Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][S:10][C:11]1[NH:15][C:14]2[CH:16]=[C:17]([Cl:21])[C:18](I)=[CH:19][C:13]=2[N:12]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[C:22]1([C:28]#[CH:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CCN(CC)CC.CN(C=O)C>CCOC(C)=O.[Cu]I>[CH2:1]([O:3][P:4]([CH2:9][S:10][C:11]1[NH:12][C:13]2[CH:19]=[C:18]([C:29]#[C:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:17]([Cl:21])=[CH:16][C:14]=2[N:15]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CCOP(=O)(CSc1nc2cc(I)c(Cl)cc2[nH]1)OCC
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOP(=O)(CSc1nc2cc(Cl)c(C#Cc3ccccc3)cc2[nH]1)OCC
Temperature: 120 °C

Procedure:
A mixture of (6-Chloro-5-iodo-1H-benzoimidazol-2-ylsulfanylmethyl)-phosphonic acid diethyl ester (Intermediate 1, 0.4 g, 1.0 mmol), phenyl acetylene (0.26 mL, 2.0 mmol), PdCl(PPh3)2 (0.34 g, 0.050 mmol), CuI (0.018 g, 0.1 mmol), Et3N (0.96 mL, 6.94 mmol), and 10.0 mL of DMF was heated to 120° C. for 10 minutes using a microwave reactor. HPLC indicated the reaction was complete. The crude mixture was diluted with 40 mL EtOAc and washed with 3×40 mL H2O. The organic fractions were separated, combined, dried over MgSO4, and concentrated in vacuo to afford an oil. This oil was purified by MPLC to afford title compound 1-1 as clear oil.
Reaction SMILES: C(N1[CH:12]=[CH:11]N=C1)(N1C=CN=C1)=O.[CH3:13][O:14][C:15]1[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[S:17][C:16]=1[C:23]([OH:25])=[O:24].[CH2:26](O)[C:27]1[CH:35]=[CH:34][C:33]2[O:32][CH2:31][O:30][C:29]=2[CH:28]=1>>[O:32]1[C:33]2[CH:34]=[CH:35][C:27]([CH:26]([O:24][C:23]([C:16]3[S:17][C:18]([C:20]([OH:22])=[O:21])=[CH:19][C:15]=3[O:14][CH3:13])=[O:25])[C:12]3[CH:11]=[CH:28][C:29]4[O:30][CH2:31][O:32][C:33]=4[CH:34]=3)=[CH:28][C:29]=2[O:30][CH2:31]1
Reactant: COc1cc(C(=O)O)sc1C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: OCc1ccc2c(c1)OCO2
Product: COc1cc(C(=O)O)sc1C(=O)OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Yield: 87.6 %

