Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: CC#N
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)CCc2ccccc21
Reaction time: 20 h
Yield: 30.5 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.185 g, 0.56 mmol) and 3-butyl-8-azabicyclo[3.2.1]octane (0.100 g, 0.60 mmol) in MeCN (0.5 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH54) (0.063 g, 30%). 1H NMR (CD3OD) d 7.29-7.19 (m, 3H), 7.03-6.99 (m, 1H), 4.03-4.00 (m, 2H), 3.14-3.13 (m, 1H), 3.07-3.05 (m, 1H), 2.90-2.86 (m, 2H), 2.62-2.57 (m, 2H), 2.28-2.19 (m, 2H), 1.97-1.82 (m, 3), 1.58-1.42 (m, 5H), 1.34-1.15 (m, 8H), 0.90-0.87 (m, 6H); 13C NMR (CD3OD) d 173.1, 140.3, 129.1, 128.4, 128.3, 124.3, 117.2, 62.2, 61.2, 58.2, 46.5, 39.0, 38.0, 32.9, 32.1, 30.3, 29.1, 27.8, 27.3, 26.3, 24.0, 17.1, 14.5.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH:7]([OH:10])CO)=[CH:5][N:4]=[C:3]1[N+:11]([O-:13])=[O:12].CO>O>[CH3:1][N:2]1[C:6]([CH:7]=[O:10])=[CH:5][N:4]=[C:3]1[N+:11]([O-:13])=[O:12]
Reactant: Cn1c(C(O)CO)cnc1[N+](=O)[O-]
Solvent: CO
Solvent: O
Product: Cn1c(C=O)cnc1[N+](=O)[O-]

Procedure:
To a solution of 3.15 g. of 1-methyl-2-nitro-5-(1,2-dihydroxyethyl)imidazole in 200 ml. of methanol, a solution of 3.6 g. of NaIO4 in 85 ml. of water is added with stirring. The precipitate which forms is filtered off and washed with methanol which is then added to the filtrate. By evaporation to dryness under vacuum a residue is obtained which is extracted several times with ethyl acetate. After concentration of the collected extracts, a crystalline product is obtained, which after recrystallization from ethyl acetate melts at 114°-115° C. Yield 2.5 g. (96%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.CCN(CC)CC.[CH3:23][C:24]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])[CH3:25]>ClCCl.CN(C1C=CN=CC=1)C>[Si:27]([O:15][CH2:14][C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])([C:24]([CH3:26])([CH3:25])[CH3:23])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a 0° C. solution of (2S,4R)-tert-butyl 4-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (1.0 equiv) and Et3N (1.05 equiv) in dichloromethane (0.5 M) was added TBSCl (1.05 equiv), followed by a few crystals of DMAP. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was then diluted with dichloromethane, and washed with sat'd. aq. NaHCO3. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound (95%), which was used without further purification.
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:20]([CH2:22][NH2:23])[OH:21]>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:23][CH2:22][CH2:20][OH:21])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: NCCO
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: OCCNc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Temperature: 120 °C

Procedure:
210 mg of product obtained in stage 1 above are mixed with 2 ml of DMSO and 0.3 ml of ethanolamine, and the mixture is then heated at 120° C. for approximately 48 hours with stirring. The mixture is allowed to return to ambient temperature. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 90-9-1 mixture for eluent. Evaporation is carried out and a paste is formed in methylene chloride-methanol (5-5). Partial drying and drying under vacuum at 50° C. are carried out. 118 mg of expected product are obtained.
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:14][C:15]([NH2:17])=[S:16]>O>[SH:16][C:15]1[N:17]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:3][N:14]=1
Reactant: NC(N)=S
Reactant: CN(C)C=CC(=O)c1ccccc1
Solvent: O
Product: Sc1nccc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
A mixture of 17.5 g. of 3-dimethylaminoacrylophenone and 30.44 g. of thiourea is intimately mixed and fused at 180°-190° C. for one hour. The mixture is cooled and water is added and the desired compound is recovered by filtration, m.p. 203°-205° C.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][CH2:15][C:14]2[NH:13][N:12]=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.[CH3:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:11]2[C:10]3[CH2:9][NH:8][CH2:17][CH2:16][CH2:15][C:14]=3[N:13]([CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[C:28]([CH3:29])[CH:27]=3)[N:12]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]nc(-c3ccc(Cl)cc3)c2C1
Reactant: Cc1cccc(CBr)c1
Product: Cc1cccc(Cn2nc(-c3ccc(Cl)cc3)c3c2CCCNC3)c1
Yield: 11.9 %

