Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:21])=[C:12]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:13]=2)[NH:8][C:7]=1[CH3:22])=[O:5])[CH3:2].[OH-].[K+]>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([Br:21])=[C:12]([CH2:15][C:16]([OH:18])=[O:17])[CH:13]=2)[NH:8][C:7]=1[CH3:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1cc2c(C(=O)OCC)c(C)[nH]c2cc1Br
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)c1c(C)[nH]c2cc(Br)c(CC(=O)O)cc12
Temperature: 45 °C
Reaction time: 4 h
Yield: 67.1 %

Procedure:
To a solution of 6-bromo-5-ethoxycarbonylmethyl-2-methyl-1H-indole-3-carboxylic acid ethyl ester (3 g, 8.1 mmol) in ethanol (30 mL) is added 4.6N KOH (3 mL; 9.8 mmol), and the reaction mixture is stirred at 45° C. for 4 hours and then at room temperature overnight. The solution is concentrated in vacuo and then ethyl acetate (150 mL) and water (150 mL) are added. The organic layer is extracted with water (50 mL), the combined water layers are then acidified with HCl (20%) to pH<2. The aqueous layers are then extracted with ethyl acetate (2×100 mL), dried (Na2SO4), filtered, and concentrated to give the desired product (1.85 g, 66%). MS: 340, 342 (M+1)+.
Reaction SMILES: [CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][O:23][CH2:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>C(Cl)Cl>[CH2:1]([NH:8][N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N+:14]([O-:34])=[CH:13][C:12]=2[N:11]=[C:10]1[CH2:22][O:23][CH2:24][CH3:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCc1nc2cnc3ccccc3c2n1NCc1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOCc1nc2c[n+]([O-])c3ccccc3c2n1NCc1ccccc1
Reaction time: 3 h
Yield: 93.5 %

Procedure:
A solution of N-benzyl-(2-ethoxymethy-1H-imidazo[4,5-c]quinolin-1-yl)amine (1.01 g, 3.04 mmol) in 50 mL of CH2Cl2 was treated with MCPBA (77% max., 1.02 g, 4.56 mmol). After stirring for 3 h, the reaction mixture was quenched with 2% Na2CO3 solution and extracted into CH2Cl2. The organic portion was washed with H2O and brine. The organic portion was dried over Na2SO4, filtered and concentrated to give N-benzyl-(2-ethoxymethy-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)amine (0.99 g) as a light-yellow solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:30][OH:31].N1C=CC=CC=1>CCO>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12](=[N:30][OH:31])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: COc1ccc(C(=O)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: COc1ccc(C(=NO)[C@@H](NC(=O)OCc2ccccc2)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of the ketone 483 (2.47 g, 6.6 mmol) in EtOH (35 mL) is added hydroxylamine hydrochloride (1.83 g, 26.4 mmol) followed by pyridine (2.13 mL, 26.4 mmol). The mixture is stirred at 80° C. for 8 h. The reaction mixture is cooled, the solvent is evaporated, and the residue dissolved in EtOAc, washed with water, brine, then dried (MgSO4), and filtered. The filtrate is evaporated, and the residue purified by chromatography on silica gel; elution with heptane:EtOAc (7:3) gives 1.95 g of the product 484. 1H NMR (CDCl3) δ 7.55 (d, 2 H), 7.50-7.10 (m, 10 H), 7.00-6.70 (m, 2 H), 6.50-6.35 (m, 1 H), 5.30-5.00 (m, 2 H), 3.80 (d, 3 H); MS: m/z 391 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[N:5]=[C:4](S)[N:3]=1.CO>O.C(Cl)Cl.[Ni]>[CH2:8]([C:6]1[N:5]=[CH:4][NH:3][C:2](=[O:1])[CH:7]=1)[CH3:9]
Reactant: CCc1cc(O)nc(S)n1
Agent: [Ni]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCc1cc(=O)[nH]cn1
Yield: 97.2 %

Procedure:
90 g (0.58 mol) 4-Hydroxy-2-mercapto-6-ethyl pyrimidine and 270 g Raney-Nickel are suspended in water (1000 mL). The suspension is heated and stirred under reflux over night. Full conversion is detected by TLC (10% MeOH in DCM). The catalyst is filtered off over celite and the filtrate is evaporated to give crude product as a pale green solid (70.0 g; 98%). The product is used without further purification for the next step.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17]([NH2:19])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(Cl)Cl>[Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]1[CH2:16][C:17](=[S:29])[NH2:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC[C@H]1CCC(=O)N1CC(N)=S
Yield: 105.6 %

