Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][C:25]=1[OH:34].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:23][C:24]1[CH:32]=[C:31]2[C:27]([CH:28]=[C:29]([CH3:33])[NH:30]2)=[CH:26][C:25]=1[O:34][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cc2cc(O)c(F)cc2[nH]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc4cc(C)[nH]c4cc3F)ncnc2cc1OCCCN1CCCC1
Yield: 57.3 %

Procedure:
Using an analogous procedure to that described in Example 248, 4-chloro-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (268 mg, 0.833 mmol), (prepared as described for the starting material in Example 9), was reacted with 6-fluoro-5-hydroxy-2-methylindole (165 mg, 1 mmol) in DMF (3.5 ml) containing potassium carbonate (173 mg, 1.25 mmol) to give 4-(6-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(pyrrolidin-1-yl)propoxy)quinazoline (215 mg, 57%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23].ClC1C2C(=CC3C=C(OC)C(OCCCl)=CC=3C=2)N=CC=1C#N.Cl.N1C=CC=CC=1.[Cl:54][C:55]1[CH:61]=[C:60]([Cl:62])[C:59]([O:63][CH3:64])=[CH:58][C:56]=1[NH2:57].C(OCCO)C>>[Cl:54][C:55]1[CH:61]=[C:60]([Cl:62])[C:59]([O:63][CH3:64])=[CH:58][C:56]=1[NH:57][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[C:14]([O:16][CH2:17][CH2:18][Cl:19])[C:13]([O:20][CH3:21])=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:22]#[N:23]
Reactant: COc1cc2cc3c(Cl)c(C#N)cnc3cc2cc1OCCCl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: COc1cc2cc3ncc(C#N)c(Cl)c3cc2cc1OCCCl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc(Nc2c(C#N)cnc3cc4cc(OCCCl)c(OC)cc4cc23)c(Cl)cc1Cl
Temperature: 135 °C
Reaction time: 1 h
Yield: 47.7 %

Procedure:
A mixture of 1.10 g (3.17 mmol) of 4-chloro-7-methoxy-8-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-chloro-8-methoxy-7-(2-chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture), 50 mg of pyridine hydrochloride, 742 mg (3.86 mmol) of 2,4-dichloro-5-methoxyaniline and 25 mL of 2-ethoxyethanol is stirred and heated to 135° C. After 1 hour, the reaction is cooled to room temperature, quenched with 1.0 mL of triethylamine and concentrated in vacuo. The residue is dissolved in 95:5 methylene chloride/methanol and chromatographed on silica gel, eluting with 1:1 hexane/ethyl acetate. The product is precipitated from ethyl acetate to provide 0.760 g (48%) of 4-(2,4-dichloro-5-methoxyanilino)-7-methoxy-8-(chloroethoxy)benzo[g]quinoline-3-carbonitrile and 4-(2,4-dichloro-5-methoxy-anilino)-8-methoxy-7(chloroethoxy)benzo[g]quinoline-3-carbonitrile (1:1 mixture) as a dull yellow solid, m.p. 239–55° C. dec.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26].[CH2:29]([S:31]([OH:33])=[O:32])[CH3:30].[Na].IC>CN1CCCC1=O.CS(C)=O.C(Cl)Cl.O.[Cu]I>[CH2:29]([S:31]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=1)[C:6]([CH3:24])=[C:5]2[C:25]([O:27][CH3:28])=[O:26])(=[O:33])=[O:32])[CH3:30]
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2cc(OC)c(Br)cc12
Reactant: CCS(=O)O
Agent: [Cu]I
Agent: [Na]
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: O
Product: CCS(=O)(=O)c1cc2c(C(=O)OC)c(C)c(-c3cccc(C(F)(F)F)c3)nc2cc1OC
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 76 %