Procedure:
The title compound (0.012 g) was prepared from 3-(4-chloro-phenyl)-4,6,7,8-tetrahydro-1H-1,2,5-triaza-azulene-5-carboxylic acid tert-butyl ester (Example 59, Step C, 0.1 g) using 3-methylbenzyl bromide (0.06 g) in place of benzyl chloride in Example 59, Step D. MS (ESI): exact mass calculated for C21H22ClN3, 351.15; found, m/z 352.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.49-7.43 (m, 4H), 7.19 (t, J=7.6 Hz, 1H), 7.08 (d, J=7.6 Hz, 1H), 7.00 (s, 1H), 6.92 (d, J=7.3 Hz, 1H), 5.34 (s, 2H), 3.88 (s, 2H), 3.16-3.13 (m, 2H), 2.88-2.85 (m, 2H), 2.30 (s, 3H), 1.80-1.77 (m, 2H).
Reaction SMILES: ClCl.BrBr.II.[N:7]([P:10](Cl)Cl)([CH3:9])[CH3:8].[C:13]1([CH3:21])[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>>[CH3:8][N:7]([P:10]([C:16]1[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=1)[C:16]1[CH:17]=[CH:18][C:13]([CH3:21])=[CH:14][CH:15]=1)[CH3:9]
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: CN(C)P(Cl)Cl
Agent: BrBr
Agent: ClCl
Agent: II
Product: Cc1ccc(P(c2ccc(C)cc2)N(C)C)cc1

Procedure:
U.S. Pat. No. 2,934,564 relates to compounds of the general formula R2PX wherein R represents an alkyl or aryl group and X represents chlorine, bromine or iodine. For example, the reaction of Me2NPCl2 (0.42 mole) with p-tolylmagnesium bromide (0.84 mole) produces dimethylamino-di-p-tolylphosphine. The isolated dimethylamino-di-p-tolylphosphine (31.88 mmoles) was treated with 1428 cc (63.75 mmoles) of anhydrous HCl yielding di-p-tolylchlorophosphine, which was purified by distillation. Similarly, Burg, et al. (J.A.C.S. 80, 1107-09, 1958) disclose the preparation of chlorodimethylphosphine from Me2NPCl2 and suggest the viability of a Grignard route to R2PR'-type phosphines. K. Issleib, et al. (Chem. Berichte 29, 2682-3008, 1959) have shown that Et2NPCl2 (Et=ethyl) and cyclohexylmagnesium chloride react in a 1:1.25 molar ratio to form diethylaminocyclohexylchlorophosphine in 57.5% yield. The authors suggest this reaction can be exploited to prepare unsymmetrical chlorophosphines of the type RR'PCl, but no mention is made of the possibility of further reaction to unsymmetrical tertiary phosphines of the type RR'R"P.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:18](I)[CH3:19].O>CN(C=O)C>[CH2:18]([O:8][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:19]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cc(F)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 24 h
Yield: 99.1 %

Procedure:
To 5-fluoro-2-nitrophenol (8.3 g, 52.83 mmol) in 50 mL of DMF was added K2CO3 (14.6 g, 105.7 mmol), and ethyl iodide (8.53 mL, 105.7 mmol). The mixture was stirred at 60° C. for 24 h in a sealed tube. The mixture was poured into 500 mL of H2O and extracted with diethyl ether, dried (Na2SO4), filtered, and rotovaped down to give the title compound of step A (9.69 g, 52.33 mmol, 99%). 1H NMR (400 MHz, CDCl3) δ ppm 7.88-7.94 (m, 1H), 6.71-6.77 (m, 1H), 6.66-6.71 (m, 1H), 4.11-4.19 (m, 2H), 1.45-1.51 (m, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:28][Mg+].[Br-]>C(Cl)Cl.CCOCC.O=[Mn]=O>[C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]2[CH:21]=[CH:22][C:23]([CH:26]([OH:27])[CH3:28])=[CH:24][CH:25]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc(-c2sccc2-c2ccccc2OCc2ccccc2)cc1
Reactant: C[Mg+]
Agent: O=[Mn]=O
Agent: [Br-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(O)c1ccc(-c2sccc2-c2ccccc2OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
To a solution of the alcohol of example 4 (200 mg, 0.536 mmol) in CH2Cl2 is added MnO2 (467 mg, 5.36 mmol) and the mixture is stirred overnight. The reaction is then filtred throught a plug of celite and the crude mixture diluted in ether (5.0 mL) and cooled at −78° C. MeMgBr was then added (3M in ether, 0.22 mL, 0.66 mmol) and the reaction was warmed to room temperature and stirred for 1 h. The mixture was quenched with saturated NH4Cl, diluted with Et2O and washed successively with HCl 10%, aq. NaHCO3 and brine. The ether layer was dried with anh. MgSO4, filtered and concentrated under reduced pressure to give a residue which was separated in two and one part was purified by flash chromatography (70% Hexanes/30% AcOEt) to provide the title compound (19.4 mg). 1H nmr (400 MHz, acetone-d6) δ ppm 7.45 (1H, d, J=7.5 Hz), 7.32-7.05 (13H, m), 6.91 (1H, t, J=7.5 Hz), 4.97 (2H, s), 4.80 (1H, m) 4.12 (1H, d, J=5.0 Hz), 3.95 (3H, d, J=7.5 Hz).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[N:5]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:4]([CH3:20])([CH3:19])[CH2:3]1.[C:21]1(=[O:27])[O:26][C:24](=[O:25])[CH2:23][CH2:22]1>>[CH2:11]([O:10][N:5]1[C:6]([CH3:8])([CH3:9])[CH2:7][CH:2]([NH:1][C:21](=[O:27])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH2:3][C:4]1([CH3:19])[CH3:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: O=C1CCC(=O)O1
Reactant: CCCCCCCCON1C(C)(C)CC(N)CC1(C)C
Product: CCCCCCCCON1C(C)(C)CC(NC(=O)CCC(=O)O)CC1(C)C
Reaction time: 2 h
Yield: 75 %

Procedure:
Following the general procedure of Example 9, 4-amino-1-octyloxy-2,2,6,6-tetramethylpiperidine is added to succinic anhydride over a 30-minute period. The reaction mixture is then stirred for two hours. The crude product is purified by flash chromatography on silica gel (9:1, ethyl acetate:methanol) followed by trituration with heptane to give the title compound in 75% yield as a white powder melting at 96°-103° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH:13]=O)=[CH:11][NH:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:15][O:16][CH:17]([O:21][CH3:22])[CH2:18][NH:19][CH3:20].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][N:19]([CH3:20])[CH2:18][CH:17]([O:21][CH3:22])[O:16][CH3:15])=[CH:11][NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=Cc1c[nH]nc1-c1ccc(F)cc1
Reactant: CNCC(OC)OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(CN(C)Cc1c[nH]nc1-c1ccc(F)cc1)OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A solution of 3-(4-fluorophenyl)-1H-pyrazole-4-carbaldehyde (3 g, 15.78 mmol, 1.00 equiv) and (2,2-dimethoxyethyl)(methyl)amine (2.3 g, 19.30 mmol, 1.22 equiv) in acetic acid (1.89 g, 31.47 mmol, 2.00 equiv) and 1,2-dichloroethane (30 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (10 g) was then added and the resulting solution was stirred at room temperature for 3 h. The resulting mixture was washed with 2×20 mL of 5% potassium carbonate solution and 2×20 mL of brine. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum to give 3.29 g (71%) of N-((3-(4-fluorophenyl)-1H-pyrazol-4-yl)methyl)-2,2-dimethoxy-N-methylethanamine as a yellow oil. LCMS (method C, ESI): RT=0.63 min, m/z=294.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[NH:50]1[CH2:53][CH:52]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)[CH2:51]1>CN(C=O)C>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:50]5[CH2:53][CH:52]([N:54]6[CH2:59][CH2:58][O:57][CH2:56][CH2:55]6)[CH2:51]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reactant: C1CN(C2CNC2)CCO1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)N2CC(N3CCOCC3)C2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reaction time: 18 h
Yield: 44.8 %

