Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].F[C:12]1[C:17]([C:18]2[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=3)[CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=3)[N:19]=2)=[CH:16][C:15]([C@H:44]([N:46]2[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][C@@H:47]2[CH3:56])[CH3:45])=[CH:14][N:13]=1.[F:57][C:58]1[CH:59]=[C:60]([NH2:66])[CH:61]=[N:62][C:63]=1[O:64][CH3:65].[NH4+].[Cl-]>C1COCC1>[F:57][C:58]1[CH:59]=[C:60]([NH:66][C:12]2[C:17]([C:18]3[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([N:25]([CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=4)[CH2:26][C:27]4[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=4)[N:19]=3)=[CH:16][C:15]([C@H:44]([N:46]3[CH2:51][CH2:50][N:49]([S:52]([CH3:55])(=[O:54])=[O:53])[CH2:48][C@@H:47]3[CH3:56])[CH3:45])=[CH:14][N:13]=2)[CH:61]=[N:62][C:63]=1[O:64][CH3:65]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3F)n2)cc1
Reactant: COc1ncc(N)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc([C@@H](C)N4CCN(S(C)(=O)=O)C[C@@H]4C)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.9 %

Procedure:
Lithium bis(trimethylsilyl)amide (1.0 M solution in THF, Aldrich; 9.23 mL, 9.23 mmol) was added dropwise over 5 min to a mixture of 4-(2-fluoro-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.000 g, 3.08 mmol) and 5-fluoro-6-methoxypyridin-3-amine (Anichem, Inc., 0.656 g, 4.62 mmol) in THF (30.8 mL) at 0° C., and the resulting reddish-brown solution was stirred at 0° C. for 1 h. Saturated NH4Cl (aq., 50 mL) was added and the reaction mixture was partitioned between EtOAc (100 mL) and half-saturated NH4Cl (aq., 50 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude material was adsorbed onto silica gel and purified by column chromatography (80 g of silica gel, 0% to 100% EtOAc/hexanes) gave 4-(2-((5-fluoro-6-methoxy-3-pyridinyl)amino)-5-((1R)-1-((2S)-2-methyl-4-(methylsulfonyl)-1-piperazinyl)ethyl)-3-pyridinyl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (1.90 g, 2.461 mmol, 80% yield) as a yellow solid. m/z (ESI, +ve) 771.8 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 11.89 (s, 1H); 8.69-8.73 (m, 1H); 8.20-8.24 (m, 1H); 8.08 (dt, J=12.37, 1.05 Hz, 1H); 7.95-7.98 (m, 1H); 7.18-7.24 (m, 4H); 6.82-6.90 (m, 4H); 4.78-4.88 (m, 4H); 4.01 (s, 3H); 3.97-4.01 (m, 1H); 3.81 (s, 3H); 3.78 (s, 3H); 3.18-3.20 (m, 1H); 3.08-3.15 (m, 2H); 2.75-2.87 (m, 2H); 2.67 (s, 3H); 2.56-2.63 (m, 1H); 2.59 (s, 3H); 2.43-2.51 (m, 1H); 1.40 (d, J=6.85 Hz, 3H); 1.07 (d, J=6.26 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH: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(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:56][C:57]1[NH:58][C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=1>C(Cl)Cl>[NH:58]1[C:59]2[CH:65]=[CH:64][CH:63]=[CH:62][C:60]=2[N:61]=[C:57]1[NH:56][C:13](=[O:15])[CH:12]([C:4]1[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Br:1])[CH:3]=1)[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2nc3ccccc3[nH]2)cc1Br
Yield: 52.9 %

