Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:6])[CH2:5][CH2:4][CH:3]=[CH:2]1.[CH:7](O)([CH3:9])[CH3:8].CC(C)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[CH:7]([O:6][CH:1]1[CH2:5][CH2:4][CH:3]=[CH:2]1)([CH3:9])[CH3:8]
Reactant: CC(C)O
Reactant: OC1C=CCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: CC(C)=O
Solvent: O
Product: CC(C)OC1C=CCC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 6 %

Procedure:
2-Cyclopentenol (0.30 g), isopropanol (0.40 g), and an aqueous solution of 0.020 g of tetrabutylammonium hydrogen sulfate in 0.25 g of water were mixed, and the two-phase system was stirred vigorously at 40° C for 4 hours. Acetone was then added to homogenize the mixture, and it was analyzed by gas chromatography. Peaks corresponding to about a 6% yield of 2-cyclopentenyl isopropyl ether and about a 12% yield of 2-cyclopentenol were observed along with a concomitant peak for the co-product acetic acid. No bis-(2-cyclopentenyl) ether was formed.
Reaction SMILES: [NH2:1][C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:41]([C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59])[C@@H:42]([C:55](O)=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])=[O:49].CCN=C=NCCCN(C)C.Cl>C(Cl)(Cl)Cl.C1C=CC2N(O)N=NC=2C=1>[NH:41]([C:58]([O:60][CH2:61][CH:62]1[C:74]2[C:69](=[CH:70][CH:71]=[CH:72][CH:73]=2)[C:68]2[C:63]1=[CH:64][CH:65]=[CH:66][CH:67]=2)=[O:59])[C@@H:42]([C:55]([NH:1][C@@H:2]([C:15]([NH:17][C@H:18]([C:23]([NH:25][C@H:26]([C:31]([O:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:32])[CH2:27][CH:28]([CH3:30])[CH3:29])=[O:24])[CH2:19][CH:20]([CH3:21])[CH3:22])=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[O:56])[CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]([O:50][C:51]([CH3:52])([CH3:54])[CH3:53])=[O:49]
Reactant: CC(C)C[C@H](NC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Product: CC(C)C[C@H](NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
The obtained wet crystals of D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) were dissolved in chloroform (15 mL), Fmoc-D-Lys(Boc)-OH (444 mg, 948 μmol) and HOBt (12.8 mg, 94.7 μmol) were added at room temperature, and EDC HCl (200 mg, 1.04 mmol) was further added under ice-cooling. The mixture was warmed to room temperature and stirred overnight. Chloroform (20 mL), Fmoc-D-Lys(Boc)-OH (89 mg, 190 μmol) and EDC.HCl (40 mg, 210 μmol) were added, and the mixture was further stirred for 1 hr and concentrated under reduced pressure. The residue was precipitated with methanol (15 mL) to give Fmoc-D-Lys(Boc)-D-Lys(Boc)-Leu-Leu-OBzl (2-MeO-4-OC12OC22) (1.35 g, 85% yield relative to Bzl (2-MeO-4-OC12OC22)OH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([S:15]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][C:20]=3[S:28](=[O:31])(=[O:30])[NH2:29])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)([N:34]1C=CN=C1)=O.N.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([S:15]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:34])=[O:24])=[CH:21][C:20]=3[S:28](=[O:31])(=[O:30])[NH2:29])(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1NS(=O)(=O)c1cccc(-c2ccc(Cl)c(Cl)c2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(NS(=O)(=O)c2cccc(-c3ccc(Cl)c(Cl)c3)c2)c(S(N)(=O)=O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 6.7 %

