Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[CH:20]1([C:23]#[C:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([OH:33])=[O:32])=[N:29][CH:30]=2)[CH2:22][CH2:21]1>>[CH:31]([OH:33])=[O:32].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:28]3[CH:27]=[CH:26][C:25]([C:24]#[C:23][CH:20]4[CH2:22][CH2:21]4)=[CH:30][N:29]=3)[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: O=C(O)c1ccc(C#CC2CC2)cn1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccc(C#CC4CC4)cn3)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A9B) and 5-cyclopropylethynyl-pyridine-2-carboxylic acid (prepared according to Suzuki, Y. et al., Int. Patent Application Publ. No. WO2009091016) yielded the title compound as an off-white solid. MS (ISP): m/z=443.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=O.[CH3:14][C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[CH:5]=[CH:14][C:15]1[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=1
Reactant: CC1=NC(C)(C)CO1
Reactant: COc1ccc([N+](=O)[O-])cc1C=O
Solvent: Cc1ccccc1
Product: COc1ccc([N+](=O)[O-])cc1C=CC1=NC(C)(C)CO1

Procedure:
A mixture of 2-methoxy-5-nitrobenzaldehyde, 16 g, (U.S. Pat. No. 4,367,234), 2,4,4-trimethyl-2-oxazoline, 30 ml, (Aldrich Chemical Company), para toluenesulfornic acid, 0.5 g, in toluene, 100 ml, is refluxed overnight under a water separator. The mixture is evaporated, the residue dissolved in diethylether, 800 ml, and washed with water. The diethyl ether layer is separated, concentrated, and filtered to give 11.1 g of 4,5-dihydro-2-[2-(2-methoxy-5-nitrophenyl)ethenyl]-4,4-dimethyloxazole after recrystallization from diisopropyl ether; mp 115°-116° C.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl.C(N(C(C)C)CC)(C)C.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46](Cl)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:54])([F:53])[F:52])[CH:41]=1>CCOC(C)=O.C(Cl)Cl>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([NH:7][C@H:8]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]3[N:24]=[C:23]([N:25]([CH3:27])[CH3:26])[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:10][CH2:9]2)(=[O:48])=[O:47])=[C:42]([O:50][C:51]([F:53])([F:52])[F:54])[CH:41]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Reactant: CN(C)c1nc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)nc2ccccc12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)c1nc(N[C@H]2CC[C@H](NS(=O)(=O)c3ccc(Br)cc3OC(F)(F)F)CC2)nc2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of trans-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-carbamic acid tert-butyl ester (500 mg, 1.30 mmol) in EtOAc (5 mL) was added 4 M hydrogen chloride in EtOAc (5 mL). The mixture was stirred at ambient temperature for 1 hr and concentrated to give a white solid. To a suspension of the above solid in CH2Cl2 (7 mL) was added diisopropylethylamine (905 μL, 5.20 mmol). The mixture was cooled to 4° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (462 mg, 1.36 mmol) in CH2Cl2 (2 mL) was added below 5° C. The reaction mixture was stirred at 4° C. for 1.5 hr. To the reaction mixture was added a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (88 mg, 0.26 mmol) in CH2Cl2 (0.5 mL) and the mixture was stirred at 4° C. for 1 hr. To the reaction mixture was added diisopropylethylamine (230 μL, 1.32 mmol) and the mixture was stirred at 4° C. for 1.5 hr. The reaction was quenched with saturated aqueous NaHCO3 The aqueous layer was extracted with CHCl3 (three times). The combined organic layer was dried over MgSO4, filtered, concentrated, and purified by flash chromatography (NH-silica gel, 50% EtOAc in hexane) to give trans-4-bromo-N-[4-(4-dimethylamino-quinazolin-2-ylamino)-cyclohexyl]-2-trifluoromethoxy-benzenesulfonamid (339 mg, 44%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Cl.O>CN(C=O)C.CCOC(C)=O>[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25][O:1][C:2]1[CH:15]=[CH:14][C:5]2[C@H:6]([CH2:9][C:10]([OH:12])=[O:11])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O)ccc21
