Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1.C([Mg]Br)C.[CH2:30]([Sn:34](Cl)([CH2:39][CH2:40][CH2:41][CH3:42])[CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:39]([Sn:34]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:35][CH2:36][CH2:37][CH3:38])[C:2]1[N:3]=[CH:4][N:5]([C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CC[Mg]Br
Solvent: ClCCl
Product: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To 4-iodo-1-triphenylmethyl-1H-imidazole (Preparation 72, 0.44 g, 0.10 mmol) in dichloromethane (8.0 ml) at room temperature was added slowly ethyl magnesium bromide (3.0 M in diethyl ether, 0.35 ml, 1.0 mmol). After 30 min, tributyltin chloride (0.3 ml, 1.1 immol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 ml) and the product was extracted with dichloromethane (3×10 ml). The combined organic layers were dried (Na2SO4) and concentrated inl vacuo. The residue was purified by flash chromatography on silica gel eluting with hexane:ethyl acetate (10:1 and then 5:1) to give the title compound (59 mg, 98%).
Reaction SMILES: C(Cl)Cl.[C:4]([N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH2:10][CH2:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)#[N:5].BrN1C(=[O:27])CCC1=O>O>[C:4]([N:6]1[C:7]2[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=2[CH:9]([OH:27])[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]1=2)#[N:5]
Reactant: N#CN1c2ccccc2CCc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: O
Product: N#CN1c2ccccc2CC(O)c2ccccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
150 ml of CH2Cl2, 25 g of (I) and 21 g of N-bromosuccinimide are loaded under nitrogen in a 500 ml pyrex round-bottom flask, and irradiated from the outside with a 300 watt halogen lamp, refluxing for 2 hours. 150 ml of water are added. 80 ml of CH2Cl2 are distilled off, 150 ml of toluene and 5 g of PEG 6000 are added while distilling off CH2Cl2 at inner temperature of 85-90° C. The mixture is left for 3 hours at said temperature, water is removed at 60° C., the mixture is washed with 2×50 ml of water and 30-40 ml of toluene are distilled off at 40 mm/Hg. The mixture is cooled at 0° C. for 2-3 hours, filtered, washed with 20 ml of toluene at 0° C. and air-dried at 60° C., to obtain 20.4 g of (VI) m.p. 110-111° C., with good purity. From mother liquors a further 1.8 g are recovered (overall yield 82%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([CH3:12])[C:7](=O)[CH2:6][CH2:5]2.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:25]([NH2:29])(=[O:28])[CH:26]=[CH2:27]>C(OCC)(=O)C.O>[F:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]3([CH3:12])[C:7](=[CH:6][CH2:5][C:4]=2[CH:3]=1)[NH:29][C:25](=[O:28])[CH2:26][CH2:27]3
Reactant: C=CC(N)=O
Reactant: CC1C(=O)CCc2cc(F)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Product: CC12CCC(=O)NC1=CCc1cc(F)ccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To 6-fluoro-1-methyl-2-tetralone (7.06 g; 39.6 mmol) in a round bottomed flask was added p-toluenesulfonic acid (1.23 g; 6.5 mmol) and the mixture was stirred at room temperature under nitrogen for 15 minutes. Acrylamide (5.62 g; 79.2 mmol) was added and the reaction mixture was heated to 88°-90° C. under nitrogen for three days. The mixture was diluted with ethyl acetate and water and stirred at room temperature for 1 hour. The resulting layers were separated. The organic layer was washed three times with water, dried over MgSO4 and concentrated to a viscous oil. The crude product was crystallized from ethyl acetate to afford 1.59 g (17% yield) of the subtitle compound. Melting point 202° C.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@@H:13]1[CH2:15][O:14]1.[F:16][C:17]([F:23])([F:22])[C:18]([OH:21])([CH3:20])[CH3:19].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[CH:13]([O:21][C:18]([CH3:20])([CH3:19])[C:17]([F:23])([F:22])[F:16])[CH2:15][OH:14]
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H]1CO1
Reactant: CC(C)(O)C(F)(F)F
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (R)-2-(1-chloro-3-methylnaphthalen-2-yl)oxirane (340 mg, 1.56 mmol) and 2-trifluoromethyl-2-propanol (4.3 mL, 38.97 mmol) in CH2Cl2 (4.3 mL), boron trifluoride diethyl etherate (1.9 mL, 15.60 mmol) was added at 0° C. The reaction mixture was stirred for 16 h at 0° C. and allowed to warm to room temperature overnight. The mixture was quenched with saturated aqueous NaHCO3, and then diluted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol. 1H-NMR: 400 MHz, (CDCl3) δ 8.27 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.57-7.49 (m, 3H), 5.90 (dd, J=9.6, 4.4 Hz, 1H), 3.98 (t, J=11.2 Hz, 1H), 3.66 (dd, J=12.0, 4.0 Hz, 1H), 2.69 (s, 3H), 2.18 (br s, 1H), 1.45 (s, 3H), 1.19 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S(O[CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])(=O)(=O)C>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:31][CH2:32][O:33][CH:34]([CH3:36])[CH3:35])[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OCCOS(C)(=O)=O
