Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=2[OH:11])[CH2:3][CH2:2]1.ClC1C=CC=CC=1Cl.[OH-].[Na+].[OH:22][C:23]1[CH:28]=[C:27]([Cl:29])[N:26]=[N:25][C:24]=1Cl>C(O)(C)(C)C>[Cl:29][C:27]1[N:26]=[N:25][C:24]([O:11][C:5]2[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:4]=2[CH:1]2[CH2:3][CH2:2]2)=[C:23]([OH:22])[CH:28]=1
Reactant: Cc1cccc(C2CC2)c1O
Reactant: Oc1cc(Cl)nnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: Clc1ccccc1Cl
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a mixture of 12.8 g (86.4 mmol) of 2-cyclopropyl-6-methylphenol and 1,2-dichlorobenzene (78.3 mL) was added 3.64 g (86.4 mmol) of 95% sodium hydroxide at room temperature. The resultant mixture was heated to 180° C. and subjected to azeotropic dehydration under reflux while stirring for 30 minutes. To the resultant solution was added dropwise the preliminarily prepared solution of 5.00 g (purity: 95%; 28.8 mmol) of 4-hydroxy-3,6-dichloropyridazine in t-butanol (95.0 g) at 160° C. over 2 hours. (The t-butanol was distilled off simultaneously with the dropwise addition of the solution.) After stirring at 180° C. for another 30 minutes, the reaction mixture was cooled to room temperature, and 78.7 g of pure water was added to the cooled mixture and stirred for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol added in an excess amount was separated. 50.0 g of toluene was added to the resultant aqueous phase and stirred at room temperature for 30 minutes, and an organic phase containing 2-cyclopropyl-6-methylphenol was separated. This operation was repeated twice. Then, the resultant aqueous solution containing a sodium salt of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol was quantitatively determined by an HPLC internal standard analysis method, which showed that 6.10 g of 6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 77%) and 39 mg of 3-chloro-6-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (yield: 0.5%) were obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[N:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(N(CC)CC)C.[Cl:27][CH2:28][C:29](Cl)=[O:30]>O1CCCC1>[Cl:27][CH2:28][C:29]([N:11]1[CH2:12][CH2:13][N:8]([C:7]2[CH:6]=[CH:5][C:4]([C:14]3[N:15]=[CH:16][CH:17]=[CH:18][N:19]=3)=[CH:3][C:2]=2[F:1])[CH2:9][CH2:10]1)=[O:30]
Reactant: Fc1cc(-c2ncccn2)ccc1N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-(3-Fluoro-4-piperazin-1-yl-phenyl)-pyrimidine (29AB) (675 mg, 2.61 mmol, 1 equiv) was dissolved in anhydrous tetrahydrofuran (5 mL), and triethylamine (1.32 mg, 1.82 mL, 13.05 mmol, 5 equiv) was added, followed by slow addition of a solution of chloroacetyl chloride (591 mg, 417 uL, 5.23 mmol, 2 equiv) in tetrahydrofuran at room temperature. The mixture was then stirred for about 1 hour at room temperature.
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][C:13](=O)[C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]>CC(O)=O.CO.[Zn]>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:18][C:8]2=[CH:9][C:10]3[C:11](=[O:17])[NH:12][CH2:13][C:14]=3[CH:15]=[C:7]2[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3=O
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)NC3
Temperature: 113 °C