Reactant: Fc1ccc(CCl)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)C[C@@H]1COc2cc(OCc3ccc(F)cc3F)ccc21
Temperature: 55 °C
Reaction time: 15 h
Yield: 34.4 %

Procedure:
To a stirred mixture of methyl(3S)-(2,3-dihydro-6-hydroxy-1-benzofuran-3-yl)acetate (20.8 mg) and K2CO3 (20.7 mg) in DMF (0.5 mL) was added 2,4-difluorobenzyl chloride (24.4 mg) at room temperature. After stirring at 55° C. for 15 h, water (2.0 mL) and EtOAc (3.0 mL) were added to the mixture with stirring. The organic layer was separated by phase separation filter kit, and the filtrate was evaporated by blowing away with the air at 60° C. The resulting residue was dissolved in MeOH (0.5 mL) and 1N LiOH (0.3 mL), and the mixture was stirred at room temperature for 1 h. To the mixture was added 1N HCl (0.2 mL) and the solution was evaporated by blowing away with the air at 60° C. The resulting residue was dissolved in DMSO (1.0 mL) and the solution was purified by preparative HPLC (C18, eluent: water/CH3CN (including 5 mM AcONH4)). The eluted fraction was evaporated by air blowing at 60° C. to give the title compound (11.0 mg, 34.4%).
Reaction SMILES: [Cl-].[Cl:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[NH2+:5].C(N(CC)CC)C.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>C(#N)C.ClCCl>[Cl:2][CH2:3][C:4](=[N:5][S:25]([C:22]1[CH:23]=[CH:24][C:19]([CH3:29])=[CH:20][CH:21]=1)(=[O:27])=[O:26])[N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [NH2+]=C(CCl)N1CCOCC1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N=C(CCl)N2CCOCC2)cc1
Temperature: 7.5 °C
Reaction time: 2 h
Yield: 25.2 %

Procedure:
To 1 g (5.02 mmol) 2-chloro-1-morpholine-4-ylethaniminium chloride and 0.7 ml triethylamine in 25 ml acetonitrile were added 0.96 g p-toluene sulfonic acid chloride at 10° C. and the mixture was stirred for 2 hours at 5-10° C. For workup, the mixture was diluted with dichlormethane, was washed with water and saturated NaCl-solution, was dried with MgSO4, was filtered and was evaporation-concentrated. Chromatography on silica gel (dichlormethane/methanol 0-3%) yielded 400 mg of the target products; ESI-MS [M+H+]=317.05.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>CN(C=O)C.O>[CH2:17]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:18]([CH3:20])[CH3:19]
Reactant: N#Cc1ccc(O)cc1
Reactant: CC(C)CBr
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)COc1ccc(C#N)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 85.6 %

Procedure:
To a solution of 4-cyanophenol (1.2 g, 10 mmol) in dry DMF (20 mL) was added triethylamine (20 mmol) followed by i-butyl bromide (2.7 g, 20 mmol). The resulting reaction mixture was stirred at 100° C. for 6 h. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (2×40 mL). The organic layer was washed with 4 M KOH (3×30 mL) and then with water, dried over Na2SO4 and concentrated under vacuum to provide 1.5 g (85%) 4-iso-butoxybenzonitrile that was used for the next step without further purification. 1H NMR (DMSO-D6): δ 0.95 (d, 6H, 2CH3), 2.0 (m, 1H, CH(CH3)2), 3.8 (d, 2H, CH2), 7.4 (AA′BB′, Δ=270 Hz, 4H, Ar).
