Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:12][C:11]2=[O:33])[CH3:9])=[CH:4][CH:3]=1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN(C)CC(O)=O>CN(C=O)C.CCOC(C)=O.[Cu]I>[Si:26]([O:25][CH2:24][CH2:23][C@@:13]1([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[O:12][C:11](=[O:33])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Reactant: CS(N)(=O)=O
Agent: [Cu]I
Agent: CN(C)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](c1ccc(NS(C)(=O)=O)cc1)N1CC[C@](CCO[Si](C)(C)C(C)(C)C)(c2ccc(F)cc2)OC1=O
Temperature: 120 °C
Reaction time: 0.03 h

Procedure:
A mixture of (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (0.0465 g, 0.0866 mmol), methanesulfonamide (0.0945 g), K3PO4 (0.2753 g), N,N-dimethylglycine (0.0686 g), and CuI (0.0687 g) in DMF (2 mL) was heated at 120° C. for 17 h. The mixture was diluted with EtOAc, filtered, washed with CH2Cl2. After the solvent was evaporated under reduced pressure, the residue was purified by reversed-phase HPLC (SunFire™ Prep C18 OBD™ 5 μm 19×50 mm column, 10%→90% CH3CN/H2O, 0.1% CF3COOH over 8 min and then 90% CH3CN/H2O, 0.1% CF3COOH over 2 min, flow rate 20 mL/min) to afford N-(4-((S)-1-((S)-6-(2-(tert-butyldimethylsilyloxy)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-3-yl)ethyl)phenyl)methanesulfonamide. LC-MS tR=2.10 min in 3 min chromatography, m/z 551 (MH+), 507.
Reaction SMILES: C([O:5][C:6](=[O:20])[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:9]1=[O:19])(C)(C)C.[O:21]=[C:22]([N:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:30][CH2:29]1)[CH2:23][CH2:24][C:25](O)=[O:26].Cl.C(N=C=NCCCN(C)C)C>C(#N)C>[CH3:18][O:17][C:15]([CH2:14][C@@H:10]1[N:11]([C:25](=[O:26])[CH2:24][CH2:23][C:22](=[O:21])[N:28]2[CH2:33][CH2:32][N:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)[CH2:30][CH2:29]2)[CH2:12][CH2:13][N:8]([CH2:7][C:6]([OH:5])=[O:20])[C:9]1=[O:19])=[O:16]
Reactant: O=C(O)CCC(=O)N1CCN(c2ccccn2)CC1
Reactant: COC(=O)C[C@@H]1NCCN(CC(=O)OC(C)(C)C)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Product: COC(=O)C[C@H]1C(=O)N(CC(=O)O)CCN1C(=O)CCC(=O)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 79 %

Procedure:
To suspension of (S)-(3-methoxycarbonylmethyl-2-oxopiperazin-1-yl)acetic acid tert-butyl ester (0.64 g) and 4-oxo-4-(4-pyridin-2-ylpiperazin-1-yl)butanoic acid (0.65 g) produced in Reference Example 3 in acetonitrile (20 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.52 g) and the suspension was stirred for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of a silica gel column chromatography (acetonitrile/methanol=9/1). To the produced ester derivative was added trifluoroacetic acid (10 ml) and the solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by means of CHP-20 column chromatography (H2O→10% acetonitrile aqueous solution). The objected fraction was concentrated and subjected to lyophilization to give the titled compound (0.84 g) as a white amorphous powdery product.
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@H:14]2[C@@H:5]([C@@H:6]3[C@@H:11]([CH2:12][CH2:13]2)[CH2:10][C@@:9]2([CH3:20])[CH2:16][C:17](=[O:19])[CH2:18][C@@H:8]2[CH2:7]3)[CH2:4][CH2:3]1.[I-].[CH3:22][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:20][C@:9]12[C@@:16]3([CH2:17][O:19]3)[CH2:22][CH2:18][C@@H:8]1[CH2:7][C@H:6]1[C@@H:11]([CH2:12][CH2:13][C@@H:14]3[C@@H:5]1[CH2:4][CH2:3][C@@H:2]([OH:1])[CH2:15]3)[CH2:10]2
Reactant: C[C@]12CC(=O)C[C@@H]1C[C@H]1[C@@H](CC[C@H]3C[C@H](O)CC[C@@H]31)C2
Reactant: C[S+](C)C
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@]12C[C@@H]3CC[C@H]4C[C@H](O)CC[C@@H]4[C@H]3C[C@H]1CC[C@]21CO1
Reaction time: 3 h
Yield: 75.3 %