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OCCn1c(N2CCCN(C(=O)OC(C)(C)C)CC2)nc2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Combine 1-(t-butoxycarbonyl)-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.54 g, 1.71 mmol), and sodium hydride (0.87 g, 3.48 mmol) in dimethylformamide (10 mL). After 30 minutes, add 2-(isopropoxy)ethyl mesylate (0.51 g, 5.5 mmol). Heat to 80° C. After 2 hours, cool the reaction mixture to ambient temperature and partition between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-(t-butoxycarbonyl)-4-(1-(2-(isopropoxy)ethyl)-1H-benzimidazol-2-yl)[1,4]diazepane.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15](Br)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6].[OH:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.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>[CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:25]2[CH:26]=[CH:27][C:22]([CH2:21][OH:20])=[CH:23][CH:24]=2)=[CH:14][CH:13]=1)(=[O:11])=[O:10])[CH:5]([CH3:7])[CH3:6]
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Reactant: OCc1ccc(B(O)O)cc1
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: COCCOC
Product: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(CO)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
Step 1B [Intermediate 2: 2-(4-Bromo-benzenesulfonylamino)-3-methyl-butyric acid methyl ester (3.4 g, 9.71 mmol), 4-hydroxymethyl phenyl boronic acid (1.48 g, 9.71 mmol, 1 equiv.), Pd(PPh3)4 (561 mg, 0.48 mmol, 0.05 equiv.) were dissolved in ethylene glycol dimethyl ether (90 mL) under N2 atmosphere and stirred at room temperature for 30 min. Then K2CO3 (2.68 g, 19.4 mmol, 2 equiv.) in H2O (30 mL) was introduced to the reaction mixture and heat to reflux overnight. After TLC confirmation of reaction completion, solvent was removed by rotovap, residue partitioned between EtOAc and brine, organic layer dried over MgSO4, solvent removed, crude residue was triturated with EtOAc to give 2-(4′-Hydroxymethyl-biphenyl-4-sulfonylamino)-3-methyl-butyric acid methyl ester in 67% yield (2.46 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[OH-].[Na+].[C:12](O)(=[O:14])[CH3:13]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in acetic acid (50 ml) and acetic (25.0 g, anhydride (250 ml) was heated at reflux for two hours. The reaction mixture was then cooled and poured into water (750 ml) with stirring. After one hour, the solution was adjusted to pH 10 with 50% sodium hydroxide and the precipitate was filtered, washed with water and dried to give 26.5 g (85%) of the title product as a white flaky solid. mp 175-176° C. 1H NMR (CDCl3): δ=8.29 (d, 1 H); 8.12 (d, 1 H); 7.96 (br, 1 H); 7.78 (d of d, 1 H); 2.19 (s, 3 H). MS (EI): m/z=214, 216 (M+, Br isotopes).
Reaction SMILES: C([C:5]1[N:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:7][N:6]=1)(C)(C)C.[C:20]1(C2CC(C3C=CC=CC=3)=C(C3C=CC=CC=3)C=2C2C=CC=CC=2)C=CC=C[CH:21]=1>CN(C=O)C.C[Rh](Cl)(C)(C)(C)(C)C1C=CC=C1.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:9]1[C:8]2[C:11]3[N:15]([CH:20]=[CH:21][C:7]=2[N:6]=[CH:5][N:10]=1)[C:14]1[C:13](=[CH:19][CH:18]=[CH:17][CH:16]=1)[N:12]=3
Reactant: c1ccc(C2=C(c3ccccc3)C(c3ccccc3)=C(c3ccccc3)C2)cc1
Reactant: CC(C)(C)c1ncc(-c2nc3ccccc3[nH]2)cn1
Agent: C[Rh](C)(C)(C)(C)(Cl)C1C=CC=C1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)nc1c3cncnc3ccn21
Temperature: 100 °C
Reaction time: 18 h

Procedure:
Preparation analogous to N. Umeda et al., Angew. Chem. Int. Ed. 2008, 47, 4019: a solution of 25.2 g (100 mmol) of 2-(2-tert-butylpyrimidin-5-yl)benzimidazole (S48) and 110 mmol of the alkyne in 400 ml of DMF is initially introduced in a pressure Schlenk tube, 1.5 g (4 mmol) of tetraphenylcyclopentadiene, 547 mg (1 mmol) of pentamethylcyclopentadienyl-rhodium chloride dimer and 21.0 (105 mmol) of copper(II) acetate monohydrate are added, and the mixture is stirred in the sealed tube at 100° C. for 18 h. After cooling, the DMF is removed in vacuo, the residue is taken up in 1000 ml of THF and filtered through a short silica-gel column. After removal of the THF in vacuo, the oily residue is taken up in hot methanol (about 75 ml). After cooling, the crystals formed are filtered off with suction and recrystallised again from methanol with addition of a little ethyl acetate. The solids obtained in this way are freed from low-boiling components and non-volatile secondary components by sublimation (p about 1×10−5 mbar, T about 180-220° C.). Purity according to 1H-NMR typically >99.5%.