Reaction SMILES: [C:1]1([C@H:7]2[C:12](=[O:13])[O:11][CH2:10][CH2:9][N:8]2[CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+].[F:35][C:36]([F:51])([F:50])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[C:40](Cl)=[O:41]>C1COCC1>[F:35][C:36]([F:50])([F:51])[C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:46]([F:49])([F:47])[F:48])[CH:45]=1)[C:40]([O:13][C@H:12]1[O:11][CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@H:7]1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:41]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: O=C1OCCN(Cc2ccccc2)[C@H]1c1ccccc1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 0.75 h
Yield: 79.7 %

Procedure:
A solution of 2.67 g (10.0 mmol) of 3-(S)-phenyl-4-benzyl-2-morpholinone (from Example 14) in 40 mL of dry THF was cooled to −78° C. The cold solution was treated with 12.5 mL of 1.0 M L-Selectride®, solution in THF, maintaining the internal reaction temperature below −70° C. The resulting solution was stirred cold for 45 minutes and the reaction was charged with 3.60 mL (20.0 mmol) of 3,5-bis(trifluoro-methyl)benzoyl chloride. The resulting yellow mixture was stirred cold for 30 minutes and the reaction was quenched with 50 mL of saturated aqueous sodium bicarbonate solution. The quenched mixture was partitioned between 300 mL of ether and 50 mL of water and the layers were separated. The organic layer was dried over magnesium sulfate. The aqueous layer was extracted with 300 mL of ether; the extract was dried and combined with the original organic layer. The combined organics were concentrated in vacuo. Flash chromatography on 150 g of silica gel using 37:3 v/v hexanes/ether as the eluant afforded 4.06 g (80%) of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[C:25]([NH:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)(=[O:27])[CH3:26]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[C:29]([NH:28][C:25](=[O:27])[CH3:26])[CH:30]=[CH:31][CH:32]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 25.3 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-acetamidophenylboronic acid (17.9 mg, 0.1 mmol). The mixture was heated at 120° C. in a microwave reactor for 30 min. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure N-(3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospir-o[chroman-4,4′-imidazole]-6-yl)phenyl)acetamide (5.8 mg, 20%). 1H-NMR (MeOD): 2.03 (s, 3H), 2.21 (t, 1H), 2.41 (t, 1H), 3.07 (s, 3H), 5.81 (d, 1H), 6.92 (d, 1H), 7.12 (t, 1H), 7.21 (t, 2H), 7.33 (t, 2H), 7.49 (m, 4H), 7.59 (d, 1H).
Reaction SMILES: [N+](=C)=[N-].BrN1C(=[O:10])CCC1=O.CN(C)[CH:14]=[O:15].[C:17]1([C:26]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22]CCNN=1.CN(C)[CH:37]=[O:38]>>[O:38]=[C:37]1[C:27]2[CH:28]=[CH:29][C:30]([C:14]([OH:15])=[O:10])=[CH:31][C:32]=2[CH:33]=[CH:34][C:26]2[CH:17]=[CH:25][CH:24]=[CH:23][C:22]1=2
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)N1Br
Reactant: C1=C(C2=NNCCCCCC2)CCCCCCC1
Agent: C=[N+]=[N-]
Product: O=C(O)c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
5-Oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared by esterifying 2-methylterephthalic acid with methanol, in the presence of acid catalyst, to afford the corresponding dimethyl ester which, in turn, is reacted with N-bromosuccinimide to afford 2-bromomethylterephthalic acid dimethyl ester. This diester is reacted with triphenylphosphine to afford 2,5-bis(carbomethoxy)benzyltriphenyl phosphonium bromide which is treated with benzaldehyde and a non-nucleophilic base, such as diazabicylononene, to afford, after alkaline hydrolysis, cis and trans stilbene 2,5-dicarboxylic acid. Hydrogenation of this latter compound with hydrogen over a 5% palladium on carbon catalyst affords 2-(2-phenethyl)terephthalic acid. Treatment with polyphosphoric acid yields 5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid which can be recystallized from aqueous dimethylformamide. 