Procedure:
To a solution of compound 45 (45 mg, 0.16 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (202 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water was added (20 mL) and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 30% EtOAc in hexanes) to give compound 46 (35 mg, 75%) as a white solid: mp 165-167° C.; [α]D25 +20.0 (c 0.12, CHCl3); 1H NMR (CDCl3) δ 4.08 (s, 1H), 2.90 (d, J=15.2 Hz, 1H), 2.60 (d, J=15.2 Hz, 1H), 0.87 (s, 3H); 13C NMR (CDCl3) δ 70.5, 66.5, 53.6, 48.3, 47.2, 47.0, 42.1, 40.4, 40.2, 37.9, 36.2, 34.2, 34.0, 32.8, 29.0, 28.8, 25.8, 23.3, 14.3; IR νmax 3418, 1443, 1378, 851 cm−1. MS (FAB) for [C19H30O2]+: 290.2246. Found: 290.2243.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C:2]1=[O:5].C([O-])([O-])=O.[K+].[K+].[C@@H]1(N)CCCC[C@H]1N.Br[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>[Cu]I.O1CCOCC1>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([N:1]2[CH2:4][CH2:3][C:2]2=[O:5])=[CH:22][CH:23]=1
Reactant: O=C1CCN1
Reactant: COc1ccc(Br)cc1
Agent: [Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccc(N2CCC2=O)cc1
Temperature: 110 °C
Reaction time: 23 h
Yield: 59.4 %

Procedure:
An oven-dried resealable Schlenk tube was charged with CuI (6.0 mg, 0.0315 mmol, 1.0 mol %), 2-azetidinone (300 mg, 4.22 mmol), K2CO3 (850 mg, 6.15 mmol), evacuated and backfilled with argon. trans-1,2-Cyclohexanediamine (40 μL, 0.333 mmol, 11 mol %), 4-bromoanisole (0.38 mL, 3.04 mmol) and dioxane (0.50 mL) were added under argon. The Schlenk tube was sealed and the reaction mixture was stirred magnetically at 110° C. for 23 h. The resulting suspension was cooled to room temperature and filtered through a 0.5×1 cm pad of silica gel eluting with 10 mL of ethyl acetate. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel (2×20 cm; hexane-ethyl acetate 1:1; 20 mL fractions). Fractions 10–22 provided 320 mg (59% yield) of the product as white crystals. 1H NMR (400 MHz, CDCl3): δ 7.35–7.29 (m, 2H), 6.91–6.86 (m, 2H), 3.81 (s, 3H), 3.60 (t, J=4.4 Hz, 2H), 3.11 (t, J=4.4 Hz, 2H).
Reaction SMILES: C([Si]([O:8][C:9]1[CH:14]=[C:13]([O:15][Si](C(C)(C)C)(C)C)[CH:12]=[CH:11][C:10]=1[CH:23]1[CH2:28][CH2:27][C:26](=[CH2:29])[CH2:25][CH2:24]1)(C)C)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:29]=[C:26]1[CH2:27][CH2:28][CH:23]([C:10]2[CH:11]=[CH:12][C:13]([OH:15])=[CH:14][C:9]=2[OH:8])[CH2:24][CH2:25]1
Reactant: C=C1CCC(c2ccc(O[Si](C)(C)C(C)(C)C)cc2O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=C1CCC(c2ccc(O)cc2O)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90 %

Procedure:
To a round bottomed flask was added tert-butyl[5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy]dimethylsilane (40 mg), tetrahydrofuran (2 ml) and tetrabutylammonium fluoride (281 μl, 1.0M in tetrahydrofuran), and the mixture stirred at room temperature for 15 hr. The solvent was removed in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml), and the combined organic phases were washed with brine (20 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification via flash chromatography (SiO2, ethyl acetate/petroleum ether 2:3 v/v) furnished the title compound (17 mg, 90%) as a white solid. δH (CD3OD): 1.42-1.53 (2H, m), 1.90-1.99 (2H, m), 2.19-2.29 (2H, m), 2.39-2.47 (2H, m), 3.02 (1H, tt), 4.67 (2H, s), 6.28 (1H, dd), 6.31 (1H, d), 6.89 (1H, d); m/z (ES+) 205 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[CH2:5][C@:6]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[NH2:7].[O-:16][C:17]#[N:18].[Na+]>C(O)(=O)C.O>[NH2:18][C:17]([NH:7][C@@:6]([CH3:12])([C:8]([O:10][CH3:11])=[O:9])[CH2:5][C:4]1[CH:13]=[CH:14][CH:15]=[C:2]([I:1])[CH:3]=1)=[O:16]
Reactant: N#C[O-]
Reactant: COC(=O)[C@](C)(N)Cc1cccc(I)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)[C@@](C)(Cc1cccc(I)c1)NC(N)=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 99 %