Procedure:
The title compound was prepared according to the procedure of Example 2 using carbonyldiimidazole (0.8 g, 4.8 mmol), 3-methoxy-2,5-thiophene-dicarboxylic acid (0.4 g, 2.0 mmol), and piperonyl alcohol (0.62 g, 4.0 mmol). Acidification of the aqueous workup mixture with dilute hydrochloric acid prior to filtration afforded 0.8 g of 3-methoxy-thiophene-2,5-dicarboxylic acid di-1,3-benzodioxol-5-ylmethyl ester. Recrystallization of a sample from acetonitrile gave product with a mp 153-155° C.
Reaction SMILES: [F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5](=S)[NH:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12].[NH3:27].C(OO)(C)(C)C>CO>[F:1][C:2]1([F:26])[C:8]([CH3:10])([CH3:9])[O:7][CH2:6][C:5]([NH2:27])=[N:4][C@@:3]1([C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)[CH:16]=[CH:15][C:14]=1[F:25])[CH3:12]
Reactant: CC1(C)OCC(=S)N[C@](C)(c2cc(-c3cncnc3)ccc2F)C1(F)F
Reactant: N
Agent: CC(C)(C)OO
Solvent: CO
Product: CC1(C)OCC(N)=N[C@](C)(c2cc(-c3cncnc3)ccc2F)C1(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
A solution of (R)-6,6-difluoro-5-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-5,7,7-trimethyl-1,4-oxazepane-3-thione (239 mg, 627 μmol) in methanol (7.2 ml), was treated with ammonia (7 M in methanol, 5.37 ml) and tert-butyl hydroperoxide (70% in water, 517 μl). The mixture was stirred at room temperature for 16 hours. For the workup, the reaction mixture was extracted with water and dichloromethane. The organic layer was washed with water and brine, the aqueous layers were reextracted with dichloromethane. The combined organic layers were dried over sodium sulphate, filtered and evaporated to give brown oil. The residue was purified by chromatography on an amino-silica phase using dichloromethane as the eluent. The (R)-6,6-difluoro-5-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-5,7,7-trimethyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (94 mg, 41% yield) was obtained as a white foam. MS (ISP): m/z=365.2 [M+H]+.
Reaction SMILES: [C:1]1([O:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]([O:22]C)=[O:21])[CH2:18][S:17][CH:16]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[Li+].[OH-]>O1CCOCC1>[C:1]1([O:11][CH2:12][C:13]([N:15]2[C@H:19]([C:20]([OH:22])=[O:21])[CH2:18][S:17][CH:16]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)[C@@H]1CSC(c2ccccc2)N1C(=O)COc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1CSC(c2ccccc2)N1C(=O)COc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.2 %

Procedure:
To a solution of (2RS,4R)-3-((1-naphthyloxy)acetyl)-2-phenylthiazolidine-4-carboxylic acid, methyl ester (2.50 g, 6.14 mmol) in dioxane(15 mL)-water(5.0 mL) at room temperature was added 1.0 N LiOH solution (6.75 mL, 6.75 mmol). After stirring at room temperature for 16 hrs, The mixture was partitioned between EtOAc-5% KHSO4. The organic phase was washed with saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to give the title compound (2.42 g, 100%) as a viscous oil. TLC(MeOH-CH2Cl2; 1:9) Rf=0.38.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([F:9])[C:3]=1[F:10].[N+:11]([O-])([OH:13])=[O:12]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N+:11]([O-:13])=[O:12])=[C:4]([F:9])[C:3]=1[F:10]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(F)c(F)c(F)c1
Agent: O=S(=O)(O)O
Product: Cc1cc(F)c(F)c(F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 85 %

Procedure:
1,2,3-Trifluoro-5-methylbenzene (40 mmol) was added to conc. H2SO4 (50 ml) at 0-5° C. Then the reaction mixture was slowly treated with conc. HNO3 (3.39 ml, 48.44 mmol, 90%) while maintaining the internal temperature below 20° C. The reaction mixture was stirred at room temperature for 16 h and poured onto ice (300 g) and the oily layer was extracted with CH2Cl2 (2×125 ml). The organic layer was washed with water (2×200 ml), brine (200 ml) and dried (MgSO4) and evaporated to obtain the crude product which was purified over flash silica gel chromatography to obtain the title product (6.5 g, 85%). 1H-NMR (300 MHz, CDCl3): δ 6.96 (septet, 1H), 2.39 (s, 3H). 19FNMR (CDCl3): δ−128.18, −141.50, −159.05.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:29]I.O>CN(C)C=O.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][N:13]=2)([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH3:29])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CI
Reactant: Cc1ccc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCCCCC
Product: Cc1ccc(C(C)(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)nc1
Reaction time: 0.25 h
Yield: 92.4 %