Procedure:
A solution of 2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (100 mg, 0.266 mmol), triethylamine (110 μL, 0.80 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (187 mg, 0.42 mmol), and 2-aminobenzimidazole (56 mg, 0.42 mmol) in methylene chloride (10 mL) was stirred at 25° C. for 1.5 h. The reaction mixture was partitioned between water and methylene chloride. The organic layer was washed sequentially with a 1N aqueous hydrochloric acid solution (1×10 mL), water (1×10 mL), and a saturated aqueous sodium bicarbonate solution (1×10 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 19/1 chloroform/methanol) afforded N-(1H-benzoimidazol-2-yl)-2-(3-bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (69 mg, 53%) as a white solid: mp>220° C.; EI-HRMS m/e calcd for C22H24BrN3O3S(M+) 489.0722, found 489.0727.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][N+:7]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][C:15]5[O:23][CH2:22][O:21][C:16]=5[CH:17]=4)[C:8]=3[CH:9]=2)[C:4]=1[O:24][CH3:25].[Cl-].[C:27]([Mg]Br)#[C:28][CH3:29]>C(OCC)C>[CH3:25][O:24][C:4]1[C:5]2[CH:6]([C:27]#[C:28][CH3:29])[N:7]3[CH2:20][CH2:19][C:18]4[C:13]([C:8]3=[CH:9][C:10]=2[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[CH:14][C:15]1[O:23][CH2:22][O:21][C:16]=1[CH:17]=4
Reactant: CC#C[Mg]Br
Reactant: COc1ccc2cc3[n+](cc2c1OC)CCc1cc2c(cc1-3)OCO2
Agent: [Cl-]
Solvent: CCOCC
Product: CC#CC1c2c(ccc(OC)c2OC)C=C2c3cc4c(cc3CCN21)OCO4
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 38.9 %

Procedure:
To a suspension of berberine hydrochloride (500 mg, 1.3 mmol) in anhydrous diethyl ether (100 mL) at 0° C. was added 1-propynylmagnesium bromide solution (0.5 M in tetrahydrofuran, 26 mL, 13 mmol) dropwise. After stirring at 0° C. for 30 min, the reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with diethyl ether (2×50 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was re-crystallized from diethyl ether to afford 9,10-dimethoxy-8-prop-1-ynyl-5,8-dihydro-6H-[1,3]dioxolo[4,5-g]isoquino[3,2-a]isoquinoline (190 mg, 37%). LC/MS m/e calcd for C23H21NO4 (M+H)+: 376.43, observed: 376.2; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.68 (d, J=2.02 Hz, 3 H) 2.76-2.86 (m, 2 H) 3.21-3.30 (m, 2 H) 3.80 (d, J=3.03 Hz, 6 H) 5.39-5.43 (m, 1 H) 6.01 (d, J=5.31 Hz, 2 H) 6.15 (s, 1 H) 6.76 (d, 2 H) 6.90 (d, J=8.34 Hz, 1 H) 7.32 (s, 1 H).
Reaction SMILES: [CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([O:8]CC)=[O:7].[OH-].[Na+]>C(O)C>[CH3:1][CH:2]([CH3:11])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CCCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)CCCC(=O)O
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
In 20 ml of ethanol was dissolved 2.0 g of ethyl 5-methylhexanoate. After adding 10 ml of 2 mol/L aqueous solution of sodium hydroxide at ambient temperature, the resulting mixture was stirred for 30 minutes. The ethanol was distilled off under reduced pressure, the residue was poured into a mixture of water and chloroform, pH was adjusted to 1.0 with 2 mol/L hydrochloric acid, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Diisopropyl ether was added to the residue, and the deposited crystal was collected by filtration. Thus, 1.56 g of 5-methylhexanoic acid was obtained as a colorless oily product.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[O:20])=[CH:15][CH:14]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2].C([O-])([O-])=O.[Na+].[Na+].Br[CH2:41][CH2:42][F:43]>C(#N)C>[C:1]([CH2:3][NH:4][C:5](=[O:33])[CH:6]([O:11][CH:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:41][CH2:42][F:43])[CH2:25][CH2:26]2)=[O:20])=[CH:15][CH:14]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:7][CH:8]([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCNCC2)cc1)C(=O)NCC#N
Reactant: FCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)CC(OC(c1ccccc1)c1ccc(C(=O)N2CCN(CCF)CC2)cc1)C(=O)NCC#N
Temperature: 85 °C