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:13][OH:14]>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([CH3:21])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:13][O:14][CH:6]1[CH2:5][CH2:4][CH2:3][CH2:2][O:1]1
Reactant: CC(CO)(CCCCBr)c1ccccc1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(CCCCBr)(COC1CCCCO1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
Under N2 atmosphere and cooling with an ice bath, 3,4-dihydro-2H-pyran (33.86 g, 0.40 mol) was added dropwise to a stirred solution of 206d (88.0 g, 0.32 mol) and p-toluenesulfonic acid hydrate (0.05 g, 0.03 mmol) in CH2Cl2 (700 mL). After the addition, the reaction mixture was allowed to warm to room temperature and stirred overnight. The solution was filtered through aluminum oxide (160 g) and the aluminum oxide was washed with CH2Cl2 (800 mL). The filtrate was concentrated in vacuo and purified by flash chromatography on silica gel (hexanes/ethyl acetate=10/1) to give 207d (80.0 g, 70%) as an oil. 1H NMR (CDCl3): δ 7.40-7.14 (m 10H), 4.53 (t, 1H, J=3.4), 4.49 (t, 1H, J=3.4), 3.82 (d, 1H, J=9.4), 3.81 (t, 1H, J=9.4), 3.76-3.60 (m, 2H), 3.44 (m, 2H), 3.36 (d, 2H, J=9.4), 3.33 (t, 4H, J=7.0), 1.90-1.42 (m, 14H), 1.79 (t, 4H, J=6.8), 1.37 (s, 6H), 1.34-1.10 (m, 6H). 13C NMR (CDCl3=77.0 ppm): δ 145.67, 127.91, 127.91, 126.39, 126.37, 125.7, 98.95, 98.81, 76.11, 76.07, 62.78, 61.77, 61.66, 41.88, 41.78, 37.93, 37.75, 33.50, 33.44, 30.59, 30.44, 25.41, 25.37, 22.77, 22.71, 22.62, 19.65, 19.23, 19.15. HRMS (LSIMS, nba): Calcd for C15H28BrO2 (MH+): 355.1272, found: 355.1272.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[O:10][C:9]=2[C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].CN(C=O)C.Cl[CH2:34][C:35]1[C:40]([CH3:41])=[CH:39][C:38]([CH3:42])=[CH:37][N:36]=1>O>[CH3:41][C:40]1[C:35]([CH2:34][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:12](=[O:13])[C:11]([CH3:14])([CH3:15])[O:10][C:9]=3[C:16]3[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=3)=[CH:6][CH:7]=2)=[N:36][CH:37]=[C:38]([CH3:42])[CH:39]=1
Reactant: CC1(C)OC(c2ccc(C#N)cc2)=C(c2ccc(O)cc2)C1=O
Reactant: Cc1cnc(CCl)c(C)c1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cnc(COc2ccc(C3=C(c4ccc(C#N)cc4)OC(C)(C)C3=O)cc2)c(C)c1
Temperature: 80 °C

Procedure:
4-(3-(4-Hydroxyphenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl)benzonitrile (1.5 g, 4.9 mmol) was added to a mixture of carbonate (6.3 g, 19.6 mmol) and DMF (100 mL) at RT under nitrogen. The reaction mixture was stirred at RT for 30 min upon which 2-(chloromethyl)-3,5-dimethylpyridine (1.14 g, 7.3 mmol) was added. The mixture was heated at 80° C. for 4 h (the reaction was monitored by TLC). The reaction mixture was diluted with water and extracted with EtOAc; the combined organics were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography using 22% ethyl acetate in n-hexane and silica gel (230-400 mesh) to afford 4-(3-(4-((3,5-dimethylpyridin-2-yl)methoxy)phenyl)-5,5-dimethyl-4-oxo-4,5-dihydrofuran-2-yl) (0.70 g, 35%) as yellow solid. 1H NMR, 200 MHz, CDCl3: δ 7.45-6.8 (Ar, 11H), 4.9 (d, 1H), 4.6 (d, 1H), 3.75 (s, 3H), 3.2 (d, 2H) 3.1 (q, 1H), 2.5 (q, 1H) 0.95 (t, 6H). MS: [M+H]+: m/z=425.2. HPLC: (96.3%, Condition-A).