Procedure:
Under ice cooling, a solution of the 2-[[(4-chlorophenyl)sulfonyl](2,5-difluorophenyl)methyl]-5-methylpyridine (52 mg, 0.132 mmol), which had been obtained in Example 137, in N,N-dimethylformamide (5 ml) was added dropwise to a suspension of sodium hydride (a 60% oil dispersion, 30 mg, 0.75 mmol) in N,N-dimethylformamide (5 ml). The reaction mixture was stirred for 15 minutes under ice cooling, and then, methyl iodide (12 μl, 0.198 mmol) was added. After stirring at room temperature for 1 hour, water was added to the reaction mixture under ice cooling, followed by concentration under reduced pressure. Water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to chromatography on a silica gel column. A fraction obtained from the eluate with hexane:ethyl acetate (=8:1) was concentrated under reduced pressure. The residue thus obtained was solidified with hexane and collected by filtration, whereby the title compound (50 mg, 0.122 mmol, 93%) was obtained as a white powder.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[S:3]([O:6][C:7]1[C:8]2[CH:9]=[C:10](C#CC3C=CC(C(OCC)=O)=CC=3)[CH:11]=[CH:12][C:13]=2[C:14]([CH3:18])([CH3:17])[CH2:15][CH:16]=1)(=[O:5])=[O:4].CC1(C)C2C=C([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:49][CH:48]=3)C=CC=2C(=O)CC1>C1COCC1>[F:33][C:2]([F:32])([F:1])[S:3]([O:6][C:7]1[C:8]2[CH:9]=[CH:10][C:11]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:49][CH:48]=3)=[CH:12][C:13]=2[C:14]([CH3:17])([CH3:18])[CH2:15][CH:16]=1)(=[O:5])=[O:4]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 800 mg (2.31 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 2 ml of THF was converted into the title compound (white solid) using 466 mg (2.5 ml, 2.54 mmol) of sodium bis(trimethylsilyl)amide (1.0M solution in THF) and a solution of 961 mg (2.54 mmol) of 2-[N,N-bis (trifluoromethylsulfonyloxy) amino]-5-chloropyridine in 2 ml of THF.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.[CH:31](=O)[CH2:32][OH:33]>>[CH3:1][C:2]1[N:3]([C:7]2[CH:8]=[CH:9][C:10]([NH:13][C:14]3[N:15]=[C:16]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:17]4[CH2:23][N:22]([CH2:31][CH2:32][OH:33])[CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:11][CH:12]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=CCO
Reactant: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CNCC3)cc1
Product: Cc1nccn1-c1ccc(Nc2nc3c(c(CC4CCOCC4)n2)CN(CCO)CC3)cc1
Yield: 11.3 %

Procedure:
2-(2-(4-(2-Methyl-1H-imidazol-1-yl)phenylamino)-4-((tetrahydro-2H-pyran-4-yl)methyl)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl)ethanol (20.00 mg, 11.3%) was synthesised from N-(4-(2-methyl-1H-imidazol-1-yl)phenyl)-4-((tetrahydro-2H-pyran-4-yl)methyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine (Example 61a) and glycol aldehyde according to the general procedure for reductive amination.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl.[Cl:12]C1C=CC(OC[CH2:19][CH2:20][CH:21]2[CH2:29][CH2:28][C:24]3[NH:25][CH:26]=[N:27][C:23]=3[CH2:22]2)=CC=1.O>CN(C=O)C>[ClH:12].[CH2:1]([O:8][CH2:19][CH2:20][CH:21]1[CH2:29][CH2:28][C:24]2[NH:25][CH:26]=[N:27][C:23]=2[CH2:22]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(OCCCC2CCc3[nH]cnc3C2)cc1
Reactant: OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc(COCCC2CCc3[nH]cnc3C2)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 31.3 %