Procedure:
To a solution of N-(cyanomethyl)-4-methyl-2-{phenyl[4-(piperazin-1-ylcarbonyl)phenyl]methoxy}pentanamide from example 17, step 7 (79 mg, 0.18 mmol) in acetonitrile (1 mL), was added Na2CO3 (37 mg, 0.36 mmol) and 2-bromofluoroethane (39 μL, 0.525 mmol). The reaction was heated in a sealed tube at 85° C. for 16 hours and was then cooled down to room temperature. The mixture was then concentrated and the crude residue chromatographed on silica gel using 1% NH4OH and 9% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [C:1]1([S:13]([N:16]=[N+]=[N-])(=[O:15])=[O:14])[C:2]([S:7]([N:10]=[N+]=[N-])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.[BH4-].[Na+]>C(O)C>[C:1]1([S:13]([NH2:16])(=[O:15])=[O:14])[C:2]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccccc1S(=O)(=O)N=[N+]=[N-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1S(N)(=O)=O
Yield: 97.6 %

Procedure:
One gram of 1,2-benzenedisulfonylazide was added portionwise to 0.4 gm sodium borohydride in 15 ml of ethyl alcohol with stirring and cooling. After addition, the mixture was stirred with cooling (ice/acetone bath) for 2 hours and filtered. The solid was washed with cold ethyl alcohol and ether to yield 0.8 g of 1,2-benzenedisulfonamide, m.p. 250° C. Mass spec. (M/e) 236.
Reaction SMILES: P([O-])([O-])([O-])=O.[Cl:6][C:7]1[C:8](=[O:26])[C:9](=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([O:24]C)=[O:23])[CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:11]=1.Cl.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>CC(C)=O>[Cl:6][C:7]1[C:8](=[O:26])[C:9](=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:10]([CH2:12][CH2:13][CH2:14][CH3:15])[CH:11]=1
Reactant: CCCCC1C=C(Cl)C(=O)C1=CCCCCCC(=O)OC
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)=O
Product: CCCCC1C=C(Cl)C(=O)C1=CCCCCCC(=O)O
Temperature: 30 °C
Reaction time: 60 h
Yield: 39.2 %

Procedure:
20 ml of phosphate buffer (pH8) was added to a solution of 200 mg (0.64 mmol) of 2-chloro-4-butyl-5-(6-methoxycarbonylhexylidene)-2-cyclopentenone in 15 ml of acetone, and then 0.4 ml of an aqueous solution of pig liver esterase was added. The mixture was stirred at 30° C. for 60 hours. 1N hydrochloric acid was added to the reaction mixture to adjust the pH to 4, and then the mixture was saturated with ammonium sulfate. It was filtered, and then extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate. The dried product was filtered, concentrated and subjected to silica gel column chromatography (silica gel, 10 g; eluent, hexane:ethyl acetate=3.2) to give 75 mg (yield 39%) of 2-chloro-4-butyl-5-(6-carboxyhexylidene)-2-cyclopentenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].Cl.[C:13]([O-])(O)=O.[Na+]>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[OH:11]
Reactant: O=C([O-])O
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)cc1O

Procedure:
To a mixture of 4-chlorosalicylic acid (16 g, 92.6 mmol) in MeOH (210 mL) was added conc. HCl solution (5 mL). The resultant solution was refluxed for 23 h. After cooled, solid NaHCO3 was added to neutralize the mixture and then was concentrated. The slurry was suspended in EtOAc and filtered through a silica gel plug, washing with EtOAc. The filtrate was washed with ¼ saturated NaHCO3 solution (2×), brine, dried over Na2SO4, filtered and concentrated to provide the title compound (17.2 g). MS ESI(−) m/e: 185.0 (M−1).
Reaction SMILES: [OH:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5].[C:22](N1C=CN(C)C1)(=[O:24])[CH3:23].O>C(Cl)Cl>[C:22]([O:1][N:2]([CH3:21])[C:3](=[O:20])[CH:4]([NH:6][C:7]1[C:12]([N+:13]([O-:15])=[O:14])=[CH:11][C:10]([CH3:16])=[CH:9][C:8]=1[N+:17]([O-:19])=[O:18])[CH3:5])(=[O:24])[CH3:23]
Reactant: CC(=O)N1C=CN(C)C1
Reactant: Cc1cc([N+](=O)[O-])c(NC(C)C(=O)N(C)O)c([N+](=O)[O-])c1
Solvent: O
Solvent: ClCCl
Product: CC(=O)ON(C)C(=O)C(C)Nc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Yield: 63.3 %

