Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[Cl:7][S:8]([C:11]1[CH:19]=[CH:18]C(C(O)=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9].CN(C)C=O>ClCCl>[Cl:7][S:8]([C:11]1[CH:19]=[CH:18][C:1]([C:2]([Cl:4])=[O:3])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(S(=O)(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Oxalyl chloride (2.2 mL) was added to a mixture of 4-(chlorosulfonyl)benzoic acid (0.662 g, 3.0 mmol) in anhydrous dichloromethane (25 mL) followed by one small drop of N,N-dimethylformamide. The mixture was stirred at room temperature overnight. Then the mixture was then concentrated to provide 4-(chlorosulfonyl)benzoyl chloride which was used without additional purification.
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]1[C:16](=[O:17])[CH2:15][NH:14][C:13](=O)[C:12]([CH3:19])=[C:7]12.O=P(Cl)(Cl)Cl.[CH:25]1([C:28]2[N:29]=[CH:30][NH:31][CH:32]=2)[CH2:27][CH2:26]1.N1C=CC=CC=1>ClCCCl>[CH:25]1([C:28]2[N:29]=[CH:30][N:31]([C:13]3[C:12]([CH3:19])=[C:7]4[C:8]5[C:3]([CH2:4][CH2:5][N:6]4[C:16](=[O:17])[CH2:15][N:14]=3)=[C:2]([I:1])[CH:11]=[CH:10][CH:9]=5)[CH:32]=2)[CH2:27][CH2:26]1
Reactant: CC1=C2c3cccc(I)c3CCN2C(=O)CNC1=O
Reactant: c1nc(C2CC2)c[nH]1
Solvent: ClCCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC1=C2c3cccc(I)c3CCN2C(=O)CN=C1n1cnc(C2CC2)c1
Temperature: 100 °C
Reaction time: 0.02 h
Yield: 29.6 %

Procedure:
107-1. A mixture of 9-iodo-1-methyl-3,4,7,8-tetrahydro-[1,4]diazepino[7,1-a]isoquinoline-2,5-dione (30 mg, 81 μmol) in DCE (2 mL) is treated with POCl3 (15 μL, 0.16 mmol) and heated to 100° C. for 3 h. The mixture was then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. phases were dried over Na2SO4, filtered and concentrated in vacuo. The brown residue obtained was taken up in DCE (2 mL) and 4-cyclopropyl-1H-imidazole (31 mg, 0.28 mmol) and pyridine (20 μL, 0.24 mmol) were then added. The mixture was heated to 100° C. for 4.5 h, and then allowed to cool to RT, poured onto H2O and extracted with DCM. The org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. Filtration through a pad of SiO2 (AcOEt) afforded a brown solid that was purified by SFC (column: Diol 5 μm, 250×30 mm, 60A, Princeton; eluent: 13% MeOH/CO2 for 1 min, then from 13% MeOH/CO2 to 18% MeOH/CO2 in 6 min; then from 18% MeOH/CO2 to 50% MeOH/CO2 in 1 min; flow 100 mL/min; UV detection at 220 nm) to give the title compound (11 mg) as a white powder. UPLC-MS: MS 459.0 (M+H+); UPLC rt 0.98 min.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:8][CH2:9][NH:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)C.[H][H].[ClH:32]>C(O)C.[Pd]>[ClH:32].[CH:12]1([CH2:11][N:10]2[CH2:9][CH2:8][C:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[O:6][CH2:5][CH2:4]2)[CH2:14][CH2:13]1
Reactant: CCOC(COC(CCNCC1CC1)(c1ccccc1)c1ccccc1)OCC
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: c1ccc(C2(c3ccccc3)CCN(CC3CC3)CCO2)cc1

