Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(NC(C2C(=O)C(=NNC3C=CC(C4C=CC(NN=C5C(=O)C(C(NC6C=CC=CC=6)=O)=CC6C5=CC=CC=6)=C([Cl:55])C=4)=CC=3Cl)C3C(=CC=CC=3)C=2)=O)=CC=1.[CH3:59][N:60]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[N:61]=[CH:62][C:63]1[CH:64]=[CH:65][C:66]2[N:67]([CH2:76][CH3:77])[C:68]3[C:73]([C:74]=2[CH:75]=1)=[CH:72][CH:71]=[CH:70][CH:69]=3>>[CH3:59][N:60]([C:78]1[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=1)[N:61]=[CH:62][C:63]1[CH:64]=[CH:65][C:66]2[N:67]([CH2:76][CH2:77][Cl:55])[C:68]3[C:73]([C:74]=2[CH:75]=1)=[CH:72][CH:71]=[CH:70][CH:69]=3
Reactant: CCn1c2ccccc2c2cc(C=NN(C)c3ccccc3)ccc21
Reactant: O=C(Nc1ccccc1)C1=Cc2ccccc2C(=NNc2ccc(-c3ccc(NN=C4C(=O)C(C(=O)Nc5ccccc5)=Cc5ccccc54)c(Cl)c3)cc2Cl)C1=O
Product: CN(N=Cc1ccc2c(c1)c1ccccc1n2CCCl)c1ccccc1

Procedure:
In Example 7, instead of Chloro Diane Blue and 9-ethylcarbazole-3-carbaldehyde-1-methyl-1-phenylhydrazone represented by the formula (5), ##STR42## was employed as the charge carrier producing pigment, and 9-(β-chloroethyl)carbazole-3-carbaldehyde 1-methyl-1-phenylhydrazone represented by the formula (13) was employed as the charge transport material. ##STR43##
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[Na].[CH2:6]1[O:8][CH:7]1[CH2:9][CH2:10][CH:11]1[O:13][CH2:12]1>O>[CH2:1]([O:4][CH2:12][CH:11]1[O:13][CH:7]([CH2:6][OH:8])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: C(CC1CO1)C1CO1
Agent: [Na]
Solvent: O
Product: C=CCOCC1CCC(CO)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
100 ml of allyl alcohol (1.47 mole, Aldrich) is cooled to 5° in an ice-bath and under a nitrogen atmosphere 0.3 g of sodium (0.013 mole, washed with hexane to remove the mineral oil) is slowly added to the rapidly stirred mixture. The addition of the sodium is made at such a rate that the temperature remains below 20°. After the addition of the sodium has been completed, the mixture is allowed to stir for 1/2 hour and slowly warmed to room temperature. Slowly, with stirring 15.0 g of 1,5-hexadiene diepoxide (0.131 mole) is added to the mixture. After the addition of the diepoxide has been completed, the reaction mixture is heated at reflux for 16 hours. The mixture is then cooled to room temperature and with stirring is poured into 350 ml of water. The aqueous mixture is extracted with 2×200 ml portions of chloroform, the CHCl3 extracts are combined and dried over anhydrous sodium sulfate. The CHCl3 is removed in vacuo and the resulting yellow oil then vacuum distilled through a 10 cm vigreux distilling column. The fraction distilling at 108°-110° @ 0.5 mm is collected yielding 14.65 g (65%) of the above compound.