Procedure:
3 g of N-hydroxy-N-methyl-2-(4-methyl-2,6-dinitrophenylamino)propanamide and 0.82 g of N-acetyl-N'-methylimidazole were added to a stirred suspension in 0.8 g of methylene chloride for 3 hours. The resulting mixture was poured into water. The methylene chloride layer was washed, dried over MgSO4, and evaporated to give a yellow residue which was crystallized from ethanol to yield 1.4 g (41% yield) of product; m.p. 137°-138° C., (d,l) isomer form.
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[CH3:6][C:7]1[CH2:12][C:11](=O)[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[N:8]=1.N12CCCN=C1CCCCC2>C(Cl)Cl>[Cl:3][C:11]1[CH:12]=[C:7]([CH3:6])[N:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH:10]=1
Reactant: CC1=NC(c2ccc(Oc3ccc(F)cc3)cc2)=CC(=O)C1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: Cc1cc(Cl)cc(-c2ccc(Oc3ccc(F)cc3)cc2)n1

Procedure:
To a flask containing 20 ml of POCl3 at 120° C. oil bath was carefully added a solution of 5 g (17 mmol) crude compound 4 and 2.6 ml of 1,8-diazabicyclo[5,4,0]undec-7-ene (DBU) (17 mmol) in 20 ml of methylene chloride. After the addition, the reaction mixture was refluxed for one hour. The resulting mixture was concentrated to dryness and diluted with ethyl acetate. Saturated aqueous NaHCO3 was carefully added to the solution to adjust pH to 5-6. The organic phase was separated and the aqueous phase was extracted with the same volume of EtOAc. The combined organic phases were then washed with brine and dried with magnisium sulfate, filtered and concentrated to dryness. The residue was purified with flash chromatography (silica gel, 5% EtOAc/hexane) to get 1.8 g of compound 5 and 850 mg of a mixture of compound 5 and unreacted compound 3. 1H NMR (CDCl3): δ 7.93 (d, 2H, J=6.7 Hz), 7.48 (d, 1H, J=1.36 Hz), 7.09 (d, 1H, J=1.5 Hz), 7.00 (m, 6H), 2.59 (s, 3H). MS: 314.1
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=1>C(O)(C)C.O>[CH2:3]([C:2]1[N:10]2[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[CH:16]=[CH:17][C:9]2=[N:8][CH:1]=1)[CH2:4][CH2:5][CH3:6]
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: CCCCCC=O
Solvent: CC(C)O
Solvent: O
Product: CCCCc1cnc2ccc(C(=O)O)cn12
Temperature: 80 °C
Reaction time: 8 h
Yield: 11.9 %

Procedure:
To hexanal (1.02 g, 10.2 mmol) in 15 mL of isopropyl alcohol-water (4:1 v/v) was added CuCl2 (1.37 g, 10.2 mmol). The mixture was heated at 80° C. for 2.5 h, then cooled. The solids were removed by filtration and the filtrate was added to 6-aminonicotinic acid (1.35 g, 10 mmol). The mixture was stirred overnight at room temperature, then heated at reflux 32 h. After cooling, the solvents were removed under reduced pressure and MeOH was added to the residue. The resulting solid was removed by filtration and the filtrate was concentrated to dryness. MeOH was again added, and the resulting solid removed by filtration. After concentration of the filtrate, the residue was chromatographed on silica gel using MeOH-dichloromethane (33/67) to give 0.26 g of 3-butylimidazo[1,2-a]pyridine-6-carboxylic acid.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1.[Cu][C:12]#[N:13]>CN1CCCC1=O>[C:12]([C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([F:10])[CH:3]=1)#[N:13]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: N#C[Cu]
Solvent: CN1CCCC1=O
Product: N#Cc1cc(F)c(N)c(F)c1

