml) and extracted twice with ethyl acetate (5 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: ethyl acetate:methanol=10:1) to obtain 27.2 mg of the title compound. Yield: 70%.
Reaction SMILES: [CH3:1][CH:2](CC)CC(=O)CC.C1C(N)=CC=C(N)C=1.C(C([NH:26][C:27]1[CH:32]=[CH:31][C:30]([NH:33][CH:34](CC)[CH2:35][CH:36]([CH3:39])[CH2:37][CH3:38])=[CH:29][CH:28]=1)CC(C)CC)C>>[CH2:1]([C:27]1([NH2:26])[CH:28]=[CH:29][C:30]([NH:33][CH2:34][CH2:35][CH:36]([CH3:39])[CH2:37][CH3:38])=[CH:31][CH2:32]1)[CH3:2]
Reactant: CCC(=O)CC(C)CC
Reactant: CCC(C)CC(CC)Nc1ccc(NC(CC)CC(C)CC)cc1
Agent: Nc1ccc(N)cc1
Product: CCC(C)CCNC1=CCC(N)(CC)C=C1

Procedure:
A mixture of 768 g. (6 moles) 5-methyl-3-heptanone and 108 g. (1 mole) p-phenylenediamine was reacted and worked up in the same manner as that of Example 1 to give 330 g. (99%) residue of crude N,N'-bis(1-ethyl-3-methylpentyl)-p-phenylenediamine product [IVa, R2 =C2H5, R3 =CH2CH(CH3)C2H5 ] containing some mono-Schiff's base III-c and some di-Schiff's base III-d.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].C1C(=O)NOC=1CN.[NH2:14][C@H:15]([C:21]([OH:23])=[O:22])[CH2:16][CH2:17][C:18]([OH:20])=[O:19]>>[NH2:14][C@H:15]([C:21]([O-:23])=[O:22])[CH2:16][CH2:17][C:18]([O-:20])=[O:19].[NH2:1][CH2:2][C:3]([OH:5])=[O:4]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: NCC(=O)O
Agent: NCc1cc(=O)[nH]o1
Product: N[C@@H](CCC(=O)[O-])C(=O)[O-]

Procedure:
Dose-response displacement assays were conducted using 2-methyl carboxylate-5,7-dichloro-4-[[(diphenylamino)-carbonyl]amino]-quinoline and [3H]-TCP (both with and without added glycine), and [3 H]-muscimol. Displacement of [3H]-TCP binding was assayed in the presence of 10 uM L-glutamic acid and 3 uM glycine. This assay was conducted twice with triplicate samples and concentrations of test compound ranging from 1 uM to 5 nM. No significant effect on [3 H]-TCP binding was observed in this assay. Repetition of the TCP displacement experiment with L-glutamate but no added glycine gave similar results over a dose range of 5 uM to 10 nM. A synaptosomal competition binding assay was also conducted using 2-methyl carboxylate-5,7-dichloro-4-[[(diphenylamino)-carbonyl]amino]-quinoline and the ligand [3H]-muscimol. The purpose of this experiment was to check for activity at the GABA-A receptor complex. No significant effects were observed. The compound 2-methyl carboxylate-5,7-dichloro4-[[(diphenylamino)-carbonyl]amino]-quinoline also tested negative for PCP activity at the NMDA receptor, and for GABA-A effects.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](Br)=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#[N:14])=[CH:8][CH:7]=[CH:6]2.C1(C)C=CC=CC=1.CN(C)C=O.[F:28][C:29]([F:37])([F:36])[C:30]([F:35])([F:34])C([O-])=O.[K+]>[Cu]I.C(Cl)Cl.O.C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[C:4]([C:30]([F:35])([F:34])[C:29]([F:37])([F:36])[F:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([C:13]#[N:14])=[CH:8][CH:7]=[CH:6]2
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Reactant: COc1ccc2c(C#N)cccc2c1Br
Agent: [Cu]I
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c(C#N)cccc2c1C(F)(F)C(F)(F)F
Reaction time: 5 h