Procedure:
To a solution of methyl 6-bromo-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (2 g, 4.40 mmol) in N-methyl-2-pyrrolidone (15 mL) and DMSO (30 mL) was added copper(I) iodide (2.52 g, 13.21 mmol) followed by ethanesulfinic acid, sodium salt (1.534 g, 13.21 mmol). The mixture was evacuated and purged with N2 three times and heated at 120° C. for 16 h. The mixture was cooled to room temperature, and iodomethane (1.377 mL, 22.01 mmol) was added. After 90 min, additional iodomethane (1.377 mL, 22.01 mmol) was added and the mixture was stirred for an additional hour. The mixture was diluted with methylene chloride and water, and the biphasic solution was filtered through Celite®. The phases were separated, and the aqueous phase was extracted with methylene chloride (50 mL). The combined organic extracts were washed with water (3×50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was loaded onto florisil and purified via column chromatography (ISCO, 40 g silica, 5-55% ethyl acetate/hexanes) to give methyl 6-(ethylsulfonyl)-3-methyl-7-(methyloxy)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.95 g, 76% yield). MS (m/z) 468.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C:5](=[O:8])[NH:6][CH:7]=1.[H-].[Li+].[CH3:30]I>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:13][CH2:12][CH2:11][N:10]2[C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:16]3[N:15]=2)[C:5](=[O:8])[N:6]([CH3:30])[CH:7]=1
Reactant: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)c[nH]c3=O)nc12
Reactant: CI
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)cn(C)c3=O)nc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a suspension of (R)-ethyl 5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylate (0.73 g, 1.97 mmol) in DMF (10 mL) at 0° C. was added LiH (20 mg, 2.36 mmol). After stirring for 30 minutes, a solution of MeI (0.56 g, 3.93 mmol) in DMF (2 mL) was added and the reaction was stirred at ambient temperature for 17 hours. The reaction mixture was cooled to 0° C. and quenched with ice-water (30 mL). The mixture was extracted with EtOAc (3×), washed with water and brine, dried with MgSO4, filtered and concentrated. The crude material was purified by silica column chromatography, eluting with 2.5% MeOH/DCM to yield the title product (0.64 g, 85%). MS (apci) m/z=386.0 (M+H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[N:10]=[C:9]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[OH:22])=[O:13])[CH:8]=[N:7][C:6]=1[C:23]#[N:24])[CH:2]=[CH2:3].[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)C=C>O1CCCC1>[CH2:30]([O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[NH:14][C:12]([NH:11][C:9]1[CH:8]=[N:7][C:6]([C:23]#[N:24])=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[N:10]=1)=[O:13])[CH:25]=[CH2:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCOc1nc(NC(=O)Nc2cc(Cl)ccc2O)cnc1C#N
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Solvent: C=CCO
Solvent: C1CCOC1
Product: C=CCOc1ccc(Cl)cc1NC(=O)Nc1cnc(C#N)c(OCC=C)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 27.6 %

Procedure:
To a solution of Example 55A (456 mg, 1.32 mmol) in anhydrous tetrahydrofuran (18 mL) was added polymer supported triphenylphosphine (659.5 mg, 1.98 mmol), di-tert-butyl azodicarboxylate (455.5 mg, 1.98 mmol), and allyl alcohol (76.6 mg, 1.32 mmol). The reaction mixture was shaken at room temperature for 5 hours. The solution was filtered, dried with silica gel powder (10 g), and purified by flash chromatography eluting with 20% ethyl acetate in hexanes (2 L) to give the title compound (140.8 mg, 28%). MS (ESI) m/z 385.95 (M+H)+; 1H NMR (500 MHz, DMSO-D6) δ ppm 4.71 (d, J=5.62 Hz, 2 H) 4.95 (d, J=5.30 Hz, 2 H) 5.29–5.36 (m, 2 H) 5.40–5.48 (m, 2 H) 6.00–6.16 (m, 2 H) 7.04–7.10 (m, 2 H) 8.20 (d, J=2.50 Hz, 1 H) 8.88 (s, 1 H) 9.05 (s, 1 H) 10.71 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:22](=[N:23][CH:24]=1)[O:21][CH2:20][CH2:19][O:18][C:17](=[O:25])[C:16]1=[C:26]3[N:27]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]2[C:22](=[O:21])[N:23]([CH:24]=1)[CH2:20][CH2:19][O:18][C:17](=[O:25])[C:16]1=[C:26]3[N:27]=[C:10]([CH:11]=[CH:12][N:13]3[N:14]=[CH:15]1)[N:9]1[C@@H:5]2[CH2:6][CH2:7][CH2:8]1
Reactant: O=C1OCCOc2ncc(F)cc2[C@H]2CCCN2c2ccn3ncc1c3n2
Solvent: O
Solvent: CC#N
Product: O=C1OCCn2cc(F)cc(c2=O)[C@H]2CCCN2c2ccn3ncc1c3n2
Yield: 9 %

