Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].II.Br[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.COCN[C:17](=[O:48])[CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29]([C:32]2([C:38]([NH:40][O:41]C3CCCCO3)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)(=[O:31])=[O:30])=[CH:25][CH:24]=1>O1CCCC1>[OH:41][NH:40][C:38]([C:32]1([S:29]([C:26]2[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][C:17]([C:5]3[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=3)=[O:48])=[CH:24][CH:25]=2)(=[O:30])=[O:31])[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1)=[O:39]
Reactant: COc1ccc(Br)cc1
Reactant: COCNC(=O)CCCCOc1ccc(S(=O)(=O)C2(C(=O)NOC3CCCCO3)CCOCC2)cc1
Agent: II
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCCCOc2ccc(S(=O)(=O)C3(C(=O)NO)CCOCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
Part A. To a mixture of magnesium turnings (344 mg, 14.18 mmol) etched with iodine in anhydrous tetrahydrofuran (4 mL) at reflux was added 4-bromoanisole (1.2 mL, 9.45 mmol) dropwise over 10 min. The reaction mixture was heated at reflux for 45 min, and then cooled to ambient temperature. The prepared grignard reagent was added to a mixture of tetrahydro-4-[[4-[[5-(methoxymethylamino)-5-oxopentyl]oxy]phenyl]sulfonyl]-N-[(tetrahydro-2H-pyran-2-yl)oxy]-2H-pyran-4-carboxamide (1.0 g, 1.9 mmol, as prepared in Example 7) in anhydrous tetrahydrofuran (10 mL) at 0° C. The reaction mixture was warmed to ambient temperature and left stirring overnight. The reaction was quenched with saturated ammonium chloride, and then partitioned between ethyl acetate and water. The layers were separated, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography using 50-100% ethyl acetate/hexanes to afford 320 mg (29%) of the desired ketone as a white powder. ESMS m/z=593 [M+NH4]+. HRMS calculated for C29H37NO9S: 593.2533 [M+NH4]+. found: 593.2555.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[BrH:26]>>[Br:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Br
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Product: CCCCCCCCCCOc1ccc(-c2ccc(CBr)cc2)cc1
Reaction time: 3 h

Procedure:
To 0.81 g (2.51 mmol) of 4-hydroxymethyl-4'-decyloxybiphenyl was added 15 ml of an aqueous solution containing 47% HBr, and then healed at 115° C. for 3 hours. After completion of the reaction, the resultant mixture was extracted with ether and washed with water, which was further washed with an aqueous solution containing saturated NaHCO3 and washed again with water. The reaction product was concentrated and, then, separated by colomun chromatography, to thereby obtain 0.92 g of 4'-bromomethyl-4-decyloxybiphenyl.
Reaction SMILES: Br[C:2]1[C:7]2[NH:8][C:9]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][C@H:12]3[CH3:27])=[N:10][C:6]=2[CH:5]=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[CH3:32][N:33]([CH3:43])[C:34]1[CH:39]=[CH:38][C:37]([C:2]2[C:7]3[NH:8][C:9]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([C:23]([F:24])([F:25])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:13][C@H:12]4[CH3:27])=[N:10][C:6]=3[CH:5]=[C:4]([C:28]([F:30])([F:29])[F:31])[CH:3]=2)=[CH:36][CH:35]=1
Reactant: CN(C)c1ccc(B(O)O)cc1
Reactant: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(Br)c2[nH]1
Product: C[C@@H]1CN(c2ncccc2C(F)(F)F)CCN1c1nc2cc(C(F)(F)F)cc(-c3ccc(N(C)C)cc3)c2[nH]1