Procedure:
A mixture of dry DMF (5 ml), benzylalcohol (216 mg, 2.0 mmol) and 60% sodium hydride (80 mg, 2.0 mmol) placed under an atmosphere of nitrogen was heated at 50° C. for 30 minutes. The mixture was allowed to cool to ambient temperature and methanesulfonic acid 2-(1(3)-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazol-5-yl)ethyl ester (0.5 g, 1.2 mmol, prepared as described in Example 34) dissolved in dry DMF (5 ml) was added and the reaction mixture was stirred for 2 days. The mixture was poured into H2O (100 ml) and extracted with diethyl ether (2×50 ml). The combined organic extracts were washed with H2O (3×50 ml) and the solvent was evaporated. The residue was dissolved in 90% acetic acid (20 ml) and the mixture was heated at reflux for 1-2 hours. The volatiles were evaporated and the residue was stirred with a mixture of H2O (25 ml) and diethyl ether (20 ml). The phases were separated and the aqueous phase was washed with diethyl ether (2×20 ml). The aqueous phase was adjusted to pH 10-11 with 4 N sodium hydroxide and the oily precipitate was extracted with ethyl acetate (2×20 ml). The combined organic extracts were evaporated and the residue was dissolved in 1 N hydrochloric acid and re-evaporated. The residue was re-evaporated with acetone several times and then stirred with acetonitrile (5 ml). The mixture was filtered and the solid was discarded. The filtrate was evaporated to give 110 mg (31%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9](N2[C@@H](C(C)C)COC2=O)=[O:10])=[CH:4][CH:3]=1.[OH:21]O.[Li+].[OH-]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([CH3:20])[C:9]([OH:10])=[O:21])=[CH:6][CH:7]=1
Reactant: OO
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](C(=O)O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.2 %

Procedure:
To a solution of (4S)-3-[(2S)-2-(4-chlorophenyl) propanoyl]-4-isopropyl-1,3-oxazolidin-2-one (678 mg, 2.30 mmol) in 45 mL THF/H2O (3:1) at 0° C., was added 30% H2O2 (2.1 mL, 18.4 mmol) followed by LiOH (193 mg, 4.6 mmol). The resulting mixture was stirred at 0° C. for 2 h and the excess peroxide was quenched at 0° C. with 1.5 N aqueous Na2SO3 (15 mL). After buffering to pH 9–10 with aqueous NaHCO3 and evaporation of the THF, the oxazolidone chiral auxiliary was recovered by EtOAc extraction (50 mL×3). The aqueous layer was acidified with 3N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 0.36 g (1.96 mmol, 85%) of (2S)-2-(4-chlorophenyl)propanoic acid; [α]D=+67° (C=1, MeOH): 1H NMR (400 MHz, CDCl3) δ 12.2–10.8 (br, 1H), 7.32–7.23 (m, 4H), 3.72 (q, 1H, J=7.3 Hz), 1.50 (d, 3H, J=7.3 Hz); ESMS m/e: 183.2 (M−H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[OH-:15].[K+].O>C(O)CCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH2:13][CH3:14])([CH2:11][CH3:12])[C:9]([NH2:10])=[O:15])=[CH:6][CH:7]=1
Reactant: [OH-]
Reactant: CCC(C#N)(CC)c1ccc(Cl)cc1
Agent: [K+]
Solvent: O
Solvent: CCCCCO
Product: CCC(CC)(C(N)=O)c1ccc(Cl)cc1

Procedure:
2-(4-Chlorophenyl)-2-ethylbutyronitrile (104.9 g) was added to a boiling solution of potassium hydroxide (40.3 g) in pentan-1-ol (450 ml) with stirring. The mixture was boiled under reflux for 24 hours. The mixture was cooled and poured into an equal volume of water. The mixture was washed with ether and then the aqueous layer was extracted with dichloromethane to give an oil which solidified on standing. The solid was triturated with cyclohexane and filtered to give 2-(4-chlorophenyl)-2-ethylbutyramide, m.p. 107°-109° C.
Reaction SMILES: [Cl:1][C:2]([Cl:19])=[CH:3][CH:4]1[C:6]([CH3:8])([CH3:7])[C:5]1(C(OCC)=O)[C:9]([O:11]CC)=[O:10].[OH-].[K+].C(O)C.Cl>O>[CH3:7][C:6]1([CH3:8])[CH:4]([CH:3]=[C:2]([Cl:19])[Cl:1])[CH:5]1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C1(C(=O)OCC)C(C=C(Cl)Cl)C1(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O

Procedure:
The mixture of ethyl 2-(2,2-dichlorovinyl)-3,3-dimethyl-1-ethoxycarbonylcyclopropanecarboxylate (1.5 g.) potassium hydroxide (2.0 g.) and ethanol (150 ml.) is refluxed for 2 hours, after which it is poured into water (500 ml.) and carefully acidified with concentrated hydrochloric acid. The white oily precipitate which is formed is collected by extraction with carbon tetrachloride, the extracts dried with anhydrous sodium sulphate, and the solvent evaporated under reduced pressure. The residual oil is heated under nitrogen to about 150°-160° C. for about 1.5 hours, and then cooled to form a crystalline mass. Recrystallisation from n-hexane yielded 2,2-dimethyl-3-(2,2-dichlorovinyl) cyclopropane carboxylic acid, m.p. 87°-90° C., believed to be principally the trans-isomer.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH:12]([OH:15])[CH2:13][OH:14])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:16][C:17]1[CH:18]=[CH:19][C:20](B2OC(C)(C)C(C)(C)O2)=[C:21]([CH:24]=1)[C:22]#[N:23].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.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.C1(C)C=CC=CC=1>[C:22]([C:21]1[CH:24]=[C:17]([CH3:16])[CH:18]=[CH:19][C:20]=1[C:2]1[CH:11]=[C:10]([CH:12]([OH:15])[CH2:13][OH:14])[CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1)#[N:23]
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: COC(=O)c1cc(Br)cc(C(O)CO)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: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)cc2C#N)cc(C(O)CO)c1

Procedure:
A mixture of methyl 3-bromo-5-(1,2-dihydroxyethyl)benzoate (100 mg, 0.36 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (130 mg, 0.54 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035 mmol), potassium carbonate (75 mg, 0.54 mmol), N,N-dimethylformamide (0.5 mL), and toluene (1 mL) under nitrogen was subjected to microwave irradiation at 110° C. for 1 h. After cooling, the mixture was diluted with water (5 mL) and extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by flash column to afford the title compound.
Reaction SMILES: [CH:1]1([CH:7](O)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.C(N(C(C)C)CC)(C)C.Cl.Cl.[F:53][C:54]1[CH:55]=[C:56]([C:60]2([CH2:66][CH2:67][N:68]3[C@H:73]4[CH2:74][CH2:75][C@@H:69]3[CH2:70][CH:71]([N:76]3[C:80]5[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=5[N:78]=[C:77]3[CH3:85])[CH2:72]4)[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]2)[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl>[CH:1]1([CH:7]([N:63]2[CH2:62][CH2:61][C:60]([C:56]3[CH:57]=[CH:58][CH:59]=[C:54]([F:53])[CH:55]=3)([CH2:66][CH2:67][N:68]3[C@H:69]4[CH2:75][CH2:74][C@@H:73]3[CH2:72][CH:71]([N:76]3[C:80]5[CH:81]=[CH:82][CH:83]=[CH:84][C:79]=5[N:78]=[C:77]3[CH3:85])[CH2:70]4)[CH2:65][CH2:64]2)[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: O=C(OCc1ccccc1)C(O)C1CCCCC1
Agent: Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(C(=O)OCc2ccccc2)C2CCCCC2)CC1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 19.5 %