Procedure:
Obtained as a by-product of Example 14, Step C, and isolated as a white solid (5 mg, 9% yield) by reverse phase column chromatography (Biotage SP4 system C-18 25+M column, 5 to 60% acetonitrile/water) of the crude material of Example 14, Step C. MS (apci) m/z=370.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([NH2:16])[CH2:12][CH:13]([CH3:15])[CH3:14].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:16][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[C:4]([Cl:10])[CH:3]=1
Reactant: O=Cc1ccc(Br)cc1Cl
Reactant: CC(C)CCN
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)CCNCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
4-bromo-2-chloro-benzaldehyde (I-3a: 10.0 g, 46.0 mmol) was dissolved in methanol and treated with isoamylamine (4.78 g, 54.7 mmol). After stirring overnight at room temperature, sodium borohydride (5.2 g, 138 mmol) was added to the reaction mixture. After stirring for 1 hour at room temperature, the reaction mixture was quenched using concentrated (37%) hydrochloric acid and the volatiles were removed under reduced pressure. The residue was taken up in an aqueous 2 N sodium hydroxide solution and extracted with ethyl acetate (2 times). The combined organic phases were washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the title product (I-3b: 12.7 g)
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11](=[O:26])[N:12]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=3[C:4]=2[CH:3]=1.[H-].[Na+].Cl[CH2:30][O:31][CH3:32].Cl>CN(C)C=O.O1CCCC1>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:30][O:31][CH3:32])[C:6]3[C:11](=[O:26])[N:12]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]=3[C:4]=2[CH:3]=1
Reactant: COCCl
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2[nH]c3ccc(F)cc3c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1cc(F)ccc1n2COC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 94.5 %

Procedure:
A suspension of 3.9 g (11 mmol) of ethyl 8-fluoro-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-carboxylate in 200 ml of dimethylformamide is added to a suspension of 0.66 g (16 mmol) of sodium hydride in 100 ml of dimethylformamide. The mixture is stirred for 1.5 h at room temperature and a solution of 1.15 ml (14.3 mmol) of chloromethoxymethane in 10 ml of tetrahydrofuran is added. The mixture is stirred for 2 h, a solution of dilute hydrochloric acid is added and the precipitate is collected by filtration and dried under reduced pressure. 4.1 g (10.4 mmol) of solid are isolated, which solid is used as is in the following stage.
Reaction SMILES: [NH2:1][CH:2]1[NH:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[F:10]OC(F)(F)F.FC1(F)CCCCNC1=O.FC1CCCNC(=O)C1(F)F>>[F:10][CH:6]1[CH2:5][CH2:4][CH2:3][CH:2]([NH2:1])[NH:9][C:7]1=[O:8]
Reactant: NC1CCCCC(=O)N1
Reactant: FOC(F)(F)F
Agent: O=C1NCCCC(F)C1(F)F
Agent: O=C1NCCCCC1(F)F
Product: NC1CCCC(F)C(=O)N1

Procedure:
ε-Aminocaprolactam (2.26 g., 0.02 mole) is dissolved in 60 ml. of liquid HF. Fluoroxytrifluoromethane (10.4 g., 0.1 mole) is passed into the solution under ultraviolet irradiation over 51/2 hours, while kept under vigorous stirring in a dry-ice-acetone cooling bath. After 11/2 hours more ultraviolet irradiation under similar conditions, the solvent is removed by distillation. The residue is quenched with ice and water and extracted 3 times with ethyl acetate. The combined extracts are washed with aqueous sodium bicarbonate solution, dried over magnesium sulfate and evaporated to dryness, to give a mixture of C-fluorinated caprolactams, with the main components being difluorocaprolactam and trifluoro-caprolactam.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][C@@H:9]3[CH:12]=[CH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[CH2:16][C@H:8]3[CH2:7]2)=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH:1]1([CH2:4][N:6]2[CH2:11][CH2:10][C@@H:9]3[CH:12]=[CH:13][C:14]4[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=4[CH2:16][C@H:8]3[CH2:7]2)[CH2:2][CH2:3]1
Reactant: O=C(C1CC1)N1CC[C@@H]2C=Cc3ccccc3C[C@H]2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: C1=C[C@H]2CCN(CC3CC3)C[C@@H]2Cc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 10.0 g of trans-2-cyclopropylcarbonyl-2,3,4,4a,11,11a-hexahydro-1H-benzo[5,6]cyclohepta[1,2-c]pyridine (obtained by reaction of trans-2,3,4,4a,11,11a-hexahydro-1H-benzo[5,6]cyclohepta[1,2-c]-pyridine with cyclopropanecarboxylic acid chloride) in 150 cc of anhydrous tetrahydrofuran is added dropwise, while stirring, at 10°-15°, to a solution of 2.5 g of lithium aluminium hydride in 350 cc of anhydrous tetrahydrofuran, and the reaction mixture is stirred at room temperature for 2 hours. The reaction mixture is decomposed at 0°-5° by the dropwise addition of 12 cc of saturated sodium sulphate solution, the inorganic portion is filtered off and washed out with methylene chloride. The combined filtrates are dried over sodium sulphate, concentrated by evaporation, and the title compound obtained as oily residue is converted into the hydrogen fumarate in isopropanol/acetone and is recrystallized. M.P. 157°-159°.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][BH:4][O:3]1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.C(N(CC)CC)C>O1CCOCC1.CC#N.CC#N.Cl[Pd]Cl>[CH3:1][C:2]1([CH3:9])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:13][CH:12]=2)[O:3]1
Reactant: CCOC(=O)C(C)c1ccc(Br)cc1
Reactant: CC1(C)OBOC1(C)C
Agent: Cl[Pd]Cl
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 110 °C