Procedure:
The solution of 6.0 g of 2-(3-cyclopropylmethylamino-1,1-diphenylpropoxy)-acetaldehyde diethyl acetal in 60 ml of 95% ethanol and 10 ml of 6N hydrochloric acid is stirred at 20°-45° for 3 hours, cooled and 0.5 g of 10% palladium on charcoal are added. The mixture is hydrogenated at 2.7 atm. and 40° until the hydrogen uptake ceases. It is filtered, the filtrate neutralized with aqueous sodium hydroxide and evaporated. The residue is partitioned between water and methylene chloride, the organic phase separated, dried and evaporated. The residue is taken up in the minimum amount of acetone, the solution acidified with hydrogen chloride and diluted with diethyl ether, to yield the 4-cyclopropylmethyl-7,7-diphenyl-hexahydro-1,4-oxazepine hydrochloride melting at 268°-270°; it is identical with compound No. 11 of Example 2.
Reaction SMILES: C(O[C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17])C.[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23].C(OC(=O)C)C>CS(C)=O>[Br:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:4]1[C:5](=[O:19])[C:6](=[O:18])[C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[OH:17]
Reactant: Nc1ccccc1Br
Reactant: CCOc1c(Nc2ccc(C#N)cc2O)c(=O)c1=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1ccc(Nc2c(Nc3ccccc3Br)c(=O)c2=O)c(O)c1
Temperature: 25 °C
Yield: 3.3 %

Procedure:
A mixture of 3-ethoxy-4-(2-hydroxy-4-cyanoanilino)-3-cyclobutene-1,2-dione (0.7 g, 2.71 mmol) and 2-bromoaniline (0.47 g, 2.73 mmol) were heated in 6 ml DMSO for overnight. The reaction mixture was cooled to room temperature, and ethylacetate was added and precipitates formed. The filtrate was partitioned between ethylacetate and water. The organic layer was dried over sodium sulfate and concentrated. After Gilson HPLC, 34 mg (3%) of purified product was obtained. LC/MS (H+) 386
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[O-]CC.[Na+].[CH2:20](Br)[CH:21]=[CH2:22].[I-].[Na+]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH:9]([CH2:22][CH:21]=[CH2:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Reactant: C=CCBr
Agent: CC[O-]
Agent: [I-]
Agent: [Na+]
Product: C=CCC(C(=O)OCC)C(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.5 %

Procedure:
Ethyl 3-(4-methylphenyl)-3-oxopropanoate (prepared as described in W. Wierenga and H. I. Skulnick, J. Org. Chem. (1979), 44, 310) (63.66 g, 309 mmol, 1 eq) was added to a freshly prepared sodium ethoxide solution (Na, 7.43 g, 323 mmol, 1.05 eq; EtOH, 250 mL). The ethanol was removed in vacuo and the residue was dissolved in DMF (250 mL). Allyl bromide (29.3 mL, 338 mmol, 1.1 eq) followed by sodium iodide (4.56 g, 304 mmol, 1 eq) were then added and the contents stirred overnight at room temperature. The DMF was removed in vacuo, water (250 mL) was added and the aqueous layer extracted with ethyl acetate (3×200 mL). The organic layers were dried (MgSO4) and the solvent removed in vacuo to yield 74.21 g of an amber oil. NMR (200 MHz, CDCl3) δ 7.81 (d, 2H, J=10 Hz); 7.30 (d, 2H, J=10 Hz); 5.96-5.72 (m, 1H); 5.21-5.00 (m, 2H); 4.41 (t, 1H, J=7 Hz); 4.16 (q, 2H, J=7 Hz); 2.78 (t, 2H, J=7 Hz); 2.42 (s, 3H); 1.18 (t, 3H, J=7 Hz). Anal. Calcd. for C15H18O3 : C, 73.15; H, 7.37. Found: C, 73.10; H, 7.38.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:15]=2[C:14](=[O:16])[N:13]([CH:17]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:31])[F:30])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=2)[CH2:18][C:19](O)=[O:20])[CH2:12]3)=[O:5])[CH2:3][CH2:2]1.C1N=C[N:37](C(N2C=NC=C2)=O)C=1.[NH4+].[OH-]>C1COCC1>[C:19]([CH2:18][CH:17]([N:13]1[C:14](=[O:16])[C:15]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH:6][C:4]([CH:1]2[CH2:3][CH2:2]2)=[O:5])[CH2:12]1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH:29]([F:30])[F:31])=[C:24]([O:32][CH2:33][CH3:34])[CH:23]=1)(=[O:20])[NH2:37]
Reactant: CCOc1cc(C(CC(=O)O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(CC(N)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC(F)F
Yield: 69.6 %

