Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH3:12][O:13][CH2:14]OCl.C(N(CC)CC)C.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: COCOCl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCOc1ccc([N+](=O)[O-])cc1Cl

Procedure:
To a solution of 2-chloro-4-nitrophenol (5.2 g) in N,N-dimethylformamide (50 ml) were successively added methoxymethoxy chloride (2.7 ml) and triethylamine (5.0 ml) with stirring under ice-cooling, and the resulting mixture was stirred at room temperature for 1 hour. After stirring, to the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed successively with water and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo to afford 3-chloro-4-methoxymethoxynitrobenzene (8.1 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[C:18]([F:23])=[CH:19][CH:20]=[C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(Br)c3O2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1ccc(S(=O)(=O)OCC2Cc3c(F)ccc(-c4ccccc4)c3O2)cc1
Yield: 53.9 %

Procedure:
Treatment of (±)-(7-bromo-4-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (2.0 g, 4.98 mmol) with phenyl boronic acid (0.91 g, 7.22 mmol), dichlorobis(tri-o-tolylphosphine)-palladium(II) (0.392 g, 0.498 mmol), and potassium carbonate (1.72 g, 12.46 mmol) acording to the procedure described for Intermediate 37 gave 1.07 g (54%) of (±)-(4-fluoro-7-phenyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a white solid. Rf=0.46 (silica, ethyl acetate:hexanes 1:4); 1H NMR (DMSO-d6) δH 7.70 (d, 2H); 7.53 (d, 2H); 7.40 (t, 2H); 7.32 (m, 4H); 6.77 (t, 1H); 5.15 (m, 1H); 4.31 (dd, 1H); 4.22 (dd, 1H); 3.30 (dd, 1H, obscured by H2O peak); 3.01 (dd, 1H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH:9]2[N:19]3[C:20]4[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=4[N:16]=[CH:17][C:18]3=[O:21])[CH2:10]2)[CH2:4][CH2:3]1.[S:23]1[C:31]2[CH:30]=[C:29]([CH:32]=O)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(Cl)(Cl)[Cl:49].CO>>[ClH:49].[S:23]1[C:31]2[CH:30]=[C:29]([CH2:32][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH:9]4[N:19]5[C:20]6[N:11]([C:12](=[O:22])[CH:13]=[CH:14][C:15]=6[N:16]=[CH:17][C:18]5=[O:21])[CH2:10]4)[CH2:4][CH2:3]3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1
Reactant: O=Cc1cc2c(cn1)OCS2
Reactant: NC1CCN(CC2Cn3c(=O)ccc4ncc(=O)n2c43)CC1
Reactant: ClC(Cl)Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: Cl
Product: O=c1ccc2ncc(=O)n3c2n1CC3CN1CCC(NCc2cc3c(cn2)OCS3)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
Racemic 2-[(4-amino-1-piperidinyl)methyl]-1,2-dihydro-3H,8H-2a,5,8a-triazaacenaphthylene-3,8-dione (for a preparation see Example 16A(j)) (400 mg, 1.327 mmol) was stirred with [1,3]oxathiolo[5,4-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144 Example 61) (200 mg, 0.9 eq.) in chloroform:methanol (9:1, v:v, 15 ml) at room temperature for 30 mins; the mixture was then treated with sodium triacetoxyborohydride (844 mg, 3.0 eq.) with vigorous stirring at room temperature for 30 mins. The reaction was quenched by addition of saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred at room temperature for 5 mins. The organic phase was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure. The crude product was purified by column chromatography on silica (eluting with 0-12% (2M ammonia in methanol) in DCM, appropriate fractions were combined and evaporated under reduced pressure to give the free base of the (racemic) title compound as a pale yellow foam (290 mg, 46.8%).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:21])=[CH:9][C:10]([O:19][CH3:20])=[CH:11][C:12]=3[C:13]2([CH:17]=[CH2:18])O)=[CH:4][CH:3]=1.[CH3:22][OH:23].S(=O)(=O)(O)O>>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:21])=[CH:9][C:10]([O:19][CH3:20])=[CH:11][C:12]=3[C:13]2=[CH:17][CH2:18][O:23][CH3:22])=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=CC1(O)c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Agent: O=S(=O)(O)O
Product: COCC=C1c2cc(Br)ccc2Oc2c(F)cc(OC)cc21
Temperature: 55 °C
Yield: 42.8 %