Procedure:
To a solution of the compound 67 (9.50 g) in methylene chloride (133 mL) was added Lawesson's reagent (6.71 g) at 0° C. and the solution was stirred for 3 Hours. To the reaction solution was added an aqueous saturated sodium bicarbonate solution and ethyl acetate and then the solution was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with an aqueous saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate:methanol=60:40:033:67:00:90:10) to give the title compound (5.30 g) having the following physical data.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16]Cl)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][S:25][C:24]=2[CH:34]=1>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:15][CH2:16][N:31]3[CH2:32][CH2:33][CH:28]([C:27]4[C:23]5[CH:22]=[CH:21][C:20]([F:19])=[CH:34][C:24]=5[S:25][CH:26]=4)[CH2:29][CH2:30]3)=[C:11]([CH2:13][CH3:14])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CCc1sc2c(c1CCCl)CCN(C(C)=O)C2
Reactant: Fc1ccc2c(C3CCNCC3)csc2c1
Agent: Cl
Product: CCc1sc2c(c1CCN1CCC(c3csc4cc(F)ccc34)CC1)CCN(C(C)=O)C2

Procedure:
The reaction and procedure are conducted in a similar manner as in Example 24 using 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine and 4-(6-fluorobenzo(b)thiophen-3-yl)piperidine hydrochloride to give 6-acetyl-3-(2-(4-(6-fluorobenzo(b)thiophen-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-ethylthieno[2,3-c]pyridine.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C(Cl)Cl>[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]#[CH:10]
Reactant: C1=COCCC1
Reactant: C#CCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C#CCCCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a flame-dried round-bottomed flask was added 9-decyn-1-ol (1 equiv, 32.4 mmol, 5.00 g), dihydropyran (1.5 equiv, 48.6 mmol, 4.09 g, 4.5 mL), CH2Cl2 (50 mL), and PPTS (0.1 equiv, 3.24 mmol, 800 mg). The reaction was stirred for 16 h at rt and quenched with sat. aq. NaHCO3 (40 mL). The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×20 mL). The combined organic layers were washed with H2O (30 mL), dried with Na2SO4, concentrated in vacuo, and purified by flash column chromatography (5% EtOAc/Hex) to afford 9-Decyn-1-ol tetrahydropyranyl ether (7.55 g, 31.7 mmol, 98%). TLC Rf=0.30 (5% EtOAc/Hex); 1HNMR (600 MHz): δ 4.55-4.62 (1H), 3.83-3.91 (m, 1H), 3.70-3.78 (m, 1H), 3.48-3.55 (m, 1H), 3.36-3.43 (m, 1H), 2.19 (td, 2H, J1=7.1 Hz, J2=2.6 Hz), 1.95 (t, 1H, J=2.6), 1.80-1.89 (1H), 1.69-1.76 (1H), 1.50-1.63 (8H), 1.28-1.44 (8H); 13CNMR (150 MHz): δ 98.8, 84.7, 68.1, 67.6, 62.3, 30.8, 29.7, 29.3, 29.0, 28.7, 28.5, 26.2, 25.5, 19.7, 18.4.
Reaction SMILES: C(P(C(C)(C)C)C1C(OC)=CC=C(OC)C=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(CC)(C)C.CS(O[C:54]1[CH:63]=[CH:62][C:61]2[C:56](=[CH:57][CH:58]=[C:59]([C:64]3[CH:69]=[C:68]([N:70]4[CH:75]=[CH:74][C:73](=[O:76])[NH:72][C:71]4=[O:77])[CH:67]=[C:66]([C:78]([CH3:81])([CH3:80])[CH3:79])[C:65]=3[O:82][CH3:83])[CH:60]=2)[CH:55]=1)(=O)=O.[CH3:84][S:85]([NH2:88])(=[O:87])=[O:86]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:78]([C:66]1[C:65]([O:82][CH3:83])=[C:64]([C:59]2[CH:60]=[C:61]3[C:56](=[CH:57][CH:58]=2)[CH:55]=[C:54]([NH:88][S:85]([CH3:84])(=[O:87])=[O:86])[CH:63]=[CH:62]3)[CH:69]=[C:68]([N:70]2[CH:75]=[CH:74][C:73](=[O:76])[NH:72][C:71]2=[O:77])[CH:67]=1)([CH3:81])([CH3:80])[CH3:79]
Reactant: COc1c(-c2ccc3cc(OS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CS(N)(=O)=O
Agent: [Pd]
Agent: COc1ccc(OC)c(P(C(C)(C)C)C(C)(C)C)c1-c1c(C(C)C)cc(C(C)C)cc1C(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCC(C)(C)O
Product: COc1c(-c2ccc3cc(NS(C)(=O)=O)ccc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) (0.0037 g, 4.04 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.0047 g, 9.7 mmol) and milled potassium phosphate tribasic (0.094 g, 0.445 mmol) were charged to a 40-mL reaction vial inside an inert atmosphere glove box. tert-Amyl alcohol (1.0 mL) was added, the contents were heated to 80° C. and stirred at this temperature for 30 minutes. The reaction mixture was cooled down to room temperature. 6-(3-tert-Butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl methanesulfonate (0.2 g, 0.404 mmol), methanesulfonamide (0.046 g, 0.485 mmol) and tert-amyl alcohol (1.5 mL) were added to a 40-mL reaction vial. The reaction temperature was raised to 110° C., and the contents were stirred for 14 hours. HPLC analysis of the reaction mixture showed that the titled compound was formed in 7 area % at 210 nm.
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:17]=[C:18]2[C:33]([CH3:34])=[N:32][N:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:19]2=[N:20][C:21]=1[N:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:8]1[CH:13]=[CH:12][C:11](Br)=[CH:10][N:9]=1.[CH:48]1(B(O)O)[CH2:50][CH2:49]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:6][N:7]([CH2:15][C:16]1[CH:17]=[C:18]2[C:33]([CH3:34])=[N:32][N:31]([C:35]([CH3:38])([CH3:37])[CH3:36])[C:19]2=[N:20][C:21]=1[N:22]([CH2:27][CH:28]1[CH2:30][CH2:29]1)[CH2:23][CH:24]1[CH2:26][CH2:25]1)[C:8]1[CH:13]=[CH:12][C:11]([CH:48]2[CH2:50][CH2:49]2)=[CH:10][N:9]=1
Reactant: OB(O)C1CC1
Reactant: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccc(Br)cn3)cc12
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nn(C(C)(C)C)c2nc(N(CC3CC3)CC3CC3)c(CN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3ccc(C4CC4)cn3)cc12
Temperature: 100 °C
Reaction time: 16 h

