Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]([CH2:9][CH:10]([CH3:37])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:23]([S:24]([NH:27][C:28]3[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=3)(=[O:26])=[O:25])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:14][CH:13]=1)[Si](C(C)(C)C)(C)C.C(=O)([O-])O.[Na+].[C:43](O)(=[O:45])[CH3:44]>C(OC(=O)C)(=O)C>[C:43]([O:1][CH2:9][CH:10]([CH3:37])[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:23]([S:24]([NH:27][C:28]3[C:33]([O:34][CH3:35])=[N:32][C:31]([CH3:36])=[CH:30][N:29]=3)(=[O:25])=[O:26])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:16][CH:17]=1)(=[O:45])[CH3:44]
Reactant: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1nc(C)cnc1NS(=O)(=O)c1cccnc1-c1ccc(CC(C)COC(C)=O)cc1
Temperature: 25 °C

Procedure:
2-[4-(3-hydroxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide from Example 19 (100 mg) was heated in a mixture of acetic acid (0.5 ml) and acetic anhydride (0.5 ml) to 80° C. for 10 minutes and allowed to cool to ambient temperature. After 6 hours excess saturated aqueous sodium hydrogen carbonate was added cautiously and the product extracted into ethyl acetate (3×20 ml). The combined organic extract was dried (MgSO4) and evaporated. The residue was purified by elution with a gradient of 0-30% ethyl acetate/hexane through a silica gel Mega Bond Elut column (1 g) to give 2-[4-(3-acetoxy-2-methylpropyl)phenyl]-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulphonamide (70 mg) as a white foam; 1H NMR (CDCl3): 0.98 (d, 3H), 1.58 (s, 3H), 2.11 (s, 3H), 2.1-2.3 (m, 1H), 2.51 (q, 1H), 2.85 (q, 1H), 3.80 (s, 3H), 3.97 (m, 2H), 6.69 (s, 1H), 7.2 (d, 2H), 7.29 (d, 2H), 8.67 (d, 1H), 8.80 (dd, 1H); mass spectrum (+ve ESP): 471.1 (M+H)+.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:34]>ClCCl>[Br:34][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)NCCCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCCBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.1 %

Procedure:
To an ice-cold solution of tert-butyl 4-hydroxybutylcarbamate (5 g, 26.41 mmol) in dichloromethane (200 mL) was added triphenylphosphine (10.38 g, 39.61 mmol) followed by carbon tetrabromide (13.15 g, 39.61 mmol) at 0° C. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed under reduced pressure and the residue was purified by column chromatography (60-120 mesh silica gel) using 10% ethyl acetate in pet-ether to give tert-butyl 4-bromobutylcarbamate (4.2 g, 63.3%) as a light green liquid. 1H NMR (400 MHz, CDCl3) δ ppm 4.53 (1H, s), 3.45-3.41 (2H, m), 3.18-3.13 (2H, m), 1.93-1.83 (2H, m), 1.68-1.61 (2H, m), 1.47 (9H, s).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[OH:23][CH2:24][CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>C(Cl)Cl>[CH:24]([CH:25]1[CH2:33][C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:26]1[C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[O:23]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1c2ccccc2CC1C=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Bis(1,1-dimethylethyl)ester dicarbonic acid (0.07615 mol) in DCM (50 ml) was added over 5 minutes to 2,3-dihydro-1H-indole-2-methanol (0.07615 mol) in DCM (150 ml) at 0° C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was concentrated under reduced pressure and submitted to a Kogel Rohr distillation, yielding 11.98 g of 1,1-dimethylethyl 2,3-dihydro-2-(hydroxymethyl)-1H-indole-1-carboxylate (intermediate 11). b) Dess-Martin Reagent (0.011 mol) was added neat over 1 minutes to intermediate (11) (0.010 mol) dissolved in DCM (35 ml). After 15 minutes, the ice bath was removed, and the mixture was allowed to warm to room temperature. More Dess-Martin Reagent (0.33 g) was added, and the mixture was stirred for 30 minutes more. The mixture was re-cooled to 0° C. and treated slowly with a partial suspension/solution of Na2S2O3 (25 g) which had attempted to dissolve in a saturated aqueous NaHCO3 (100 ml) solution. After 10 minutes, the mixture was removed from ice, and the layers were separated. More DCM was added, and the mixture was filtered. The organic was separated from the filtrate, and the combined organic phases were dried, filtered, concentrated and purified through flash column chromatography (eluent: 10% ethyl acetate:hexane, dissolving the sample in 3:1 ethyl acetate:hexane (5 ml)), yielding 1,1-dimethylethyl 2-formyl-2,3-dihydro-1H-indole-1-carboxylate (intermediate 12, mp. 85-87° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:22]=[CH:21][C:20](B4OC(C)(C)C(C)(C)O4)=[CH:19][CH:18]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:38]1[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@:8]2([CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[O:13][C:12](=[O:14])[N:11]([C@H:15]([C:17]3[CH:18]=[CH:19][C:20]([C:38]4[CH:39]=[CH:40][C:41](=[O:45])[N:42]([CH3:44])[CH:43]=4)=[CH:21][CH:22]=3)[CH3:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: Cn1cc(Br)ccc1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(-c2ccc(=O)n(C)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Yield: 22.2 %

Procedure:
A mixture of (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (700 mg, 1.41 mmol), 5-bromo-1-methylpyridin-2(1H)-one (398 mg, 2.12 mmol), PdCl2(Ph3P)2 (70 mg), Cs2CO3 (1.5 mL, 3.0 mmol) in 1,4-dioxane (15 mL) was heated under reflux for 2 h. The mixture was diluted with EtOAc, and washed with water. The organic phase was separated, and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)phenyl)ethyl)-1,3-oxazinan-2-one (150 mg, 22%). 1H NMR (CDCl3): δ=1.12 (s, 3H), 1.13 (s, 3H), 1.51 (t, 3H), 2.16 (m, 2H), 2.21 (m, 2H), 2.41 (m, 1H), 2.92 (m, 1H), 3.63 (s, 3H), 5.69 (q, 1H), 6.69 (m, 1H), 6.99 (m, 4H), 7.18 (m, 2H) δ 7.27 (m, 2H) δ 7.42 (m, 1H), 7.52 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.C([O:13][C:14](=O)[CH2:15][CH2:16]C(OCC)=O)C.C([O-])C.[Na+]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][CH:7]2[NH:8][C:14](=[O:13])[CH2:15][CH2:16]2)=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(Cl)cc1
Reactant: CCOC(=O)CCC(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Product: O=C1CCC(Cc2ccc(Cl)cc2)N1

Procedure:
Condense 4-chlorobenzylcyanide with succinic acid diethyl ester in the presence of sodium ethanolate, boil the condensation product (without further purification) with a mixture of glacial acetic acid/semi-concentrated hydrochloric acid for 20 hours under reflux, convert (with hydroxylamine) the thus-obtained 5-(4-chlorophenyl)-4-oxo-pentanoic acid (m.p. 91° to 93°) into 5-(4-chlorophenyl)-4-hydroxyiminopentanoic acid (m.p. 116° to 117°), hydrogenate the latter with platinum/activated charcoal/hydrogen in acetic acid to 5-(4-chlorophenyl)-4-aminopentanoic acid and cyclize the thus-substituted pentanoic acid (through boiling in dioxane) to obtain 5-(4-chlorobenzyl)pyrrolidin-2-one (m.p. 95° to 98°).
Reaction SMILES: [H-].[Na+].[CH2:3]([N:7]1[CH:12]=[CH:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5].C1(C)C=CC(S([CH:25]([N+:27]#[C-:28])[CH3:26])(=O)=O)=CC=1>C1COCC1>[CH2:3]([N:7]1[C:12]2=[C:25]([CH3:26])[NH:27][CH:28]=[C:11]2[C:10](=[O:13])[N:9]([CH3:14])[C:8]1=[O:15])[CH:4]([CH3:6])[CH3:5]
Reactant: CC(C)Cn1ccc(=O)n(C)c1=O
Reactant: [C-]#[N+]C(C)S(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1[nH]cc2c(=O)n(C)c(=O)n(CC(C)C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 63.6 %

Procedure:
Sodium hydride (95%, 116 mg, 4.6 mmol) is suspended in 10 mL of anhydrous THF, and then a mixture of 1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione (300 mg, 1.65 mmol) and 1-(p-toluenesulfonyl)-ethyl isocyanide (413 mg, 1.98 mmol) in 5 mL of anhydrous THF is added dropwise over 1 h at 0° C. The mixture is stirred at room temperature for 3 h at room temperature after the completion of the addition, and then carefully quenched with water. The mixture is diluted with saturated NaHCO3, and then extracted with CH2Cl2 five times. The combined organic phase is washed with brine, and then dried with anhydrous Na2SO4. After filtration, the filtrate is evaporated to dryness under reduced pressure, and the residue is purified by basic alumina column chromatography to give 247 mg of product (yield: 64%). MS (ESI) m/z 236.1 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]#[C:30][Si](C)(C)C)[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[C:1]([O:5][C:6](=[O:41])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[C:22]([C:29]#[CH:30])[CH:23]=[CH:24][CH:25]=4)[O:20][C:19]=3[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:14][CH:13]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(C#C[Si](C)(C)C)cccc4c3=O)cc2)CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1cccc2c(=O)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
A solution of {1-[4-(4-oxo-2-phenyl-8-trimethylsilanylethynyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (51 mg, 0.091 mmol) in MeOH (2 mL) and DCM (1 mL) was treated with potassium carbonate (15 mg, 0.109 mmol) and the reaction stirred at RT for 3 h. The reaction mixture was quenched with water, diluted with EtOAc, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a foamy solid (45 mg, 100%). 1H NMR (400 MHz, CDCl3): δ 8.27 (dd, J=7.7 and 1.6 Hz, 1H), 7.86 (dd, J=7.5 and 1.6 Hz, 1H), 7.48 (d, J=7.5 Hz, 2H), 7.41-7.30 (m, 5H), 7.25-7.19 (m, 3H), 5.06 (s, 1H), 3.47 (s, 1H), 2.65-2.27 (m, 4H), 2.14-2.00 (m, 1H), 1.91-1.76 (m, 1H), 1.37 (s, 9H).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>CCO.O>[CH2:3]([O:10][C:11]1[CH:18]=[CH:17][C:14](/[CH:15]=[CH:19]/[C:20]([CH:22]2[CH2:24][CH2:23]2)=[O:21])=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)C1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(OCc2ccccc2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
1M NaOH (4.8 ml) was added to a solution of 4-benzyloxybenzaldehyde (5 g) and cyclopropyl methyl ketone (3.96 g) in EtOH (24 ml) and the mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with H2O and EtOH. The mixture was stirred at ambient temperature for 20 minutes. Pale yellow crystals were collected and washed with H2O and 50% aqueous EtOH to give (2E)-3-[4-(benzyloxy)phenyl]-1-cyclopropyl-2-propen-1-one (6.29 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=O)[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:14][OH:15].[OH-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[N:14][OH:15])[CH3:11])=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC(=O)C=Cc1ccc(F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C=Cc1ccc(F)cc1)=NO
Yield: 63.3 %

Procedure:
In a 250 ml single neck flask was charged 4.92 g (30 mmoles, 1.0 eq.) of 4-(4-fluorophenyl)-3-buten-2-one and 5.2 g (75.4 mmoles, 2.5 eq) of hydroxylamine hydrochloride and 6 g of 50% sodium hydroxide (75 mmoles, 2.5 eq) and 100 ml of methanol. The reaction mixture was stirred at reflux for 2 hours. The reaction mixture was concentrated, diluted with water (50 ml), and then extracted with ethyl acetate (2×50 ml). The organic phase was dried and concentrated, to obtain 3.4 of 4-(4-fluorophenyl)-3-buten-2one 2-oxime (E/Z mixture of isomers) as an oil in 63.3% yield.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12]([OH:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C>[CH2:12]([O:19][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N+:9]([O-:11])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: O=[N+]([O-])c1c(F)cccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1c(F)cccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 1,3-difluoro-2-nitrobenzene (1.0 g, 6.29 mmol), benzyl alcohol (0.81 mL, 7.86 mmol) and potassium carbonate (1.74 g, 12.6 mmol) in DMF (5 mL) is heated at 60° C. for 18 h. The reaction mixture is poured into EtOAc, and washed with water and brine. The organic phase is concentrated and purified to give the title compound: 1H NMR (CDCl3) 7.36 (m, 6H), 6.83 (m, 2H), 5.20 (s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=1)#[CH:2].C(NC(C)C)(C)C.[C:18]([C:22]1[CH:27]=[CH:26][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>O1CCCC1.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:22]1[CH:23]=[CH:24][C:25](/[C:28](/[C:45]2[CH:50]=[CH:49][C:48]([C:2]#[C:1][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][CH:4]=3)=[CH:47][CH:46]=2)=[CH:29]/[CH2:30][O:31][C:32]2[CH:43]=[CH:42][C:35]([O:36][CH2:37][C:38]([O:40][CH3:41])=[O:39])=[C:34]([CH3:44])[CH:33]=2)=[CH:26][CH:27]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Reactant: C#Cc1ccc(CO)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#Cc3ccc(CO)cc3)cc2)c2ccc(C(C)(C)C)cc2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Ethynyl-4-(hydroxymethyl)benzene (169 mg, 1.28 mmol) and diisopropylamine (0.40 mL, 2.85 mmol) were added to a solution of methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-(4-iodophenyl)allyloxy]-2-methylphenoxy]acetate (364 mg, 0.638 mmol; prepared as described in example 30) in tetrahydrofuran (10 mL). The mixture was degassed and copper(I) iodide (10 mg, 0.053 mmol) and bis(triphenylphosphine)palladium(II) dichloride (22 mg, 0.031 mmol) were added. The reaction mixture was stirred at ambient temperature overnight, filtered and the filtrate was evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, dichloromethane/methanol 99:1) yielding methyl (Z)-[4-[3-(4-tert-butylphenyl)-3-[4-[4-(hydroxymethyl)phenylethynyl]phenyl]allyloxy]-2-methylphenoxy]acetate as brown oil.
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][CH:7]2[CH:9]([NH2:10])[CH:4]([CH2:5][CH2:6]2)[CH2:3]1.[Cl:11][C:12]1[S:16][C:15]([S:17](Cl)(=[O:19])=[O:18])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:1][CH:2]1[CH2:3][CH:4]2[CH:9]([NH:10][S:17]([C:15]3[S:16][C:12]([Cl:11])=[CH:13][CH:14]=3)(=[O:19])=[O:18])[CH:7]([CH2:6][CH2:5]2)[CH2:8]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC1CC2CCC(C1)C2N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1CC2CCC(C1)C2NS(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 66 h
Yield: 10 %

Procedure:
3-Methyl-bicyclo[3.2.1]oct-8-ylamine (prepared in Step 2, 0.165 mmol) was dissolved in DCM (1.5 mL) and treated with 5-chlorothiophenesulphonyl chloride (53.7 mg, 0.248 mmol) followed by pyridine (100 μL). The reaction was stirred at room temperature for 66 h, followed by heating at 60° C. for 18 h. The reaction mixture was evaporated and purified by mass-directed preparative HPLC to give the desired product (5.3 mg, 10%) as a mixture of four isomers. m/z 320 (M+H+).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11](F)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:16])[C:10]([F:15])=[C:11]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)[CH:12]=3)[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: Cc1c(F)c(F)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: C1CNCCN1
Solvent: CC#N
Product: Cc1c(F)c(N2CCNCC2)cc2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.4 %

Procedure:
A suspension of 0.70 g (2.50 mmol) of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-5-methyl-4-oxo-3-quinolinecarboxylic acid, 0.86 g (10.0 mmol) of anhydrous piperazine and 20 ml of acetonitrile was refluxed for five hours, then stirred at room temperature overnight. The precipitate was filtered, washed with water and acetonitrile, and dried to give 0.85 g of the title compound, mp 226°-228° C.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32].CN1CCOCC1.Cl>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:19])[CH:14]=[C:13]2[CH2:20][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][C:22]=1[O:31][CH3:32])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(Cc2cn(C)c3ccc(N)cc23)c(OC)c1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)c(Cc1ccc(C(=O)OC)cc1OC)cn2C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
Hexanoylchloride (0.029 g.) was added to a stirred solution of methyl 4-(5-amino-1-methylindol-3-ylmethyl)-3-methoxybenzoate (D) (0.05 g.) and N-methylmorpholine (0.05 g.) in dichloromethane (3 ml.), under an atmosphere of nitrogen. The mixture was stirred for 2 hours and then poured into 1M hydrochloric acid (15 ml.). This mixture was extracted with ethyl acetate (2×20 ml.). The combined extracts were dried (MgSO4), and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 4:6 v/v ethyl acetate:hexane, to give a colorless oil, which was crystallized from a mixture of toluene and hexane to give the title compound (0.05 g, 65%) as a white powder; NMR: 0.86(t, 3H, CH2.CH3), 1.28(m,4H, CH2.CH2.CH3), 1.57 (quintet, 2H, CH2.CH2.CON), 2.25(t, 2H, CH2.CH2.CON), 3.69(s,3H, NCH3), 3.82(s,3H, CO.OCH3), 3.92(s,3H, OCH3), 3.97(s, 2H, CH2.Ar), 7.05(s,1H), 7.13(d,1H), 7.27(d,1H), 7.28(d,1H), 7.40(dd,1H), 7.48(s,1H), 7.74(s,1H), 9.61(s,1H).
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][CH:17]([O:19]C)[CH2:16][N:15]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH2:14]2)=[CH:9][CH:8]=1)[CH3:6].C(=O)(O)[O-].[Na+].O>ClCCl>[CH2:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][N:15]([C:21]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)=[O:22])[CH2:16][CH:17]([OH:19])[CH2:18]2)=[CH:9][CH:8]=1)[CH3:6]
Reactant: CCc1ccc(C2CC(OC)CN(C(=O)N3CCOCC3)C2)cc1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCc1ccc(C2CC(O)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under argon and at 0° C., 4.6 ml of a boron tribromide solution (1 molar in dichloromethane, 4.6 mmol, 2 eq.) were added to a solution of 890 mg (2.3 mmol) of 4-{[3-(4-ethylphenyl)-5-methoxypiperidin-1-yl]carbonyl}morpholine in 22 ml of dichloromethane. The reaction mixture was stirred at RT for 2 h, then poured onto ice, neutralized with solid sodium bicarbonate and, after addition of water and phase separation, extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude product was then purified by preparative HPLC (Reprosil C18, water with 0.1% trifluoroacetic acid/acetonitrile gradient). Yield: 314 mg (43% of theory)
Reaction SMILES: [NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13](O)=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.C([N:25]1CCOCC1)C.C(OC(Cl)=O)C(C)C.N>O1CCCC1.C(OCC)(=O)C>[NH:1]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C@@H:2]([C:13]([NH2:25])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1
Reactant: Cc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: CCN1CCOCC1
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(CSC[C@@H](NC(=O)OC(C)(C)C)C(N)=O)cc1
Reaction time: 0.17 h

Procedure:
5 g of BOC-D-Cys(MBzl)-OH are dissolved in 60 cc of dry tetrahydrofuran, the solution is cooled to -15°, 1.85 cc of N-ethylmorpholine are added, and then 1.92 cc of chloroformic acid isobutyl ester are added, and the mixture is stirred for 10 minutes. Dry ammonia gas is subsequently passed through the solution at -15° while stirring, stirring is continued for 2 hours, whereby the temperature rises to room temperature. The reaction mixture is diluted with approximately 800 cc of ethyl acetate, is washed with water, and the organic phase is dried over sodium sulphate. Concentration, filtration, washing with ethyl acetate/ether and drying are effected, and the title compound is obtained. M.P. 140°; [α]D20 = +26° in dimethyl formamide.
Reaction SMILES: C[O-].[Na+].CO.[N+](C1C=CC=CC=1S([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O)([O-])=O.Cl>C(#N)C>[CH:19]([NH2:18])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 77.9 %

Procedure:
A 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was added to a solution of N-(2-nitrobenzenesulfonyl)benzhydrylamine (402.1 mg) in dry acetonitrile (3 ml) at room temperature in a nitrogen atmosphere, followed by stirring for 27 hours at room temperature. On the way, a 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was further added after 10 hours. The reaction mixture was cooled with ice, 1 N hydrochloric acid (5 ml) was added, and the reaction solvents were removed by evaporation under reduced pressure. Water (5 ml), 1 N hydrochloric acid (5 ml) and ether (30 ml) were added to the resulting concentrate, followed by extraction and solution separation, and the organic layer was extracted again with water (5 ml). Sodium hydroxide (0.62 g) was added to the resulting aqueous layer, and extraction was conducted three times with ether (20 ml), followed by drying over sodium sulfate, filtration, concentration and drying under vacuum to obtain benzhydrylamine (155.9 mg; yield: 77.9%).