Procedure:
4,4,5,5-Tetramethyl-1,3,2-dioxaborolane (1.3 mL, 9.0 mmol) was added to a mixture of ethyl 2-(4-bromophenyl)propanoate (1.3 g, 5.0 mmol), bis(acetonitrile)palladium(II) chloride (26 mg, 0.10 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (160 mg, 0.40 mmol) and triethylamine (2.1 mL, 15 mmol) in 1,4-dioxane (3.0 mL) and then the mixture was evacuated under reduced pressure and then refilled with nitrogen thrice. The reaction was then heated at 110° C. for 4 h. The mixture was cooled to r.t. and filtered through a short pad of silical gel and then washed with ethyl acetate. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with ethyl acetate in hexane (0-10%) to afford the desired product.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([Si](OC)(OC)OC)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[F:41][C:42]1[CH:43]=[C:44](Br)[CH:45]=[CH:46][C:47]=1[F:48].O>C1(C)C=CC=CC=1.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>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:15]=[CH:14][C:13]([C:45]3[CH:44]=[CH:43][C:42]([F:41])=[C:47]([F:48])[CH:46]=3)=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCC1CCC(c2ccc([Si](OC)(OC)OC)cc2)CC1
Reactant: Fc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2ccc(-c3ccc(F)c(F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To 0.645 g (2 mmol) of 4-(4-propylcyclohexyl)-phenyltrimethoxysilane (Ih) was added 2.1 ml of TBAF (2.1 mmol, 1M in THF) under nitrogen, and the mixture was stirred at room temperature for 30 minutes. After the solvent was removed under reduced pressure, a solution of 3,4-difluorobromobenzene (0.463 g, 2.4 mmol) in toluene (1 ml) was added, followed by the addition of a suspension of tetrakis(triphenylphosphine)palladium(0) (0.116 g, 0.1 mmol) in toluene (3 ml). The resulting mixture was refluxed for 3 hours. After cooling, to the reaction mixture were added water and toluene. The organic layer was separated and the aqueous layer was extracted with toluene three times. The combined organic layer was dried over magnesium sulfate. After the magnesium sulfate was removed by filtration, the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (heptane) to obtain 0.594 g (40%) of white crystals.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.O[NH:31][C:32]([C:34]1[CH:42]=[CH:41][CH:40]=[C:39]2[C:35]=1[CH2:36][CH2:37][C@H:38]2[NH:43][C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[NH:33]>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:6]2[O:8][N:33]=[C:32]([C:34]3[CH:42]=[CH:41][CH:40]=[C:39]4[C:35]=3[CH2:36][CH2:37][C@H:38]4[NH:43][C:44](=[O:50])[O:45][C:46]([CH3:48])([CH3:47])[CH3:49])[N:31]=2)[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])#[N:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NC(=O)OC(C)(C)C)no2)cc1C#N
Temperature: 95 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
Prepared using General Procedure 4. To a solution of 3-cyano-4-isopropoxybenzoic acid (7.74 g, 37.7 mmol) in DMF (50 mL) was added HOBt (6.02 g, 44.6 mmol) and EDC (8.53 g, 44.6 mmol) at room temperature. The reaction was stirred for 2 h until complete formation of the HOBt-acid complex. (R)-tert-butyl 4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-10 (10.0 g, 34.3 mmol) was added and the reaction mixture stirred at room temperature for 2 h until the formation of INT-11, (R)-tert-butyl 4-(N-(3-cyano-4-isopropoxybenzolyloxy) carbamimidoyl)-2,3-dihydro-1H-inden-1-ylcarbamate. The mixture was partitioned between EA and NaHCO3 and the organic layer was collected and dried over MgSO4. INT-11 (16.3 g, 34.0 mmol) was re-dissolved in DMF (50 mL) and the mixture was heated to 95° C. for 12 hrs. The reaction was diluted with NaHCO3 (200 mL) and extracted with EA (3×50 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to produce 12.8 g (81%) of (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate INT-12 as a light brown solid and used without further purification in the next step. LCMS-ESI (m/z) calculated for C26H28N4O4: 460.5; found 483.2 [M+Na]+, tR=4.25 min. 1H NMR (400 MHz, CDCl3) δ 8.43 (d, J=2.1, 1H), 8.34 (dd, J=8.9, 2.2, 1H), 8.09 (d, J=7.6, 1H), 7.51 (d, J=7.5, 1H), 7.39 (t, J=7.6, 1H), 7.12 (d, J=9.0, 1H), 5.28 (d, J=8.2, 1H), 4.80 (hept, J=6.0, 1H), 3.47 (ddd, J=17.4, 8.9, 3.5, 1H), 3.27-3.03 (m, 1H), 2.68 (d, J=8.7, 1H), 1.87 (td, J=16.7, 8.5, 1H), 1.53-1.43 (m, 15H). 13C NMR (101 MHz, CDCl3) δ 173.00, 168.82, 162.70, 155.68, 145.31, 142.96, 134.05, 133.83, 128.25, 127.21, 126.79, 123.99, 116.78, 115.24, 113.52, 103.87, 79.52, 72.70, 55.72, 33.86, 31.47, 28.39, 21.70. Chiral HPLC: (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-ylcarbamate was eluted using 20% i-PrOH in hexanes: >99.9% ee, tR=13.33 min. The (S)-enantiomer INT-13 was prepared in an analogous fashion using (S)-tert-butyl 4-cyano-2,3-dihydro-1H-inden-1-ylcarbamate using General Procedures 3 and 4 (tR for (S)-enantiomer=16.31 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH3:19][NH:20][NH2:21]>>[CH3:19][NH:20][NH:21][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CNN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Product: CNNc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]