Procedure:
To a 250 mL of RBF were added 7-bromo-4-fluoro-2-methoxy-9-vinyl-9H-xanthen-9-ol (8.69 g, 24.75 mmol), methanol (100 mL, 2475 mmol) and sulfuric acid (0.2M in water) (12.4 mL, 2.48 mmol). The mixture was heated to 55° C. for 25 min. The solvent was removed and the residue was diluted with EtOAc. The organic layer was washed by saturated aqueous NaHCO3. The aqueous layer was further extracted with EtOAc. The organic layers were combined and washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the crude material as an oil. The crude product was purified by 35% to 50% to 75% to 100% DCM in Heptane to yield 7-bromo-4-fluoro-2-methoxy-9-(2-methoxyethylidene)-9H-xanthene (3.87 g, 10.60 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH2:20][N:21]3[C@@H:25]([CH3:26])[C@@H:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)[O:23][C:22]3=[O:35])=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.Cl.[F:37][CH:38]1[CH2:41][NH:40][CH2:39]1.CCN(CC)CC.Cl>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:11]([CH2:20][N:21]3[C@@H:25]([CH3:26])[C@@H:24]([C:27]4[CH:32]=[C:31]([F:33])[CH:30]=[C:29]([F:34])[CH:28]=4)[O:23][C:22]3=[O:35])=[N:12][C:13]([N:40]3[CH2:41][CH:38]([F:37])[CH2:39]3)=[N:14][CH:15]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1-c1cnc(S(C)(=O)=O)nc1CN1C(=O)O[C@H](c2cc(F)cc(F)c2)[C@@H]1C
Reactant: FC1CNC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(F)cc(F)c2)[C@@H]1C
Temperature: 100 °C

Procedure:
(4S,5R)-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-5-(3,5-difluorophenyl)-4-methyl-1,3-oxazolidin-2-one (Step A, 519 mg, 0.989 mmol) and 3-fluoroazetidine hydrochloride (331 mg, 2.97 mmol) were placed in a microwave vial and suspended in THF (3 mL). Et3N (0.689 mL, 4.94 mmol) was added, the vial was sealed and the reaction heated to 100° C. for 20 minutes in a microwave reactor. LCMS showed complete conversion to product. The reaction was diluted with ethyl acetate (50 mL) and poured into 0.1N HCl solution (50 mL). The ethyl acetate layer was washed with brine (50 mL), dried over sodium sulfate and concentrated on rotary evaporator. Silica gel purification employing a 0-50% ethyl acetate/hexanes linear gradient followed by isocratic elution at 50% ethyl acetate/hexanes gave the product as a pale yellow solid. LCMS (M+H)+: 520.3. 1H NMR (500 MHz, CDCl3): δ 8.19 (d, J=2.5 Hz, 1H), 8.14 (s, 1H), 7.48 (d, J=2.5 Hz, 1H), 6.84 (m, 3H), 5.52 (m, 1.5H), 5.42 (m, 0.5H), 4.64 (d, J=17.3 Hz, 1H), 4.49 (m, 2H), 4.35 (m, 2H), 3.98 (d, J=17.3 Hz, 1H), 4.07 (m, 4H), 3.95 (s, 3H), 0.78 (d, J=6.6 Hz, 3H). SPA IC50: 728 nM.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1([C:11]#[N:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CC[O-].[Na+].[NH4+:18].[Cl-:19].N>CCO>[ClH:19].[C:1]([O:5][C:6](=[O:13])[NH:7][C:8]1([C:11](=[NH:18])[NH2:12])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NC1(C#N)CC1
Reactant: [Cl-]
Agent: CC[O-]
Agent: N
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(C(=N)N)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.2 %

Procedure:
(1-Cyano-cyclopropyl)-carbamic acid tert-butyl ester (2.12 g, 11.6 mmol) was dissolved in anhydrous EtOH (29 mL) and NaOEt (21 wt % in EtOH, 6.5 mL, 17.5 mmol) was added via syringe in one portion. The yellow solution was stirred at room temperature for 1 h. An additional amount of NaOEt (21 wt % in EtOH, 2.2 mL, 2.9 mmol) was added and stirring was continued for 2 h. To the reaction was added solid NH4Cl (2.5 g, 47 mmol) followed by NH3 (7N in MeOH, 1.7 mL, 12 mmol). The flask was sealed and the suspension was allowed to stir for 88 h. The solids were filtered off, using anhydrous EtOH to rinse. The filtrate was concentrated and re-suspended in EtOAc (10 mL). This mixture was heated to reflux for 30 min then allowed to cool to room temperature. The solids were collected by filtration to give 2.22 g of the title compound as a white powder, m/z 200.44 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:24]=[N:25][C:26]([O:32][CH2:33][CH3:34])=[CH:27][C:28]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1.[N:35]1([CH2:41][CH2:42][OH:43])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:38]3[CH2:39][CH2:40][N:35]([CH2:41][CH2:42][OH:43])[CH2:36][CH2:37]3)=[O:21])[C:10]([C:23]3[CH:24]=[N:25][C:26]([O:32][CH2:33][CH3:34])=[CH:27][C:28]=3[O:29][CH2:30][CH3:31])=[N:9]2)=[CH:4][CH:3]=1
Reactant: OCCN1CCNCC1
Reactant: CCOc1cc(OCC)c(C2=NC(c3ccc(Cl)cc3)C(c3ccc(Cl)cc3)N2C(=O)Cl)cn1
Product: CCOc1cc(OCC)c(C2=N[C@@H](c3ccc(Cl)cc3)[C@@H](c3ccc(Cl)cc3)N2C(=O)N2CCN(CCO)CC2)cn1
Product: Cl

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 32) was reacted with 2-piperazine-1-yl-ethanol (Aldrich) to give cis-[4,5-bis-(4-chloro-phenyl)-2-(4,6-diethoxy-pyridin-3-yl)-4,5-dihydro-imidazol-1-yl]-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-methanone hydrochloride in an analogous manner as described in example 1.
Reaction SMILES: [Br:1][C:2]1[C:3]([F:11])=[C:4]([CH2:8][C:9]#N)[CH:5]=[CH:6][CH:7]=1.[OH:12]S(O)(=O)=O.[CH3:17][CH2:18][OH:19]>>[CH2:18]([O:19][C:9](=[O:12])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[F:11])[CH3:17]
Reactant: O=S(=O)(O)O
Reactant: N#CCc1cccc(Br)c1F
Reactant: CCO
Product: CCOC(=O)Cc1cccc(Br)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 3-bromo-2-fluorophenylacetonitrile (2.5 g, 11.7 mmol) in absolute EtOH (25 mL) at room temperature was added concentrated H2SO4 (4 mL) and the mixture was warmed to reflux. After 48 hrs, the reaction was cooled to room temperature, evaporated under reduced pressure, diluted with EtOAc (100 mL) and partitioned with saturated aqueous sodium bicarbonate (50 mL). The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to afford the title compound.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH2:14][CH3:15])=[CH:8][CH:7]=1)=O.[CH3:17][N:18]=[C:19]=[O:20].C(N(CC)CC)C.FC(F)(F)C(O)=O>CC(C)=O>[CH2:12]([C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:18]([CH3:17])[C:19](=[O:20])[NH:2][C:3]=2[CH3:16])=[CH:7][CH:8]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCc1ccc(C(=O)C(C)N)cc1
Reactant: CN=C=O
Agent: Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1ccc(-c2c(C)[nH]c(=O)n2C)cc1
Reaction time: 0.67 h

Procedure:
2-Amino-4'-n-butylpropiophenone hydrochloride (5.36 g, 22.2 mmol) was suspended in acetone (180 ml) under ice-cooling, and methyl isocyanate (1.61 g, 28.2 mmol) was added thereto. After addition of triethylamine (4.49 g, 44.5 mmol), the mixture was stirred for 40 minutes under ice-cooling. Trifluoroacetic acid (16 ml) was added thereto, and the mixture was stirred for 5 hours at room temperature. The solvent was removed by evaporation under vacuum, and the residue was taken in dichloromethane. The organic mixture was washed successively with water and saturated aqueous sodium chloride, and dried over magnesium sulfate. Evaporation of the solvent provided a crude product, which was purified by column chromatography (chloroform/ ethanol=50/1 (v/v)) and recrystalization (hexane-ethyl acetate) to give the title compound. Yield: 3.85 g (71%), m.p. 180°-180.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([NH2:9])[CH:3]=1.O(C)[C:11]([S-])=[S:12].[K+].Cl>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:11]([SH:12])=[N:9][C:4]=2[CH:3]=1
Reactant: COC(=S)[S-]
Reactant: Nc1cc(Cl)ccc1O
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc2cc(Cl)ccc2o1
Reaction time: 3 h
Yield: 96.4 %

