Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[CH:25][CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33]([NH:1][CH:2]([CH2:12][C:13]2[O:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:34])=[CH:25][CH:24]=1
Reactant: NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)o1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(5-(trifluoromethyl)-2-furanyl)-1-propanol (300 mg, 0.99 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (188 mg, 0.99 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (283 mg, 1.48 mmol) and 1-hydroxy-1H-benzotriazole (151 mg, 0.99 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (191 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11](I)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[CH3:24][N:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[CH2:27][CH2:26]1>>[Cl:1][C:2]1[C:3]2[C:11]([C:35]#[C:34][CH2:33][CH2:32][CH2:31][N:28]3[CH2:27][CH2:26][N:25]([CH3:24])[CH2:30][CH2:29]3)=[CH:10][N:9]([CH2:13][C:14]3[C:19]([CH3:20])=[C:18]([O:21][CH3:22])[C:17]([CH3:23])=[CH:16][N:15]=3)[C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: COc1c(C)cnc(Cn2cc(I)c3c(Cl)nc(N)nc32)c1C
Reactant: C#CCCCN1CCN(C)CC1
Product: COc1c(C)cnc(Cn2cc(C#CCCCN3CCN(C)CC3)c3c(Cl)nc(N)nc32)c1C

Procedure:
Sonogashira coupling of 4-chloro-5-iodo-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo [2,3-d]pyrimidin-2-amine with 1-methyl-4-(pent-4-ynyl)piperazine, according to the general procedure A gave the title compound, as a solid. Mp=160.1-162.3° C. HPLC Rt=4.08 min.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:9][OH:10].[H-].[Na+].[OH2:26]>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][O:19]1)[CH2:9][O:10][CH2:9][C:8]1[O:26][CH2:14][CH2:13][CH2:12][CH:11]=1
Reactant: OCC(CCCCCCOC1CCCCO1)OC1CCCCO1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C1=C(COCC(CCCCCCOC2CCCCO2)OC2CCCCO2)OCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.049 g of 2,8-bis(tetrahydropyran-2-yloxy)-1-octanol (prepared as described in Preparation 72) in 10 ml of dimethylformamide was added, whilst ice-cooling, to a mixture of 0.152 g of sodium hydride (as a 55% dispersion in mineral oil) and 10 ml of dimethylformamide. The mixture was then stirred at room temperature for 1 hour. At the end of this time, a solution of the residue prepared as described in step (a) above dissolved in 15 ml of dimethylformamide was added to the mixture, which was then stirred at room temperature for 19 hours. It was then poured into 350 ml of water and extracted twice with ethyl acetate. The combined extracts were washed with water, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 60 g of silica gel. 0.934 g of the title compound was obtained, as a colorless oil, from the fractions eluted with a 9:1 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+]>O1CCCC1>[CH2:1]([O:8][CH2:10][C:11](=[O:18])[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: CCOC(=O)CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)COCc1ccccc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
A mixture of 112 g (1.04 mol) of benzyl alcohol and 155 g (0.94 mol) of ethyl 4-chloro-3-oxobutyrate was added dropwise to a suspension of 82.9 g (2.07 mol) of 60% sodium hydride in 775 ml of tetrahydrofuran at 35 to 40° C. After the addition, the reaction mixture was stirred at 40° C. for 1 hour. Tetrahydrofuran was recovered from the reaction mixture, and 500 ml of heptane was added to the residue. The resulting solution was added dropwise to 800 ml of water to precipitate crystals, which were separated at room temperature and washed with heptane. To the crystals were added 800 ml of butyl acetate and 1000 ml of 1N hydrochloric acid to conduct extraction. The organic phase was washed successively with 500 ml of a 5% sodium chloride aqueous solution, 500 ml of a 5% sodium hydrogencarbonate aqueous solution, and 500 ml of a 5% sodium chloride aqueous solution to adjust the pH to 6 to 7. Butyl acetate was recovered, and 100 ml of heptane was added to the residue. The mixture was stirred, followed by liquid-liquid separation to obtain 173 g (78%) of ethyl 4-benzyloxy-3-oxobutyrate.
Reaction SMILES: Cl[C:2]1[C:3]2[N:11]([CH3:12])[N:10]=[C:9]([CH3:13])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.[NH2:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17].[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:12][N:11]1[C:3]2[C:2]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][OH:17])=[N:7][C:6]([CH3:8])=[N:5][C:4]=2[C:9]([CH3:13])=[N:10]1
Reactant: Cc1nc(Cl)c2c(n1)c(C)nn2C
Reactant: CCC(N)CO
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCC(CO)Nc1nc(C)nc2c(C)nn(C)c12
Yield: 30.1 %

