Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:3]=1[O:4][C:5]1[C:6]([C:11]2(C)CS[C:13](N)=[N:12]2)=NC=C[CH:10]=1.[CH3:23][C:24]1[N:25]=[C:26]([NH2:29])[S:27][CH:28]=1.ClC1C=C(OC2C(F)=CC=CC=2F)C=CN=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[C:3]=1[O:4][C:5]1[CH:10]=[CH:13][N:12]=[C:11]([NH:29][C:26]2[S:27][CH:28]=[C:24]([CH3:23])[N:25]=2)[CH:6]=1
Reactant: CC1(c2ncccc2Oc2c(Cl)cccc2Cl)CSC(N)=N1
Reactant: Cc1csc(N)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Fc1cccc(F)c1Oc1ccnc(Cl)c1
Product: Cc1csc(Nc2cc(Oc3c(Cl)cccc3Cl)ccn2)n1
Yield: 50 %

Procedure:
Preparation of N-(4-(2,6-dichlorophenoxypyridin-2-yl)-4-methylthiazol-2-amine: Using the method of Example 3, Step B, 4-methylthiazol-2-amine (0.291 g, 2.55 mmol), 2-chloro-4-(2,6-difluorophenoxy)pyridine (0.700 g, 2.55 mmol), potassium phosphate (0.595 g, 2.80 mmol), Pd2(dba)3 (0.117 g, 0.127 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.074 g, 0.127 mmol) were reacted to provide N-(4-(2,6-dichlorophenoxy)pyridin-2-yl)-4-methylthiazol-2-amine (0.450 g, 50% yield). 1H NMR (d-DMSO) δ 10.99 (s, 1H), 8.20 (d, 1H), 7.71 (d, 2H), 7.45 (t, 1H), 6.50-6.54 (m, 2H), 6.47 (s, 1H), 2.20 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:17][CH3:18]>CN(C=O)C>[CH2:17]([O:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[F:9])[CH3:18]
Reactant: CCBr
Reactant: Nc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1ccc(N)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 18.3 %

Procedure:
To a solution of 4-amino-2-fluorophenol (2.15 g, 16.9 mmol) in dry DMF (60 mL) in a 100 mL round-bottomed flask equipped with a magnetic stirrer was added Cs2CO3 (10.6 g, 25.4 mmol) and the mixture was stirred for 10 min at RT before addition of bromoethane (1.5 mL, 20.3 mmol). The reaction mixture was then stirred for 7 h at RT, concentrated to dryness, and the residue was partitioned between CH2Cl2 (100 mL) and water (20 mL). The organic layer was washed with brine (20 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent cyclohexane:EtOAc=100:0 to 88:12) gave 4-ethoxy-3-fluoroaniline SMA 44094 as a brown oil (480 mg, 18% yield).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH2:31]([N:33]=[C:34]=[O:35])[CH3:32]>C(#N)C>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:34]([NH:33][CH2:31][CH3:32])=[O:35])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCN=C=O
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Solvent: CC#N
Product: CCNC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 4 ml of dry acetonitrile is added at RT 16 μl (0.2 mmol) of ethyl isocyanate (Fluka, Buchs, Switzerland). After stirring for 16 h at RT, working-up is effected by partitioning between water and ethyl acetate. The organic layer is dried over magnesium sulfate and evaporated to dryness to provide trans-1-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-ethyl-urea. Analytical HPLC: tR=6.77 min (Grad 2); ES-MS: m/eo=471.1.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[N+:28]([C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)([O-:30])=[O:29].O>CN(C)C=O>[CH3:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:34]1[CH:35]=[CH:36][C:31]([N+:28]([O-:30])=[O:29])=[CH:32][CH:33]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCOCCc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
A portion of 13 (9.0 g, 28.3 mmol) was dissolved in 50 mL of dimethylformamide. Potassium carbonate (11.75 g, 85.0 mmol) and 4-nitrophenol (3.82 g, 27.5 mmol) were added. The solution was stirred at 80° C. for 16 hours. After cooling to room temperature, the solution was poured into water and extracted three times with methylene chloride. The combined organic layers were washed with water, then brine, dried over magnesium sulfate, filtered, and the solvent was removed by distillation at reduced pressure. Chromatography (silica, hexane:ethyl acetate, 1:2) was employed to isolate the product (5.71 g, 73% yield). IR (neat) 3109.2, 3078.2, 2878.5, 1726.3, 1588.1, 1511.2, 1337.1, 1106.7, 1050.3, 932.6, 845.5, 753.3, 656.1 cm−1. 1H NMR (CDCl3) δ 8.07 (d, J=9.3 Hz, 2H), 6.88 (d, J=9.3 Hz, 2H), 4.12 (app t, 2H), 3.79 (app t, 2H), 3.62 (m, 2H), 3.58 to 3.53 (m, 4H), 3.44 to 3.42 (m, 2H), 3.26 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 164.29, 141.93, 126.24, 114.99, 72.29, 71.29, 71.03, 70.98, 69.77, 68.60, 59.44.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[Li]CCCC.[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](=[O:39])N(OC)C)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]>C1COCC1>[C:21]([O:25][C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34](=[O:39])[C:2]2[CH:15]=[CH:14][CH:13]=[C:4]([O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7])[CH:3]=2)[CH2:30][CH2:29]1)=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2cccc(O[Si](C)(C)C(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.3 %