Procedure:
The product was obtained by reacting 2,4-dichloro-3,5-dinitrobenzotrifluoride with methylhydrazine and found to melt at 136°-137° C.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([C:19]1[C:24]([CH:25]([OH:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=[CH:21][C:20]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH:39]([OH:45])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:34]=1[CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[CH2:12]([C:19]1[C:24]([C:25](=[O:31])[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=[CH:21][C:20]=1[O:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39](=[O:45])[CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:34]=1[CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCCCCC(O)c1cccc(Oc2cccc(C(O)CCCCC)c2Cc2ccccc2)c1Cc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCCCCC(=O)c1cccc(Oc2cccc(C(=O)CCCCC)c2Cc2ccccc2)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a suspension of pyridinium chlorochromate (32.3 g) in methylene chloride (200 ml) was added a solution of benzyl-3-[1-hydroxyhexyl]phenyl ether (28.4 g.) in methylene chloride (25 ml). The reaction was stirred at room temperature for 11/2 hours. The excess methylene chloride was decanted and residual black solid was triturated with ethyl ether (four times.) The combined organic extract was purified on flurosil using ethyl ether as an eluent (27.5 g., 98% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[Cl:13].[Br:15]Br>C(O)(=O)C.Br.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH2:11][Br:15])[CH:7]=[CH:6][C:5]=1[Cl:13]
Reactant: COC(=O)c1cc(C(C)=O)ccc1Cl
Reactant: BrBr
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)c1cc(C(=O)CBr)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution of 5-acetyl-2-chloro-benzoic acid methyl ester (100 mg, 0.47 mmol) in glacial acetic acid (5 mL) was added bromine (0.05 mL, 0.94 mmol). The mixture was stirred at room temperature for 2 h. Hydrobromic acid-acetic acid (2 drops, 30%) was added and the mixture was stirred for 10 minutes. The mixture was concentrated in vacuo to afford the title compound (140 mg).
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:11]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)([O-:14])(=[O:13])=[S:12].[K+]>CN(C=O)C>[O:1]([CH2:8][CH2:9][O:14][S:11]([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[S:12])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: Cc1ccc(S(=O)([O-])=S)cc1
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=S)OCCOc2ccccc2)cc1

Procedure:
The title compound was prepared as described in General Method 2 using 2-phenoxyethyl bromide (0.025 mmol), potassium thiotosylate (0.025 mmol) and DMF (100 mL) to give a solid. 1H NMR (CDCl3) δ 2.45 (s, 3 H), 3.34 (t, 2 H), 4.14 (t, 2 H), 6.80 (d, 2 H), 6.95 (t, 1 H), 7.26 (t, 2 H), 7.35 (d, 2 H), 7.82 (d, 2 H).