Procedure:
5-(((3,5-bis(trifluoromethyl)benzyl)(5-bromopyridin-2-yl)amino)methyl)-1-(tert-butyl)-N,N-bis(cyclopropylmethyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-6-amine (0.05 g, 0.069 mmol) as prepared above, cyclopropyl boronic acid (0.007 g, 0.083 mmol) were dissolved in toluene (10 ml). To this tricyclohexylphosphine (0.002 g, 0.0069 mmol), Pd(OAc)2 (0.0007 g, 0.0034 mmol), K3PO4 (0.051 g, 0.241 mmol) were added. The mixture was stirred at 100° C. for 16 hr. The reaction mixture was diluted with water, extracted with EtOAc. The combined organic layer was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product thus obtained, was purified by column chromatography using silica gel 60-120 mesh, 10% EtOAc in petroleum ether as the eluent to obtain the title compound.
Reaction SMILES: C=O.N1CCNC[CH2:4]1.C(O)(=O)C.[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[O:30])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O>[CH2:13]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](=[CH2:4])[CH:29]=[O:30])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=CCCCCCNC(=O)OCc1ccccc1
Reactant: C1CNCCN1
Agent: C=O
Solvent: CC(=O)O
Solvent: O
Product: C=C(C=O)CCCCNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
2.44 g (30 mmol) of 37% aqueous formaldehyde solution are added to a solution of 1.5 g (17 mmol) of anhydrous piperazine and 2.03 g (34 mmol) of acetic acid in 18.7 ml of water. The mixture is stirred at 25° for 15 minutes, and then 7.48 g (30 mmol) of 6-(N-benzyloxycarbonylamino)hexanal are added thereto. The reaction mixture is heated under reflux for 2 hours and then cooled with ice-water and extracted twice with 50 ml of methylene chloride each time. The extracts are combined, washed twice with 25 ml of saturated sodium hydrogen carbonate solution each time and with 25 ml of saturated sodium chloride solution, dried and concentrated to dryness by evaporation. 6-(N-benzyloxycarbonylamino)-2-methylene-hexanal is obtained in the form of a yellowish liquid.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(O)=O)=C(C)N=1.[CH:18]1([C:21]2[NH:22][C:23]([C:27]3[C:28]([CH3:38])=[CH:29][C:30]([CH3:37])=[C:31]([CH:36]=3)[C:32]([O:34]C)=[O:33])=[C:24]([CH3:26])[N:25]=2)[CH2:20][CH2:19]1.CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1>>[CH:18]1([C:21]2[NH:22][C:23]([C:27]3[C:28]([CH3:38])=[CH:29][C:30]([CH3:37])=[C:31]([CH:36]=3)[C:32]([OH:34])=[O:33])=[C:24]([CH3:26])[N:25]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)c1cc(-c2[nH]c(C3CC3)nc2C)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: Cc1nc(C)c(-c2cc(C(=O)O)ccc2C)[nH]1
Product: Cc1cc(C)c(-c2[nH]c(C3CC3)nc2C)cc1C(=O)O