Procedure:
Cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide was prepared by the procedure of example 6 from 3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(4-difluoromethoxy-3-ethoxy-phenyl)-propionic acid (0.8 g, 1.7 mmol), CDI (0.41 g, 2.5 mmol) and NH4OH (0.25 ml, 3.4 mmol) in THF (30 ml) to give cyclopropanecarboxylic acid {2-[2-carbamoyl-1-(4-difluoromethoxy-3-ethoxy-phenyl)-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as white solid (0.56 g, 70%): mp, 179-181° C.; 1HNMR (CDCl3): δ 0.92 (m, 2H, c-CH2), 1.44 (t, J=6.8 Hz, 3H, OCH2CH3), 1.68 (m, 1H, c-CH), 2.99 (dd, J=5, 15 Hz, 1H, CH2), 3.44 (dd, J=10, 15 Hz, 1H, CH2), 4.08 (q, J=7.0 Hz, 2H, OCH2CH3), 4.20 (d, J=17.5 Hz, 1H, CH2N), 4.40 (d, J=17.5 Hz, 1H, CH2N), 5.42 (broad, 1H, NH2), 5.58 (m, 1H, CHN), 6.07 (broad, 1H), 6.56 (t, JH-F=75 Hz, 1H, CF2H), 6.98 (m, 3H, Ar), 7.15 (d, J=7.5 Hz, H, Ar), 7.46 (t, J=7.5 Hz, 1H, Ar), 8.45 (d, J=8 Hz, 1H, Ar), 10.49 (s, 1H, NHCO). 13CNMR (CDCl3): δ 8.31, 14.6, 16.2, 38.9, 48.6, 53.9, 64.8, 101.57, 102.3, 113.2, 116.7, 117.3, 117.8, 119.2, 122.9, 113.5, 137.3, 138.1, 141.4, 141.2, 150.9, 170.9, 171.4, 172.7; Anal. Calcd. for C24H25F2N3O5: C, 60.88; H, 5.32; N, 8.87. Found: C, 60.82; H, 5.11; N, 8.80.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+].Cl>>[C:17]([NH:25][CH:26]1[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:9][CH:8]=2)=[O:6])[CH2:28][CH2:27]1)(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(NC1CCNCC1)c1ccccc1
Reactant: CC(C)(C)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)c1ccc(C(=O)CCCN2CCC(NC(=O)c3ccccc3)CC2)cc1
Yield: 57.4 %

Procedure:
4-Chloro-4'-tert-butylbutyrophenone (3.58 g.), 4-benzamidopiperidine (3.06 g.) and anhydrous potassium carbonate (2.67 g.) were reacted together in the manner of Example 68 to give the title compound (3.495 g.) as the hydrochloride, colourless microcrystals, m.p. 268.0° .
Reaction SMILES: [CH3:1][C:2]([CH3:18])([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][O:4][C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.[ClH:19].N([O-])=O.[Na+].C[C:25]([CH3:27])=[O:26]>O.C(OCC)(=O)C=C>[Cl:19][CH:2]([CH2:1][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH2:3][C:2]([CH3:18])([CH3:1])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:7]=1)[C:3]([O:26][CH2:25][CH3:27])=[O:4]
Reactant: CC(C)(COc1ccc(N)cc1)c1ccccc1
Reactant: CC(C)=O
Reactant: Cl
Agent: C=CC(=O)OCC
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C(Cl)Cc1ccc(OCC(C)(C)c2ccccc2)cc1