Procedure:
With the use of the apparatus described in Example 1, 143.6 g (1 mol) of 4-chloro-2-aminophenol and 181.3 g (1.02 mols) of potassium methyl xanthate (90%) in 500 ml of water were refluxed. The reaction was complete within 3 hours. The dark reaction solution was acidified with concentrated hydrochloric acid, the precipitate was suction-filtered and washed neutral with water. After drying in vacuo at 80° C., 179 g (96.7% of th.) of 5-chloro-2-mercaptobenzoxazole having a melting point of 269°-271° C. were obtained.
Reaction SMILES: Cl.[OH:2][CH:3]([C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH:4]([NH2:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][CH:7]=1.[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([NH:16][CH:4]([CH2:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]([F:13])([F:14])[F:15])=[CH:8][CH:7]=2)[CH:3]([OH:2])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc2ccccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.4 %

Procedure:
To a solution of (1RS,2SR)-1-hydroxy-1-(1-naphthalenyl)-3-(4-(trifluoromethyl)phenyl)-2-propylamine hydrochloride (150 mg, 0.39 mmol) in ethyl acetate (5 ml) were added 4-fluorobenzoyl chloride (70 ml, 0.59 mmol) and saturated aqueous sodium hydrogen carbonate (5 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (50 ml) and extracted with ethyl acetate (50 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (152 mg, 83%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:20]I.[C:22]([C:26]1[CH:27]=[C:28]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][CH2:43]O)[N:41]=2)[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23].N1C=CN=C1>C(Cl)Cl>[C:22]([C:26]1[CH:27]=[C:28]([C:37]2[O:38][CH:39]=[C:40]([CH2:42][CH2:43][I:20])[N:41]=2)[CH:29]=[C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])[C:31]=1[OH:32])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(-c2nc(CCO)co2)cc(C(C)(C)C)c1O
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)c1cc(-c2nc(CCI)co2)cc(C(C)(C)C)c1O
Yield: 96.1 %

Procedure:
A solution of triphenylphosphine (118.8 mmole, 31.12 g), in methylene chloride (460 ml) was treated with iodine (approximately 30.17 g) until a dull yellow color persisted. The reaction stirred fifteen minutes, then a solution of 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (79.2 mmole, 25.10 g) and imidazole (158.3 g, 10.77 g) in methylene chloride (300 ml) was added over a ten minute period. At 3.0 hours the reaction was concentrated in vacuo then taken up into methylene chloride and subjected to flash silica gel filtration. Desired product was eluted with 1:1 ethyl acetate:hexane, collecting 500 ml tractions. Desired fractions were combined, washed with 1×250 ml 1N sodium thiosulfate and 1×250 ml brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 32.53 g (96%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:3]1[CH2:4]N[CH2:6]2.[I:11][C:12]1[N:13]=[N:14][C:15](I)=[CH:16][CH:17]=1.[CH:19](N(C(C)C)CC)(C)C.[OH-].[Na+]>O1CCOCC1>[I:11][C:12]1[N:13]=[N:14][C:15]([CH:9]2[CH2:8][CH:7]3[N:2]([CH3:1])[CH:3]([CH2:4][CH2:19][CH2:6]3)[CH2:10]2)=[CH:16][CH:17]=1
Reactant: Ic1ccc(I)nn1
Reactant: CN1C2CCCC1CNC2
Reactant: CCN(C(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CN1C2CCCC1CC(c1ccc(I)nn1)C2
Temperature: 75 °C
Reaction time: 96 h