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.7, except methyl 5-(2-cyclopropyl-4-methyl-1H-imidazol-5-yl)-2,4-dimethylbenzoate (compound 160.3) was used in place of methyl 3-(2,4-dimethyl-1H-imidazol-5-yl)-4-methylbenzoate (compound 5.6). m/z (ES+) 271 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:8]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:9]=3[S:10](=O)[C:11]=2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].OS([O-])(=O)=O.[Na+]>C1COCC1>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[C:8]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:9]=3[S:10][C:11]=2[C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2=C(Oc3ccc(Br)cc3)c3ccc(OC)cc3S2=O)cc1
Agent: O=S(=O)([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2sc3cc(OC)ccc3c2Oc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene 1-oxide (970 mg, 2.12 mmol) in THF (5 mL) was cooled to 0° C. To the cooled solution was added LAH (129 mg, 3.39 mmol) in one portion. The reaction mixture was stirred at 0° C. for 30 min after which the mixture was poured into 1 M aq. NaHSO4 solution and extracted with DCM. The organic layer was collected (phase separator) and concentrated in vacuo to afford the crude product which was purified by column chromatography (SiO2, 0-30% EtOAc/Heptane) to afford 3-(4-bromophenoxy)-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (850 mg, 1.93 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm=3.83 (s, 3 H), 3.90 (s, 3 H), 6.80-6.99 (m, 5 H), 7.22-7.32 (m, 2 H), 7.32-7.44 (m, 2 H), 7.65 (d, J=9.09 Hz, 2 H).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[CH2:78][CH2:77]1>CN(C)C=O>[C:85]([O:84][C:82]([N:79]1[CH2:80][CH2:81][CH:76]([NH:75][C:26](=[O:28])[C:25]2[CH:29]=[CH:30][C:22]([NH:21][C:19]3[N:18]=[CH:17][C:8]4[N:9]([CH3:16])[C:10](=[O:15])[C:11]([F:13])([F:14])[CH2:12][N:6]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5]5)[C:7]=4[N:20]=3)=[C:23]([CH3:31])[CH:24]=2)[CH2:77][CH2:78]1)=[O:83])([CH3:88])([CH3:86])[CH3:87]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.17 h
Yield: 90.5 %