Reaction SMILES: O=[C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:3][C:4](OCC)=[O:5].[NH2:15][NH2:16]>CCO>[O:5]=[C:4]1[NH:16][NH:15][C:2]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3]1
Reactant: NN
Reactant: CCOC(=O)CC(=O)CC(=O)OCC
Solvent: CCO
Product: CCOC(=O)Cc1cc(=O)[nH][nH]1
Temperature: 80 °C
Reaction time: 3 h
Yield: 44.6 %

Procedure:
To a solution of diethyl 3-oxopentanedioate (26.0 g, 129 mmol) in EtOH (250 mL) was added hydrazine (4.38 g, 129 mmol) at room temperature, and the mixture was stirred at 80° C. for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from diethyl ether-hexane to give the title compound as a white powder (9.79 g, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:7]1([CH2:11][CH2:10][NH:9][CH2:8]1)[CH2:6][CH:5]2[OH:15].C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:23][CH2:24][CH2:25][C:26]1([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)OCC[O:27]1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[C:7]1([CH2:11][CH2:10][N:9]([CH2:23][CH2:24][CH2:25][C:26]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[O:27])[CH2:8]1)[CH2:6][CH:5]2[OH:15]
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Reactant: OC1CC2(CCNC2)c2ccc(Cl)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(CCCN1CCC2(CC(O)c3cc(Cl)ccc32)C1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
15 g of 5-chlorospiro[indane-1,3'-pyrrolidin]-3-ol (mixture of diastereoismers of 50 % of the 1RS,3SR and 50 % of the 1RS,3RS isomer) are dissolved in 200 cc of dimethyl formamide and heated to 100° for 6 hours together with 18 g of sodium carbonate and 23 g of 2-(3-chloropropyl)-2-(p-fluorophenyl)-1,3-dioxolane. Filtration is subsequently effected, the filter residue is washed with chloroform and the organic phase is concentrated. The resulting yellow oil is taken up in 300 cc of chloroform and stirred at room temperature for 1 hour with 250 cc of 2 N hydrochloric acid. The reaction mixture is subsequently made alkaline with caustic soda solution while cooling, is extracted with chloroform and the chloroform phase is concentrated. The crude title compound is obtained together with the 1RS,3SR isomer as brown oil. After adding a solution of hydrogen chloride in ethanol, the 1RS,3RS form crystallizes alone. The hydrochloride form of the pure title compound has a M.P. of 203°-206° after recrystallization from ethanol/ether.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.O.Cl.[NH:14]1[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([C:6]([C:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH:16]=3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2cc[nH]c2c1Cl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: Clc1ccc2c(C3=CCNCC3)c[nH]c2c1Cl

Procedure:
The title compound was prepared in a fashion similar to that described in Preparation 30 from 6,7-dichloroindole (1.4 g, 7.5 mmol) and 4-piperidone hydrochloride hydrate (2.3 g, 15 mmol). The product was isolated as a white solid. Yield 1.8 g (89%). mp 252°-254° C. FDMS m/e=268 (M+ of free base).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([NH:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)[CH2:10][CH:9]1[C:29]([OH:31])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[F:54][C:55]([F:69])([F:68])[C:56]1[CH:57]=[C:58]([N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)[CH:59]=[CH:60][CH:61]=1>ClCCl.C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:16]=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=[C:19]([C:21]([F:23])([F:22])[F:24])[CH:20]=2)[CH2:10][C@H:9]1[C:29]([N:65]1[CH2:64][CH2:63][N:62]([C:58]2[CH:59]=[CH:60][CH:61]=[C:56]([C:55]([F:68])([F:69])[F:54])[CH:57]=2)[CH2:67][CH2:66]1)=[O:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: O=C(O)C1CC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C([C@@H]1C[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CN1Cc1ccccc1)N1CCN(c2cccc(C(F)(F)F)c2)CC1