Procedure:
To the solution of (3-bromophenoxy)-tert-butyldimethylsilane (from Example 5, 6.12 g) in THF (120 mL) at −75° C. was slowly added nBuLi (9.37 mL of 2.5 M solution) under nitrogen. After 15 minutes, the solution of 4-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (5.80 g) in THF (10 mL) was dropwise added. The reaction was stirred under nitrogen overnight while it warmed to room temperature. The reaction was quenched by slow addition of aqueous NH4Cl solution (80 mL). The resulting mixture was extracted by EtOAc (120 mL). The organic layer was washed by water (80 mL×3) and brine (80 mL×1), dried by Na2SO4 and concentrated to give crude product (9.13 g), which was purified to afford pure 4-[3-(tert-butyl-dimethylsilanyloxy)benzoyl]piperidine-1-carboxylic acid tert-butyl ester (5.12 g; 57%). 1H NMR (600 MHz, DMSO-d6) δ 7.60 (d, 1H, J=8.0 Hz), 7.41 (dd, 1H, J=8.0, 8.0 Hz), 7.32 (m, 1H), 7.11 (dd, 1H, J=8.0, 2.5 Hz), 3.94 (m, 2H), 3.57 (m, 1H), 2.90 (bs, 2H), 1.72 (m, 2H), 1.38 (s, 9H), 1.37 (m, 2H), 0.94 (s, 9H), 0.19 (s, 6H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[Si:11]([O:18][C@H:19]1[CH2:23][N:22]([CH3:24])[C@H:21]([CH2:25][OH:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[Si:11]([O:18][C@H:19]1[CH2:23][N:22]([CH3:24])[C@H:21]([CH:25]=[O:26])[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CN1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 109.6 %

Procedure:
Dimethyl sulfoxide (174 μL, 2.45 mmol) was dissolved in 20 mL of dichloromethane in a dry ice bath. After the system temperature was stable, oxalyl chloride (156 μL, 1.80 mmol) was added dropwise slowly. After stirring for 30 minutes, a solution of [(2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidin-2-yl]methanol 3d (300 mg, 1.20 mmol) in 2 mL of dichloromethane was added dropwise. After stirring for 45 minutes, the reaction mixture was added with triethylamine (510 μL, 3.67 mmol), and stirred for 10 minutes, then warmed up to room temperature and stirred for 1 hour. The reaction mixture was diluted with 100 mL of dichloromethane, washed with saturated sodium bicarbonate (20 mL), saturated ammonium chloride (20 mL) and saturated brine (20 mL) successively, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound (2S,4R)-4-(tert-butyl(dimethyl)silyl)oxy-1-methyl-pyrrolidine-2-carbaldehyde 3e (320 mg) crude product as a yellow oil, which was directly used in the next step.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])=O>[Ni].CO>[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]([OH:11])=[CH:8][C:9]=1[OH:10])[CH3:1]
Reactant: CC(=O)c1ccc(O)cc1O
Agent: [Ni]
Solvent: CO
Product: CCc1ccc(O)cc1O
Temperature: 70 °C
Reaction time: 8 h