Procedure:
reacting 4-bromo-2,6-difluoroaniline with copper (I) cyanide and N-methyl-2-pyrrolidone to yield 4-cyano-2,6-difluoroaniline;
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[C:4]([NH:6][C:7](=[O:26])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:21][CH2:20][CH:19]([C:22]([O:24]C)=[O:23])[CH2:18][CH2:17]1)=[O:5].[OH-].[Li+].O.CO>C1COCC1>[Cl:1][C:2]1[CH:30]=[C:29]([F:31])[C:28]([F:32])=[CH:27][C:3]=1[C:4]([NH:6][C:7](=[O:26])[NH:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[CH2:17][CH2:18][CH:19]([C:22]([OH:24])=[O:23])[CH2:20][CH2:21]1)=[O:5]
Reactant: COC(=O)C1CCN(c2ccc(Cl)cc2NC(=O)NC(=O)c2cc(F)c(F)cc2Cl)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC(=O)c1cc(F)c(F)cc1Cl)Nc1cc(Cl)ccc1N1CCC(C(=O)O)CC1
Reaction time: 36 h

Procedure:
The mixture consisting of 90 mg of methyl 1-{2-[3-(2-chloro-4,5-difluoro-benzoyl)ureido]-4-chlorophenyl}piperidine-4-carboxylate (Ex.15), 9.6 mg of lithium hydroxide, 3 ml of water, 3 ml of methanol and 3 ml of THF is allowed to stand at room temperature for 36 hours. The volatile fractions are removed at RT under reduced pressure and the remainder is adjusted to pH=4 using 2N hydrochloric acid. The precipitate formed is filtered off with suction and purified by column chromatography (silica gel, solvent: methylene chloride:methanol=9:1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[C:24]4=[CH:27][S:28][CH:29]=[C:23]4[NH:22][C:21]3=[O:30])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:31]2[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=2)=[C:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:20]3[C:25](=[O:26])[C:24]4=[CH:27][S:28][CH:29]=[C:23]4[N:22]([CH2:40][CH2:39][C:38]([O:42][CH3:43])=[O:41])[C:21]3=[O:30])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC
Reactant: O=c1[nH]c2cscc2c(=O)n1CCCCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: COC(=O)CCn1c(=O)n(CCCCCN2CCC(=C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c(=O)c2cscc21
Yield: 57 %

Procedure:
The title compound was prepared by starting with 3-[5-[4-(bis(4-fluorophenyl)methylene]piperidin-1-yl]pentyl]thieno[3,4-d]pyrimidine-2,4-dione. This material (11.0 g, 21 mmol) was reacted with methyl acrylate as described in Example 1 to produce 8.06 g (57%) of methyl 3-[3-[5-[4-[bis(4-fluorophenyl)methylene]piperidin-1-yl]pentyl]-2,4-dioxothieno[3,4-d]pyrimidin-1-yl]propanoate as a yellow oil. A portion of this material was converted to its crystalline oxalate salt by dissolving in acetone and treating with 1.1 equivalents of oxalic acid. There was obtained a cream-colored solid, mp 129°-136° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[Br:11][CH2:12][C:13](Br)=[O:14]>CN(C=O)C.O1CCOCC1.O>[Br:11][CH2:12][C:13]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1)=[O:14]
Reactant: O=C(Br)CBr
Reactant: N#CCc1ccc(N)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: N#CCc1ccc(NC(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.9 %