Procedure:
A mixture of methyl 3-iodo-α-methyl-D-phenylalaninate (0.73 g) in acetic acid (3 ml) and water (1 ml) was treated with sodium cyanate (0.4 g) and stirred for 2 days at 20° C. The solvents were removed under reduced pressure and the residue was diluted with EtOAc. The solution was washed with water, brine, dried (MgSO4) and evaporated to give the title compound (0.82 g) LCMS RT=2.74 min.
Reaction SMILES: O[CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5].CC[N:24](CC)CC.C(Cl)Cl.CS(Cl)(=O)=O>O.CO.C(Cl)(Cl)Cl>[NH2:24][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([NH:18][C:19](=[O:21])[CH3:20])[S:16][CH:17]=2)=[CH:9][CH:8]=1)(=[O:6])=[O:5]
Reactant: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)CCO)cc2)cs1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1nc(-c2ccc(S(=O)(=O)CCN)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N-(4-{4-[(2-Hydroxyethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamide (200 mg), Et3N (0.102 ml) and CH2Cl2 (4 ml) were combined under N2 atmosphere, and then MsCl (0.05 ml) was added to the suspension at 0° C. The reaction mixture was stirred at r.t. for 2 hours. MeOH/CHCl3 and water were added to the mixture, and the mixture was extracted. The organic layer was washed with brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residual solid (221.6 mg) was suspended in CH3CN (10 ml), and then 28% ammonia solution (0.5 ml) was added to the suspension at 0° C. The reaction mixture was stirred at r.t. for 15 hours, and concentrated in vacuo. The residue was purified by flash column chromatography over silica gel with [MeOH/CHCl3 (1:30), then NH4OH/MeOH/CHCl3 (1:10:60)] as an eluent, and triturated with EtOH/ethyl ether to give N-(4-{4-[(2-aminoethyl)sulfonyl]phenyl}-1,3-thiazol-2-yl)acetamide (60.4 mg) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C>>[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1
Reactant: COc1ccc(Br)cn1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cn1
Temperature: -75.0999984741211 °C
Yield: 88 %

Procedure:
5-Bromo-2-methoxypyridine (152 g) was dissolved in tetrahydrofuran anhydride (1520 mL) under stirring in nitrogen atmosphere, followed by cooling to −75.1° C. as bulk temperature. Under cooling and stirring, 380 mL of a 2.46 mol/L butyl lithium solution was added dropwise thereinto, followed by the dropwise addition of 192 mL of trimethoxyborane. The cooling bath was removed 30 minutes after completion of the dropwise addition, and the mixture was stirred at room temperature overnight. On the next day, 1.5 L of a 2 mol/L aqueous solution of hydrochloric acid, was added thereto, followed by stirring for 1.5 hours. Then, it was neutralized with 460 mL of a 5 mol/L aqueous solution of sodium hydroxide. It was then extracted with 1 L of ethyl acetate, and the resulting aqueous layer was extracted again with 1 L of ethyl acetate. The combined organic layer was washed twice with 1 L of 10% saline water, dried over anhydrous magnesium sulfate, and then evaporated, to give 105 g (88%) of the title compound as a slightly yellowish white solid.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Cl:19][C:20]1[S:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[S:24][C:23]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:18])[N:10]([CH3:17])[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: OB(O)c1ccc(Cl)s1
Reactant: CN(C(=O)Oc1ccc(I)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(-c2ccc(Cl)s2)cc1)c1ccccc1

Procedure:
The title compound was prepared from methyl-phenyl-carbamic acid 4-iodo-phenyl ester and 5-chloro-2-thiopheneboronic acid. The crude product was purified by flash chromatography (Quad flash 12, EtOAc-heptane 1:9) (53%, pink crystals).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.[Mg]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]3[CH2:15][CH2:14][CH2:13][CH:7]3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(F)ccc2c2c1CCC2
Agent: [Mg]
Product: O=C1Nc2cc(F)ccc2C2CCCC12
Yield: 16.9 %

Procedure:
7-Fluoro-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (1.0 g, 4.9 mmol) and magnesium (1.2 g, 49.2 mmol) are reacted to form 170 mg (17%) of product analogously to Example 7.
Reaction SMILES: Cl[C:2]1[C:11]([CH3:12])=[C:10]([Cl:13])[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)(C)C>[Cl:13][C:10]1[C:9]2[C:4](=[CH:5][C:6]([F:15])=[CH:7][C:8]=2[F:14])[N:3]=[C:2]([N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)[C:11]=1[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1c(Cl)nc2cc(F)cc(F)c2c1Cl
Solvent: CC(C)O
Product: Cc1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2cc(F)cc(F)c2c1Cl