Procedure:
To a mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (500 mg, 1.19 mmol), 2-chloro-1-methylpyridinium iodide (729 mg, 2.86 mmol) and DIPEA (500 μL, 2.87 mmol) in DMF (10 mL) was added 4-azetidin-3-ylmorpholine (288 mg, 2.0 mmol) and the resulting mixture allowed to stir at r.t for 18 h. The reaction mixture was concentrated in vacuo and the resulting residue dissolved in EtOAc which was washed with H2O and brine, then dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-5%) affording 799 as a cream solid (290 mg, 45%). LCMS (method G): RT 5.90 min, [M+H]+ 544.5. 1H NMR (CDCl3, 400 MHz): δ 7.99-7.99 (1 H, m), 7.67-7.67 (1 H, m), 7.28-7.20 (2 H, m), 4.73-4.72 (1 H, m), 4.70-4.00 (4 H, brd s), 4.53-4.51 (1 H, m), 4.29-4.21 (1 H, m), 4.18-4.08 (4 H, m), 3.87 (4 H, t, J=4.67 Hz), 3.78 (4 H, t, J=4.60 Hz), 3.30-3.30 (1 H, m), 2.88-2.88 (1 H, m), 2.47-2.45 (4 H, m), 1.35-1.34 (2 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13](=O)[CH2:14][C:15](=O)[C:16]([F:19])([F:18])[F:17])[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10].[NH2:24][C:25]1[C:29]([C:30]2[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=2)=[CH:28][NH:27][N:26]=1>>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[N:26]3[N:27]=[CH:28][C:29]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=4)=[C:25]3[N:24]=2)[CH:6]=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10]
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: Nc1n[nH]cc1-c1ccncc1
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4ccncc4)c3n2)cc1C(F)(F)F
Yield: 34.9 %

Procedure:
Reaction of 1-(3,4-bis-trifluoromethyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (176 mg, 0.5 mmol), prepared from commercially available 3,4-bis-trifluoromethyl-acetophenone [CAS No. 129604-25-7] according to general procedure A, and 3-amino-4-(4-pyridinyl)-pyrazole [CAS No. 216661-87-9; prepared from 4-cyanomethyl-pyridine as described in Bioorg. Med. Chem. Lett. 12 (2002) 3537-3541] (80 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (83 mg, 35%). Yellow solid. MS (ISP) 477.2 [(M+H)+]; mp 209° C.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[Br:11][C:12]1[CH:13]=[N:14][C:15](Br)=[N:16][CH:17]=1>O1CCCC1>[Br:11][C:12]1[CH:13]=[N:14][C:15]([CH:5]([C:3]#[N:4])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N:16][CH:17]=1
Reactant: Brc1cnc(Br)nc1
Reactant: CCOC(=O)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)c1ncc(Br)cn1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a chilled stirred suspension of sodium hydride (60% in oil, 34.55 mmol) in tetrahydrofuran (20 mL) was added 1.17 g of ethyl cyanoacetate (10.34 mmol) portionwise over 10 minutes. After effervescence has ceased, the yellow cloudy mixture was left to warm up to room temperature whilst stirring. 2.00 g of 5-bromo,2-bromo-pyrimidine (10.34 mmol) in 30 mL of tetrahydrofuran was added. And the mixture was left to stir at room temperature for six hours. The resultant brown mixture was concentrated under reduced pressure to give a bright brown precipitate to which water (200 mL) was added. After extraction with heptane (200 mL), the aqueous phase was acidified by the addition of HCl 1M and the resultant precipitate was collected by filtration to give on drying ethyl (5-bromopyrimidin-2-yl)(cyano)acetate as a bright brown powder (0.67 g, yield=24%).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[CH:27]1([C:32]([Cl:34])=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1.CS(C)=O>N1C=CC=CC=1>[ClH:34].[CH:27]1([C:32]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]4[CH:24]5[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]5)[CH2:20]4)=[O:18])=[CH:14][CH:15]=3)=[CH:6][CH:5]=2)=[O:33])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=C(Cl)C1CCCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1)C1CCCC1