Procedure:
2,4-dihydroxy acetophenone (76 g, 0.5 mole) was charged in a 1 liter autoclave reactor along with methanol (300 ml), and Raney Nickel (15.2 g—washed several times with water and water/methanol to a pH of 7.0) and 750 mg of Pd/C. The autoclave was checked for leaks with 100-200 psi of nitrogen. The autoclave was pressurized to 300 psi with hydrogen and stirred at 70° C. for 8 hrs. During this time 95% of the theoretical value for hydrogen was consumed. The reaction was vented and the contents were filtered through a milipore filter to give a light yellow solution. Concentration of this solution in vacuo gave a solid. This solid was crystalized from 1,2-dichloroethane to give 4-ethyl resorcinol in 70% isolated yield. The unreacted 2,4-dihydroxy acetophenone was recovered (˜27%) from the reaction mixture and was recycled. The structure of 4-ethyl resorcinol was characterized by using the NMR, Gas Chromatography, IR and Mass spectroscopy.
Reaction SMILES: Br.C[O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1>C(O)(=O)C>[OH:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]([OH:17])=[O:16])=[CH:6][CH:5]=1
Reactant: COc1ccc2cccc(CC(=O)O)c2c1
Agent: Br
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc2ccc(O)cc12

Procedure:
In a 250 ml round-bottomed flask, dissolve 2-(7-methoxynaphth-1-yl)acetic acid in acetic acid. Add hydrobromic acid and reflux the reaction mixture for 4 hours. Remove the acetic acid and hydrobromic acid by evaporation under reduced pressure. Take up the solid in water and suction it off. Wash the precipitate with petroleum ether and recrystallise it from toluene.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:19]([OH:21])=O)[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.Cl.Cl.[CH2:35]([NH:42][NH2:43])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[CH2:35]([NH:42][NH:43][C:19](=[O:21])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:22][CH:23]([CH3:25])[CH3:24])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NNCc1ccccc1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)C[C@@H](C(=O)NNCc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Yield: 41.6 %

Procedure:
A mixure of 3.46 g of (E)-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvaleric acid, 4.0 g of N-methyl morpholine, 2.95 g of benzylhydrazine dihydrochloride and 1.7 g of 1-hydroxybenzotriazole hydrate in 25 ml of dimethylformamide was cooled to 0° C. while stirring under nitrogen and 2.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide were added. The mixture was gradually allowed to come to room temperature and was then stirred overnight. The dimethylformamide was evaporated and the residue was partitioned between ethyl acetate and saturated sodium hydrogen carbonate solution. The ethyl acetate phase was washed in sequence with water, 5% citric acid solution, water and saturated sodium chloride solution. After drying over anhydrous magnesium sulphate the ethyl acetate was evaporated to give a yellow gum. Crystallization from hexane gave 1.87 g of (E)-2′-benzyl-2(R)-[1(S)-(tert.-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methylvalerohydrazide as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[N:33][C:32]([CH:35]=[C:36]([CH3:38])[CH3:37])=[CH:31][N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[N:33][C:32]([CH:35]=[C:36]([CH3:38])[CH3:37])=[CH:31][N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CC(C)=Cc1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)=Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 930 mg, 2.82 mmol) in methylene chloride (10 mL) was treated with oxalyl chloride (490 μL, 5.64 mmol) and N,N-dimethylformamide (1 drop). The mixture was stirred at 25° C. for 2 h. The reaction mixture was concentrated in vacuo, and the residue was dried in vacuo. The residue was then dissolved in benzene, and the solvents were concentrated in vacuo. The residue was dried in vacuo. This material was dissolved in methylene chloride (10 mL), cooled to 0° C., and then treated with a mixture of 2-amino-5-(2,2-dimethylvinyl)-pyrazine (420 mg, 2.82 mmol) and pyridine (340 μL) in methylene chloride (10 mL). The ice bath was removed, and the solution was stirred at 25° C. overnight. The mixture was extracted with methylene chloride and a 0.1N aqueous hydrochloric acid solution. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 2/1 hexanes/ethyl acetate) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2-methylpropenyl)-pyrazin-2-yl]-propionamide (1.10 g, 85%) as a light yellow foam.
Reaction SMILES: [CH2:1]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=[C:3]2[CH2:2]1.CO[CH2:11][Cl:12].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:12][CH2:11][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[CH2:1][CH2:2][C:3]=12
Reactant: c1ccc2c(c1)CC2
Reactant: COCCl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: ClCc1cccc2c1CC2
Temperature: 0 °C
Yield: 41 %