Procedure:
Essentially prepared according to Procedure G using 2,4-dichloro-5,7-difluoro-3-methylquinoline (610.0 mg, 2.50 mmol) and tert-butyl piperazine-1-carboxylate in isopropanol to give tert-butyl 4-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)-piperazine-1-carboxylate. Mass Spectrum (ESI) m/e=398.2 (M+1).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16](C=O)[CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8].[OH-].[K+]>CCO>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14][CH2:13]2)(=[O:9])=[O:8]
Reactant: O=CN1CCCc2cc(S(=O)(=O)Nc3nccs3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(Nc1nccs1)c1ccc2c(c1)CCCN2
Yield: 100 %

Procedure:
A solution of 1-Formyl-1,2,3,4-tetrahydroquinoline-6-sulfonic acid thiazol-2-ylamide (0.50 g, 1.6 mmol) and KOH (0.75 g, 13.4 mmol) in EtOH (5.0 mL) was stirred at room temperature for 1 h. The formed precipitate was filtered and washed with 1:1-EtOH:ET2O to obtain the desired amine (480 mg, 1.6 mmol, 100% yield) as a white solid. LC/MS (10-99%) M/Z: M+1 obs=296.3; tR=1.90 min.
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH2:8][C:4]=2[C:3]([C:9]#[N:10])=[N:2]1.Br[CH2:12][C:13]1[C:18]([F:19])=[CH:17][C:16]([O:20][CH2:21][CH3:22])=[CH:15][C:14]=1[F:23].C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>CN(C=O)C.O>[CH2:21]([O:20][C:16]1[CH:15]=[C:14]([F:23])[C:13]([CH2:12][N:1]2[C:5]3[CH2:6][CH2:7][CH2:8][C:4]=3[C:3]([C:9]#[N:10])=[N:2]2)=[C:18]([F:19])[CH:17]=1)[CH3:22]
Reactant: N#Cc1n[nH]c2c1CCC2
Reactant: CCOc1cc(F)c(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: CCOc1cc(F)c(Cn2nc(C#N)c3c2CCC3)c(F)c1
Temperature: 25 °C

Procedure:
3.40 g of 1,4,5,6-tetrahydrocyclopenta[c]pyrazole-3-carbonitrile (CAS-RN 851776-29-9) (25.5 mmol, 1.00 eq) were dissolved in 35 mL dry DMF under nitrogen atmosphere. 7.05 g 2-(bromomethyl)-5-ethoxy-1,3-difluorobenzene (28.1 mmol, 1.10 eq.) and 9.98 g cesiumcarbonate (30.1 mmol, 1.20 eq.) were added and stirred over night at rt. DCM and water were added, the aqueous phase was washed twice with DCM, the organic phase was washed with brine and was dried with magnesiumsulfate, was concentrated in vacuo and purified by flash chromatography (hexane/tert-butyl methyl ether-gradient with hexane 100-70%) to provide 1.07 g (3.45 mmol, 14%) of the analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2.[CH3:16][O:17]C(Cl)Cl>ClCCl.Cl[Ti](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([CH:16]=[O:17])=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]2[C:10]=1[CH2:9][C:8]([CH2:12][CH3:13])([CH3:11])[CH2:7]2
Reactant: COC(Cl)Cl
Reactant: CCC1(C)Cc2c(Cl)cc(C)c(C)c2C1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CCC1(C)Cc2c(C)c(C)c(C=O)c(Cl)c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82 %

Procedure:
To a solution of 9.98 g of the 7-chloro-2-ethyl-2,4,5-trimethylindane in 100 ml of dry dichloromethane was continuously added 6.2 ml of α,α-dichloromethyl methyl ether and 7.5 ml of TiCl4 at 0° C. The reaction mixture was stirred at room temperature for 2 hours, quenched with 100 ml of water, and separated the organic layer. The aqueous layer was extracted with dichloromethane. The combined organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica-gel column chromatography to afford 9.23 g of the title compound as yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].[F:34][C:35]([F:56])([F:55])[O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[NH:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1.C(N(CC)CC)C.[I-].[Na+]>C(#N)C>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([N:29]2[CH:33]=[N:32][N:31]=[N:30]2)=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:52]2[CH2:53][CH2:54][CH:49]([NH:48][C:40]3[N:39]([CH2:38][CH2:37][O:36][C:35]([F:56])([F:34])[F:55])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:50][CH2:51]2)([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: FC(F)(F)OCCn1c(NC2CCNCC2)nc2ccccc21
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCC(Nc3nc4ccccc4n3CCOC(F)(F)F)CC2)(c2ccccc2)C1
Reaction time: 48 h