Procedure:
A mixture of 9-methyl-3,9-diazabicyclo[3.3.1]nonane (4.0 g, 28.5 mmol), 3,6-diiodopyridazine (9.5 g, 28.5 mmol), diisopropylethylamine (7.4 g, 57.0 mmol) and dioxane (50 ml) was stirred at 75° C. for 4 days. Aqueous sodium hydroxide (75 ml, 1 M) was added, dioxane was evaporated and the mixture was extracted twice with dichloromethane (2×75 ml). Chromatography on silica gel with dichloromethane, 10% methanol and 1% aqueous ammonia as solvent gave the title compound. Yield 4.61 g (47%). Mp 163-166° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=1.[Li]CCCC.[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]#[N:26])=[N:23][CH:24]=1.C[Si](C)(C)Cl.[CH2:32]([Mg]Cl)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>CCOCC.C1COCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([F:12])[CH:3]=2)([NH2:26])[CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[N:23][CH:24]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(Cc1ccccc1)(c1cc(F)cc(C(F)(F)F)c1)c1ccc(Cl)cn1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
A dry 250 mL round bottomed flask was equipped a stirring bar and fitted to an adapter connected to the vacuum line. The flask was dried under vacuum and then purged several times with nitrogen. Under a stream of nitrogen, 1-bromo-3-fluoro-5-(trifluoromethyl)benzene (2.5 g, 10.3 mmoles) was added to the flask and dissolved in anhydrous ether (100 mL). The flask was fitted with a septum which was connected to the nitrogen line via a 16 gauge 1½ PrecisionGlide® needle. The stirring solution was cooled to −78° C. for 10 minutes, n-BuLi (1.6M in hexanes, 6.4 mL. 10.3 mmoles) was added drop wise. After 15 minutes, a solution of 5-chloro-2-cyanopyridine (1.42 g, 10.3 mmoles) in anhydrous THF (10 mL) was added from a syringe. The reaction was stirred for 2 hours at −78° C. and trimethylchlorosilane (1.41 mL, 10.3 mmoles) was added. The reaction vessel was removed from the acetone/dry ice bath and the reaction was allowed to warm up to room temperature. After 30 minutes, the reaction vessel was cooled to −78° C., Benzylmagnesium chloride (2.0M in THF, 5.15 mL, 10.3 mmoles) was added and the reaction was allowed to slowly warm to room temperature for 2 h. The reaction was quenched with H2O (10 mL). The crude product was poured into 200 mL ethyl acetate in a 1000 mL separatory funnel. The light brown solution was washed with saturated aqueous NH4Cl (3×100 mL), then with water (2×100 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude residue was purified by column chromatography on silica gel ISCO with 95-75% hexanes in ethylacetate to yield 1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-(trifluoromethyl)phenyl)-2-phenylethanamine 994 mg (24% yield). LC-MS (methanol) [M+1]=394. 1H NMR (500 MHz, CDCl3) δ ppm 8.58 (1H, d, J=2.75 Hz), 7.57-7.64 (2H, m), 7.45 (2H, d, J=8.25 Hz), 7.09 -7.24 (4H, m), 6.81 (2H, d, J=6.60 Hz), 3.93 (1H, d, J=13.20 Hz), 3.46 (1H, d, J=13.20 Hz), 1.87 (2H, broad s).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C@@H:10]([CH3:14])[CH2:9]1)=O)(C)(C)C.N1C=CC=CC=1.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][C@@H:10]1[CH3:14])(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CNCCN1S(C)(=O)=O
Reaction time: 8 h
Yield: 38.8 %

Procedure:
First step: To a stirred solution of commercially available (S)-3-methyl-piperazine-1-carboxylic acid tert-butyl ester (2.38 g, 12 mmol) in CH2Cl2 (25 mL) at 0° C. were added pyridine (1.91 mL, 24 mmol) and methanesulfonyl chloride (0.92 mL, 12 mmol). Stirring was continued at RT overnight, the reaction was poured onto water and extracted with CH2Cl2. The combined organic phases were dried on Na2SO4 and concentrated under vacuo. The crude product was dissolved in CH2Cl2 (20 mL) and TFA (4 mL) was added. After 2 hours at RT, the volatiles were removed under vacuo, the crude was dissolved in CH2Cl2 and washed with aq. NaHCO3 (until pH=8). The organic phase was dried on Na2SO4 and concentrated under vacuo to yield 0.83 g (39%) of (s)-1-methanesulfonyl-2-methyl-piperazine as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].C([N:29]([CH2:32]C)CC)C.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=[O:36]>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([C:32](=[O:36])[NH2:29])[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)N1CCC(N2CCC(n3c(=O)n(C(N)=O)c4ccccc43)CC2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.2 %

Procedure:
1-[1-(1-Methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-dihydro-2H-benzimidazol-2-one (49 mg) and 30 mg of triethylamine were dissolved in 4 ml of chloroform, and to which 30 mg of (4-nitrophenyl) chloroformate was added, followed by 30 minutes' stirring at room temperature. Thereafter the solvent was distilled off, and the resulting residue was dissolved in 5 ml of tetrahydrofuran. To the solution 1 ml of aqueous ammonia was added and stirred for 30 minutes at room temperature. Then water was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=20/1) to provide 38 mg of the title compound as a colorless solid.