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].[C:10](OC(=O)C)(=[O:12])[CH3:11].[OH-].[Na+:18]>O>[Na+:18].[C:10]([N:2]([OH:1])[CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[O-:9])(=[O:12])[CH3:11]
Reactant: O=P(O)(O)CCCNO
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)N(O)CCCP(=O)([O-])O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A suspension of 3.8 g (0.02 mol) 3-(N-hydroxyamino)-propylphosphonic acid is introduced into 20 ml water and 4.51 g (0.044 mol) acetic anhydride are added drop by drop at room temperature. After the solution has been stirred for 1.5 hours at room temperature a pH of 2.5 is adjusted with 0.2 n NaOH, the solution is concentrated in the entire diaphragm pump vacuum, taken up twice in 40 ml water in each case, which are again removed by concentration and the oil is washed twice with 30 ml ether in each case, taken up in 50 ml water and a pH of 6.5 is adjusted with 1.6 g NaHCO3. After removal of volatile constituents under vacuum, 20 ml n-butanol are added to remove the residual water and are also removed under reduced pressure. The oil is boiled up twice with isopropanol, the isopropanol phase is discarded and the remaining glassy resin is pulverised with a spatula to a yellow solid (5.65 g). In order to recrystallise it, it is taken up in only a little methanol, filtered from the undissolved component and acetone is added dropwise to the filtrate. A first filtering results in 1 g product with a melting point of 175° C. Recrystallisation as described above is carried out again for further purification. (DE-A-27 33 658)
Reaction SMILES: [N+:1]([C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6])([O-])=O>C(O)C.ClCCl.[Pt](=O)=O>[NH2:1][C:4]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:5]=1[OH:6]
Reactant: O=[N+]([O-])c1c(O)cccc1O
Agent: O=[Pt]=O
Solvent: CCO
Solvent: ClCCl
Product: Nc1c(O)cccc1O
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A suspension of 2-nitroresorcinol (4.995 g) and platinum (IV) oxide (356 mg) in ethanol (90 ml) was hydrogenated, at room temperature, at 100 p.s.i. for 4 hours. The reaction mixture was filtered through celite, the filter cake washed with methanol (50 ml), and the combined filtrate evaporated in-vacuo to yield a brown solid. The solid was suspended in dichloromethane (100 ml) and evaporated to dryness to yield the title compound (3.83 g, 95%) as a brown solid.
Reaction SMILES: [N+](=[C:3]([C:8]([O:10][CH:11]([C:16]([Cl:19])([Cl:18])[Cl:17])[CH:12]=[C:13]([CH3:15])[CH3:14])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[N-]>CCCCCCCC.C(OCC)(=O)C.[Cu]>[Cl:17][C:16]([Cl:19])([Cl:18])[CH:11]1[CH:12]2[C:3]([C:4]([O:6][CH3:7])=[O:5])([C:13]2([CH3:15])[CH3:14])[C:8](=[O:9])[O:10]1
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC(C=C(C)C)C(Cl)(Cl)Cl
Agent: [Cu]
Solvent: CCCCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)C12C(=O)OC(C(Cl)(Cl)Cl)C1C2(C)C
Yield: 96 %

Procedure:
To a refluxing suspension of copper powder (6.6 g, 0.104 mole) in 320 ml of n-octane was added dropwise in one hour a solution of methyl (±)-3-methyl-1-trichloromethyl-2-butenyl diazomalonate (6.6 g, 0.02 mole, prepared as described above for the ethyl ester) in 30 ml of n-octane. The reaction mixture was heated for 21/2 hours under reflux and then filtered while hot. The n-octane was evaporated from the filtate under vacuum to produce a residue which was dissolved in ethyl acetate. The solution was washed successively with aqueous 1 N hydrochloric acid, aqueous sodium bicarbonate, and aqueous sodium chloride. After drying the solution over magnesium sulfate, the ethyl acetate was removed by evaporation, yielding methyl (±)-4-trichloromethyl-6,6-dimethyl-2-oxo-3-oxabicyclo[3.1.0]hexane-1-carboxylate (5.77 g, 96% yield) as an oil. Trituration of the oil with ether afforded the crystalline lactone; mp, 118°-120°.