Procedure:
In 150 ml of acetone is dissolved 16.8 g of 4-(2,2-dimethyl-2-phenylethyloxy)aniline and, under cooling with ice and stirring, 20 ml of hydrochloric acid, a solution of 6 g sodium nitrite in 20 ml water, 75 ml of ethyl acrylate and 0.3 g of finely divided cuprous oxide are added in the order mentioned. The mixture is stirred at 10° C for 30 minutes and at room temperature for 2 hours. After the reaction has been completed, the reaction mixture is concentrated under reduced pressure and extracted with ether. The ether is distilled off and residual oil is purified by chromatography on silica gel. The described procedure yields 17.7 g of ethyl 2-chloro-3-[4-(2,2-dimethyl-2-phenylethyloxy)phenyl]propionate as a yellowish oily product. Cyclohexane/benzene is used as the eluant solvent (1:1). Boiling point: 205°-206° C/0.9 mmHg
Reaction SMILES: [C@@H:1]12[C:10](=[O:11])[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C(Cl)Cl>[N:12]1([C:7]([CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]2[C:10]([OH:9])=[O:11])=[O:8])[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Solvent: ClCCl
Product: O=C(O)C1CCCCC1C(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 89.4 %

Procedure:
To a solution of cis-1,2-cyclohexane dicarboxylic anhydride (1.0 g, 6.49 mmol) in CH2Cl2 (16 mL) was added morpholine (0.56 g, 6.49 mmol) at 0° C., the resulting mixture was allowed to stir a room temperature overnight (20 h). When complete the reaction mixture was washed with HCl (1.0 N, 20 mL) then with H2O (2×20 mL). The combined aqueous layers were extracted with CH2Cl2 (3×10 mL), and the combined organic layers were dried over MgSO4, the solvent was evaporated in vacuo to give the title compound (1.4 g, 90%) as a white solid which was used later without further purification.
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24]Br)[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2].C([O-])=[O:28].[K+]>CO>[CH2:1]([C@H:3]1[CH2:8][C@H:7]2[C@H:9]3[C@H:18]([CH2:19][CH2:20][C@:5]2([CH3:6])[C@H:4]1[O:22][C:23](=[O:26])[CH2:24][OH:28])[C@@H:17]1[C:12](=[CH:13][C:14](=[O:21])[CH2:15][CH2:16]1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: O=C[O-]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Agent: [K+]
Solvent: CO
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CO
Yield: 75.2 %