5-oxo-5H-dibenzo[a,d]cycloheptene-2-carboxylic acid is prepared by successively treating 5-oxo-5H-dibenzo[a,d]cycloheptane-2-carboxylic acid with diazomethane, N-bromosuccinimide, and dimethylformamide/diazabicyclononene, followed by base hydrolysis and acidification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]#[N:9])[CH:2]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br.[H-].[Na+].O>C1COCC1.CS(C)=O>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2([C:8]#[N:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:2]=1
Reactant: BrCCCCCBr
Reactant: N#CCc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(c2cccnc2)CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of pyridin-3-yl-acetonitrile (14.65 g) and 1,5-dibromo-pentane (28.52 g) in THF (450 mL) and DMSO (450 mL) is added NaH (60% in mineral oil, 10.42 g) portionwise at 0° C. over 1 h. The mixture is allowed to warm to RT and stirred overnight. The reaction mixture is poured into water and extracted twice with EtOAc. The extract is concentrated and the residue is purified by silica gel chromatography to give 1-pyridin-3-yl-cyclohexanecarbonitrile.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3](=O)[C:4](=[CH:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[O:22][C:21]([CH3:24])=[CH:20][C:19]2=[O:25])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[NH2:29]/[C:30](/[CH3:37])=[CH:31]\[C:32]([O:34][CH2:35][CH3:36])=[O:33]>CC(O)C>[C:5]([C:4]1[CH:13]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[O:22][C:21]([CH3:24])=[CH:20][C:19]3=[O:25])[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:30]([CH3:37])[NH:29][C:3]=1[C:2]([F:28])([F:1])[F:27])(=[O:6])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)/C=C(/C)N
Reactant: Cc1cc(=O)c2cccc(C=C(C(=O)c3ccccc3)C(=O)C(F)(F)F)c2o1
Solvent: CC(C)O
Product: CCOC(=O)C1=C(C)NC(C(F)(F)F)=C(C(=O)c2ccccc2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
A solution of 410 mg (1.06 mmol) of 4,4,4-trifluoro-2-[(2-methyl-4-oxo-4H-chromen-8-yl)-methylene]-1-phenylbutane-1,3-dione in 10 ml of 2-propanol is mixed with 137.3 mg (1.06 mmol) of ethyl 3-aminocrotonate and stirred under reflux for 12 h. After cooling, the reaction mixture is concentrated, and the residue is taken up in 5 ml of acetic acid and again stirred under reflux for 12 h. The reaction solution is concentrated and the residue is purified by preparative HPLC. 160.3 mg (30.3% of theory) of the title compound are obtained.
Reaction SMILES: [OH:1][C@H:2]1[C:7](=[O:8])[CH2:6][CH2:5][O:4][C@@H:3]1[CH2:9][OH:10].[C:11](Cl)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:20]1[CH:27]=[CH:26][C:23]([O:24][CH3:25])=[CH:22][CH:21]=1)[C:12]1[CH:19]=[CH:18][C:15]([O:16][CH3:17])=[CH:14][CH:13]=1>N1C=CC=CC=1.CCOC(C)=O.CCCCCC>[CH3:25][O:24][C:23]1[CH:22]=[CH:21][C:20]([C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:16][CH3:17])=[CH:18][CH:19]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:10][CH2:9][C@@H:3]2[C@@H:2]([OH:1])[C:7](=[O:8])[CH2:6][CH2:5][O:4]2)=[CH:27][CH:26]=1
Reactant: O=C1CCO[C@H](CO)[C@H]1O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2OCCC(=O)[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 8 h

Procedure:
Dissolve (2R,3R)-3-hydroxy-2-(hydroxymethyl)dihydro-2H-pyran-4(3H)-one (662 mg, 4.53 mmol) and DMTCl (1.688 g, 4.98 mmol) in pyridine (5 mL). The reaction was stirred overnight and a TLC was taken in 30% EtOAc/Hexane. The crude reaction mixture was partitioned with 1M CuSO4 (10 mL) and the aqueous layer extracted with DCM (3×30 mL). The combined organic fractions were washed once with water (20 mL) and dried over Na2SO4. The crude product was chromatographed using a gradient from 10%-30% EtOAc/Hexane to yield 1.51 g (74%). 1H NMR (400 MHz, CDCl3) δ 7.49 (dd, J=8.4, 1.2 Hz, 2H), 7.40-7.35 (m, 4H), 7.29 (t, J=4.3, 2H), 7.20 (t, J=7.3 Hz, 1H), 6.86-6.80 (m, 4H), 4.39 (ddd, J=11.3, 7.5, 1.0 Hz, 1H), 4.26 (ddd, J=9.5, 3.8, 1.4 Hz, 1H), 3.79 (s, 6H), 3.70-3.61 (m, 1H), 3.47 (dd, J=5.8, 2.8 Hz, 2H), 3.43-3.34 (m, 2H), 2.90-2.78 (m, 1H), 2.60-2.53 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 208.13, 158.91, 145.38, 136.50, 130.62, 129.60, 128.70, 128.25, 127.20, 113.56, 86.57, 84.09, 74.84, 67.87, 64.25, 55.67, 41.45; IR (neat film) 3458, 2938, 1720, 1509, 1250, 1178, 1110; LRMS for C27H28O6 (M+Na) 471.02.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH3:22])=[C:18](B5OC(C)(C)C(C)(C)O5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:33]1[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]([C:33]5[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[C:35]([Cl:41])[CH:34]=5)[C:19]([CH3:22])=[CH:20][CH:21]=4)=[O:14])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: N#Cc1ccc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1-c1ccc(C#N)c(Cl)c1
Temperature: 80 °C

Procedure:
1-(Benzo [d][1,3]dioxol-5-yl)-N-(4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)cyclopropanecarboxamide (0.084 g, 0.20 mmol), 4-bromo-2-chlorobenzonitrile (0.043 g, 0.20 mmol), aqueous potassium carbonate (520 μL, 1M), FibreCat 1007 (7 mg), and DMF (1 mL) were combined. The mixture was heated at 80° C. for 18 hours. After cooling, the mixture was filtered and purified by preparative HPLC to provide 1-(benzo[d][1,3]dioxol-5-yl)-N-(3′-chloro-4′-cyano-6-methylbiphenyl-3-yl)cyclopropanecarboxamide.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([S:13][CH:14]2[CH2:16][CH2:15]2)=[C:9]([Br:17])[CH:8]=1)=[O:6])C.[OH-].[Na+].O.Cl>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:17][C:9]1[CH:8]=[C:7]([C:5](=[O:6])[C:4]([OH:18])=[O:3])[CH:12]=[CH:11][C:10]=1[S:13][CH:14]1[CH2:15][CH2:16]1
Reactant: CCOC(=O)C(=O)c1ccc(SC2CC2)c(Br)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(O)C(=O)c1ccc(SC2CC2)c(Br)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
A solution of ethyl[3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetate (30 g) in toluene (60 mL) was heated to 50° C., and a 3 M aqueous sodium hydroxide solution (36 mL) was added thereto at an internal temperature of 60° C. or lower, followed by stirring at 50° C. for 1 hour. After leaving it to be cooled at room temperature, water (150 mL) and ethyl acetate (100 mL) were added to the reaction mixture. To the aqueous layer was added concentrated hydrochloric acid (12 mL) under ice-cooling, followed by extraction with ethyl acetate (100 mL×3). The organic layer was washed with saturated brine (100 mL) and dried over anhydrous magnesium sulfate, and the solvent was then evaporated under reduced pressure. The residue was sequentially washed with hexane/ethyl acetate (19/1, 200 mL) and diethyl ether/hexane (1/2, 200 mL) to obtain [3-bromo-4-(cyclopropylsulfanyl)phenyl](oxo)acetic acid (14.7 g) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[O:4][C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:6][C:7]=1[C:8]([O:10]C)=O.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[CH:26][CH:25]=1>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]3[O:4][C:5]([C:12]4[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=4)=[CH:6][C:7]=3[CH2:8][OH:10])[CH2:32][CH2:31]2)=[CH:28][CH:29]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: COC(=O)c1cc(-c2ccc(C(F)(F)F)cc2)oc1CBr