Reaction SMILES: [CH2:1]([C:4]1[CH:8]=[C:7]([C:9]([OH:11])=O)[O:6][N:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C@H:37]([CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[C:57]([Cl:59])[CH:56]=[CH:55][C:54]=2[F:60])=[CH:49][CH:48]=1)[CH2:38][C@:39]([CH2:44][OH:45])([CH3:43])[C:40]([OH:42])=[O:41].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:59][C:57]1[CH:56]=[CH:55][C:54]([F:60])=[C:53]([C:50]2[CH:49]=[CH:48][C:47]([CH2:46][C@@H:37]([NH:36][C:9]([C:7]3[O:6][N:5]=[C:4]([CH2:1][CH2:2][CH3:3])[CH:8]=3)=[O:11])[CH2:38][C@:39]([CH2:44][OH:45])([CH3:43])[C:40]([OH:42])=[O:41])=[CH:52][CH:51]=2)[CH:58]=1
Reactant: C[C@@](CO)(C[C@H](N)Cc1ccc(-c2cc(Cl)ccc2F)cc1)C(=O)O
Reactant: CCCc1cc(C(=O)O)on1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N[C@H](Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@](C)(CO)C(=O)O)on1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 1.8 %

Procedure:
3-Propylisoxazole-5-carboxylic acid (9 mg, 55 μmol) and HATU (20.8 mg, 55 μmol) were combined in DMF (0.2 mL) and allowed to stand at room temperature for 10 minutes. (2S,4R)-4-Amino-5-(5′-chloro-2′-fluorobiphenyl-4-yl)-2-hydroxymethyl-2-methylpentanoic acid (20 mg, 55 μmol) in DMF and DIPEA (28.6 μL, 164 μmol) were added, and the resulting mixture was stirred for 20 minutes at room temperature. The mixture was concentrated under reduced pressure and the residue was dissolved in AcOH purified by preparative HPLC to yield the title compound (0.5 mg). MS m/z [M+H]+ calc'd for C26H28ClFN2O5, 503.17. found 504.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[N:26]2)=[CH:21][CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:30]([C:27]3[CH:28]=[CH:29][N:25]([C:22]4[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=4)[N:26]=3)=[O:31])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccn(-c2ccncc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2ccncc2)n1
Yield: 83 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.058 g, 0.307 mmol), 1-(pyridin-4-yl)-1H-pyrazole-3-carboxylic acid (0.080 g, 0.307 mmol), DIPEA (0.160 ml, 0.921 mmol), HOBt hydrate (0.071 g, 0.460 mmol) and EDCI (0.088 g, 0.460 mmol) using the method of Example 274 affording 0.110 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.19 (d, 3H), 4.36 (m, 2H), 4.49 (m, 1H), 6.90 (d, 1H), 6.94 (d, 1H), 7.85 (d, 1H), 7.90 (m, 2H), 7.94 (m, 2H), 8.02 (s, 1H), 8.38 (d, 1H), 8.69 (m, 2H), 8.75 (d, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([O:10][CH2:11][CH2:12][C:13]1[CH:22]=[CH:21][C:16]([O:17][CH2:18][CH2:19][NH2:20])=[C:15]([CH3:23])[CH:14]=1)[CH3:9].Cl[C:25]1[C:30]([Cl:31])=[C:29]([CH3:32])[N:28]=[C:27]([CH3:33])[N:26]=1>C1(C)C=CC=CC=1>[Cl:31][C:30]1[C:25]([NH:20][CH2:19][CH2:18][O:17][C:16]2[CH:21]=[CH:22][C:13]([CH2:12][CH2:11][O:10][CH2:8][CH3:9])=[CH:14][C:15]=2[CH3:23])=[N:26][C:27]([CH3:33])=[N:28][C:29]=1[CH3:32]
Reactant: CCOCCc1ccc(OCCN)c(C)c1
Reactant: Cc1nc(C)c(Cl)c(Cl)n1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOCCc1ccc(OCCNc2nc(C)nc(C)c2Cl)c(C)c1
Reaction time: 5 h
Yield: 55.8 %

Procedure:
1.0 g of triethylamine and 2.2 g of 2-[4-(2-ethoxyethyl)-2-methylphenoxy]ethylamine were added to 1.8 g of 4,5-dichloro-2,6-dimethylpyrimidine dissolved in 50 ml of toluene. The mixture was heated under reflux, whilst stirring, for 5 hours. At the end of this time, the reaction product was washed with water and dried over anhydrous sodium sulfate. Toluene was then removed by distillation under reduced pressure, and the oily product obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and etyl acetate) to isolate the product. The crystals obtained were recrystallized from hexane, to give 2.0 g of the title compound as colorless granular crystals melting at 61°-63° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13].[CH:15]([N-]C(C)C)(C)C.[Li+].IC>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([C:5]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:6]=1[Cl:13])[CH3:15]