Procedure:
Combine 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.86 g, 1.83 mmol), (1-(2-(trifluoromethoxy)ethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydrochlorici acid salt (1.66 mmol), triethylamine (1.0 mL, 7.2 mmol), and sodium iodide (0.31 g) in acetonitrile (24 mL). Heat to reflux. After 48 hours, evaporate in vacuo to give a residue. Partition the residue between dichloromethane and a saturated aqueous sodium, bicarbonate solution. Separate the layers and extract the organic layer with a saturated aqueous sodium bicarbonate solution and then brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([O:13][C:14]([F:15])([F:16])[F:17])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(OC(F)(F)F)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(OC(F)(F)F)cc1C(=O)O
Yield: 97.7 %

Procedure:
To a solution of 2-nitro-5-trifluoromethoxybenzoic acid (56.8 g, 0.23 mol; see step (i) above) in EtOH (1000 mL) was added 10% Pd/C (5.7 g). The resulting solution was flushed with H2 for 5 h, filtered through Celite® and concentrated in vacuo to give the crude sub-title compound (49.7 g, 98%) as a solid that was used in the next step without further purification.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[H][H]>CO.[Pd]>[Cl-:2].[C:6]1([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH3:32])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH2+:14]3)[CH2:12][CH2:11][CH2:10]2)[CH:5]=[CH:4][CH:3]=[CH:8][CH:7]=1
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)[NH2+]CC2
Reactant: [H][H]
Agent: [Pd]
Agent: [Cl-]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccccc3)CCC1)[NH2+]CC2

Procedure:
1-(1-(4-Chlorophenyl)cyclobutyl)-7-(2-(propylsulfonamido)ethoxy)-1,2,3,4-tetrahydroisoquinolinium chloride (187 mg, 0.374 mmol, example 4), triethylamine (91 mg, 0.897 mmol), Pd/C (11.95 mg, 0.011 mmol) were suspended in dry MeOH (5 ml) and treated with hydrogen gas at ambient pressure for 14 h. The solvent was removed and the residue was purified by column chromatography using silica gel dichloromethane/methanol (97:3→95:5) as the eluent. The product was transferred into the hydrochloride with isopropylether and HCl dissolved in isopropanol (6%). The product was obtained as a white powder (68.0 mg, 0.146 mmol, 39%.)
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].Cl.[F:9][C:10]([F:25])([S:21]([O-:24])(=[O:23])=[O:22])[C:11]([F:20])([F:19])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[Na+].ClCCl>O.C(OCC)C>[F:25][C:10]([F:9])([S:21]([O-:24])(=[O:23])=[O:22])[C:11]([F:19])([F:20])[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14].[CH2:1]([NH+:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=S(=O)([O-])C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: O
Product: CC[NH+](CC)CC

Procedure:
Triethylamine was dissolved in cold water, and hydrochloric acid was added thereto to adjust the pH of the reaction liquid to fall within a range of 1 to 3. Then sodium perfluorobutylsulfonate and dichloromethane were added thereto and stirred. The separated organic layer was washed with water, and dichloromethane was removed under reduced pressure from the washed organic layer. To the residue thus obtained, diethyl ether was added for recrystallization. The resultant was filtrated and dried to obtain a desired product at a yield of 75%. The structure of the obtained product was identified using 1H-NMR, IR and TOFMS spectra.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C([Br:15])C=C.CCOC(C)=O>CC#N.[Cl-].[Na+].O>[Br:15][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1
Reactant: C=CCBr
Reactant: OCCCc1cccc(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Clc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 3-(3-chloro-phenyl)-propan-1-ol (12.54 g, 73.6 mmol) and N,N′-carbonyl diimidazole (13.12 g, 81 mmol) in CH3CN was stirred at room temperature for 1 h. Allyl bromide (53.43 g, 442 mmol) was added and the reaction was heated at reflux for 24 h. The reaction was cooled to room temperature and brine and EtOAc were added. The aqueous solution was extracted with EtOAc and the organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography provided the title compound in about 85% yield. 1H NMR (400 MHz, CDCl3) δ 7.30-7.09 (m, 4H), 3.38 (t, 2H), 2.76 (t, 2H), 2.15 (t, 2H).