Procedure:
A mixture of 8 g (0.04 mol) of 7-chloro-1,3,5-trimethyl-1H-pyrazolo[4,3-d]pyrimidine (Ex. 3) and 9 g (0.1 mol) of 2-amino-1-butanol in 75 ml of toluene is heated on the steam bath four hours. The warm solution is shaken with 100 ml of 4N ammonium hydroxide. The aqueous extract is concentrated in vacuo to give 3 g of 2-[1,3,5-trimethyl-1-H-pyrazolo[4,3-d]pyrimidin-7-yl]amino-1-butanol, mp 165°-168° C. Another 2.2 g of product is obtained by concentrating the toluene solution.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10]([CH:12]1[O:14][CH2:13]1)Cl>>[O:14]1[CH2:13][CH:12]1[CH2:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1
Reactant: ClCC1CO1
Reactant: N#Cc1ccc(O)cc1
Product: N#Cc1ccc(OCC2CO2)cc1
Yield: 75 %

Procedure:
The sub-title compound was prepared in 75% yield according to the procedure described International Patent Application WO 99/31100 (i.e. by reaction between p-cyanophenol and epichlorohydrin).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]#[N:19])[CH2:15][CH2:14][S:13](=[O:17])(=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH2:20]>C(O)C.CCOC(C)=O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:18]([NH2:19])=[O:20])[CH2:11][CH2:12][S:13](=[O:17])(=[O:16])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O
Reactant: N#CC1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: NC(=O)C1(c2ccc([N+](=O)[O-])cc2)CCS(=O)(=O)CC1

Procedure:
A solution of 4-(4-nitro-phenyl)-1,1-dioxo-hexahydro-1λ6-thiopyran-4-carbonitrile (as prepared in the previous step) in ethanol and water is treated with NaBO3 (Synthetic Communications, 20(4), 563-71, (1990)). The mixture is diluted with EtOAc and washed with water. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue is purified by silica gel chromatography with the appropriate solvent to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20]4)=[CH:15][CH:14]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.[ClH:32].CCOCC>O1CCOCC1>[ClH:32].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([C@@H:19]4[O:24][CH2:23][CH2:22][NH:21][CH2:20]4)=[CH:17][CH:18]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(-c3nnc(-c4ccc(F)cc4)o3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Fc1ccc(-c2nnc(-c3ccc([C@H]4CNCCO4)cc3)o2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
(S)-tert-Butyl 2-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)morpholine-4-carboxylate (45 mg, 0.105 mmol) was dissolved in dioxane (1 ml) and a solution of HCl in dioxane (4M, 0.317 ml, 1.27 mmol) was added. The reaction mixture was stirred for 2 h at 60° C. After cooling ether (2 ml) was added and the solid was filtered off. It was washed with ether and dried in vacuo to afford (S)-2-(4-(5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl)phenyl)morpholine hydrochloride (32 mg, 84%) as a white solid. MS (ISP): 326.1 ([M+H]+).
Reaction SMILES: Br[C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9]([O-:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cs+]>CN(C=O)C.CCOCC>[C:9]([S:16][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: [O-]C(=S)c1ccccc1
Reactant: CC(C)[C@@H](Br)C(=O)O
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)[C@H](SC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.6 %