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)Cc1cc(OC)ccc1Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)C(C)c1cc(OC)ccc1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
2-Chloro-5-methoxy-benzeneacetic acid methyl ester (994 mg) was dissolved in THF and cooled to −78° C. Lithiumdiisopropylamide (2M in THF, 3.72 mL) was added drop wise and stirring was continued for 30 minutes. Iodomethane (879 mg, 0.39 mL) was added and stirring was continued for 30 minutes. The cooling bath was removed and the reaction was allowed to warm for 45 minutes. The mixture was poured into water and extracted with ethyl acetate. The organic extract was washed with brine, dried over Na2SO4 and evaporated. The residue was purified by flash chromatography (silica gel, ethyl acetate: heptane 1:3) to give the desired compound as a yellow oil (859 mg). 1H-NMR (□, CDCl3): 7.27 (d, 1H), 6.85 (d, 1H), 6.74 (dd, 1H), 4.17 (q, 1H), 3.78 (s, 3H), 3.69 (s, 3H), 1.48 (d, 3H).
Reaction SMILES: [NH2:1][C@H:2]([CH2:13][O:14][CH:15]([F:17])[F:16])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>C(OCC)(=O)C>[CH2:6]([NH:5][C:3](=[O:4])[C@H:2]([NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[CH2:13][O:14][CH:15]([F:16])[F:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: N[C@H](COC(F)F)C(=O)NCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@H](COC(F)F)C(=O)NCc1ccccc1
Reaction time: 0.25 h
Yield: 22.3 %

Procedure:
A solution of (2R)-2-amino-N-benzyl-3-(difluoromethoxy)propanamide (113 mg, 0.46 mmol) in ethyl acetate was cooled in an ice bath. To the cooled solution was added triethylamine (139 mg, 1.38 mmol) followed by methanesulfonylchloride (63 mg, 0.55 mmol). The reaction mixture was stirred for 15 minutes and then quenched with water, extracted with ethyl acetate and washed with brine. The organic layer was dried, concentrated and triturated with diethyl ether to give the product (33 mg, 22%) as a white solid. 1H NMR (300 MHz, CDCl3): (ppm) 7.31 (m, 5H), 6.73 (br, 1H), 6.24 (t, 1H), 5.21 (d, 1H), 4.48 (d, 2H), 4.21 (m, 3H), 3.01 (s, 3H)
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([OH:24])[C:17]4[CH2:23][NH:22][CH2:21][CH2:20][C:18]=4[N:19]=3)=[CH:9][CH:8]=2)[CH:4]=[CH:5][N:6]=1.C=O.[C:27](O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH3:27][N:22]1[CH2:21][CH2:20][C:18]2[N:19]=[C:14]([NH:13][C:10]3[CH:11]=[CH:12][C:7]([N:3]4[CH:4]=[CH:5][N:6]=[C:2]4[CH3:1])=[CH:8][CH:9]=3)[N:15]=[C:16]([OH:24])[C:17]=2[CH2:23]1
Reactant: CC(=O)O
Reactant: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCNC3)cc1
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1nccn1-c1ccc(Nc2nc(O)c3c(n2)CCN(C)C3)cc1
Reaction time: 0.17 h
Yield: 345.7 %

Procedure:
A suspension of 2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (1.4 g, 4.34 mmol, Example 9c), formaldehyde (0.423 g, 5.21 mmol) and acetic acid (0.025 mL, 0.43 mmol) in MeOH (25 mL) was stirred for 10 min. Sodium cyanoborohydride (0.273 g, 4.34 mmol) was added and the reaction was stirred for an additional 10 min after which water (2 mL) was added. Solvent was evaporated and EtOAc (2 mL) was added followed by the addition of potassium carbonate solution (sat. aq., 1 mL). The solution was stirred and the formed precipitate was filtered off to give 6-methyl-2-(4-(2-methyl-1H-imidazol-1-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-ol (0.500 g, 34.