Procedure:
To a stirred solution of 10 g of benzocyclobutene and 18.25 mL of chloromethyl methyl ether in 100 mL of methylene chloride at -78° C. under a nitrogen atmosphere, 11.1 g tin tetrachloride was added slowly over a period 1 hour and stirring was continued for 6 more hours at -78° C. The reaction mixture was then poured into an ice cold sodium hydroxide solution (10%) and extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. Removal of the solvent followed by purification by flash chromatography afforded 6 g of 4-chloromethylbenzocyclobutene (41%) as a colorless liquid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:2].[O-]S([O-])(=O)=O.[Mg+2].CC(C)([O-])C.[Na+].Br[C:22]1[C:30]2[NH:29][C:28]3[CH2:31][CH2:32][N:33]([CH3:35])[CH2:34][C:27]=3[C:26]=2[CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C>[CH3:35][N:33]1[CH2:32][CH2:31][C:28]2[NH:29][C:30]3[C:22]([C:2]#[C:1][C:3]4[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=4)=[CH:23][CH:24]=[CH:25][C:26]=3[C:27]=2[CH2:34]1
Reactant: CN1CCc2[nH]c3c(Br)cccc3c2C1
Reactant: C#Cc1cccnc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3c(C#Cc4cccnc4)cccc3c2C1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Bis(tri-t-butylphosphino)palladium (18.9 mg, 0.057 mmol; Aldrich), 3-ethynylpyridine (117 mg, 1.131 mmol; Aldrich), MgSO4 (68 mg, 0.57 mmol), sodium t-butoxide (136 mg, 1.41 mmol; Aldrich) and the product of Example 1A (150 mg, 0.57 mmol) were suspended in dioxane (5 mL). The mixture was purged with a nitrogen stream for 2 minutes, then stirred under nitrogen at 100° C. for 2 hours in a sealed tube. The mixture was cooled to room temperature, filtered though a glass microfiber frit, rinsed with CH3OH (3 mL) and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 40-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (400 MHz, methanol-d4) δ ppm 2.54 (s, 3H), 2.88 (t, J=6.0 Hz, 2H), 2.98 (t, J=5.6 Hz, 2H), 3.68 (s, 2H), 7.01 (t, J=7.6 Hz, 1H), 7.27 (dd, J=7.3, 0.9 Hz, 1H), 7.43 (dd, J=7.9, 0.9 Hz, 1H), 7.46 (ddd, J=7.9, 5.0, 0.8 Hz, 1H), 8.06 (dt, J=7.9, 1.8 Hz, 1H), 8.49 (dd, J=5.0, 1.7 Hz, 1H), 8.81 (dd, J=2.1, 0.9 Hz, 1H); MS (APCI) m/z 288 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH3:14])[C:9]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:24]([OH:26])[CH3:25]>>[CH2:2]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:16]=[C:17]([C:18](=[NH:19])[O:26][CH2:24][CH3:25])[CH:20]=[CH:21][CH:22]=2)[CH3:14])[C:9]1=[O:23])[CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C#N)c1
Reactant: CCO
Agent: Cl
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(C(=N)OCC)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Hydrogen chloride gas was bubbled through a solution of 3-(3-hexyl-6-methyl-2-oxo-3-azabicyclo[3.1.0]hex-6-yl)benzonitrile (Preparation 36, 0.55 g, 1.86 mmol) in ethanol (8 ml) at 0° C. for 1 h. The reaction vessel was then sealed and left standing in the fridge for 48 h. The mixture was allowed to warm to room temperature and the solvent was removed in vacuo (to afford the title compound as its hydrochloride salt). The residue was dissolved in dichloromethane (20 ml) and washed with 10% w/v potassium carbonate solution (2×10 ml). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The crude title compound (700 mg) was isolated as a colourless oil which was taken on without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[C:17](Cl)(=[O:19])[CH3:18]>ClCCl>[C:17]([O:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)(=[O:19])[CH3:18]
Reactant: Oc1ccc(F)c(Br)c1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(F)c(Br)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
A solution of 3-bromo-4-fluorophenol (4.5 g, 23 mmol) [Ark Pharm, AK-26802] in dichloromethane (96 mL) at 0° C. was treated with triethylamine (4.9 mL, 35 mmol) followed by acetyl chloride (2.3 mL, 33 mmol) dropwise and stirred at 20° C. for 30 minutes. The reaction mixture was diluted with dichloromethane (100 mL), washed with 0.5 M hydrogen chloride in water (100 mL), saturated sodium bicarbonate (100 mL), and brine (50 mL), dried with sodium sulfate, filtered, and concentrated to give the desired product (5.5 g, quantitative) as a tan solid. This material, which did not ionize in the mass spectrometer, was used without further purification.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1.Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[CH:6][CH:5]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: FC(F)(F)Oc1ccc(-c2cccnc2)cc1
Temperature: 85 °C
Reaction time: 3 h
Yield: 83.5 %