Procedure:
To a solution of 4-aminobenzyl cyanide (4 g, 0.03 mol) in anhydrous DMF (20 mL) and anhydrous dioxane (20 mL) in a 3-necked flask, fitted with magnetic stirrer and a constant additional funnel, was added, dropwise, bromoacetyl bromide (6.12 g, 2.7 mL, 100 mol %) while keeping the internal temperature between 0° C. and 2° C. After the addition was completed (~25 min), the reaction mixture was stirred overnight at rt. The reaction mixture was diluted with water (100 mL) and then the yellow crystalline compound which precipitated was filtered, washed sequentially with 5% HBr (100 mL) and water (200 mL), and then dried in a vacuum oven at 40°-45° C., affording 5.0 g (66%) of the title compound: mp 129°-131° C.; 1H NMR (DMSO-d6) δ10.46 (s, 1H , NH), 7.60 (d, 2H, J=8.4), 7.31 (d, 2H, J=8.8), 4.04 (s, 2H), 3.98 (s, 2H): 13C NMR (DMSO-d6) δ164.82; 137.99; 128.60; 126.42; 119.61; 30.30; 21.82; MS (EI, m/z) 252 (M+). HRMS (EI) calcd for C10H9N2OBr 251.9898, found 251.9882.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[CH:41]=[C:40]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)[CH:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cc(COC3CCCCO3)cn2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cc(COC4CCCCO4)cn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (479 mg, 1.5 mmol) and (RS)-3-oxo-3-{3-[4-(tetrahydro-pyran-2-yloxymethyl)-pyrazol-1-yl]-phenyl}-propionic acid tert.-butyl ester (Example K17) (601 mg, 1.5 mmol) according to the general procedure M. Obtained as a pink amorphous substance (641 mg).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH:21]=O)[O:16][N:15]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]1([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]2[CH:18]=[C:17]([CH2:19][CH2:20][CH2:21][N:32]3[CH2:33][CH2:34][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:30][CH2:31]3)[O:16][N:15]=2)[CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CCCc1cc(-c2cccc(Oc3ccccc3)c2)no1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: c1ccc(Oc2cccc(-c3cc(CCCN4CCN(c5ccccc5)CC4)on3)c2)cc1
Yield: 127.4 %

Procedure:
About 2 min after dissolving 3-[3-(3-phenoxyphenyl)isoxazol-5-yl]propanal (20 mg, 0.07 mmol) and 1-phenylpiperazine (10.4, 0.07 mmol) in 2 mL of dry methylene chloride, were added NaBH(OAc)3 (43.4 mg, 0.2 mmol) and molecular sieves (5 beads). The reaction mixture was reacted for 16 hr and followed the same processes as in Example 1 to obtain 39.2 mg (100%) of the target compound.
Reaction SMILES: C[C@H]1CC[C@H]([C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[C:26]4C=CC=C[C:25]=4[N:24]=[CH:23]3)=[C:15]([O:31][CH3:32])[CH:14]=2)[C:9]([NH2:11])=[O:10])CC1>[C].[Pd].CO>[CH3:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([NH:11][C:9](=[O:10])[CH2:8][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]3[CH:26]=[CH:25][N:24]=[CH:23]3)=[C:15]([O:31][CH3:32])[CH:14]=2)[CH2:15][CH2:14]1
Reactant: COc1cc(C=C(C(N)=O)[C@H]2CC[C@H](C)CC2)ccc1OCCn1cnc2ccccc21
Agent: [Pd]
Solvent: CO
Product: COc1cc(CCC(=O)N[C@H]2CC[C@H](C)CC2)ccc1OCCn1ccnc1

Procedure:
Using 0.2 g of N-(trans-4-methylcyclohexyl-4-[2-[1-benzimidazolyl)ethoxy]-3-methoxycinnamamide Example 166), 0.01 g of 10% palladium-carbon, and 35 ml of methanol, a reaction similar to that conducted in Example 147 was carried out. As a result, 0.11 g of N-(trans-4-methylcyclohexyl)-3-{4-[2-(1-imidazolyl)ethoxy}-3-methoxyphenyl}propionamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties: