Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([S:19]([CH3:22])(=[O:21])=[O:20])=[C:6]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>C(#N)C>[CH3:22][S:19]([C:5]1[CH:4]=[CH:3][C:2]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:7][C:6]=1[NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][CH:10]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)c1ccc(F)cc1Nc1cccc2ccccc12
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CS(=O)(=O)c1ccc(N2CCNCC2)cc1Nc1cccc2ccccc12
Yield: 18.5 %

Procedure:
N-(5-Fluoro-2-(methylsulfonyl)phenyl)naphthalen-1-amine (0.56 g, 1.7 mmol), piperazine (0.46 g, 5.3 mmol), N,N-diisopropylethylamine (0.89 g, 6.8 mmol) were stirred at 80° C. in dry acetonitrile (5 mL) for 48 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated and the crude compound was purified by silica chromatography using 10% methanol in dichloromethane to afford the title compound (120 mg, 18% yield). 1H NMR (400 MHz, CDCl3): δ 8.10 (s, 1H), 7.89 (d, 1H), 7.83 (d, 1H), 7.66 (d, 1H), 7.62 (m, 1H), 7.39 (m, 4H), 6.35 (d, 1H), 6.26 (s, 1H), 3.09 (s, 3H), 2.98 (m, 4H), 2.79 (m, 4H); MS (ESI) m/z: Calculated for C21H24N3O2S: 382.2; Observed: 382.4 (M+).
Reaction SMILES: COC([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15])[CH:9]=[CH:8]2)=O.O.[Cl-].[NH4+:25]>C(Cl)Cl.[Fe]>[C:17]1([S:14]([N:10]2[C:11]3[C:7](=[CH:6][C:5]([NH2:25])=[CH:13][CH:12]=3)[CH:8]=[CH:9]2)(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Reactant: [NH4+]
Agent: [Fe]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Yield: 82.2 %

Procedure:
To the suspension of 2 (1.16 g, 3.84 mmol) in WA (38 mL) and water (9 mL), iron (0.64 g, 11.51 mmol) and ammonium chloride (0.41 g, 7.67 mmol) were added and refluxed overnight. After the reaction was filtrated with celite, the solvent was concentrated under reduced pressure to give a brown residue, which was dissolved in CH2Cl2 and quenched with water, followed by extracted with CH2Cl2 (20 mL×3). The combined organic layer was dried over anhydrous MgSO4 and concentrated under reduced pressure to give a brown residue, which was purified by silica gel chromatography (EtOAc:n-hexane=1:2:1% NH3(aq)) to afford 27 (0.86 g). 1H NMR (500 MHz, CD3OD): δ 3.60 (s, 2H), 6.48 (d, J=3.6 Hz, 1H), 6.69 (dd, J=8.7, 2.1 Hz, 1H), 6.76 (d, J=1.8 Hz, 1H), 7.39-7.42 (m, 2H), 7.44 (d, J=3.5 Hz, 1H), 7.49-7.51 (m, 1H), 7.77 (d, J=8.7 Hz, 1H), 7.82 (d, J=7.9 Hz, 2H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]4=[O:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.C[Li].O.[C:35](=O)([O-])O.[Na+]>C1COCC1.C(OCC)C>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[C:17]([C:19]3[CH:28]=[C:27]4[C:22]([C:23]([CH3:31])([CH3:30])[CH2:24][CH2:25][C:26]4([CH3:35])[OH:29])=[CH:21][CH:20]=3)[CH:16]=[CH:15][CH:14]=2)[CH2:11][CH2:12]1
Reactant: O=C([O-])O
Reactant: CC1(C)CCC(=O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Agent: [Li]C
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(O)c2cc(-c3cccc(N4CCN(CCCCCO)CC4)n3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
50 mg (0.12 mmol) of 7-{6-[4-(5-hydroxypentyl)piperazin-1-yl]pyridin-2-yl}-4,4-dimethyl-3,4-dihydro-2H-naphthalen-1-one are dissolved in 5 ml of THF, cooled to 0° C., and 224 μl (0.36 mmol) of methyllithium in diethyl ether (5%) are added. The reaction mixture is stirred at 0° C. for 30 min and warmed to room temperature. Water added to the reaction mixture, sodium hydrogencarbonate solution added, and the mixture extracted with ethyl acetate, dried and evaporated. The crude product is purified by means of column chromatography on silica gel.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]([O:17]CC)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>O1CCCC1.O.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]([OH:17])=[O:16])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(CC(=O)O)CC1
Reaction time: 1 h