Procedure:
A suitable reaction vessel was charged with 8.1 g of 6-methoxy-5-bromo-1-cyanonaphthalene, 11.8 g of CuI, 35 ml of toluene, and 55 ml of N,N-dimethylformamide. The reaction mixture was heated to 165° C. with concurrent azeotropic removal at toluene/water (25 ml) and then maintained at 155° C. when 11.8 g of potassium pentafluoropropionate was added. The reaction was monitored by VPC. After five hours no starting material was detected and the reaction mixture was poured into 150 ml of water and 125 ml of methylene chloride. The two phases were filtered, after which the organic layer was separated, washed with brine, and concentrated in vacuo to provide a crude 6-methoxy-5-pentafluoroethyl-1-cyanonaphthalene (6-MPCN) having a purity of greater than 95%.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:9]=[C:10]3[CH:16]=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[F:19][C:20]1[C:25]([CH:26]=[O:27])=[C:24]([F:28])[CH:23]=[CH:22][C:21]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]>CO>[F:19][C:20]1[C:25]([CH:26]([OH:27])[C:16]2[C:10]3[C:11](=[N:12][CH:13]=[C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH:9]=3)[NH:14][CH:15]=2)=[C:24]([F:28])[CH:23]=[CH:22][C:21]=1[NH:29][S:30]([CH2:33][CH2:34][CH3:35])(=[O:32])=[O:31]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C=O)c1F
Reactant: c1ccc(Nc2cnc3[nH]ccc3c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncc(Nc4ccccc4)cc23)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To phenyl-(-1H-pyrrolo[2,3-b]pyridine-5-yl)-amine (70, 17.0 mg, 0.09 mmol) in methanol (5.0 mL) were added potassium hydroxide (92.0 mg, 1.6 mmol) and propane-1-sulfonic acid (2,4-difluoro-3-formyl-phenyl)-amide (73, 19.0 mg, 0.072 mmol, prepared as described in Example 7) under an atmosphere of nitrogen. The reaction was stirred for 12 hours at room temperature. The reaction was concentrated and purified by silica gel column chromatography eluting with 1% methanol in dichloromethane to give the compound (71, 17 mg, 50%). MS(ESI) [M+H+]+=473.5.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CO.[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30]>C(OCC)(=O)C>[C:26]([OH:33])(=[O:32])/[CH:27]=[CH:28]/[C:29]([OH:31])=[O:30].[O:23]([C:2]1[CH:3]=[N:4][C:5]([O:8][CH:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Oc1ccccc1
Reactant: Brc1cnc(OC2CN3CCC2CC3)nc1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: c1ccc(Oc2cnc(OC3CN4CCC3CC4)nc2)cc1
Yield: 93.3 %

Procedure:
The product of Example 29A (284 mg, 1.0 mmol) was treated with phenol (Aldrich, 188 mg, 2 mmol) according to the procedure of Example 14C. The free base of the title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3H2O, 90:10:2, Rf. 0.15) as an oil (42 mg, yield, 14%). The free base of the title compound (42 mg, 0.14 mmol) in ethyl acetate:MeOH (3 mL, 10:1) was treated with fumaric acid (18 mg, 0.15 mmol) at room temperature for 10 hours. The title compound was obtained as a solid (22 mg, 36%). 1H NMR (MeOH-d4, 300 MHz) δ 1.84–2.18 (m, 3H), 2.25–2.38 (m, 1H), 2.50–2.58 (m, 1H), 3.23–3.44 (m, 5H), 3.80–3.88 (m, 1H), 5.32 (m, 1H), 6.69 (s, 2.5H), 7.00–7.06(m, 2H), 7.15–7.20 (m, 2H), 8.39 (s, 2H) ppm. MS (DCl/NH3) m/z 298 (M+H)+. Anal. Calculated for C17H19N3O2.1.26C4H4O4: C, 59.67; H 5.46; N, 9.47. Found: C, 59.43; N, 9.51.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)=[C:7]([C:19]([O:21][CH3:22])=[O:20])[N:8]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:9]2=[O:12])=[CH:4][C:3]=1[O:35][CH3:36].Cl.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH2:44][Cl:45].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[ClH:45].[CH3:36][O:35][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:44][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][N:38]=1)[C:9](=[O:12])[N:8]([N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[C:7]([C:19]([O:21][CH3:22])=[O:20])=[C:6]2[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1
Reactant: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(O)cc2c(=O)n1N1CCOCC1
Reactant: ClCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2cc(OC)c(OC)c(OC)c2)c2cc(OC)c(OCc3ccccn3)cc2c(=O)n1N1CCOCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 74.1 %

Procedure:
To a solution of the compound obtained in Example 2 (300 mg) in dimethylformamide (3 ml) are added 2-picolyl chloride hydrochloride (118 mg) and potassium carbonate (182 mg), and the mixture is stirred at 50° C. overnight. To the mixture are added ethyl acetate and water. The ethyl acetate layer is separated, washed, dried, and concentrated under reduced pressure. The residue (chemical name; 6-methoxy-3-methoxycarbonyl-2-morpholino-7-(2-pyridylmethyloxy)-4-(3,4,5-trimethoxyphenyl-1(2H)-isoquinolinone) is dissolved in ethyl acetate, and thereto is added a 4M solution of hydrogen chloride in ethyl acetate (150 μl). The mixture is stirred at room temperature for 30 minutes. The precipitated crystals are collected by filtration, and washed with ethyl acetate to give 6-methoxy-3-methoxycarbonyl-2-morpholino-7-(2-pyridylmethyloxy)-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone hydrochloride (279 mg) as listed in Table 1.
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].CN(C=O)C.[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38](Cl)(=[O:40])=[O:39]>N.CO>[O:29]1[C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=2[CH:31]=[C:30]1[S:38]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:40])=[O:39]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Agent: N
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=S(=O)(c1cc2ccccc2o1)n1ccc2c3c(ccc21)OCCNC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 2.2 %