Procedure:
To a solution of (R)-(+)-2-bromo-3-methylbutyric acid (4.20 g, 23.2 mmol) in DMF (41 mL) was added cesium thiobenzoate (6.08 g, 22.5 mmol). The mixture was stirred at rt for 20 h. The resulting solution was diluted with ether (200 mL) and washed with H2O (4×40 mL). The ethereal layer was dried (Na2SO4), and concentrated. The crude residue was recrystallized from hexanes to afford (S)-2-benzoylthio-3-methylbutanoic acid as a pale yellow solid (3.89 g, 72%); 1H NMR (300 MHz, CDCl3) δ 1.09 (d, J=7.4 Hz, 3H), 1.11 (d, J=7.4 Hz, 3H), 2.40 (m, 1H), 4.37 (d, J=5.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 12.0 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.8, 20.6, 30.5, 53.1, 127.6, 128.8, 133.9, 136.3, 177.9, 190.3; IR (neat) 3100, 2967, 1709, 1669 cm−1; [α]D22=−94.2 (c 1, CH2Cl2).
Reaction SMILES: O1[CH2:3][CH:2]1[CH:4]([CH3:27])[CH2:5][S:6]([C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7].NC(N)=[S:30]>CO.C(Cl)Cl>[S:30]1[CH2:3][CH:2]1[CH:4]([CH3:27])[CH2:5][S:6]([C:9]1[CH:26]=[CH:25][C:12]([O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: COC(=O)Cc1ccc(Oc2ccc(S(=O)(=O)CC(C)C3CO3)cc2)cc1
Reactant: NC(N)=S
Solvent: ClCCl
Solvent: CO
Product: COC(=O)Cc1ccc(Oc2ccc(S(=O)(=O)CC(C)C3CS3)cc2)cc1
Reaction time: 8 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1.9 (500 mg, 1.38 mmol) in MeOH—CH2Cl2 (10:1, 11 mL) was added thiourea (262 mg, 3.45 mmol) at room temperature, and the mixture was stirred overnight. After concentration under reduced pressure, the residue was dissolved in ethyl ether. The ethyl ether solution was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=2/5) to give 1.3 (400 mg, 77%) as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.15 (dd, 1H, J=5.5, 2.0 Hz), 2.53 (dd, 1H, J=6.5, 2.0 Hz), 3.05 (m, 1H), 3.17 (dd, 1H, J=14.5, 7.0 Hz), 3.51 (dd, 1H, J=14.5, 5.5 Hz), 3.65 (s, 2H), 3.72 (s, 3H), 7.03-7.05 (m, 2H), 7.08-7.10 (m, 2H), 7.33-7.34 (m, 2H), 7.85-7.86 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 24.2, 26.0, 40.3, 52.1, 62.6, 117.7, 120.5, 130.7, 130.9, 131.1, 131.9, 153.8, 162.8, 171.8; HRMS (FAB) calcd for C18H19O5S2 (M+H+) 379.0674, found 379.0645.
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:15][C@H:14]2[CH:16]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19]>C1C=CC=CC=1>[C:1]1([C:7]#[C:8][C:9]#[C:10][C:11]#[C:12][C@@H:13]2[O:15][C@H:14]2[CH:16]=[CH:20][CH:18]=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: c1ccccc1
Product: O=CC=C[C@@H]1O[C@H]1C#CC#CC#Cc1ccccc1
Temperature: 70 °C
Yield: 51.9 %

Procedure:
(trans)-3-(6-Phenyl-1,3,5-hexatriynyl)oxiranecarboxaldehyde (80 mg, 0.36 mmole; see Example 4) and formylmethylenetriphenylphosphorane (122 mg, 0.40 mmole) were dissolved in 10 ml of dry benzene and the mixture was heated at 70° C. for 10 minutes. The mixture was then cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in ether and filtered through a plug of silica gel. Removal of solvent afforded a brown oil which was purified by chromatography (silica gel, ether-hexane 1:1) to afford 46 mg of the title compound, melting point 91°-92.5° C.
Reaction SMILES: [Br:1]Br.[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[N:7]=1)(=[O:5])[CH3:4].Cl.C(OC(C)C)(C)C>O1CCOCC1>[C:14]([NH:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:3](=[O:5])[CH2:4][Br:1])[N:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCc1cccc(C(C)=O)n1
Reactant: BrBr
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)OC(C)C
Product: CC(=O)NCc1cccc(C(=O)CBr)n1

Procedure:
Bromine (9.9 ml) was added dropwise to a mixture of 2-acetyl-6-(acetylaminomethyl)pyridine (37.0 g) in dioxane (740 ml) and 4N-dioxanic hydrogen chloride (48.1 ml) at ambient temperature with stirring. After the mixture was stirred at 50° C. for 3 hours. To the mixture was added a diisopropyl ether (600 ml) and the mixture was stirred under ice-cooling for 30 minutes. The isolated precipitate was collected by filtration. The precipitate was added to water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate. The aqueous mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was dried over magnesium sulfate and evaporated in vacuo to give 2-(acetylaminomethyl)-6-bromoacetylpyridine (50.3 g) as an oil.
Reaction SMILES: [CH2:1]1[C@@:5]2([CH2:9][CH2:8][NH:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][CH:20]=[C:21]([OH:26])[CH:22]=3)[C:17]2=[O:27])=[CH:12][CH:11]=1.[CH3:28][C:29]1([CH3:32])[CH2:31][O:30]1>>[OH:26][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[C:17](=[O:27])[N:16]([C:13]1[CH:14]=[CH:15][C:10]([N:2]3[CH2:3][CH2:4][C@:5]4([CH2:9][CH2:8][N:7]([CH2:28][C:29]([OH:30])([CH3:32])[CH3:31])[CH2:6]4)[CH2:1]3)=[CH:11][CH:12]=1)[CH:25]=[CH:24]2
Reactant: CC1(C)CO1
Reactant: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@]3(CCNC3)C2)cc1
Product: CC(C)(O)CN1CC[C@]2(CCN(c3ccc(-n4ccc5cc(O)ccc5c4=O)cc3)C2)C1

Procedure:
According to Method U, 2-[(S)-4-(2,7-diaza-spiro[4.4]non-2-yl)-phenyl]-6-hydroxy-2H-isoquinolin-1-one was reacted with 2,2-dimethyl-oxirane. In this way the product was obtained with molecular weight 433.56 (C26H31N3O3); MS (ESI): 434 (M+H+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1.O[C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C(P(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[C:3]([CH3:14])=[C:4]([CH:8]([O:13][C:16]2[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:18]([CH3:29])[CH:17]=2)[CH2:9][CH2:10][CH2:11][CH3:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)COc1ccc(O)cc1C
Reactant: CCCCC(O)c1cccc(Br)c1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCCCC(Oc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(Br)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
To a solution of 1-(3-bromo-2-methylphenyl)-1-pentanol (495 mg, 1.92 mmol) in anhydrous THF (40 mL) under nitrogen at 0° C. was added portion-wise ethyl (4-hydroxy-2-methylphenoxy)acetate (405 mg, 1.93 mmol), followed by slow addition (over 25 min) of ADDP (971 mg, 3.85 mmol) and drop-wise addition of tributylphosphine (0.96 mL, 3.85 mmol). The resulting mixture was then stirred for 16 h with gradual warming to ambient temperature. The solvent was then removed under vacuum and the residue partitioned between EtOAc (100 mL) and water (150 mL), the layers separated, and the aqueous re-extracted with EtOAc (100 mL). The combined organic layer was then dried (Na2SO4), filtered and reduced under vacuum and the resulting residue purified by SPE (silica, 50 g cartridge), eluting with cyclohexane:EtOAc (gradient 99:1 to 4:1) to afford the title compound as a colourless oil (495 mg).
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][OH:16])[CH:12]=[CH:11][CH:10]=1.[H-].[Na+].Br[CH2:21][CH2:22][CH3:23]>CN(C)C=O>[C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[N:14]=[C:13]([CH2:15][O:16][CH2:21][CH2:22][CH3:23])[CH:12]=[CH:11][CH:10]=1
Reactant: Cc1cc(C)c(-c2cccc(CO)n2)c(C)c1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCOCc1cccc(-c2c(C)cc(C)cc2C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
(6-Mesitylpyridin-2-yl)methanol (1.03 g, 4.54 mmol) was dissolved in N,N-dimethylformamide (5 mL) and the solution was charged with sodium hydride (60% dispersion in mineral oil, 0.23 g, 5.7 mmol). The reaction stirred for 0.5 h at room temperature. Bromopropane (0.52 mL, 5.7 mmol) was added last. The reaction ran for 2.5 h. The solution was quenched with water, extracted with ether, dried, and concentrated. Flash chromatography (15% ethyl acetate/hexanes) gave 0.65 g (53% yield) of the desired product.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:18]([CH3:20])[CH3:19])[CH:13]([OH:17])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH:18]([CH3:20])[CH3:19])[CH:13]([O:17][C:27](=[O:29])[CH3:28])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(O)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OC(C(=O)O)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 8 h
Yield: 79.9 %

Procedure:
To a solution of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-hydroxy-4-methylpentanoic acid (1.70 g, 6.04 mmol) and pyridine (4.9 mL) was added acetic anhydride (5.7 mL, 6.17 g, 60.4 mmol) dropwise at room temperature. The reaction was allowed to stir overnight and was diluted with ethyl acetate and washed with water (2×). The organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo to give a thick oil. The residue was purified by column chromatography on silica gel with 15% methanol/dichloromethane to afford 1.56 g (80%) of 3-(S)-[(benzyloxycarbonyl)amino]-2-(R,S)-acetoxy-4-methyl pentanoic acid as a light yellow viscous oil. FAB MS [M+H] m/z; Calcd: 324, Found: 324.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][N:15](C(OCC4C=CC=CC=4)=O)[C@@H:14]([CH3:28])[CH2:13]3)[C:11]([NH:29][CH3:30])=[N:10][C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1>CO>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[C@@:12]3([CH2:17][CH2:16][NH:15][C@@H:14]([CH3:28])[CH2:13]3)[C:11]([NH:29][CH3:30])=[N:10][C:9]2=[O:31])[CH:5]=[CH:6][CH:7]=1
Reactant: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN(C(=O)OCc1ccccc1)[C@@H](C)C2
Solvent: CO
Product: CNC1=NC(=O)N(c2cccc(F)c2)[C@@]12CCN[C@@H](C)C2
Temperature: 25 °C

Procedure:
The product from step 1 above, benzyl (5R,7S)-1-(3-fluorophenyl)-7-methyl-4-(methylamino)-2-oxo-1,3,8-triazaspiro[4.5]dec-3-ene-8-carboxylate (370 mg, 0.86 mmol) was dissolved in 8 mL MeOH. The solvent was degassed with a nitrogen flow for 10 min and Pd(OH)2 (30 mg, 20% wt. Pd) added. The mixture was purged with a hydrogen balloon for 10 min and then maintained under atmospheric hydrogen at rt overnight with stirring. The reaction was then filtered over Celite, the cake rinsed with EtOAc and the filtrate concentrated to dryness under reduced pressure to give after drying under vacuum the product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:6]2.[Br:17]Br>C(O)(=O)C>[Br:17][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8]2
Reactant: CCOC(=O)c1cc2cc(OC)ccc2[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2c(Br)c(OC)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100 %

Procedure:
To a suspension of ethyl 5-methoxy-1H-indole-2-carboxylate (5 g, 22.81 mmol) in acetic acid (100 mL) was added bromine (1.169 mL, 22.81 mmol) slowly at room temperature. The reaction mixture was stirred at room temperature for 2 days. The solid was filtered off, washed with acetic acid and hexanes, and dried to give the title compound as a white solid (6.8 g). LCMS m/z=298.6 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17]#N)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=CC=[CH:3][CH:2]=1.C(OC([C:31]1C2C(=CC=CC=2)C=C[N:32]=1)(C)C)(=O)C1C=CC=CC=1>>[CH:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:31]#[N:32])[C:11]=2[CH:10]=[CH:9][N:8]=1)([CH2:2][CH3:3])[CH3:6]
Reactant: N#Cc1cccc2c(-c3ccccc3)nccc12
Reactant: CC(C)(OC(=O)c1ccccc1)c1nccc2ccccc12
Product: CCC(C)c1nccc2c(CC#N)cccc12

Procedure:
1-sec-Butylisoquinoline and N-hydroxymethyl dichloroacetamide were reacted in the same way as in step (b) of Example 18 to afford 1-sec-butyl-5-dichloroacetylaminomethylisoquinoline. The product was reacted successively in the same way as in steps (c), (d), (e) and (f) of Example 18 to obtain 1-sec-butylisoquinoline-5-acetonitrile. The product was treated in the same way as in Example 3 to afford 1-sec-butylisoquinoline-5-acetic acid as an oil.
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][CH:13]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]([CH:22]([CH3:24])[CH3:23])[C:20]=1[OH:21])[CH3:14].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(OCC)C>[CH:22]([C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:13]([CH3:14])[CH3:12])[C:20]=1[O:21][C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([OH:6])=[O:11])=[O:5])([CH3:24])[CH3:23]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C1OC(=O)c2ccccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1OC(=O)c1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a mixture of phthalic anhydride (0.84 g, 5.6 mmol) and propofol (1 g, 5.6 mmol) was added triethylamine (0.65 g, 6.4 mmol) and a catalytic amount of DMAP. The reaction mixture was brought to 90° C., stirred for 14 h, cooled to room temperature and diluted with ethyl ether (100 mL). The organic layer was washed with 10% aqueous citric acid solution (2×50 mL). The phases were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was sufficiently pure to be carried to the subsequent step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2.Br[CH2:13][CH2:14][CH2:15][CH3:16]>CCOC(C)=O>[CH2:13]([N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[O:2][CH3:1])[CH:8]=[CH:9]1)[CH2:14][CH2:15][CH3:16]
Reactant: COc1cccc2cc[nH]c12
Reactant: CCCCBr
Solvent: CCOC(C)=O
Product: CCCCn1ccc2cccc(OC)c21
Yield: 74 %

Procedure:
Compound 2 was synthesized from commercially available 7-Methoxyindole using the general procedure and 1-bromobutane to afford 0.51 g (74% yield) as a clear oil. TLC system: 10% EtOAc/90% n-hexanes. Spectral data matched previously reported data.35