Procedure:
(Ref. Brewster, J. H.; Fusco A. M. J.Org. Chem., 28, 501-503 (1963)) A solution of 6-(dipropylamino)-6,7-dihydrocyclopent[f]isoindole-1,3(2H,5H)-dione 93 (0.45 g, 1.6 mmol) in glacial HOAc (50 mL) was treated with Zinc dust (1.05 g, 16.0 mmol) then refluxed at 113° C. for 24 h. The reaction was cooled to r.t., diluted with MeOH and filtered through a pad of celite. The filtrate was concentrated and the residue was diluted with H2O, basified with sat'd Na2CO3, and extracted with CH2Cl2. The organic layers were washed with brine, dried (MgSO4), and concentrated. The resulting solid was purified using silica gel, eluting with 2:1 heptane/acetone to give 94 as a white solid (m.p. 206-208° C.).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]#[N:16])=[C:10]([Cl:17])[N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]#[N:16])=[C:10]([Cl:17])[N:9]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C#N)c(Cl)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1c(Cl)cc(N)nc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl(4,6-dichloro-5-cyanopyridin-2-yl)carbamate (2.1 g, 7.2 mmol) in dichloromethane (30.0 mL) was added TFA (3.0 mL) at 0° C. and stirred at the room temperature for 3 h. After confirming the completion of starting material by TLC, the reaction mixture was concentrated and the crude product was purified by column chromatography (dichloromethane:methanol=9:1) to afford titled compound. 1H NMR (ppm, 400 MHz, DMSO-d6): δ 7.81 (bs, 2H), 6.59 (s, 1H), MS ES calc'd. for C6H3C12N3 [M+H]+ 188. Found 188.
Reaction SMILES: [NH2:1][C:2](=[S:19])[C@@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH2:20](OC(OCC)CBr)[CH3:21]>CC(C)=O.Cl.O1CCOCC1>[C:5]1([CH2:4][C@H:3]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:15])[CH3:17])[C:2]2[S:19][CH:20]=[CH:21][N:1]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(CBr)OCC
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(N)=S
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)c1nccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 10.2 %

Procedure:
To a mixture of #13 (5.65 g, 20.2 mmol, 1 eq.) in acetone (101 mL, 0.2 M) was added bromoacetaldehyde diethyl acetal (8.76 mL, 58.2 mmol, 2.89 eq.) and 2 drops of 4 M hydrochloric acid in dioxane. The mixture was degassed with nitrogen three times before being heated to reflux. After 2 hours, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and washed with brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude orange oil was diluted with ethyl acetate before being concentrated in vacuo onto silica and purified by silica gel chromatography (Gradient: 0% to 35% ethyl acetate in heptane) and then by reverse phase chromatography (Method A) to give #14 (625 mg, 10%); HPLC (Protocol E): m/z 304.5 [M+H+], 248.9 [(M−2-methylprop-1-ene)+H+], retention time=7.416 minutes; 1H NMR (400 MHz, DMSO-d6), presumed to be a mixture of rotamers, major rotamer: δ 7.75 (d, J=3.3 Hz, 1H), 7.75 (br d, J=8.6 Hz, 1H), 7.61 (br d, J=3.1 Hz, 1H), 7.25-7.30 (m, 5H), 4.99 (ddd, J=10.5, 8.9, 4.5 Hz, 1H), 3.29-3.36 (m, 1H, assumed; partially obscured by water signal), 2.98 (dd, J=13.8, 10.6 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.C([O:17][C:18]1[CH:27]=[C:26]([CH2:28]Br)[C:25]([Br:30])=[CH:24][C:19]=1[C:20]([O:22]C)=[O:21])(=O)C>CC(C)=O>[Br:30][C:25]1[C:26]([CH2:28][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:27][C:18]([OH:17])=[C:19]([CH:24]=1)[C:20]([OH:22])=[O:21]
Reactant: COC(=O)c1cc(Br)c(CBr)cc1OC(C)=O
Reactant: C1COCCN1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1O
Reaction time: 0.5 h

Procedure:
Triethylamine (0.37 ml, 2.63 mmol) and morpholine (0.15 ml, 1.71 mmol) were added to a solution of methyl 2-(acetyloxy)-5-bromo-4-(bromomethyl)benzoate (may be prepared as described in Description 4; 481 mg, 1.31 mmol) in acetone (10 ml). The mixture was stirred for 30 minutes then the solvent was removed in vacuo. The residue was redissolved in dichloromethane (10 ml), washed with water (10 ml), dried (MgSO4) and the solvent removed in vacuo to give the morpholine intermediate.
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:8]=1[C:9](Cl)=[O:10]>CN(C)C=O.N1C=CC=CC=1>[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[CH:13]=[C:12]([CH3:17])[C:8]=1[C:9]([NH:1][NH:2][C:3]([NH2:5])=[S:4])=[O:10]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: NNC(N)=S
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C(=O)NNC(N)=S)c(C)c1
Temperature: 80 °C

Procedure:
37.25 g of thiosemicarbazide was dissolved in 400 ml dimethylformamide and 32.05 g of pyridine, after which 74 g of 2,4,6-trimethylbenzoyl chloride was added at 0° C. in 20 minutes. The reaction mixture was heated at 80° C. for 2 hours and then concentrated to three-quarters in vacuo and the remaining mixture was poured into 1500 ml of cold water. The resulting white precipitate was filtered, washed in water and dried.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCOCC1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 28.9 %

Procedure:
To an ice cold solution of chloroacetyl chloride (1.29 g, 11 mmol) in 10 mL of methylene chloride was added morpholine (1 g, 11 mmol) in 10 mL of methylene chloride containing triethylamine (2.32 g, 23 mmol). The reaction mixture was stirred at 5° C. for 30 minutes then warmed to room temperature and stirred for 18 hours. After quenching with water (20 mL) at 5° C., additional methylene chloride (100 mL) was added. The organic layer was separated, washed with 1N HCl (1×50 mL), saturated aqueous NaHCO3 (1×50 mL), brine (1×50 mL), dried over MgSO4, filtered and concentrated at reduced pressure. The concentrated residue was dried in vacuo to give 0.52 g (28.8%) of 4-(2-chloroacetyl)morpholine as a brown oil. 1H NMR (300 MHz / CDCl3): δ 3.51-3.54 (m, 2H), 3.61-3.64 (m, 2H), 3.68-3.74 (m, 4H), 4.06 (s, 2H). HRMS: calcd for C6H10N1O2 Cl1 164.0478, found 164.0498.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.[Na+].[CH3:12][S:13]([O-:15])=[O:14]>CN(C=O)C>[CH3:12][S:13]([CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1)(=[O:15])=[O:14]
Reactant: CS(=O)[O-]
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(=O)[nH]c(=O)[nH]1
Temperature: 125 °C
Yield: 112.3 %

Procedure:
6-(Chloromethyl)-1H-pyrimidine-2,4-dione (175 g, 1.09 mol) was dissolved in DMF (2 L) and methanesulphinic acid sodium salt (133.5 g, 1.31 mol) was added. The reaction was heated to 125° C. for 2 hours then allowed to cool and the suspension filtered and concentrated in vacuo to give a yellow solid. The crude material was washed with water, filtered, then triturated with toluene. The solid was filtered then triturated with isohexane to leave the desired compound as a yellow solid (250 g). The material was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].Cl[C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:9])=[O:10])[CH:5]=[CH:4][C:3]=1[O:12][C:14]1[N:19]=[CH:18][N:17]=[C:16]2[N:20]([C@H:23]3[CH2:28][CH2:27][C@H:26]([C:29]4[O:33][N:32]=[C:31]([CH:34]([CH3:36])[CH3:35])[N:30]=4)[CH2:25][CH2:24]3)[N:21]=[CH:22][C:15]=12
Reactant: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Cl)ncnc43)CC2)n1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1noc([C@H]2CC[C@H](n3ncc4c(Oc5ccc(S(C)(=O)=O)cc5F)ncnc43)CC2)n1
Temperature: 180 °C

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 93 mg, 0.49 mmol), 4-chloro-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 26; 170 mg, 0.49 mmol) and potassium carbonate (81 mg, 0.59 mmol) in anhydrous DMF (5 mL) was heated in a microwave at 180° C. for 10 min. The mixture was filtered. The filtrate was concentrated and purified using a Supelco 23 g column, eluting with 0-3% methanol/dichloromethane to give 4-(2-fluoro-4-methanesulfonyl-phenoxy)-1-[4-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-trans-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidine (153 mg, 62%).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>>[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:13](=[O:15])[C:12]1[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)(=[O:8])=[O:9])[CH:11]=1
Reactant: COc1ccccc1N
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Product: COc1ccccc1NC(=O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 73 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-methoxyaniline as the starting materials.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][CH2:15][C:16]([O:18][CH3:19])=[O:17].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[CH:36]=[O:37])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1>[CH3:13][O:14][CH:15]([CH:36]([OH:37])[C:35]1[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: O=Cc1ccccc1CCCCCCCCc1ccccc1
Reactant: COCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COC(=O)C(OC)C(O)c1ccccc1CCCCCCCCc1ccccc1
Reaction time: 0.25 h

Procedure:
To tetrahydrofuran (50 ml), cooled to -78° C. under argon, was added diisopropylamine (5.7 ml, 0.041 mole) followed by n-butyllithium (16 ml, 0.041 mole) slowly. After 15 minutes, methyl methoxyacetate (4.25 g, 0.041 mole) in tetrahydrofuran (10 ml) was added dropwise. The resulting solution was stirred for 30 minutes after which a solution of 2-(8-phenyloctyl)benzaldehyde in tetrahydrofuran (10 ml) was added dropwise. After 2 hours the reaction mixture was quenched with a solution of saturated ammonium chloride and then diluted with ice water. The aqueous layer was extracted with ether. The combined ether extract was washed with 10% sodium hydroxide (ice cold), dried over magnesium sulfate, filtered and evaporated to give the desired product.
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH2:27]>>[F:22][C:23]([F:32])([F:33])[C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][NH:27][CH2:18][C:17]1[CH:20]=[CH:21][C:14]([C:12]2[O:11][N:10]=[C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[N:13]=2)=[CH:15][CH:16]=1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: NCc1ccccc1C(F)(F)F
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccccc3C(F)(F)F)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. M+(LC/MS(ESI)): 446.4. HPLC (Condition A), Rt: 4.23 min (HPLC purity: 96.5%).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH2:14]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[CH3:15]>ClCCl>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([CH2:14][CH3:15])[CH:17]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N)c1
Reactant: CCc1cccc(N(C)C#N)c1
Agent: Cl
Solvent: ClCCl
Product: CCc1cccc(NC(=N)N(C)c2cccc(CC)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56 %

Procedure:
A mixture of N-(m-ethylphenyl)-N-methylcyanamide (640 mg, 4 mmol) and m-ethylaniline hydrochloride (630 mg, 4 mmol) was placed in a pre-heated oil bath at 160° C. for 2.5 hours and then allowed to cool to room temperature. The resulting solid was taken up in dichloromethane and washed with 10% NaOH solution. The organic layer concentrated and the residue was flash chromatographed on SiO2 to give N,N'-di-(m-ethylphenyl)-N-methylguanidine (630 mg, 56%) as a colorless liquid:
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:8]=[CH:9][C:10]=1[CH3:11].C1C(=O)N([Br:28])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:28][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)=[CH:6][C:5]=1[O:4][CH2:3][O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCOc1cc(-c2nc3ccccc3o2)ccc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COCOc1cc(-c2nc3ccccc3o2)ccc1CBr
Temperature: 25 °C

Procedure:
A solution of 2-[3-(methoxymethoxy)-4-methylphenyl]-1,3-benzoxazole (200 mg, 0.74 mmol, 84%), NBS (179 mg, 0.81 mmol), and benzoyl peroxide (50 mg) in CCl4 (10 mL), was refluxed for 12 h. After cooling to rt, CCl4 was removed in vacuo and residue was purified by flash column (silica gel, hexanes:EtOAc 5:1) to afford 2-[4-(bromomethyl)-3-(methoxymethoxy)phenyl]-1,3-benzoxazole. MS (ESI) 349 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[NH:7][C:6]=2[CH:5]=[C:4]([C:27]([F:30])([F:29])[F:28])[CH:3]=1.C(B(CC)[C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1)C.C([O-])([O-])=O.[Na+].[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(COC)OC>[N:36]1[CH:37]=[CH:38][CH:39]=[C:34]([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:12][CH2:13][N:14]([C:17]5[C:22]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:15][CH2:16]4)[NH:7][C:6]=3[CH:5]=[C:4]([C:27]([F:30])([F:28])[F:29])[CH:3]=2)[CH:35]=1
Reactant: CCB(CC)c1cccnc1
Reactant: FC(F)(F)c1cc(Br)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
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: [Na+]
Solvent: COCCOC
Product: FC(F)(F)c1cc(-c2cccnc2)c2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2c1
Reaction time: 0.67 h

Procedure:
A mixture of 4-bromo6-trifluoromethyl-2-[4-(3-trifluoromethylpyridin-2-yl)piperazin-1-yl]-1H-benzoimidazole (99 mg, 0.2 mmol, Example 7), diethyl(3-pyridyl)borane (37 mg, 0.25 mmol, Aldrich), Pd(PPh3)4 (23 mg, 0.02 mmol, Aldrich), Na2CO3 (32 mg, 0.3 mmol) and dimethoxyethane (1 mL) was subjected to microwave irradiation at 200° C. with stirring for 40 min. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with 60% EtOAc/hexane, to give the title compound as a yellow amorphous solid. MS (ESI, pos. ion) m/z: 493 (M+1).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][C:5]([C:10]([OH:12])=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.S(Cl)(Cl)=O.[F:17][C:18]1[CH:19]=[C:20]([CH2:24]O)[CH:21]=[CH:22][CH:23]=1>>[N:2]12[CH2:9][CH2:8][C:5]([C:10]([O:12][CH2:24][C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C12CCN(CC1)CC2
Reactant: OCc1cccc(F)c1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(OCc1cccc(F)c1)C12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 29.9 %

