Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][C:11]([CH3:13])=[CH2:12])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[S:8][CH2:9][CH2:10][C:11]2([CH3:13])[CH3:12]
Reactant: C=C(C)CCSc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)CCSc2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
1-Bromo-4-[(3-methylbut-3-en-1-yl)sulfanyl]benzene (1.05 g, 4.08 mmol) dissolved in dichloromethane (24.0 mL) was cooled to 0° C., and aluminum chloride (0.60 g, 4.49 mmol) was added portionwise. The reaction mixture was stirred at 0° C. for 1 hour and warmed to room temperature for another hour. It was then poured into an Erlenmeyer flask containing a 10% aqueous NaOH solution and ice. The mixture was extracted with dichloromethane (2×, 40.0 mL), and the combined organic layers were dried over Na2SO4, filtered, and concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-10% EtOAc/Hexanes to give 6-bromo-4,4-dimethyl-3,4-dihydro-2H-thiochromene as a pale-yellow oil. 6-Bromo-4,4-dimethyl-3,4-dihydro-2H-thiochromene (798 mg, 3.10 mmol) in THF (21.0 mL) was cooled to −78° C. and n-BuLi (1.50 mL, 3.72 mmol) was added dropwise. The reaction mixture was stirred at −78° C. for 10 minutes and then DMF (961 μl, 12.4 mmol) was added dropwise via a syringe. The resulting mixture was allowed to warm to room temperature and wet silica gel (5.0 g/0.5 mL of water) was added. The mixture was allowed to stir at room temperature for 10 minutes before it was filtered. The silica gel was rinsed with EtOAc and the filtrate was concentrated under vacuum. The crude residue was purified by silica gel chromatography eluting with 0-20% EtOAc/hexanes to obtain the desired product as a pale-yellow oil.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:12])([O:8][CH:9]([CH3:11])[CH3:10])[O:4][CH:5]([CH3:7])[CH3:6].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH:28]([F:30])[F:29])[C:22]=1[S:31](Cl)(=[O:33])=[O:32]>CCOCC.C(OCC)(=O)C.C(Cl)Cl>[F:30][CH:28]([F:29])[O:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([CH3:20])[C:22]=1[S:31]([O:1][CH2:2][P:3](=[O:12])([O:4][CH:5]([CH3:7])[CH3:6])[O:8][CH:9]([CH3:11])[CH3:10])(=[O:33])=[O:32]
Reactant: Cc1cccc(OC(F)F)c1S(=O)(=O)Cl
Reactant: CC(C)OP(=O)(CO)OC(C)C
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cccc(OC(F)F)c1S(=O)(=O)OCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 20 ml of ether, 8.6 g of diisopropyl P-(hydroxymethyl)phosphonate, prepared in Example 17, and 6.9 ml of triethylamine was added dropwise over 25 minutes to 15.2 g of crude 2-methyl-6-(difluoromethoxy)benzenesulfonyl chloride, prepared in Example 3, in 70 ml of ether. After the mild exotherm, the reaction was allowed to stir overnight at room temperature and was then diluted with 200 ml of ethyl acetate, the resulting ethyl acetate solution washed with two 80 ml portions of water, dried with magnesium sulfate, filtered, and concentrated to yield 10.2 g of the very crude desired product as a black oil. The crude product was dissolved in 10 ml of methylene chloride and flash chromatographed on Merck silica gel using ethyl acetate and hexanes. After combining similar fractions, the desired product was isolated as an amber oil in low yield.