Procedure:
tert-Butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 14 mg, 0.050 mmol), NaH (60% in mineral oil, 6.4 mg, 0.10 mmol) and dry DMF (0.2 mL) were shaken at room temperature for 10 minutes. 1-Benzofuran-2-sulfonyl chloride (22 mg, 0.10 mmol, in 0.15 mL of dry DMF) was added to the solution. The reaction mixture was shaken at room temperature for another 20 minutes and a mixture of MeOH/1 M HCl (3:1, 1 mL) was added. The reaction mixture was stirred overnight and evaporated. The residue was dissolved in 1 M NH3 in MeOH (1 mL, 1 mmol) and MeOH (1 mL). The crude product was purified by preparative HPLC (XTerra C18, 50 mM NH4HCO3 pH 10-CH3CN) to give the title compound as an off-white solid (0.4 mg). MS m/z 369 [M+H]+.
Reaction SMILES: C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.[CH:16]1([CH2:19][N:20]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38](=[O:49])(=[O:48])[N:39]([CH2:44][CH2:45][O:46][CH3:47])C(C)(C)C)=[CH:34][CH:33]=4)[N:26]=3)=[CH:23][N:22]=[C:21]2[CH2:50][CH3:51])[CH2:18][CH2:17]1>>[CH:16]1([CH2:19][N:20]2[C:24]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38](=[O:48])(=[O:49])[NH:39][CH2:44][CH2:45][O:46][CH3:47])=[CH:36][CH:37]=4)[N:26]=3)=[CH:23][N:22]=[C:21]2[CH2:50][CH3:51])[CH2:18][CH2:17]1
Reactant: CCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)N(CCOC)C(C)(C)C)cc3)n2)n1CC1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCc1ncc(-c2ccnc(Nc3ccc(S(=O)(=O)NCCOC)cc3)n2)n1CC1CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.9 %

Procedure:
Anisole (4.57 ml) followed by trifluoroacetic acid (22 ml) was added to 4-(1-cyclopropylmethyl-2-ethylimidazol-5-yl)-2-{4-[N-(2-methoxyethyl)-N-(t-butyl)sulphamoyl]anilino}pyrimidine (Method 76; 3.7 g, 7.22 mmol). The mixture was stirred at ambient temperature for two hours, the volatiles were evaporated and the residue dissolved in water and then extracted with EtOAc. The aqueous layer was neutralised with saturated aqueous sodium hydrogen carbonate solution and extracted with EtOAc. The extract was dried and the solvent removed by evaporation. The residue was purified by chromatography on silica gel eluting with EtOAc/MeOH (100:0 increasing in polarity to 98:2) to give the title compound (1.58 g, 48%) as a foam. NMR: 0.00-0.02 m, 2H), 0.18-0.20 m, 2H), 0.86-0.90 (m, 1H), 1.10 (t, 3H), 2.60 (q, 2H), 2.75 (q, 2Hy, 3.01 (s, 3H>, 3.18 (q, 2H), 4.40 (d, 2H), 7.10 (d, 1H), 7.35 (t, 1H), 7.52 (s, 1H), 7.57 (d, 2H), 7.77 (d, 2H), 8.30 (d, 1H), 9.70 (s, 1H); m/z 457.
Reaction SMILES: OS(O)(=O)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([N:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH2:29][CH2:28]2)([C:25]#[N:26])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1>[CH2:12]([N:19]1[CH2:24][CH2:23][C:22]([CH2:25][NH2:26])([N:27]2[CH2:28][CH2:29][N:30]([C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH2:31][CH2:32]2)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NCC1(N2CCN(c3ccncc3)CC2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
H2SO4 (1.5 equiv.) was added to a suspension of LAH (3 equiv.) in THF (32 ml) at 0° C. and the mixture was stirred at room temperature for 0.5 h. A solution of 1-benzyl-4-(4-(pyridin-4-yl)piperazin-1-yl)piperidine-4-carbonitrile (5.54 mmol, 1 equiv.) in THF was added under cooled conditions and the resulting reaction mixture was heated to 50° C. for 16 h. The reaction was quenched with THF/H2O solution, filtered and the solid residue washed with excess ethyl acetate. The organic layer was given a brine wash, dried over sodium sulfate and the solvent was removed under reduced pressure. The resulting crude product was used for the next step without further purification. Yield: 85%.
Reaction SMILES: OS(O)(=O)=O.[Cl:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].CC(C)=[O:18].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O.[O-2].[O-2].[O-2].[Cr+6]>[Cl:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][C:14]([OH:18])=[O:15]
Reactant: CC(C)=O
Reactant: OCCOCCOCCCl
Agent: O=[Cr](=O)=O
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Product: O=C(O)COCCOCCCl
Temperature: 0 °C
Reaction time: 6 h
Yield: 70 %