Procedure:
To a solution of 4-[[3-(3,4-dichlorophenyl)phenyl]sulfonylamino]-3-sulfamoylbenzoic acid (0.20 g, 0.39 mmol) in DMF (5 mL) was added carbonyldiimidazole (0.06 g, 0.39 mmol). The reaction mixture was heated at 80° C. for 2 h, then aqueous ammonia solution (30%, 2 mL) was added and the resulting solution was stirred at RT for 2 h. The pH of the reaction mixture was then adjusted to pH 5 using 6N HCl and the resulting white precipitate was collected by filtration. The crude product was purified by preparative HPLC to afford the title compound (13 mg, 7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([N:13]3[C:21](=[O:22])[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH:14]3[O:23][CH2:24][C:25](O)=[O:26])=[N:10]2)=[CH:5][CH:4]=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CN(C)C=O>[OH:28][CH:29]1[CH2:34][CH2:33][N:32]([C:25](=[O:26])[CH2:24][O:23][CH:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:21](=[O:22])[N:13]2[C:9]2[CH:8]=[CH:7][C:6]3[C:11](=[N:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[N:10]=2)[CH2:31][CH2:30]1
Reactant: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)O)nc2n1
Reactant: OC1CCNCC1
Solvent: CN(C)C=O
Product: COc1ccc2ccc(N3C(=O)c4ccccc4C3OCC(=O)N3CCC(O)CC3)nc2n1
Yield: 101.8 %

Procedure:
The procedure is as in Example 44, but starting with [2-(7-methoxy-1,8-napthyridin-2-yl)-3-oxo-1-isoindolinyloxy] acetic acid (3.5 g) in anhydrous dimethylformamide (70 cc), N,'-carbonyldiimidazole (1.6 g) and 4-hydroxypiperidine (0.82 g). After recrystallization in ethanol, 3-[2-(4-hydroxy-1-piperidyl)-2-oxoethoxy]-2-(7-methoxy-1,8-naphthyridin-2-yl)-1-isoindolinone (3.7 g), m.p. 167° C., is obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15](O)=[O:16])=[CH:9][CH:8]=1.O[N:22]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.N>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]([NH2:22])=[O:16])=[CH:9][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)C#Cc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
50 mg (0.19 mmol) of [4-(3-fluoro-benzyloxy)-phenyl]-propynoic acid is dissolved in 3 ml of THF and treated with 27 mg (0.2 mmol) of 1-hydroxybenzotriazole and 37 mg (0.19 mmol) of N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride. The resulting mixture is stirred at RT for 30 minutes, cooled to 0° C. and treated with 1 ml of concentrated ammonia. The suspension is stirred overnight at RT, diluted with water and extracted three times with dichloromethane. Flash-chromatography (silica gel, dichloromethane/methanol) yields 29 mg (59%) of a colorless solid. MS: m/e=270.2 (M++H).
Reaction SMILES: [CH3:1][C:2]([O-])([CH3:4])[CH3:3].[K+].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[C:20]([CH2:21][CH3:22])=[CH:19]C(C(=O)C)=[N:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:20]([CH2:21][CH3:22])=[CH:19][C:1]([C:2]([CH3:4])=[CH2:3])=[N:17]2)=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC(C)(C)[O-]
Reactant: CCc1cc(C(C)=O)nn1-c1ccc([N+](=O)[O-])cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)c1cc(CC)n(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70 %

Procedure:
To a solution of methyl triphenylphosphonium bromide (3.47 g, 9.72 mmol) in THF (20 mL) was added 1 M KOt-Bu in THF (9.73 mL, 9.73 mmol) followed by the above ketone (2.10 g, 8.10 mmol). The mixture was stirred at room temperature for 4 hrs, quenched with water and extracted with ethyl acetate. The extract was dried over Na2SO4 and concentrated. The residue was slurried with hexane and filtered. The filtrate was concentrated to give the title compound as a white solid (1.46 g, 70%). mp: 61-63° C.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[CH:19]=[C:20]([CH:22]=[CH:23][CH:24]=3)[NH2:21])=[CH:7][CH:8]=2)[N:3]=1.[C:25]([O:29][C:30]([NH:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][N:34]=1)=[O:31])([CH3:28])([CH3:27])[CH3:26].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[NH2:21][C:20]1[CH:19]=[C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:36]4[CH:37]=[N:38][C:33]([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])=[N:34][CH:35]=4)=[N:3]3)=[CH:8][CH:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Nc1cccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Reactant: CC(C)(C)OC(=O)Nc1ncc(B(O)O)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(N)c4)cc3n2)cn1
Temperature: 95 °C
Reaction time: 2 h
Yield: 33.4 %

Procedure:
In 50 mL round bottom flask, 3-(2-chloro-4-morpholinoquinazolin-7-yl)aniline (0.6 g, 0.0018 mol), (2-((tert-butoxycarbonyl)amino)pyrimidin-5-yl)boronic acid (0.506 g, 0.0022), potassium phosphate (1.08 g, 0.0054 mol), 1,4-dioxane (20 mL) and water (5 mL) were added. The reaction mixture was degassed with N2 for 5-10 minutes. To the same reaction mixture, Pd (PPh3)4 (0.098 g, 0.00009 mol) was added and degassed with N2 for 5-10 minutes. The reaction mixture was stirred at 95° C. for 2 hours. The reaction mass was cooled to room temperature and water was added. The crude product was extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to provide the crude product. The crude product was purified by flash column chromatography (2% methanol in chloroform) to provide the title compound (0.3 g, 34%). 1H NMR (400 MHz, DMSO-d6): δ 10.40 (s, 1H), 9.49 (s, 2H), 8.12 (d, J=8.8 Hz, 1H), 8.01 (d, J=1.6 Hz, 1H), 7.75 (dd, J′=8.8 Hz, J″=1.6 Hz, 1H), 7.20 (t, J=7.6 Hz, 1H), 7.04 (br s, 1H), 6.98 (d, J=7.6 Hz, 1H), 6.66 (d, J=8.4 Hz, 1H), 5.29 (s, 2H), 3.90 (d, J=4.4 Hz, 4H), 3.84 (d, J=4.0 Hz, 4H), 1.49 (s, 9H): LC-MS (ESI): Calculated mass. 499.2, Observed mass [M+H]+: 500.4. (RT=0.78 min).
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12](=[NH:14])[NH2:13])[CH2:11][CH2:10]1)([CH3:5])([CH3:4])[CH3:3].CN([C:19]([CH:21]=[CH2:22])=O)C.CNC>CCO>[C:2]([O:6][C:7](=[O:15])[NH:8][C:9]1([C:12]2[N:13]=[CH:22][CH:21]=[CH:19][N:14]=2)[CH2:11][CH2:10]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Reactant: C=CC(=O)N(C)C
Agent: CNC
Agent: Cl
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(c2ncccn2)CC1
Temperature: 70 °C

Procedure:
To a solution of (1-Carbamimidoyl-cyclopropyl)-carbamic acid tert-butyl ester hydrochloride (3.62 g, 15.4 mmol) in anhydrous EtOH (62 mL) was added dimethylaminoacrolein (3.6 mL, 36. mmol) and dimethylamine (2 M in THF, 10. mL, 20. mmol). The reaction was heated at 70° C. for 18 h. The EtOH was removed in vacuo and the residue was dissolved in EtOAc (150 mL) and washed with water (3×100 ml). The organic phase was dried with Na2SO4 and concentrated to give a red oil. The product was crystallized from the oil using warm hexanes (30 mL) and the light orange solids were collected by filtration. The filtrate was re-processed in the same manner two additional times. In total 2.23 g of the title compound was isolated as a light orange powder, m/z 236.40 [M+1]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:9]=1[CH3:25])=[O:7].[H-].[Na+].CI.[C:36](=O)(O)[O-].[Na+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[N+:29]([O-:31])=[O:30])[C:6]([C:8]1[N:16]2[C:11]([CH:12]=[CH:13][CH:14]=[CH:15]2)=[C:10]([N:17]([CH3:36])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:21])[CH3:22])[C:9]=1[CH3:25])=[O:7]
Reactant: COc1cc(C(=O)c2c(C)c(NC(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(C)c(N(C)C(=O)OC(C)(C)C)c3ccccn23)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
3.05 g (7.2 mmol) of tert-butyl 3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-ylcarbamate in solution in 50 ml of tetrahydrofuran are added dropwise to 315 mg (7.9 mmol) of sodium hydride (at 60% as a dispersion in oil) in suspension in 10 ml of tetrahydrofuran, cooled to 0° C. After stirring for 1 hour at 0° C., 0.59 ml (9.5 mmol) of methyl iodide is added while the medium is maintained at 0° C. It is allowed to return to room temperature and it is stirred for 1 hour. The reaction medium is poured over a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic phase is separated after settling out, washed with a saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. 3.47 g of an orange-coloured foam are obtained.
Reaction SMILES: FC1C=CC(CN)=CC=1.[CH3:10][C:11]1[O:17][C:14]([CH2:15][NH2:16])=[CH:13][CH:12]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36](O)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([N:25]1[CH2:29][CH2:28][N:27]([C:30]2[S:31][C:32]([C:36]([NH:16][CH2:15][C:14]3[O:17][C:11]([CH3:10])=[CH:12][CH:13]=3)=[O:37])=[C:33]([CH3:35])[N:34]=2)[C:26]1=[O:39])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(CN)o1
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Agent: NCc1ccc(F)cc1
Product: Cc1ccc(CNC(=O)c2sc(N3CCN(Cc4ccccc4)C3=O)nc2C)o1
Yield: 29 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 4-fluorobenzylamine with 5-methylfurfurylamine to react with 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a white powder in 29% yield: mp 138-139° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.25 (m, 5H), 6.10 (d, J=2.7 Hz, 1H), 5.90-5.86 (m, 2H), 4.50-4.44 (m, 4H), 4.04 (t, J=8.1 Hz, 2H), 3.43 (t, J=8.1 Hz, 2H), 2.58 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 162.1, 157.3, 155.4, 153.1, 152.1, 148.9, 135.5, 128.8, 128.3, 128.0, 117.1, 108.5, 106.3, 47.9, 42.0, 41.6, 37.0, 17.1, 13.5; MS (ES+) m/z 411.3 (M+1).
Reaction SMILES: O[Li].O.O.[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:17]([O:19]C)=[O:18])[OH:16]>C1COCC1>[Cl:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[O:12][CH2:11][CH2:10][C:9]2([C:17]([OH:19])=[O:18])[OH:16]
Reactant: COC(=O)C1(O)CCOc2ccc(Cl)cc21
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(O)CCOc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
LiOH.H2O (0.19 g; 4.6 mmol) and water (4 mL) were added to a solution of 6-chloro-4-hydroxychroman-4-yl-carboxylic acid, methyl ester (0.56 g, 2.3 mmol; from step (i) above) in THF (6 mL). The reaction mixture was stirred at room temperature for 3 h, THF was evaporated and the water solution was washed with methylene chloride. The reaction mixture was acidified with HCl (2M) and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and evaporated, yielding a slowly crystallizing oil. Yield: 490 mg (93%).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:13]=[CH:12][C:5]2[CH2:6][C:7]([NH:9][C:10](=[O:11])[C:4]=2[CH2:3]1)=[O:8].[H-].[Na+].[Cl:17][C:18]([Cl:22])([Cl:21])[S:19]Cl>O1CCCC1.CCCCCC>[Cl:17][C:18]([Cl:22])([Cl:21])[S:19][N:9]1[C:10](=[O:11])[C:4]2[CH2:3][C:2]([CH3:14])([CH3:1])[CH:13]=[CH:12][C:5]=2[CH2:6][C:7]1=[O:8]
Reactant: CC1(C)C=CC2=C(C1)C(=O)NC(=O)C2
Reactant: ClSC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC1(C)C=CC2=C(C1)C(=O)N(SC(Cl)(Cl)Cl)C(=O)C2
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To 4,4-dimethyl homophthalimide (5.6 g) in 200 ml dry tetrahydrofuran was added 1.73 g sodium hydride. The mixture was stirred for one hour, then 5.75 g (3.38 ml) trichloromethyl sulfenyl chloride was added dropwise. The mixture was refluxed overnight, stripped of solvent, slurried in hexane and decanted. The brown crystalline residue was purified by tlc and recrystallized in ethanol to yield 3.2 g of the brown crystalline product, m.p. 129°-130° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]([F:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14](I)[CH:15]=2)[N:10]=1)=[O:8])[CH3:2].C(N(CC)CCN[C:29]([C:31]1[CH:32]=[C:33]([Sn:42](CCCC)([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:43][CH2:44][CH2:45][CH3:46])C=C2C=1N=CC=C2F)=O)C>>[CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:18]=[C:17]([F:19])[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Sn:42]([CH2:43][CH2:44][CH2:45][CH3:46])([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:33][CH2:32][CH2:31][CH3:29])[CH:15]=2)[N:10]=1)=[O:8])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)NCCN(CC)CC)c2nccc(F)c2c1
Reactant: CCN(CC)CCNC(=O)c1cc(F)c2cc(I)ccc2n1
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2nc(C(=O)NCCN(CC)CC)cc(F)c2c1
Yield: 57 %

Procedure:
This compound was prepared, starting from compound 106 (206 mg, 0.50 mmol), according to the procedure developed for compound 112. The purification was performed using column chromatography (Al2O3, cyclohexane/AcOEt, 5/5, v/v) to give compound 113 (165 mg, 0.29 mmol) as an orange oil. Yield 57%; Rf (Al2O3, cyclohexane/AcOEt, 5/5, v/v) 0.73; IR (CCl4) ν 1521, 1684, 2929, 2962 cm−1; 1H NMR (200 MHz, CDCl3) δ 0.88 (t, 9H, J=7.0 Hz), 1.10 (t, 6H, J=7.1 Hz), 1.17 (m, 6H), 1.33 (m, 6H), 1.55 (m, 6H), 2.64 (q, 4H, J=7.1 Hz), 2.74 (t, 2H, J=6.3 Hz), 3.59 (q, 2H, J=6.3 Hz), 7.88 (d, 1H, J=8.3 Hz), 7.94 (d, 1H, 3JH-F=10.4 Hz), 8.04 (dd, 1H, J=1.4, 8.3 Hz), 8.20 (d, 1H, 3J119Sn/117Sn-H=40.8 Hz), 8.61 (m, 1H); ESI-MS m/z 580.2 [M+H]+.
Reaction SMILES: [Na].Cl.Cl[CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1.[CH2:10]([OH:14])[CH2:11][CH2:12][OH:13]>>[OH:13][CH2:12][CH2:11][CH2:10][O:14][CH2:4][C:5]1[N:6]=[CH:7][NH:8][CH:9]=1
Reactant: ClCc1c[nH]cn1
Reactant: OCCCO
Agent: Cl
Agent: [Na]
Product: OCCCOCc1c[nH]cn1
Reaction time: 8 h

Procedure:
Sodium (13.5 g.) was added over 3 hours to propane-1.3-diol (450 ml.) under nitrogen at 70° with stirring. This solution was added over 20 minutes to a stirred solution of 4-chloromethylimidazole hydrochloride (50.0 g.) under nitrogen at 40°-60 °. Subsequent heating at 60°-65° for 3 hours followed by overnight cooling. filtration and concentraction gave 4-(3-hydroxypropoxy)methylimidazole. Subsequent reaction with thionyl chloride give 4-(3-chloropropoxy)methylimidazole hydrochloride (38.3 g.).
Reaction SMILES: [CH2:1]([C:3]([OH:36])([CH2:34][CH3:35])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH2:31][CH3:32])([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[C:17]([CH3:30])[CH:16]=2)[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:33])[CH3:2].[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][C:45](Br)=[CH:46][CH:47]=1)[CH3:38].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CN(C)C=O>[CH2:37]([O:39][C:40](=[O:49])[CH2:41][C:42]1[CH:43]=[N:44][C:45]([C:18]2[CH:19]=[CH:20][C:15]([C:12]([CH2:13][CH3:14])([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[C:3]([CH2:34][CH3:35])([OH:36])[CH2:1][CH3:2])=[C:7]([CH3:33])[CH:8]=3)[CH2:31][CH3:32])=[CH:16][C:17]=2[CH3:30])=[CH:46][CH:47]=1)[CH3:38]
Reactant: CCOC(=O)Cc1ccc(Br)nc1
Reactant: CCC(O)(CC)CCc1ccc(C(CC)(CC)c2ccc(B3OC(C)(C)C(C)(C)O3)c(C)c2)cc1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-c2ccc(C(CC)(CC)c3ccc(/C=C/C(O)(CC)CC)c(C)c3)cc2C)nc1
Temperature: 140 °C
Yield: 45.7 %

Procedure:
N,N-Dimethylformamide (0.7 mL) was added to 3-ethyl-1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-pentan-3-ol (Example 29; 50 mg, 0.102 mmol), (6-bromo-pyridin-3-yl)acetic acid ethyl ester (Example 74-(1); 40 mg, 0.165 mmol), tetrakis(triphenylphosphine)palladium (0) (23 mg, 0.02 mmol) and potassium phosphate (63.9 mg, 0.30 mmol). The mixture was stirred with microwave heating at 140° C. for seven minutes in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=10/1, then dichloromethane/methanol=20/1) to give the title compound (24.6 mg, 58%).
Reaction SMILES: Cl.[F:2][C:3]([F:26])([F:25])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=3)=[CH:9][CH:10]=[N:11]2)=[CH:6][CH:5]=1.Cl.[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl.O>[F:28][C:29]1[CH:42]=[CH:41][C:32]([C:33]([N:35]2[CH2:40][CH2:39][N:38]([S:21]([C:18]3[CH:19]=[CH:20][C:15]([NH:14][C:8]4[C:7]5[C:12](=[CH:13][C:4]([C:3]([F:26])([F:25])[F:2])=[CH:5][CH:6]=5)[N:11]=[CH:10][CH:9]=4)=[CH:16][CH:17]=3)(=[O:23])=[O:22])[CH2:37][CH2:36]2)=[O:34])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(C(F)(F)F)ccc23)cc1
Reactant: O=C(c1ccc(F)cc1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(c1ccc(F)cc1)N1CCN(S(=O)(=O)c2ccc(Nc3ccnc4cc(C(F)(F)F)ccc34)cc2)CC1
Temperature: 25 °C
Yield: 20.1 %

Procedure:
4-(7-Trifluoromethyl-4-quinolinylamino)benzenesulphonyl chloride hydrochloride (3.5 g, 0.008 mol) was added portionwise to a cold (10°), well stirred mixture of 1-(4-fluorobenzoyl)piperazine hydrochloride (2.0 g, 0.008 mol) in chloroform (50 ml) and sodium carbonate (10.0 g) in water (50 ml). The cooling bath was removed and the mixture was allowed to warm to room temperature. After half an hour, the mixture was filtered and the filtrate separated. The chloroform layer was dried (MgSO4). The solvent was removed by evaporation to give a yellow gum. The gum was crystallised from ethanol-water, then purified by column chromatography (basic Al2O3-chloroform) followed by recrystallisation from ethanol, to give the pure title compound (0.9 g), m.p. 172°-174.5° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9]Br)=[CH:4][CH:3]=1.[N+:11]([C:14]1[CH:19]=[CH:18][C:17]([O-:20])=[CH:16][CH:15]=1)([O-:13])=[O:12].[Na+]>CN(C)C=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:20][C:17]2[CH:18]=[CH:19][C:14]([N+:11]([O-:13])=[O:12])=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Reactant: Cc1ccc(CCBr)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(CCOc2ccc([N+](=O)[O-])cc2)cc1
Yield: 73.8 %

Procedure:
2-(4-Methylphenyl)ethyl bromide (X: X=Br) (10 g, 0.05 mole) and sodium 4-nitrophenolate (XI) (8.1 g, 0.05 mole) were added to dimethylformamide (60 ml), and the mixture was reacted at 90° C. for 5 hours. Thereafter, the reaction mixture was treated in the same manner as in Example 12 to obtain 9.5 g of 4-[2-(4-methylphenyl)ethoxy]-nitrobenzene (VI) as white crystals (yield, 73.9%).