Reaction SMILES: C1COCC1.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=4)[C:17](=[O:28])[CH:16]=3)=[CH:14][C:9]=2[O:8][CH2:7]1.CCN(CC)CC>CO>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH3:27])=[CH:21][CH:22]=4)[C:17](=[O:28])[CH2:16]3)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: CCCOc1ccc2c(c1)C(=O)C=C2c1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CO
Product: CCCOc1ccc2c(c1)C(=O)C[C@H]2c1ccc2c(c1)OCO2
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A 250 mL three-necked flask equipped with air driven stirrer and 250 mL addition funnel was charged with anhydrous THE (50 mL) and (R)-MeCBS (1.6 mL, 1 M, 1.6 mmol). The solution was cooled to -15° C. and BH3 -THF (32.4 mL, 1 M, 32.4 mmol) added in a steady stream. Charge the 250 mL addition funnel with 3-(1,3-Benzodioxol-5-yl)-6-propoxy-1H-inden-1-one (10 g, 32.4 mmol) and anhydrous TEF (50 mL) and add the solution dropwise over 1.5 h period while maintaining the internal reaction temperature between -10 to -15° C. Upon complete addition, stir the reaction mixture for 0.5 h at -15° C., cool the solution to -25° C. and add CH3OH (20 mL) dropwise over 20 minutes while maintaining the internal reaction temperature below -15° C. Warm the solution to 20° C. over 0.5 h and stir the solution for an additional 0.5 h at ambient temperature. Cool the solution to 0° C. and add Et3N (11 mL, 81 mmol) to the reaction mixture dropwise over 15 minutes while maintaining the internal reaction temperature below 5° C. Add 1,1-bis(triphenylphosphine) nickel(II) chloride (211 mg, 3.24 mmol) and warm the reaction mixture to 60° C. for 4 h. Concentrate the solution to 1/4 volume, cool to room temperature, add Celite (12 g) and then hexanes (85 ml). Stir the mixture vigorously for 10 min and filter through a SiO2 (10 g) and Celite (10 g) pad. Wash the filter pad with THF/hexane (45 mL/120 mL), combine the filtrates, and transfer to a 500 mL round-bottomed flask. Concentrate the solution in vacuo until a precipitate forms, add hexane (40 mL) and cool the solution to -15° C. for 8 h. Filter the precipitate, wash the filter cake with cold (0° C.) hexane solution and dry under vacuum to afford (S)-3-(1,3-Benzodioxol-5-yl)-2,3-dihydro-6-propoxy-1H-inden-1-one as a light yellow solid (8.1 g, 81%, 88% e.e.): mp 68.0-69.5° C.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[O:25]1[C:30]2([CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:38]=[C:39]([CH2:44][CH2:45][OH:46])[CH:40]=[CH:41][C:42]=3[F:43])[CH2:32][CH2:31]2)[CH2:29][NH:28][CH2:27][CH2:26]1.[CH:47]([C:50]1[S:51][CH:52]=[C:53]([C:55](O)=[O:56])[N:54]=1)([CH3:49])[CH3:48].C(N(CC)CC)C>CN(C=O)C>[F:43][C:42]1[CH:41]=[CH:40][C:39]([CH2:44][CH2:45][OH:46])=[CH:38][C:37]=1[CH2:36][N:33]1[CH2:34][CH2:35][C:30]2([O:25][CH2:26][CH2:27][N:28]([C:55]([C:53]3[N:54]=[C:50]([CH:47]([CH3:49])[CH3:48])[S:51][CH:52]=3)=[O:56])[CH2:29]2)[CH2:31][CH2:32]1
Reactant: OCCc1ccc(F)c(CN2CCC3(CC2)CNCCO3)c1
Reactant: CC(C)c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cc(CCO)ccc4F)CC3)C2)cs1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
HATU (1.1 g) was added in one portion to a cooled solution of 2-(3-(1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)-4-fluorophenyl)ethanol [Example 44, step c] (0.7 g) and 2-isopropylthiazole-4-carboxylic acid (0.39 g) and triethylamine (0.95 mL) in DMF (15 mL). The reaction mixture was stirred at 20° C. for 1 hour and then partitioned between ethyl acetate and brine. The organic layer was washed with brine (×2), dried, filtered and the solvent removed under reduced pressure. The crude product was purified by flash silica chromatography, using 3% methanol in ethyl acetate containing 1% triethylamine as solvent. Fractions containing the product were evaporated to dryness to afford the subtitled compound. Yield 0.61 g.
Reaction SMILES: C([Si]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+].[CH3:40][S:41](Cl)(=[O:43])=[O:42]>O1CCCC1.C(N(CC)CC)C>[CH3:40][S:41]([O:8][CH2:9][CH2:10][O:11][CH2:12][CH:13]1[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14]1)(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)OCC(COCCO[Si](C)(C)C(C)(C)C)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)OCC(COCCOS(C)(=O)=O)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl{2-[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]ethoxy}dimethylsilane (1.03 g) was dissolved in tetrahydrofuran (20 mL), a 1.0 M solution (4 mL) of tetrabutylammonium fluoride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (20 mL) and subjected the reaction similar to that in Example 203 (ii) using methanesulfonyl chloride (0.3 mL) and triethylamine (2 mL) to give the title compound (857 mg) as a yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([NH:14][C:15](=[O:17])[CH3:16])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH2:28].Cl.N1C=CC=CC=1>C(OCCO)C>[C:18]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:28][C:22]1[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:21]=1[Cl:20])=[CH:10][C:9]([O:12][CH3:13])=[C:8]([NH:14][C:15](=[O:17])[CH3:16])[CH:7]=2)#[N:19]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1NC(C)=O
Reactant: Nc1ccc(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cc1NC(C)=O
Temperature: 135 °C
Yield: 91.8 %

Procedure:
An amount of 6 g .(0.022 mol) of N-(4-chloro-3-cyano-6-methoxy-7-quinolinyl)acetamide was stirred in 60 ml of 2-ethoxyethanol. To this were added 2,4-dichloro-phenylamine (3.9 g, 0.024 mol), and 2.8 g (0.024 mol) pyridine hydrochloride, and the mixture was heated at 135° C. for 3 hours. The solvent was evaporated and the solid was stirred in ethyl acetate and filtered to give the HCl salt (8.1 g, 84%). A small portion was stirred in ethyl acetate and sodium hydroxide (1M). After separation of the layers, the organic layer was washed with saturated brine solution, dried over sodium sulfate, and evaporated to dryness to give a yellowish solid (92 mg, 1% yield), mp 245-246° C.; 1H NMR (DMSO-d6) δ 9.65 (s, 1H), 9.56 (s, 1H), 8.72 (s, 1H), 8.43 (s, 1H), 7.90 (s, 1H), 7.80 (m, 1H), 7.53 (m, 2H), 4.04 (s, 3H), 2.22 (s, 3H); HRMS (EI) m/z 401.05647 (M+1). Analysis for C19H14Cl2N4O2.0.1H2O: Found: C, 56.35; H, 3.42; N, 13.67. Calcd: C, 56.57; H, 3.52; N, 13.89.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]2[NH:11][C:12](=[O:23])[C:13]3[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=3[N:15]=2)=[CH:8][C:7]([S:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH3:34])[CH2:29][CH2:28]2)(=[O:26])=[O:25])=[CH:6][N:5]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:45][O:46]CCO>>[CH2:33]([N:30]1[CH2:31][CH2:32][N:27]([S:24]([C:7]2[CH:8]=[C:9]([C:10]3[NH:11][C:12](=[O:23])[C:13]4[N:18]([CH3:19])[N:17]=[C:16]([CH2:20][CH2:21][CH3:22])[C:14]=4[N:15]=3)[C:4]([O:3][CH2:1][CH2:2][O:46][CH3:45])=[N:5][CH:6]=2)(=[O:26])=[O:25])[CH2:28][CH2:29]1)[CH3:34]
Reactant: COCCO
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCC)nc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(S(=O)(=O)N4CCN(CC)CC4)cnc3OCCOC)nc12
Yield: 64 %

Procedure:
A mixture of the title compound of Example 124 (111 mg, 0.23 mmol) and potassium bis(trimethylsilyl)amide (226 mg, 1.13 mmol) in 2-methoxyethanol (5 ml) was stirred under reflux for 18 hours. The cooled mixture was evaporated under reduced pressure and the residue purified by column chromatography on silica gel, using dichloromethane: methanol (96:4) as eluant, and triturated with ether to afford the title compound (75 mg, 64%) as a white crystalline solid.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[N+:20]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([O-])=O.[OH-].[K+]>C(O)CC(C)C.[Cu].O>[C:8]1([N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:1]2[CH:2]=[CH:3][C:4]([C:26]3[CH:27]=[CH:28][C:23]([NH:20][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:24][CH:25]=3)=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)CCO
Product: c1ccc(Nc2ccc(-c3ccc(N(c4ccccc4)c4ccccc4)cc3)cc2)cc1
Yield: 72.2 %

Procedure:
Subsequently, 13.2g (0.032 mol) of N-(4'-iodo-4-biphenyl)acetanilide thus obtained, 6.60 g (0.039 mol) of diphenylamine, 5.53 g (0.040 mol) of anhydrous potassium carbonate, 0.45 g (0.007 mol) of copper powder, and 10 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 200° to 212° C. for 15 hours. The reaction product was then extracted with 100 ml of toluene. The insoluble contents were then removed by filtration. The filtrate was then concentrated to obtain an oily matter. The oily matter thus obtained was then dissolved in 60 ml of isoamyl alcohol. The material was then hydrolyzed with 1 ml of water and 2.64 g (0.040 mol) of 85% potassium hydroxide at a temperature of 130° C. The reaction solution was then subjected to steam distillation to distill off isoamyl alcohol. The residue was extracted with 250 ml of toluene, washed with water, and then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 1/2 mixture of toluene and n-hexane) to obtain 10.5 g (yield: 72.2%) of N,N,N'-triphenylbenzidine. The melting point of the product was from 167.5° C. to 168.5° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.C(N(CC)CC)C.[S:14](Cl)([CH3:17])(=[O:16])=[O:15].O>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][CH:3]([O:6][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:2]1
Reactant: CS(=O)(=O)Cl
Reactant: OC1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCOC1
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A solution of tetrahydrofuran-3-ol (4.6 g, 52.2 moles) in methylene chloride (70 ml) at 0° C. was added with triethylamine (8.36 ml, 60 moles) and mesyl chloride (4.44 ml, 57.4 moles) in methylene chloride (85 ml). The temperature was left to rise to room value and after 1 hour the mixture was poured into water and in methylene chloride. The organic phases were anhydrified and dried to give 8.12 g of the title product (yield: 93%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:20][CH2:19][CH2:18]5)[O:16][C:13]4=[CH:14][CH:15]=3)=[CH:6][N:5]2[CH:31]=1.C(O)(=O)C.[H][H]>CCO.O=[Pt]=O>[CH3:1][C:2]1[N:3]=[C:4]2[CH2:9][CH2:8][CH:7]([C:10]3[CH:11]=[C:12]4[C:25]5([CH2:29][O:28][C:27]([NH2:30])=[N:26]5)[C:21]5([CH2:24][O:23][CH2:22]5)[C:17]5([CH2:18][CH2:19][CH2:20]5)[O:16][C:13]4=[CH:14][CH:15]=3)[CH2:6][N:5]2[CH:31]=1
Reactant: [H][H]
Reactant: Cc1cn2cc(-c3ccc4c(c3)C3(COC(N)=N3)C3(COC3)C3(CCC3)O4)ccc2n1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cn2c(n1)CCC(c1ccc3c(c1)C1(COC(N)=N1)C1(COC1)C1(CCC1)O3)C2
Temperature: 25 °C
Reaction time: 38 h
Yield: 83.2 %

Procedure:
A suspension of 6′-(2-methylimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (66 mg, 0.16 mmol), acetic acid (27 μl, 0.06 mmol) and PtO2 (13 mg) in EtOH (3.3 ml) was stirred at room temperature under the hydrogen atmosphere at 3 atm for 8 hours. To the mixture was added acetic acid (63 μl), and the mixture was stirred at room temperature under hydrogen atmosphere at 3 atm for 38 hours. The mixture was filtrated through celite pad. And then the filtrate was concentrated under reduced pressure. The obtained residue was purified by silicagel column chromatography (28% NH4OH/EtOH/CHCl3=2:20:80) followed by trituration in iPr2O and filtration to give 6′-(2-methyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridin-6-yl)trispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (56 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])/[CH:14]=[C:15](\[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)/[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C1C=C(NC(N[C@H]([C@@H]2C[C@@H]3CCN2C[C@@H]3CC)C2C3C(=CC=C(OC)C=3)N=CC=2)=S)C=C(C(F)(F)F)C=1.[Cl-].[NH4+].[N+:74]([CH3:77])([O-:76])=[O:75]>>[C:1]([O:5][C:6](=[O:30])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:28])[CH2:14][C@@:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([CH2:77][N+:74]([O-:76])=[O:75])[C:16]([F:17])([F:19])[F:18])=[CH:9][C:8]=1[CH3:29])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Agent: CC[C@H]1CN2CC[C@H]1C[C@H]2[C@@H](NC(=S)Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccnc2ccc(OC)cc12
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 60 h
Yield: 77 %

Procedure:
4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-benzoic acid tert-butyl ester (0.0928 g, 0.198 mmol) and 1-[3,5-bis(trifluoromethyl)phenyl)-3-{(S)[(2S,4S,5R)-5-ethyl-1-aza-bicyclo[2.2.2]oct-2-yl]-(6-methoxy-4-quinolinyl)methyl}thiourea (0.0121 g, 0.020 mmol) were dissolved in nitromethane (0.6 ml) and the resulting solution was stirred at 50° C. for 2.5 days. The reaction mixture was cooled to room temperature and aqueous saturated ammonium chloride was added. The resulting mixture was extracted with dichloromethane (3×) and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 5% ethyl acetate in cyclohexane) to afford 4-[(R)-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-3-nitromethyl-butyryl]-2-methyl-benzoic acid tert-butyl ester (0.080 g, 77%) as a beige solid. Chiral HPLC analysis (Chiralpack AS-RH, MeCN:MeOH:H2O=75:5:20, 1 ml/min, retention time 3.26 minutes (major enantiomer), 2.86 minutes (minor enantiomer) indicated that the reaction proceeded with 97.4% enantioselectivity.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([Cl:14])[C:3]=1N.N([O-])=O.[Na+].[I-:19].[K+]>Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([Cl:14])[C:3]=1[I:19]
Reactant: [I-]
Reactant: Nc1c(Cl)cc(OC(F)(F)F)cc1Cl
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: FC(F)(F)Oc1cc(Cl)c(I)c(Cl)c1
Temperature: 40 °C
Reaction time: 0.25 h

Procedure:
2,6-Dichloro-4-(trifluoromethoxy)aniline (4.65 g, 13.2 mmol) suspended in 1 M of HCl solution (100 mL) was treated at 0° C. with sodium nitrite (0.913 g, 13.2 mmol) in water dropwise. After 15 minutes at 0° C., potassium iodide (2.20 g, 13.2 mmol) in water was added and the solution was heated at 40° C. for 15 min. The solution was quenched with saturated aq. Na2S2O3 solution (100 mL), and extracted with ethyl acetate (300 mL). The organic phase was washed with 0.1 N HCl solution satd. aq. NaHCO3 sol. (500 mL), and dried over sodium sulfate. Purification by silica gel chromatography (10-40% EtOAc/hexanes) afforded the desired product as a yellow solid.