Procedure:
Chromium trioxide (25 g, 164 mmol) was dissolved into 300 mL of 1.5 M H2SO4 and the solution was cooled to 0° C. Compound 2-[2-(2-chloroethoxy)ethoxy]ethanol (8.3 g, 49 mmol) in 150 mL acetone was added into the Jones reagent dropwise and the reaction mixture was stirred at room temperature for 6 h. The acetone was removed by evaporation under vacuum and the aqueous phase was extracted with DCM (3×100 mL). After the combined organic phase was dried over MgSO4, the 2-[2-(2-chloroethoxy)ethoxy]acetic acid (6.3 g, 70% yield) was obtained by removed the solvent by rotary evaporation. IR: (cm−1) 1734 (C═O). 1H NMR (CDCl3, 300 MHz): δ 10.49 (b, 1H), 4.23 (s, 2H), 3.80 (t, J=5.8 Hz, 4H), 3.74 (t, J=5.7 Hz, 2H), 3.66 (t, J=5.8 Hz, 2H). 13C NMR (CDCl3, 75 MHz): δ 174.4, 71.4, 71.1, 70.4, 68.5, 42.6.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][S:8][C:4]=2[CH:3]=1.Br[CH2:18][CH2:19][N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30]>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][N:20]4[C:24](=[O:25])[C:23]5=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]5[C:21]4=[O:30])[CH2:13][CH2:14]3)=[N:7][S:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)nsc2c1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)N1CCN1CCC(c2nsc3cc(F)ccc23)CC1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisothiazole (4.72 g, 0.03 mole) and N-(2-bromoethyl)phthalimide (6.35 g, 0.025 mole) in 200 ml of acetonitrile is heated at reflux for 4 hours. The solids are then removed by filtration and the filtrate is concentrated under reduced pressure. The residue is purified by chromatography over silica gel to provide N-[2-[4-(6-fluoro-1,2-benzisothiazol-3-yl)-1-piperidinyl]ethyl]phthalimide.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:16]=[CH:15][C:10]([O:11][CH2:12][CH2:13][OH:14])=[CH:9][CH:8]=1)[CH2:3][CH2:4][CH3:5].[H-].[Na+].Cl[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CN(C=O)C>[CH3:1][CH:2]([O:6][C:7]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH2:13][O:14][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)=[CH:15][CH:16]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)Oc1ccc(OCCO)cc1
Reactant: Clc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCC(C)Oc1ccc(OCCOc2ccccn2)cc1

Procedure:
Following the procedure of Example 1, 2-[4-(1-methyl-n-butoxy)phenoxy]ethanol (0.80 g, 3.6 mmol) in 5 ml of DMF is added to sodium hydride (0.26 g, 5.3 mmol) in 5 ml of DMF, followed by addition of 2-chloropyridine (0.50 g, 5.3 mmol) to give 2-{2-[4-(1-methyl-n-butoxy)phenoxy]ethoxy}pyridine.
Reaction SMILES: [BrH:1].[CH2:2]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:17])[C:14]([OH:16])=[CH:15][C:8]=2[CH2:7][CH2:6]1)[CH:3]=[CH2:4].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.[C:32]1([SH:38])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[BrH:1].[CH2:2]([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([OH:17])[C:14]([OH:16])=[C:15]([S:38][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]=2[CH2:7][CH2:6]1)[CH:3]=[CH2:4]
Reactant: Sc1ccccc1
Reactant: C=CCN1CCc2cc(O)c(O)cc2CC1
Agent: Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Product: C=CCN1CCc2cc(O)c(O)c(Sc3ccccc3)c2CC1

Procedure:
Following the procedures outlined in Example 2 the 3-allyl-7,8-dihydroxy-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide was treated with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to give the 7,8-dione which was then reacted with, for example, thiophenol to obtain the corresponding 3-allyl-7,8-dihydroxy-6-phenylthio-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 103°-123° C.