Product: COc1ccc(N2CCN(Cc3oc(-c4ccc(C(F)(F)F)cc4)cc3CO)CC2)cc1

Procedure:
The title compound was prepared using methyl 2-(bromomethyl)-5-[4-(trifluoromethyl)phenyl]-3-furoate (intermediate 44) and 1-(4-methoxyphenyl)piperazine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11].[H-].[Na+].Br[CH2:17][CH2:18][CH3:19].Cl>CS(C)=O>[CH2:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH3:13])=[O:11])[CH2:18][CH3:19]
Reactant: CCCBr
Reactant: COC(=O)c1cc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCn1c(C(=O)OC)cc2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
A suspension of methyl 1H-indole-2-carboxylate (5.0 g) and sodium hydride (60% dispersion in oil, 1.3 g) in dry dimethylsulphoxide was stirred at 60° C. for 30 minutes. The reaction mixture was cooled to room temperature before adding 1-bromopropane (2.85 ml) and then heated at 60°-80° C. for 3 hours. The cooled reaction mixture was poured into dilute hydrochloric acid and extracted with diethyl ether. The combined organic extracts were washed with water, dried (MgSO4) and the solvent removed in vacuo. The crude product was purified by chromatography on silica, and elution with 10% v/v diethyl ether in petroleum ether (bp 40°-60° C.) gave methyl 1-propyl-1H-indole-2-carboxylate (5.23 g) as a clear oil; NMR (CDCl3) δ0.93 (3H,t,J=7 Hz, C--CH3), 1.82 (2H, sext,J=7 Hz,C--CH2 --C), 3.89 (3H,s,OCH3), 4.52 (2H,t,J=7 Hz, N--CH2), 7.15 (4H,m,Ar--H), 7.67 (1H,m,Ar--H). The ester was converted to 2-(2-imidazolin-2-yl)-1-propyl-1H-indole hydrochloride using trimethylaluminium and ethylenediamine as described in Example 1(a); mp 186.5°-187° C.
Reaction SMILES: C([Zn]CC)C.[C:6](O)([C:8](F)(F)F)=[O:7].IC.[CH3:15][C:16]([CH3:35])([CH3:34])[CH2:17][N:18]1[C:26]2[C:21](=[N:22][C:23](/[CH:27]=[CH:28]/[CH2:29]CO)=[CH:24][CH:25]=2)[N:20]([CH3:32])[C:19]1=[O:33]>C(Cl)Cl>[CH3:35][C:16]([CH3:15])([CH3:34])[CH2:17][N:18]1[C:26]2[C:21](=[N:22][C:23]([C@@H:27]3[CH2:28][C@H:29]3[CH2:8][CH2:6][OH:7])=[CH:24][CH:25]=2)[N:20]([CH3:32])[C:19]1=[O:33]
Reactant: O=C(O)C(F)(F)F
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(/C=C/CCO)nc21
Agent: CC[Zn]CC
Solvent: CI
Solvent: ClCCl
Product: Cn1c(=O)n(CC(C)(C)C)c2ccc([C@@H]3C[C@H]3CCO)nc21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Diethyl zinc (0.53 mL, 0.53 mmol, 2.0 equiv, 1M in hexanes) was added to anhydrous DCM (0.53 mL) and cooled to 0° C. To this solution was added TFA (41 μL, 0.53 mmol, 2.0 equiv) in anhydrous DCM (0.27 mL), and the resulting mixture was stirred at 0° C. for 15 min. Following this duration, iodomethane (43 μL, 0.53 mmol, 2.0 equiv) in anhydrous DCM (0.27 mL) as added and the resulting reaction mixture was stirred for and additional 20 min. 1-(2,2-Dimethylpropyl)-5-[(1E)-4-hydroxybut-1-en-1-yl]-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (32-3, 77 mg, 0.27 mmol, 1.0 equiv) in anhydrous DCM (0.27) as then added. After 1 h, the reaction vessel was removed from the 0° C. bath and allowed to gradually warm to RT. After 2.5 h, LCMS showed consumption of 32-3. The reaction was quenched with saturated NH4Cl (5 mL) and extracted with ethyl acetate (3×5 ml). The combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give 32-4 as a white solid. Since the material was determined to be of >95% purity by 1H NMR, further purification was deemed unnecessary. MS m/z (M+H): calculated=303.4; observed=304.1.