Procedure:
A solution of 50 mg (0.13 mmol) of ((3R)—N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 38.5 μl (0.32 mmol) of cyclopentanecarbonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is mixed with 3 ml of DMSO and purified by preparative HPLC. The product fractions are concentrated, mixed with 5 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 22 mg (38.2% of theory) of the title compound are obtained.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([C:13](=[O:15])[CH3:14])=[CH:11][C:10]([Cl:16])=[C:9]([CH3:17])[C:8]=1[C:18]#[N:19])(=O)=O.[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.O.N#N>C1(C)C=CC=CC=1.[Na].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>[C:13]([C:12]1[CH:11]=[C:10]([Cl:16])[C:9]([CH3:17])=[C:8]([C:18]#[N:19])[C:7]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[CH:28]=1)(=[O:15])[CH3:14]
Reactant: OB(O)c1cccc(F)c1
Reactant: CC(=O)c1cc(Cl)c(C)c(C#N)c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)c1cc(Cl)c(C)c(C#N)c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
A biphasic solution of 6-acetyl-4-chloro-2-cyano-3-methylphenyl trifluoromethanesulfonate (2.537 g, 7.425 mmol) and (3-fluorophenyl)boronic acid (1.56 g, 11.1 mmol) in toluene (70 mL) and 0.8 M sodium hydrogenecarbonate in water (70 mL, 50 mmol) was bubbled with N2 to degas. Tetrakis(triphenylphosphine)palladium(0) (0.429 g, 0.371 mmol) was added. The mixture was degassed with N2 for an additional 5 minutes and then heated at 80° C. for 2 hours. After cooling to room temperature, the mixture was diluted with ethyl acetate. The layers were separated and the aq. layer was extracted with ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to a dark solid. The material was dissolved in CHCl3 and was purified on silica gel column, eluting with 0 to 40% ethyl acetate in hexane, to give the desired product (2.105 g, 99%). LCMS calculated for C16H12ClFNO (M+H)+: m/z=288.1; Found: 288.1.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][CH:14]=1)[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].Cl[CH2:21][C:22]([O:24][CH3:25])=[O:23]>O>[CH3:25][O:24][C:22](=[O:23])[CH2:21][NH:11][C:10]1[CH:12]=[CH:13][CH:14]=[C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:9]=1
Reactant: COC(=O)CCl
Reactant: Nc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)CNc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 53 %

Procedure:
A mixture of 3-phenoxyaniline (25 g, 0.135 mol), sodium bicarbonate (22.7 g, 0.27 mol) and methyl chloroacetate (15.5 ml, 0.2025 mol) was heated at 90°-100° C. with vigorous stirring for 20 h. The mixture was allowed to cool to room temperature and was then poured into water (200 ml) and extracted with dichloromethane (2×100 ml). The organic extract was washed with 2N hydrochloric acid (2×100 ml), water (2×100 ml) and then dried and evaporated to give a grey/green solid. This was triturated with hexane (400 ml) and filtered to give the title compound as a grey/green solid (18.4 g, 53%), m.p 44°-45°.
Reaction SMILES: [OH-].[K+].[CH2:3]([C:10]1[NH:14][C:13]2[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:12]=2[N:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH3:21]>CC(C)=O.C(Cl)Cl>[CH2:3]([C:10]1[N:11]([CH3:21])[C:12]2[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:13]=2[N:14]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: Brc1ccc2[nH]c(Cc3ccccc3)nc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: ClCCl
Product: Cn1c(Cc2ccccc2)nc2ccc(Br)cc21
Reaction time: 1 h

Procedure:
Powdered KOH (5.25 g, 93.50 mmol) was added to a stirred solution of 2-benzyl-5-bromo-1H-benzimidazole (5.37 g, 8.70 mmol) in acetone (100 mL), after 10 min, iodomethane (1.28 mL, 20.57 mmol) was added and the mixture was stirred for 1 h and diluted with DCM. The mixture was washed with water and brine, then dried over Na2SO4 and concentrated. The residue was taken up in DCM and hexanes and the resulting suspension filtered. The filtrate was concentrated and the oily residue taken up in hexanes and stirred for about 1 h. The resulting solid was filtered and the filter cake washed with hexanes and dried (2.0 g, 34%). LC-MS [M+H]+=302.1, RT=2.47 min.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([F:17])([F:16])[C:3]([Cl:19])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(F)(F)F
Product: FC(F)(F)C(Cl)=Nc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
An intimate mixture of 120.3 g of the product of Step A and 106.6 g of phosphorus pentachloride was heated at 80° C. under an inert atmosphere for 5 hours and phosphorus oxychloride was distilled at 25° C. at 40 mm Hg to obtain 31.44 g of 2,2,2-trifluoro-N-(3-trifluoromethylphenyl)-ethanimidoyl chloride with a boiling point of 75° C. at 30 mm Hg.