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:19][C:20]1[CH:21]=[C:22]([C:26]2([CH2:32][CH2:33][N:34]3[CH:39]4[CH2:40][CH2:41][CH:35]3[CH2:36][CH:37]([N:42]3[C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=5[N:44]=[C:43]3[CH3:51])[CH2:38]4)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.ClC1C(C(N2CCC(C3C=CC=C(F)C=3)(CCN3C4CCC3CC(N3C5C=CC=CC=5N=C3C)C4)CC2)=O)=C(Cl)C=CC=1S(NC)(=O)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([N:29]1[CH2:28][CH2:27][C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([F:19])[CH:21]=2)([CH2:32][CH2:33][N:34]2[CH:35]3[CH2:41][CH2:40][CH:39]2[CH2:38][CH:37]([N:42]2[C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=4[N:44]=[C:43]2[CH3:51])[CH2:36]3)[CH2:31][CH2:30]1)=[O:6]
Reactant: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNS(=O)(=O)c1ccc(Cl)c(C(=O)N2CCC(CCN3C4CCC3CC(n3c(C)nc5ccccc53)C4)(c3cccc(F)c3)CC2)c1Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2ccccc2n1C1CC2CCC(C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NC(C)(C)C)ccc2Cl)CC1
Yield: 35 %

Procedure:
Prepared from a mixture of 2-chloro-5-{[(1,1-dimethylethyl)amino]sulfonyl}benzoic acid 2b, 1-(8-{2-[4-(3-fluorophenyl)-4-piperidinyl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole (100 mg, 0.16 mmol, 1 equiv), DIEA (117 μL, 0.66 mmol, 4 equiv) and HATU (62 mg, 0.16 mmol, 1 equiv) following the general procedure for 2,4-dichloro-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]-N-methylbenzenesulfonamide example 880. The crude product was purified by column chromatography on silica gel eluting with 10% 2M NH3 in methanol in ethyl acetate to afford 4-chloro-N-(1,1-dimethylethyl)-3-[(4-(3-fluorophenyl)-4-{2-[3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]benzenesulfonamide as a white solid (40.3 mg, 35% yield).
Reaction SMILES: N1N=C(C2C=CC=CC=2C(N2CC3CN(C(OC(C)(C)C)=O)CC3C2)=O)NC=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][NH:41][CH2:42]3)[CH2:38]2)[N:31]=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.[F:60][C:61]1[CH:69]=[CH:68][CH:67]=[C:66]([C:70]2[O:74][N:73]=[C:72]([CH3:75])[N:71]=2)[C:62]=1[C:63](O)=[O:64].N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][N:41]([C:63]([C:62]4[C:66]([C:70]5[O:74][N:73]=[C:72]([CH3:75])[N:71]=5)=[CH:67][CH:68]=[CH:69][C:61]=4[F:60])=[O:64])[CH2:42]3)[CH2:38]2)[N:31]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: Cc1noc(-c2cccc(F)c2C(=O)O)n1
Agent: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4c(F)cccc4-c4nc(C)no4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 59 substituting Intermediate 23 for Intermediate 15 and Intermediate 64 for 2-(4H-[1,2,4]triazol-3-yl)-benzoic acid. MS (ESI) mass calculated for C22H23FN6O2, 422.19; m/z found, 423.2. 1H NMR (500 MHz, CDCl3): 7.96-7.86 (m, 1H), 7.55-7.47 (m, 1H), 7.38-7.29 (m, 1H), 6.32-6.23 (m, 1H), 3.99-3.46 (m, 7H), 3.27-2.95 (m, 3H), 2.49-2.37 (m, 3H), 2.36-2.21 (m, 6H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])(=O)=O)=CC=1.[Br:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:34])=[C:24]([CH:33]=1)[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O>[Br:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:34])=[C:24]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:12][CH2:13][O:14][CH2:15][CH:16]([F:18])[F:17])=[CH:28][CH:27]=2)[CH:33]=1
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)F)cc1
Reactant: Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)COCCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Reaction time: 24 h
Yield: 92.2 %

Procedure:
2-(2,2-difluoroethoxy)ethyl 4-methylbenzenesulfonate (3 g, 10.7 mmol), 4-(5-bromo-2-chlorobenzyl)phenol (3.8 g, 12.8 mmol), and Cs2CO3 (8.7 g, 26.8 mmol) were suspended in DMF (8 mL) at 50° C. The mixture was stirred for 24 hours at this temperature. The mixture was diluted with water and the aqueous layer was extracted with PE two times. The combined organic layers were washed with brine, concentrated and purified by flash chromatography (PE/EtOAc=50:1) to obtain a yellow solid (4 g, yield 91.9%), which was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[C:30]#[CH:31])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1.ClCCl.CO.N>>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([NH:28][C:29](=[O:32])[C:30]#[C:31][C:2]3[CH:14]=[CH:13][C:5]([CH2:6][N:7]4[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]4)=[CH:4][CH:3]=3)=[CH:24][CH:23]=2)=[CH:20][CH:21]=1
Reactant: Ic1ccc(CN2CCCCC2)cc1
Reactant: C#CC(=O)Nc1ccc(-c2ccc(Cl)cc2)cc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C(C#Cc1ccc(CN2CCCCC2)cc1)Nc1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
Prepared analogously to Example 1.1.d. from 1-(4-iodobenzyl)piperidine and propynoic acid-(4′-chlorobiphenyl-4-yl)amide. Yield: 6 mg (4% of theory); melting point: 179.5° C.; C27H25ClN2O (M=428.96); calc.: molecular ion peak (H+ H)+: 429/431; found: molecular ion peak (M+H)+: 429/431; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (10:1:0.1)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH:8]1[CH2:11][C:10](=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1(P(=[CH:33][C:34]([O:36][CH3:37])=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1(C)C=CC=CC=1>[CH3:37][O:36][C:34](=[O:35])[CH:33]=[C:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13])[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C=C1CC(NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 96.1 %

Procedure:
To a solution of (3-oxo-cyclobutyl)-carbamic acid tert-butyl ester (5.6 g, 30.2 mmol) in anhydrous toluene (100 mL) was added methyl (triphenylphosphoranylidene)acetate (10.7 g, 45.4 mmol) and heated to reflux overnight under N2. After cooling to room temperature, the mixture was poured into water and extracted with EA. The organic phase was dried over Na2SO4, concentrated under reduced pressure to give a residue, which was purified by column chromatography on silica gel (eluted with PE:EA=20:1) to give the title compound (7 g, yield 96%) as a white solid.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][C@H:9]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([CH3:29])=[CH:7][CH2:6]1)([O:3][CH3:4])=[O:2].C[O:31]CCOCCOC>>[Si:12]([O:11][C@@H:9]1[C@H:8]([CH3:29])[C@@H:7]([OH:31])[CH2:6][C@H:5]([C:1]([O:3][CH3:4])=[O:2])[CH2:10]1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)[C@H]1CC=C(C)[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1
Reactant: COCCOCCOC
Product: COC(=O)[C@@H]1C[C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@H](C)[C@@H](O)C1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
To a stirred solution of this cyclohexene (110 mg, 0.27 mmol) in 2 ml of diglyme at 0° C. was added dropwise a borane-THF complex solution (1.0 M, 325 μL, 0.325 mmol, 1.5 eq). The resulting solution was stirred for 4 h at 0° C. THF was removed and TAO (trimethyl amine N-oxide, 90 mg, 0.81 mmol) was added. The mixture was heated and refluxed for 2 h. The resulting mixture was cooled to room temperature, extracted with EtOAc (4×40 ml) and dried over MgSO4. The residue was separated by flash chromatography on silica, then was purified by HPLC (Cyclohexane/EtOAc: 9:1) to afford compound 3.2.c (R=Me, P=TBDPS, A=COOCH3) (46 g, 40.5%) as a colorless oil.