Procedure:
A mixture of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.52 mmol) and thionyl chloride (500 μl, 6.85 mmol) was refluxed for 2 hours. The reaction was cooled to room temperature, and the solvent was accurately removed. The residue was suspended in dry DCM and treated with (3-fluorophenyl)methanol (65.8 mg, 0.52 mmol). The reaction was stirred at room temperature for 24 hours. The solvent was evaporated, and the residue was dissolved in water (1 ml), basified with NaHCO3 and extracted twice with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and evaporated to obtain 3-fluorobenzyl quinuclidine-4-carboxylate (41 mg, 29.8% yield), which was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.ClC1C=C(C=CC=1)C(OO)=[O:22]>>[Cl:1][C:2]1[CH:7]=[CH:6][N+:5]([O-:22])=[CH:4][C:3]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1
Reactant: COc1ccc(Cc2cnccc2Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: COc1ccc(Cc2c[n+]([O-])ccc2Cl)cc1

Procedure:
The product of step A is oxidized to the title compound with m-chloroperoxybenzoic acid (1.1 molar equivalents).
Reaction SMILES: [O-]CC.[Na+].C(=O)(O)O.[NH2:9][C:10]([NH2:12])=[NH:11].[C:13]1([NH:19][C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:32][C:31](=O)[C:30](=[CH:34]N(C)C)[CH2:29]3)[CH:25]=[CH:24][N:23]=2)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[C:13]1([NH:19][C:20]([C:22]2[CH:27]=[C:26]([N:28]3[CH2:29][C:30]4[CH:34]=[N:9][C:10]([NH2:12])=[N:11][C:31]=4[CH2:32]3)[CH:25]=[CH:24][N:23]=2)=[O:21])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C1CN(c2ccnc(C(=O)Nc3ccccc3)c2)CC1=O
Agent: CC[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1ncc2c(n1)CN(c1ccnc(C(=O)Nc3ccccc3)c1)C2
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 46.4 %

Procedure:
To a solution of sodium ethoxide (0.18 mL, 0.56 mmol, 3M) in ethanol (10 mL) was added guanidine carbonate (50 mg, 0.56 mmol). The suspension was stirred for 45 minutes, then added to a suspension of 4-(3-((Dimethylamino)methylene)-4-oxopyrrolidin-1-yl)-pyridine-2-carboxylic acid phenylamide (95 mg, 0.28 mmol) in ethanol (10 mL). The reaction mixture was heated at 80° C. for 18 hours. Water (20 mL) was added and the mixture stirred for 1 hour. The solid was isolated by filtration and vacuum dried at 50° C. for 115 h and gave the title compound (44 mg, 0.13 mmol, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26]Cl>CN(C=O)C>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:25]=1[CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][C:6]=2[CH:16]=1
Reactant: Fc1cccc(F)c1CCl
Reactant: COC(=O)C1=Cc2cc(O)ccc2CCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C1=Cc2cc(OCc3c(F)cccc3F)ccc2CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To methyl 2-hydroxy-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (327 mg, 1.50 mmol) dissolved in DMF (6 ml) were added potassium carbonate (415 mg, 3.00 mmol) and 2,6-difluorobenzyl chloride (268 mg, 1.65 mmol), and the resulting mixture was stirred at room temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (40 ml) was added to the residue and the resulting mixture was washed with water (5 ml×2) and an aqueous saturated solution of sodium chloride (5 ml). The organic layer was dried with anhydrous magnesium sulfate and was then concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: 15 g, ethyl acetate/hexane=1/25). The objective fractions were concentrated under reduced pressure to obtain methyl 2-(2,6-difluorobenzyloxy)-6,7-dihydro-5H-benzocycloheptene-8-carboxylate (507 mg, 1.47 mmol, 98%).