Procedure:
4-(Trifluoromethoxy) phenyl boronic acid (1.3 g, 6.31 mmol) was dissolved in ethylene glycol dimethyl ether (50 ml). 3-Bromopyridine (1 ml, 9.5 mmol), aqueous sodium carbonate (2M, 30 ml), and Pd(dppb)Cl2 (100 mg) were added and the reaction mixture was stirred at 85° C. for 3 hours. The mixture was allowed to cool to room temperature, then water (200 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/ether (60:40) to give the title compound as an oil (1.26 g, 84%). 1H NMR (250 MHz, CDCl3) δ 8.84 (1H, s), 8.60 (1H, br d), 7.87 (1H, m), 7.61 (2H, m), and 7.36 (3H, m). m/z (ES+) 240 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[C:15]([F:16])=[C:14](I)[CH:13]=[CH:12][N:11]=1.[CH3:18][I:19]>O1CCCC1>[Cl:9][C:10]1[C:15]([F:16])=[C:14]([CH3:13])[C:18]([I:19])=[CH:12][N:11]=1
Reactant: CI
Reactant: Fc1c(I)ccnc1Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(I)cnc(Cl)c1F
Temperature: -78 °C
Reaction time: 4 h
Yield: 81 %

Procedure:
To a solution of 2.0 M of lithium diisopropylamide in tetrahydrofuran (5.5 mL) in tetrahydrofuran (20 mL, 200 mmol) at −78° C. was slowly added 2-chloro-3-fluoro-4-iodopyridine (2.589 g, 10.06 mmol) as a solution in tetrahydrofuran (8 mL). The reaction mixture was then stirred at −78° C. for 4 hours. Methyl iodide (0.70 mL, 11 mmol) was then added. After an additional 1 hour, the reaction was then quenched with saturated aqueous NH4Cl and warmed to room temp. The reaction mixture was poured into ethyl acetate and washed sequentially with water and brine, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via flash chromatography on silica gel (80 g silica, solvent gradient: 0-30% ethyl acetate in heptanes) to yield 2.212 g (57%) of 2-chloro-3-fluoro-5-iodo-4-methylpyridine. LCMS (ESI): M+H=272.0; 1H NMR (500 MHz, CDCl3) δ 8.46 (s, 1H), 2.44 (d, J=1.2 Hz, 3H).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27](O)=[O:28])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37](=[N:39]O)[NH2:38])=[CH:33][CH:32]=1>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]2[N:39]=[C:27]([CH:13]3[CH2:14][CH:15]([C:17]4[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=4)[CH2:16][N:11]([C:9]([N:6]4[CH2:7][CH2:8][CH:3]([C:1]#[N:2])[CH2:4][CH2:5]4)=[O:10])[CH2:12]3)[O:28][N:38]=2)=[CH:33][CH:32]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1ccc(F)cc1
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4ccc(F)cc4)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 41.4 mg (0.269 mmol) of 4-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 78.2 mg (59% of theory).