Procedure:
7-Bromo-2-{(2R)-2-methyl-4-[3-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl}-5-(trifluoromethyl)-1H-benzoimidazole (152 mg, 0.3 mmol, Example 79) and 4-dimethylaminophenylboronic acid (83 mg, 0.5 mmol, Aldrich) reacted under the conditions of Example 51a to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 549 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH2:15]([N:18]([CH2:23][CH:24]=[CH2:25])[S:19]([NH2:22])(=[O:21])=[O:20])[CH2:16][CH3:17].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([N+:12]([O-:14])=[O:13])=[CH:7][C:3]=1[C:4]([NH:22][S:19]([N:18]([CH2:23][CH2:24][CH3:25])[CH2:15][CH:16]=[CH2:17])(=[O:21])=[O:20])=[O:5]
Reactant: C=CCN(CCC)S(N)(=O)=O
Reactant: O=C(Cl)c1cc([N+](=O)[O-])c(F)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CCC)S(=O)(=O)NC(=O)c1cc([N+](=O)[O-])c(F)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
At from −5° C. to 0° C., 11.62 g (0.0474 mol) of 2-chloro-4-fluoro-5-nitrobenzoyl chloride in 50 ml methylene chloride were added with stirring, over 30 minutes, to a mixture of 8.50 g (0.048 mol) of N′-propyl-N′-allylsulfamide, 10.38 g (0.103 mol) of triethylamine and 0.09 g (0.736 mmol) of 4-N,N-dimethylaminopyridine in 90 ml of methylene chloride. The funnel was rinsed with 10 ml of the solvent. The mixture was initially stirred at 0° C. for 1 hour and then at 22° C. for 2 hours. 50 ml of 1N hydrochloric acid were then added, the mixture was stirred and the phases were separated. The organic phase was washed two more times with 1N hydrochloric acid and the aqueous phase was extracted with methylene chloride. Drying of the organic phase over magnesium sulfate was followed by filtration and concentration of the solution. The residue was triturated with diethyl ether/pentane, filtered off with suction and dried, giving 18.41 g (91.9% of theory) of the title compound of melting point (m.p.) of 110-112° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:42])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([N:24]([CH3:42])[CH3:23])=[CH:30][CH:29]=1)[C:33]1[CH:38]=[CH:37][C:36]([CH:39]([CH3:40])[CH3:41])=[CH:35][CH:34]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 65.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.45 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.6 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:26])=[C:6]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[F:24])=[CH:12][C:11]=2[Cl:25])=[O:9])[CH:7]=1.[OH:27][CH:28]([CH3:32])[CH2:29][CH:30]=O>CO>[Cl:25][C:11]1[CH:12]=[C:13]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=2[F:24])[CH:14]=[CH:15][C:10]=1[C:8]([C:6]1[CH:7]=[C:2]([NH:1][CH2:30][CH2:29][CH:28]([OH:27])[CH3:32])[CH:3]=[CH:4][C:5]=1[CH3:26])=[O:9]
Reactant: Cc1ccc(N)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: CC(O)CC=O
Solvent: CO
Product: Cc1ccc(NCCC(C)O)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Compound 494 (0.033 g, 0.09 mmol) was suspended in MeOH (1 mL). 3-Hydroxy-butyraldehyde (0.023 g, 0.27 mmol) and NaCN(BH3) (0.055 g, 0.88 mmol) were added. The suspension was stirred at room temperature for 18 h. 3-Hydroxy-butyraldehyde (0.023 g, 0.27 mmol) and NaCN(BH3) (0.055 g, 0.88 mmol) were added again and the suspension was stirred at room temperature for 24 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in EtOAc and the organic phase was washed with brine. The water phase was extracted with EtOAc and the combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude product was purified by flash chromatography using MeOH/CH2Cl2 1:50 as the eluent. This afforded the title compound as oil. 13C NMR (CDCl3) δ 196.7, 159.0 (dd), 155.4 (dd), 147.3, 146.0, 139.6, 135.0, 133.5, 132.0, 129.9, 126.7, 124.6 (dd), 124.0 (dd), 116.3, 115.9, 114.6, 112.8, 111.6 (dd), 104.9 (dd), 67.5, 42.1, 38.0, 24.0, 19.4
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:29]1C=CC(C2(N(C)C)CCC(=O)CC2)=CC=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2([N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH3:27])[CH2:16][CH2:17][C:18](=[O:21])[CH:19]([CH3:29])[CH2:20]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCN(C)C1(c2cccc(OCc3ccccc3)c2)CCC(=O)CC1
Reactant: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Product: CCCCN(C)C1(c2cccc(OCc3ccccc3)c2)CCC(=O)C(C)C1

Procedure:
Following the procedure of Preparation VIIA but substituting 4-(m-benzyloxyphenyl)-4-n-butylmethylamino)cyclohexanone (prepared according to Preparation VI) for 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone there is obtained 4-(m-benzyloxyphenyl)-4-(n-butylmethylamino)-2-methylcyclohexanone.
Reaction SMILES: [OH:1][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])N1C1C=CC=CC=1.C(O)(=[O:28])C>Cl.O1CCOCC1>[OH:28][C:2]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4](=[O:13])[O:1]1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)N(c1ccccc1)C2=O
Reactant: CC(=O)O
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(O)(c1ccccc1)OC2=O
Reaction time: 4 h
Yield: 55 %

Procedure:
A solution of 2 (3.11 g, 9.39 mmol) in a mixture of 6N hydrochloric acid (150 mL) and dioxane (150 mL) was heated at reflux under Ar for 18 h. Acetic acid (50 mL) was added and heating was continued for an additional 4 h. The organic solvents were removed in vacuo and the remaining aqueous was extracted with ethyl acetate (3×), washed with brine and dried with sodium sulfate (anh.). Filtration followed by removal of the solvent in vacuo gave 3 as a white solid (1.32 g, 55%)
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[CH3:21])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[CH2:9]([N:16]1[C:20]([Br:1])=[CH:19][N:18]=[C:17]1[CH3:21])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nccn1Cc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1ncc(Br)n1Cc1ccccc1
Reaction time: 6 h
Yield: 84.2 %

Procedure:
Add N-bromosuccinimide (7.85 g, 44 mmol) to a solution of 1-benzyl-2-methyl-1H-imidazole (8.0 g, 46 mmol) in chloroform (200 mL) and stir for 6 h. Wash with saturated aqueous sodium hydrogen carbonate and saturated aqueous NaCl, dry over MgSO4, and filter through a pad of silica gel. Concentrate filtrate and suspend the residue in diethyl ether (600 mL), heat to reflux, and filter hot. Concentrate ether filtrate to give the title compound as a tan solid (9.3 g).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([OH:20])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].F[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH3:30])[CH:23]=1>CCOCC>[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([O:20][C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[C:24]([CH3:30])[CH:23]=2)[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Cc1cc(F)ccc1C#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Product: Cc1cc(OC2CCN(C(=O)OC(C)(C)C)CC2)ccc1C#N
Reaction time: 7 h
Yield: 115.3 %

Procedure:
22.6 g Potassium tert. butoxide, 33.2 g 4-Hydroxy-piperidine-1-carboxylic acid tert-butyl ester and 300 mL MTB ether were stirred for 1 h at reflux. A solution of 20.3 g 4-Fluoro-2-methyl-benzonitrile, dissolved in 250 mL MTB ether was added within 20 min to the suspension and heating to reflux was continued for 7 h. The reaction was quenched with water. The organic layer was separated and washed with water and concentrated to give 54.8 g (yield 92%) of 4-(4-Cyano-3-methyl-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (500 MHz, d6-DMSO) δ 1.40 (s, 9H), 1.47-1.55 (m, 2H), 1.88-1.95 (m, 2H), 2.43 (s, 3H), 3.13-3.22 (m, 2H), 3.63-3.70 (m, 2H), 4.66-4.73 (m, 1H), 6.96 (dd, J=8.6, 2.4 Hz, 1H), 7.07 (d, J=2.3 Hz, 1H), 7.67 (d, J=8.7 Hz, 1H).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH:12]([OH:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1>CC(C)=O>[CH3:23][C:22]1([CH3:27])[O:1][CH:2]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])[CH2:11][CH:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:21]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)C=Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 3,5-dihydroxy-7-phenyl-6-heptenoate (5.5 g, 19 mmol) in acetone (2.3 g, 40 mmol) was added a catalyic amount of p-toluenesulfonic acid. After stirring for 2 hours, the mixture had solidified and was dissolved in excess acetone and filtered through a pad of sodium carbonate. The excess acetone was removed in vacuo and the residue crystallized from isopropyl ether to give 3.4 g of the title compound; m.p.=91°-93° C.
Reaction SMILES: CC([N:5]([CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[Cl:32])[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)C(=O)[O-])(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:5][CH2:9][CH:10]([NH:18][C:19]([C:21]1[S:22][CH:23]=[C:24]([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][C:27]=2[Cl:32])[CH:25]=1)=[O:20])[CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cn1ncc(Cl)c1-c1csc(C(=O)NC(Cc2ccccc2)CN(C(=O)[O-])C(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc(Cl)c1-c1csc(C(=O)NC(CN)Cc2ccccc2)c1
Reaction time: 0.5 h

Procedure:
A solution of 1,1-dimethylethyl[2-({[4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thienyl]carbonyl}amino)-3-phenylpropyl]carbamate (crude from part c) in TFA-DCM (3 mL, 1:2) was stirred at 25° C. After 30 min, the solution was concentrated and the residue neutralized through a silica plug (4% MeOH in DCM (1% NH4OH)) affording the free base of the title compound.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)(=O)=O)=CC=1.[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[C:39]1[CH2:40][CH2:41][NH:42][CH2:43][CH:44]=1>CS(C)=O.C(OCC)(=O)C>[F:29][C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[NH:35][CH:34]=[C:33]2[C:39]1[CH2:40][CH2:41][N:42]([CH2:12][CH:13]2[O:28][C:17]3=[C:18]4[C:23](=[CH:24][CH:25]=[C:16]3[O:15][CH2:14]2)[N:22]=[C:21]([CH3:26])[C:20]([CH3:27])=[N:19]4)[CH2:43][CH:44]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4nc(C)c(C)nc4c3O2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1nc2ccc3c(c2nc1C)OC(CN1CC=C(c2c[nH]c4ccc(F)cc24)CC1)CO3
Temperature: 80 °C

Procedure:
To a solution of [(2R)-8,9-dimethyl-2,3-dihydro[1,4]dioxino[2,3-f]-quinoxalin-2-yl]methyl 4-methylbenzenesulfonate (0.400 g, 1.000 mmole) in methyl sulfoxide (20 mL) was added 5-fluoro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole (0.540 g, 2.497 mmole) and the reaction mixture was heated to 80° C. for 12 hours. The reaction mixture was allowed to cool to room temperature and was diluted with ethyl acetate (250 mL), washed with water (2×100 mL), aqueous sodium chloride (100 mL), dried (magnesium sulfate) and the solvent was removed in vacuo to give a crude solid. Purification by flash column chromatography (silica, methanol:ethyl acetate 1:9) followed by recrystallization from ethanol provided 0.239 g (54%) of the (S)-enantiomer of the title compound as a pale yellow solid. Rf=0.35 (silica, methanol:ethyl acetate 1:9); mp 138–141° C.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6](B(O)O)=[CH:5][CH:4]=1)=[O:2].[I:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](I)[CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[I:11][C:12]1[CH:13]=[C:14]([C:6]2[O:7][C:3]([CH:1]=[O:2])=[CH:4][CH:5]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Ic1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1ccc(-c2cccc(I)c2)o1
Yield: 25.9 %

Procedure:
5-Formyl-2-furanboronic acid (280 mg, 2 mmol) and 1,3-diiodobenzene (660 mg, 2 mmol) were dissolved in 1,2-dimethoxyethane (15 mL), tetrakis(triphenylphosphine)palladium (114 mg, 0.1 mmol) was added thereto, 2 mol/L sodium carbonate (4.6 mL) was then added thereto, and the mixture was heated to reflux for 3 hours while stirring. After the reaction was completed water (20 mL) was added, and extraction with ethyl acetate (20 mL×2) was carried out. The organic layer was washed with saturated brine, water was removed using anhydrous sodium sulfate, the solvent was then removed by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography using ethyl acetate/hexane (3/7 (volume ratio)) as an eluent, to give 5-(3-iodophenyl)furan-2-carbaldehyde in a yield of 155 mg (yield 25.9%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:11][CH2:10][N:9]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=3)[CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(#N)C>[Cl:18][C:17]1[C:12]([N:9]2[CH2:10][CH2:11][C:3]3[C:2]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[N:7][CH:6]=[N:5][C:4]=3[CH2:8]2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: Clc1cccnc1N1CCc2c(Cl)ncnc2C1
Reactant: Nc1ccccc1
Solvent: CC#N
Product: Clc1cccnc1N1CCc2c(ncnc2Nc2ccccc2)C1
Temperature: 180 °C
Yield: 32.9 %

Procedure:
4-Chloro-7-(3-chloro-pyridin-2-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine (150 mg, 0.54 mmol) was dissolved in acetonitrile (2 mL). To the mixture was added aniline (60 mg). The mixture was heated in a sealed tube at 180° C. for 30 minutes in a Personal Chemistry Microwave (Smith Creator). The solvent was removed under vacuum and the resulting orange residue was purified by flash chromatography over silica gel using a 0-100% ethyl acetate-hexane gradient to give the product as an off white solid (60 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(c2nncc3cc(Br)ccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCN(C)CC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A mixture of 6-bromo-1-(4-methylpiperazin-1-yl)phthalazine (0.13 g, 0.42 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzamide (0.13 g, 0.42 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.021 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4: 1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.15g) as a yellow solid. Found MS (ES+): 402(M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][OH:13])[C:5]#[N:6].[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33](O)=[O:34])=[CH:29][CH:28]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>C(Cl)(Cl)Cl>[C:14]([O:18][C:19]([N:21]1[CH2:25][CH2:24][CH:23]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][C:33](=[O:34])[NH:1][C:2]3[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=3[NH:10][CH2:11][CH2:12][OH:13])=[CH:36][CH:37]=2)[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)C1
Reactant: N#Cc1ccc(NCCO)c(N)c1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)Nc3cc(C#N)ccc3NCCO)cc2)C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 75.6 %

Procedure:
To a solution of 3-amino-4-(2-hydroxyethylamino)benzonitrile (1.21 g) and 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)phenoxyacetic acid (2.30 g) in chloroform (50 ml) was added 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (2.19 g), and the mixture was stirred at room temperature for 15 hours. After completion of the reaction, the solvent was evaporated and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to give the title compound (2.56 g).
Reaction SMILES: C[O:2][C:3](=[O:27])[C@@H:4]([N:12]1[CH2:16][C:15]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)=[CH:14][C:13]1=[O:26])[CH2:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+]>O1CCCC1.O>[CH:6]1([CH2:5][C@H:4]([N:12]2[CH2:16][C:15]([O:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=3)=[CH:14][C:13]2=[O:26])[C:3]([OH:27])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)[C@H](CC1CCCCC1)N1CC(Oc2cccc(OC)c2)=CC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(OC2=CC(=O)N([C@@H](CC3CCCCC3)C(=O)O)C2)c1
Temperature: 23 °C
Reaction time: 2 h
Yield: 62.1 %

Procedure:
To a stirred solution of (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid methyl ester (1.12 g, 0.003 mol) in tetrahydrofuran-water (3:1, 10 mL) was added lithium hydroxide (387 mg, 0.009 mol). The reaction mixture was stirred at 23° C. for 2 h. After this time, the mixture was concentrated and the reaction mixture was diluted with water. The reaction mixture was acidified with 2N hydrochloric acid, during which time precipitation occurred. The precipitate was removed by filtration, washed with cold water and dried in vacuo to obtain (S)-3-cyclohexyl-2-[4-(3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-propionic acid (670 mg, 62%) as a light yellow solid.