Reaction SMILES: [OH-].[OH-].[C:3]1([B+2])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1.O1CCOCC1>[CH3:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:20][CH:21]=1
Reactant: [B+2]c1ccccc1
Reactant: COc1ccc(Cl)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 94.2 %

Procedure:
An oven dried resealable Schlenk tube was purged with argon and charged with palladium acetate (2.2 mg, 0.01 mmol, 0.5 mol %), ligand 2 [Example 1] (5.9 mg, 0.015 mmol, 0.75 mol %), phenylboron dihydroxide (366 mg, 3.0 mmol), and potassium phosphate (850 mg, 4.0 mmol). The tube was purged with argon, and dioxane (6 mL), and 4-chloroanisole (0.24 mL, 2.0 mmol) were added through a rubber septum. The septum was removed, the tube was sealed with a teflon screw cap and the mixture was stirred at room temperature for two minutes, then heated to 100° C. with stirring until the starting aryl chloride had been completely consumed as judged by GC analysis. The reaction mixture was then diluted with ether (40 mL) and poured into a separatory funnel. The mixture was washed with 1M NaOH (40 mL), and the layers were separated. The aqueous layer was extracted with ether (40 mL), and the combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude material was then purified by flash chromatography on silica gel to give 347 mg (94%) of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:12](OC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:12][OH:13])[CH:16]=[C:17]([CH3:19])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C)cc(OCc2ccccc2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CO)cc(OCc2ccccc2)c1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A solution of methyl 3-(benzyloxy)-5-methylbenzoate (1.29 g) in THF (10 mL) was added dropwise to a suspension of lithium aluminum hydride (0.229 g) in THF (10 mL) at 0 C. The obtained mixture was stirred at 0 C for 2 hours, then sodium sulfate decahydrate was added thereto in small portions at 0 C, and the precipitate was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (1.01 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([C:8]#[CH:9])=[CH:6][CH:7]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1.C(N(CC)CC)C>C(#N)C.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.[Cu](I)I>[NH2:1][C:2]1[C:3]([C:10]#[N:11])=[N:4][C:5]([C:8]#[C:9][C:16]2[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(I)cc1
Reactant: C#Cc1ccc(N)c(C#N)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1nc(C#Cc2ccc(Cl)cc2)ccc1N

Procedure:
This compound is prepared in a manner analogous to that of Step C of Example 9, using 3.1 grams (0.022 mole) of 3-amino-2-cyano-6-ethynylpyridine, 7.4 grams (0.031 mole)of 4-chlorophenyl iodide, 10.7 grams (0.077 mole) of triethylamine, 0.5 gram (catalyst) of bis(triphenylphosphine)palladium(II) chloride, and 0.5 gram (catalyst) of copper iodide in 100 mL of acetonitrile, yielding 3-amino-2-cyano-6-[(4-chlorophenyl)ethynyl]pyridine.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][CH:27]=[C:26]2[CH3:33]>C1C=CC=CC=1>[Br:1][CH2:33][C:26]1[C:25]2[C:30](=[CH:31][CH:32]=[C:23]([O:22][CH3:21])[CH:24]=2)[N:29]=[CH:28][CH:27]=1
Reactant: COc1ccc2nccc(C)c2c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Product: COc1ccc2nccc(CBr)c2c1
Reaction time: 5 h
Yield: 19.8 %

Procedure:
N-Bromosuccinimide (0.92 g, 5.2 mmol) and 2,2′-azobisisobutyronitrile (0.095 g, 0.58 mmol) were added to a solution of 6-methoxy-4-methylquinoline (1.0 g, 5.8 mmol) in anhydrous benzene (15 mL) at room temperature, and the mixture was stirred for 5 hours under reflux. Further 2,2′-azobisisobutyronitrile (0.19 g, 1.2 mmol) was added thereto, and the mixture was stirred for 17 hours under reflux. The solvent was evaporated under reduced pressure, and the resulting residue was roughly purified by silica gel chromatography to give 0.26 g of mixture containing the title Reference Compound as green oil.