Procedure:
A mixture of 5.0 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 5.0 g of potassium formate is refluxed in 100 ml of methanol for 4 hours. The solvent is distilled off under reduced pressure and water is added to the residue. The mixture is extracted with 150 ml of ethyl acetate, and the ethyl acetate layer is washed with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent is then distilled off under reduced pressure and the resulting crystalline precipitate is recrystallized from diethyl ether-n-hexane (1:2) to give 3.2 g of the above-identified compound as colorless crystals.
Reaction SMILES: C[O:2][CH2:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=[C:6]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[C:5]=1[CH3:28].B(Br)(Br)Br.C(OCC)C.[ClH:38]>ClCCl.C(O)C>[ClH:38].[OH:2][CH2:3][C:4]1[N:9]=[C:8]([NH:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:7]=[C:6]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])[C:5]=1[CH3:28]
Reactant: COCc1nc(Nc2ccccc2)nc(N2CCc3ccccc3C2C)c1C
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCO
Product: Cc1c(CO)nc(Nc2ccccc2)nc1N1CCc2ccccc2C1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of 6-methoxymethyl-5-methyl-2-phenylamino-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(4.0 g, 9.7 mmol) in dichloromethane (50 ml) was cooled under 0° C. Boron tribromide (1M-dichloromethane solution, 38.8 ml, 38.8 mmol) was added dropwise to the solution. The reaction mixture was stirred for 30 minutes at 0° C. and poured into ice water. The separated dichloromethane layer was washed with aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, concentrated under a reduced pressure. Ethyl ether was added to the resulting residue to give a solid, which was then dissolved in ethanol and treated with ethyl ether saturated with hydrochloric acid to give 2.3 g of the titled compound.
Reaction SMILES: [CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][NH:16][CH:17]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:9]=3[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26]C#N.CI.CCN(C(C)C)C(C)C>O>[CH:1]1([C:7]2[S:25][C:10]3[N:11]=[C:12]([CH3:24])[N:13]=[C:14]([CH2:15][N:16]([CH3:26])[CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]4)[C:9]=3[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC#N
Reactant: Cc1nc(CNC2CCCCCC2)c2cc(C3CCCCC3)sc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CI
Solvent: O
Product: Cc1nc(CN(C)C2CCCCCC2)c2cc(C3CCCCC3)sc2n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a mixture of N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]cycloheptaneamine (132 mg) and CH3CN (3 mL) were added CH3I (100 μL) and DIPEA (200 μL), followed by stirring at room temperature for 15 hours. To the reaction mixture was added water, followed by extraction with EtOAc. The organic layer was dried over MgSO4 and then concentrated under reduced pressure. The residue was purified by silica gel column (hexane/EtOAc) to obtain N-[(6-cyclohexyl-2-methylthieno[2,3-d]pyrimidin-4-yl)methyl]-N-methylcycloheptaneamine (77 mg).
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18])([CH2:9][CH2:10][CH3:11])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1.[CH2:19](I)[CH3:20].[OH-].[Na+]>CN(C)C=O>[OH:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH2:19][CH3:20])([CH2:9][CH2:10][CH3:11])[CH2:3][N:4]1[CH:8]=[CH:7][N:6]=[CH:5]1
Reactant: CCCC(O)(Cn1ccnc1)c1ccccc1O
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCC(O)(Cn1ccnc1)c1ccccc1OCC
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.1 %

Procedure:
34 mg of 1-[2-hydroxy-2-(2-hydroxyphenyl)pentyl]imidazole (Compound 18) was dissolved into 10 ml of dimethylformamide, and 33 mg of ethyl iodide and 10 mg of sodium hydroxide was added to this solution. The mixture was stirred at room temperature for 20 hours. The reaction mixture, after being charged into ice water, was subjected to extraction with ether. The ether layer was then washed with water, followed by drying over anhydrous magnesium sulfate. The extract thus obtained was purified by means of silica gel column chromatography (eluent: methylene chloride) to produce 22 mg of the title compound at a yield of 58%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:15](Cl)(=[O:17])=[O:16])[CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[NH:30][N:29]=[N:28][N:27]=4)[CH:21]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: COc1ccc(-c2cccc(S(=O)(=O)Cl)c2)cc1
Product: COc1ccc(-c2cccc(S(=O)(=O)Nc3cccc(-c4nnn[nH]4)c3)c2)cc1
Yield: 58.9 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting from [3-(4-methoxyphenyl)phenyl]sulfonyl chloride (16 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8 mg, 0.05 mmol) giving 12 mg (60%) of the title compound. MS (ESI+) calcd for C20H17N5O3S 407.10521, found 407.10532.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1.[H][H].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CS(C)=O.O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][N:9]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NCCCNc1ccc(Br)cn1
Reactant: BrCc1ccccc1
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCCN(Cc1ccccc1)c1ccc(Br)cn1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a suspension of sodium hydride (0.83 g) in DMSO (25 ml) was added 2-(3-aminopropylamino)-5-bromopyridine (4.6 g). The mixture was stirred and heated slowly, to 85° C. After the evolution of hydrogen had ceased the mixture was cooled to room temperature and benzyl bromide (3.42 g) in DMSO (5 ml) added dropwise maintaining the temperature below 30° C. After standing overnight, water was added and the mixture extracted with ether. The ether extract was washed with 2N hydrochloric acid. The pH of the acid extract was raised to 2.5 (NaOH) and extracted with chloroform. The pH was raised further to 14 and again extracted with chloroform. After drying (K2CO3), the final extract was stripped to give 2-[N-(3-aminopropyl)-N-benzylamino]-5-bromopyridine (4.6 g) as an oil which was used without further purification. (ii) 2-[N-(3-aminopropyl)-N-benzylamino]-5-bromopyridine (1.97 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.34 g) were heated together under reflux in pyridine (15 ml) for 20 hr. After stripping, the residue was triturated with ether, recrystallised from methanol and chromatographed (silica gel, 1-2% methanol/chloroform) to give 2-[3-[N-benzyl-N-(5-bromopyrid-2-yl)-amino]propylamino]-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one, 0.2H2O, 1.01 g (38%) mp 150°-55° C. (from ethanol).
Reaction SMILES: ClC(N(C)C)=C(C)C.[NH:9]([C:25]([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[C@H:10]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:11][C:12](=[O:14])O.[C:42]([NH2:61])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCCl.C(OCC)(=O)C>[NH:9]([C:25]([O:27][CH2:28][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:26])[C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12](=[O:14])[NH:61][C:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
0.8 ml of 1-chloro-N,N,2-trimethyl-prop-1-enylamine (A. Devos et al., J. Chem. Soc., Chem. Commun., Vol. 1979, p. 1180) is added to a stirred solution of 2.09 g of Fmoc-Asp-OBzl in 20 ml of 1,2-dichloroethane at 0° under an argon atmosphere. After 10 minutes, a solution of 1.2 g of tritylamine in 4 ml of 1,2-dichloroethane is added, and then the mixture is stirred for 2 hours, diluted with ethyl acetate and washed with water. The organic phase is dried and evaporated. The residue is taken up in chloroform and chromatographed on 250 g of silica gel. The fractions containing the Fmoc-Asn(Trt)-OBzl are combined and evaporated; the product is obtained as an amorphous foam.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1.[Na].C1(C)C(S([N:21]2[C:30]([CH3:32])([CH3:31])[CH2:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22]2)(=O)=O)=CC=CC=1>C(COC)OC.COCOC>[CH3:31][C:30]1([CH3:32])[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][NH:21]1
Reactant: Cc1ccccc1S(=O)(=O)N1Cc2ccccc2CC1(C)C
Agent: [Na]
Solvent: COCOC
Solvent: COCCOC
Solvent: c1ccc2ccccc2c1
Product: CC1(C)Cc2ccccc2CN1
Yield: 85.3 %

Procedure:
To a stirred solution of naphthalene (5.8 g, 0.045 mol) in dimethoxyethane (50 mL) was added sodium metal (1.09 g, 0.039 mol.). The mixture was allowed to stir for four (4) hours until a dark green color persisted. To this was added of N-toluenesulfonyl-3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline (5.0 g, 0.016 mol.) in 20 mL of dimethoxymethane. The reaction was monitored by gas chromatography. When the reaction was complete (≈2 hours), the mixture was quenched with saturated sodium chloride (70 mL). The mixture was partitioned between ethyl acetate (250 mL) and 10% HCL (250 mL) and the organic layer was discarded. 10% Sodium hydroxide was added to the aqueous layer until a pH=7 was obtained. The aqueous layer was further extracted over methylene chloride (2×100 mL), dried over magnesium sulfate, filtered and concentrated (25° C./150 torr) to produce 2.2 g (86%) of 3,3-dimethyl-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][O:5][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]
Reactant: CCOC(=O)Cc1ccccc1O
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)Cc1ccccc1OCc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of 2,6-Dimethylbenzyl alcohol (2.72 g, 19.9 mmol) and diisopropyl azodicarboxylate (DIAD, 3.67 g, 18.2 mmol) in THF (30 ml) was added drop wise to a solution of Ethyl 2-(2-hydroxyphenyl)acetate (3 g, 16.6 mmol) and triphenylphosphine (4.76 g, 18.2 mmol) in THF (80 ml). The reaction mixture was stirred at room temperature for 6 hours, diluted with ether and washed with water and brine. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 4:1) to give the title compound.