Procedure:
To a mixture of 0.060 g (0.139 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoic acid (I-184) and 8 mL of dimethylformamide was added 0.0282 g (0.209 mmole) of 1-hydroxybenzotriazole, 0.079 g (0.208 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 0.072 g (0.555 mmole) of diisopropylethylamine. The mixture was stirred for 10 minutes, then 0.0417 g (0.208 mmole) of 4-amino-1-Boc-piperidine was added. The reaction mixture was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 80 mL of ethyl acetate and washed three times with 10 mL of 1M sodium hydroxide, twice with 15 mL of brine, dried, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-90:10) gave 0.0772 g of 4-[4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methyl-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-191) as a white solid.
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=[O:4])=[O:3].[OH:10][C:11]1[C:20]2[C:15](=[CH:16][C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:18][CH:19]=2)[N+:14]([O-])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>ClCCl>[CH3:1][S:2]([O:5][C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:11]=1[OH:10])=[CH:19][CH:18]=[C:17]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH:16]=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: [O-][n+]1ccc(O)c2ccc(-c3ccccc3)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)Oc1cnc2cc(-c3ccccc3)ccc2c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methanesulphonic anhydride (3.05 g) in dichloromethane (10 ml) was added to a mixture of 4-hydroxy-7-phenylquinoline-1-oxide (3.28 g), potassium carbonate (2.13 g) and dichloromethane (160 ml) at 0°, the mixture was stirred at 0° for 2 hours, then allowed to warm to room temperature. Water (250 ml) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (3×100 ml). The combined dichloromethane layer and extracts were dried over magnesium sulphate and the solvent was removed by distillation. The residue was subjected to flash chromatography on two successive silica gel columns eluted with dichloromethane: industrial methylated spirit (19:1) to give crude 4-hydroxy-7-phenylquinol-3-yl methanesulphonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.Cl.[NH2:14]O.[OH-].[Na+].C(=O)=O.C(OC(=O)C)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:6]#[N:14]
Reactant: COc1ccc(C=O)cc1OC
Reactant: NO
Agent: Cl
Agent: O=C=O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CCO
Product: COc1ccc(C#N)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,4-Dimethoxy-benzaldehyde (287 g, 1.73 moles) in ethanol (1 liter) is treated with a solution of hydroxylamine hydrochloride (147 g, 2.12 moles) in water (200 ml) followed by addition of 17N sodium hydroxide (150 ml). The reaction mixture is stirred overnight at room temperature, poured on ice, and solid carbon dioxide is added until the solution is neutral. Extraction with methylene chloride followed by drying and evaporation of the extracts gives an orange oil. Distilled acetic anhydride (410 g, 4.0 moles) is added dropwise to the oil. When the addition is complete, the mixture is heated at reflux for 0.5 hour, poured into water and stirred for 0.5 hour. The reaction mixture is extracted with diethyl ether and the organic extract is dried and evaporated to give an orange oil. The oil is distilled at 135°-140° C/0.5 mm and dissolved in methylene chloride. The solution is washed with 2N sodium hydroxide, dried and evaporated to give the title compound; nmr (CDCl3) δ 3.94 (s, 6H) and 7.2 (m, 3H). EXAMPLE 2
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[OH:25])[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]([O:25][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:26]2[CH:31]=[CH:30][C:29]([S:32][CH3:33])=[CH:28][CH:27]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: CSc1ccc(C(O)c2cccc(F)c2)cc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: CSc1ccc(C(OC(=O)O[C@H]2CN3CCC2CC3)c2cccc(F)c2)cc1

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3-fluoro-phenyl)-(4-methylsulfanyl-phenyl)-methanol.
Reaction SMILES: [CH3:1][Li].C[Mg]Cl.[CH3:6][C:7](=[O:28])[C@@H:8]1[C@:25]2([CH3:26])[C@H:11]([C@H:12]3[C@H:22]([CH2:23][CH2:24]2)[C@:20]2([CH3:21])[C@H:15]([CH2:16][C:17](=[O:27])[CH2:18][CH2:19]2)[CH2:14][CH2:13]3)[CH2:10][CH2:9]1>O1CCCC1.C(OCOCC)C>[CH3:6][C:7]([C@@H:8]1[C@@:25]2([CH3:26])[CH2:24][CH2:23][C@@H:22]3[C@@:20]4([CH3:21])[CH2:19][CH2:18][C@:17]([OH:27])([CH3:1])[CH2:16][C@@H:15]4[CH2:14][CH2:13][C@H:12]3[C@@H:11]2[CH2:10][CH2:9]1)=[O:28]
Reactant: [Li]C
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: C[Mg]Cl
Solvent: CCOCOCC
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@](C)(O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -50 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
A mixture of ferric chloride (anhydrous, 1.63 g, 10.06 mmol) in tetrahydrofuran (anhydrous, 35 ml) is cooled to −50° C. under nitrogen. Methyllithium (3M, 3.4 mL, 10.2 mmol) in diethoxymethane is added to the ferric chloride mixture, maintaining the temperature below −40° C. After this addition is complete methyl magnesium chloride solution (3M, 10.1 ml, 30.18 mmol) in tetrahydrofuran is added maintaining the internal temperature below −40° C. After 10 min. at −40° C., 5α-pregnane-3,20-dione (2.84 g, 9 mmol) is added in one portion with stirring. The temperature is brought to −20° C. and stirred for 3.5 hours. The reaction is quenched by addition of 3 ml of acetic acid and the tetrahydrofuran was removed in vacuo. The residue is partitioned between 100 ml of 3N HCl and 200 ml of ethyl acetate. The organic layer is washed with 1N sodium hydroxide and brine and the solvent is removed in vacuo to afford crude ganaxolone (94.8% purity by HPLC) (Table 1, entry 5)