Procedure:
To a −78° C. solution of benzyl cyclohexyl(hydroxy)acetate (61 mg, 0.25 mmol) and 4A molecular sieves in 1.2 mL CH2Cl2 was added trifluoromethanesulfonic anhydride (0.05 mL, 0.30 mmol). After stirring for 10 min at this temperature, 2,6-lutidine (0.06 mL, 0.49 mmol) was added. After 15 min, diisopropylethylamine (0.09 mL, 0.49 mmol) was added and after another 15 min, a solution of 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole dihydrochloride (153 mg, 0.30 mmol) in 1 mL CH2Cl2 was added. The reaction mixture was stirred at −78° C., then allowed to warm to room temperature overnight, washed with saturated aqueous NaHCO3, and purified by preparatory TLC using 5% MeOH in CHCl3 to afford benzyl cyclohexyl(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}piperidin-1-yl)acetate (33 mg, 20%) as an oil. 1H NMR (400 MHz, CDCl3), δ 7.68-7.64 (m, 1H), 7.33-7.23 (m, 7H), 7.20-7.12 (m, 2H), 7.05 (m, 1H), 6.97 (m, 1H), 6.89 (m, 1H), 5.05 (ABq, 2H, J=12.3 Hz), 4.61 (m, 1H), 3.26-3.18 (m, 2H), 2.92 (d, 1H, J=10.4 Hz), 2.70 (m, 1H), 2.64-2.50 (m, 2H), 2.57 (s, 3H), 2.46-2.30 (m, 3H), 2.12-0.81 (m, 25H); ESI-MS 677 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[OH:12].CN(C)C1C=CC=CC=1.O1CCCC1.Br[CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](Cl)=[O:30]>C(OCC)(=O)C>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]2[O:12][C:3]3[CH:4]=[CH:5][C:6]4[C:11]([C:2]=3[NH:1][C:29]2=[O:30])=[CH:10][CH:9]=[CH:8][CH:7]=4)=[CH:33][CH:34]=1
Reactant: Nc1c(O)ccc2ccccc12
Reactant: O=C(Cl)C(Br)c1ccc(Cl)cc1
Solvent: CN(C)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1Nc2c(ccc3ccccc23)OC1c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of 1-amino-2-naphthol (9.4 g), N,N-dimethylaniline (17.87 g) and tetrahydrofuran (160 ml) is added dropwise α-bromo-4-chlorophenylacetyl chloride (18.97 g) under ice cooling, and the mixture is stirred for one hour. To the reaction mixture is added ethyl acetate, and the ethyl acetate layer is washed, dried and distilled to remove the solvent. The resulting oil is dissolved in acetone (500 ml) and thereto is added potassium carbonate (40.8 g), and the mixture is refluxed for 2 hours, and acetone is distilled off. To the residue is added water, and the precipitate is separated by filtration, washed, dried and recrystallized from tetrahyrofuran to give 3-(4-chlorophenyl)-1H-naphtho[2,1-b][1,4]oxazin 2(3H)-one (13.29 g, yield 72.8%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:37][C:32]1[CH:31]=[C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:29])[F:28])[N:25]=[C:20]([C:16]3[CH:15]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=4)[CH:19]=[CH:18][CH:17]=3)[N:21]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cc(C(F)(F)F)n3)c2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 68 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[6-(3,4-dichloro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.39 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (4 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration and further purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield the title compound as an off-white solid (0.24 g, 51%). MS (ISN) 527.9 [(M−H)−]; mp 203° C.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Br)=[CH:5][CH:4]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].[NH:17]1[CH2:21][CH2:20][NH:19][C:18]1=[O:22].O>CS(C)=O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:17]2[CH2:21][CH2:20][NH:19][C:18]2=[O:22])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1NCCN1
Reactant: N#Cc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccc(CN2CCNC2=O)cc1
Reaction time: 0.5 h
Yield: 20.2 %

Procedure:
A mixture of 20.95 g (0.107 mole) of 4-cyanobenzyl bromide, 14.7 g (0.107 mole) K2CO3, 5.0 g KI, and 10.32 g (0.12 mole) 2-imidazolidinone in 125 ml dimethylsulfoxide was stirred at 100°-110° for 30 minutes, cooled, and poured into 400 ml cold tap water. The mixture was stirred at room temperature for 30 minutes and extracted with 250 ml chloroform. The chloroform extract was washed with 3 × 250 ml H2O, dried (MgSO4), and concentrated to dryness in vacuo to give an oily residue. Crystallization from 60 ml toluene gave 5.50 g of the crude product. Further recrystallization from toluene gave 4.34 g (20%) of the nitrile, m.p. 127°-133°. The analytical sample, m.p. 134°-136°, was obtained by recrystallization from toluene.