Reaction time: 8 h
Yield: 10.6 %

Procedure:
The mixture of 1-benzyl-4-(3,5-bis-trifluoromethyl-benzylamino)-pyrrolidine-2-carboxylic acid (65 mg, 0.146 mmol), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (54.5.0 mg, 0.292 mmol), N-hydroxybenzotriazole (20.7 mg, 0.146 mmol), and 1-(3-trifluoromethyl-phenyl)-piperazine (29.67 mg, 0.219 mmol), triethylamine (0.08 ml) in dry dichloromethane (2 mL) was stirred overnight, and then concentrated. The residue was purified by preparative HPLC on reversed phase eluting with an acetonitrile/water [0.1% aq NH3 (25%)] gradient to afford the title compound (10.2 mg, 10.6%) as a light yellow oil. MS m/e=659.4 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH2:29][CH3:30])[N:3]=1.[NH2:31][C:32]1[CH:33]=[CH:34][C:35]([C@@H:43]2[CH2:48][CH2:47][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:45][CH2:44]2)=[C:36]2[C:40]=1[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]2>>[CH2:20]([O:19][P:18]([CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:31][C:32]3[CH:33]=[CH:34][C:35]([C@@H:43]4[CH2:44][CH2:45][C@H:46]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:47][CH2:48]4)=[C:36]4[C:40]=3[C:39](=[O:41])[N:38]([CH3:42])[CH2:37]4)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[C:14]([O:28][CH2:29][CH3:30])[CH:15]=1)([O:22][CH2:23][CH3:24])=[O:25])[CH3:21]
Reactant: CCOC(=O)[C@H]1CC[C@@H](c2ccc(N)c3c2CN(C)C3=O)CC1
Reactant: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Cl)n1
Product: CCOc1cc(CP(=O)(OCC)OCC)ccc1Nc1ncc(C(F)(F)F)c(Nc2ccc([C@H]3CC[C@@H](C(=O)OCC)CC3)c3c2C(=O)N(C)C3)n1

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-ethoxybenzyl)phosphonate (Compound 244A 123.2 mg, 0.26 mmol) and ethyl cis-4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylate (100.0 mg, 0.32 mmol). The reaction mixture was concentrated in vacuo and purified by on an ISCO CombiFlash®Rf System eluting with: 0→5% MeOH in DCM] to afford 143.3 mg (73%) of the desired product. 1H NMR (400 MHz, MeOD) δ ppm 8.44 (d, J=10.36 Hz, 1H), 8.35 (s, 1H), 7.89 (d, J=8.34 Hz, 1H), 7.24 (d, J=8.59 Hz, 1H), 7.06 (t, J=2.15 Hz, 1H), 6.92 (dt, J=8.21, 2.21 Hz, 1H), 4.52 (s, 2H), 4.26 (q, J=7.16 Hz, 2H), 4.05-4.19 (m, 6H), 3.29 (s, 2H), 3.19 (s, 3H), 2.79 (br. s., 1H), 2.63-2.73 (m, 1H), 2.30 (d, J=7.33 Hz, 2H), 1.76 (d, J=6.06 Hz, 6H), 1.42 (t, J=6.95 Hz, 3H), 1.27-1.38 (m, 9H). MS (ES+): m/z 749.30/750.31 (100/25) [MH+] HPLC: tR=1.82 min (Micromass TOF: polar—3 min).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[Li]CCCC.[C:20]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28])([O:22][CH3:23])=[O:21].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[CH2:9]([N:8]([CH2:11][CH3:12])[C:6]([C:5]1[CH:13]=[CH:14][C:2]([CH:27]([OH:28])[C:26]2[CH:25]=[C:24]([CH:31]=[CH:30][CH:29]=2)[C:20]([O:22][CH3:23])=[O:21])=[CH:3][CH:4]=1)=[O:7])[CH3:10]
Reactant: COC(=O)c1cccc(C=O)c1
Reactant: CCN(CC)C(=O)c1ccc(I)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)c1ccc(C(O)c2cccc(C(=O)OC)c2)cc1
Temperature: -78 °C
Yield: 48.8 %

Procedure:
INTERMEDIATE 5 (2.8 g, 9.0 mmol) was dissolved in TBF (100 mL) and cooled to −78° C. under nitrogen atmosphere. Then n-BuLi (8.4 mL, 1.07 M solution in hexane, 9.0 mmol) was added dropwise during 10 min at −65 to −78° C. The solution was canulated into 3-carbomethoxybenzaldehyde (1.49 g, 9.1 mmol) in toluene/THF (approx. 1:1, 50 mL) at −78° C. NH4Cl (aq.) was added after 30 min. After concentration in vacuo, extraction with EtOAc/water, drying (MgSO4) and evaporation of the organic phase, the residue was purified by chromatography on silica (0-75% EtOAc/heptane) to give INTERMEDIATE 6 (1.5 g, 49%).