Procedure:
Combine 1-t-butoxycarbonyl-4-carboethoxymethylpiperazine (20.8 g, 76.5 mmol) and lithium hydroxide (6.71 g, 160 mmol) in tetrahydrofuran (100 mL) and water (100 mL). After 60 minutes, concentrate in vacuo to give a solid. Combine the solid and water, extract with diethyl ether. Combine the aqueous layer and a 1M aqueous solution of potassium hydrogensulfate (160 mL). Extract three times with chloroform. Evaporate the aqueous layer to give a solid. Triturate the solid repeatedly with warm ethyl acetate and isopropanol and filter. Evaporate each triturate to give solids. Combine the solids obtained by evaporation of the triturates, dissolve in chloroform and evaporate to remove solvent. Dry in vacuo at 50° C. to give 1-t-butoxycarbonyl-4-carboxymethylpiperazine as a solid, mp: 195-197° C. IR (KBr) nmax 3007, 2934, 1691, 1631, 1479, 1453, 1427, 1415, 1393, 1366, 1301, 1283, 1232, 1209, 1177, 1139, 1084 cm-1 ; 1H NMR (CDCl3) ppm 3.71 (br s, 4 H), 3.56 (br s, 2 H), 3.12 (br s, 4 H), 1.46 (s, 9 H); 13C NMR (CDCl3) ppm 169.10, 154.13, 80.70, 58.49, 52.38, 28.25; MS (CI/NH3) m/z 245 (M+1)+.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:16]=[C:15](F)[C:14]([F:18])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10].[CH2:19]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:19]([N:26]1[CH2:31][CH2:30][N:29]([C:15]2[C:14]([F:18])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([F:6])[CH:16]=2)[CH2:28][CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COC(=O)c1cc(F)c(F)cc1F
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(N2CCN(Cc3ccccc3)CC2)cc1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33.7 %

Procedure:
To a 30 ml tetrahydrofuran solution of 4.25 g (22.35 mmol) of methyl 2,4,5-trifluorobenzoate, 3.89 ml (22.35 mmol) of N-benzylpiperazine was added with ice cooling. The mixture was stirred at 0° C. for 0.5 hour, and at room temperature for 2.5 hours. Then, the reaction mixture was diluted with ethyl acetate, and the dilution was washed with water and a saturated aqueous solution of sodium chloride in this order. The washed system was dried over sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to obtain 2.61 g (34%) of the captioned compound.
Reaction SMILES: O=[C:2]([CH3:14])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1.N.[N:16]1([CH2:22][CH2:23][C:24]2[S:28][C:27]([NH:29][C:30]([NH2:32])=[S:31])=[N:26][N:25]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[CH3:14][C:2]1[N:32]=[C:30]([NH:29][C:27]2[S:28][C:24]([CH2:23][CH2:22][N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)=[N:25][N:26]=2)[S:31][C:3]=1[C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: NC(=S)Nc1nnc(CCN2CCOCC2)s1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Agent: N
Product: Cc1nc(Nc2nnc(CCN3CCOCC3)s2)sc1-c1ccc(S(N)(=O)=O)cc1

Procedure:
The titled compound is prepared from 4-(2-oxo-propyl)-benzenesulfonyl chloride (prepared as described in European patent specification EP 91749 A2) following the procedures described in Example 1, using ammonia and [5-(2-morpholin-4-yl-ethyl)-[1,3,4]thiadiazol-2-yl}-thiourea (54c).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]Cl)=[CH:5][CH:4]=1.[OH:11][C:12]1[CH:20]=[C:19]2[C:15]([CH2:16][CH2:17][C:18]2=[O:21])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][O:11][C:12]2[CH:20]=[C:19]3[C:15]([CH2:16][CH2:17][C:18]3=[O:21])=[CH:14][CH:13]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2ccc3c(c2)C(=O)CC3)cc1
Yield: 99.4 %

Procedure:
4-methoxybenzylchloride (9.19 mL, 67.5 mmol) was added to a mixture of 6-hydroxy-1-indanone (10 g, 67.5 mmol) and potassium carbonate (14 g, 101 mmol) in 15 mL DMF. The mixture was reacted at RT for 14 h. The reaction mixture was diluted with water and extracted with DCM. The organic layer was separated and the solvents were removed by evaporation. The residue was dissolved in DCM and filtered through a plug of activated basic alumina. 6-(4-Methoxy-benzyloxy)-indan-1-one (18 g, 99%) was obtained after evaporation of the filtrate. The material was taken to the next step without further purification.
Reaction SMILES: [C-]#N.[K+].CC(C)(O)[C:6]#[N:7].[Cl:10][C:11]1[CH:12]=[C:13](/[C:18](/[C:41]([F:44])([F:43])[F:42])=[CH:19]\[C:20]([C:22]2[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=2)=[O:21])[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>C1(C)C=CC=CC=1>[C:6]([C@@:18]([C:13]1[CH:12]=[C:11]([Cl:10])[CH:16]=[C:15]([Cl:17])[CH:14]=1)([C:41]([F:44])([F:42])[F:43])[CH2:19][C:20]([C:22]1[CH:39]=[CH:38][C:25]([C:26]([NH:28][CH2:29][C:30](=[O:37])[NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:27])=[C:24]([CH3:40])[CH:23]=1)=[O:21])#[N:7]
Reactant: CC(C)(O)C#N
Reactant: Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Agent: [C-]#N
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)C[C@](C#N)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1C(=O)NCC(=O)NCC(F)(F)F
Reaction time: 96 h
Yield: 31.7 %

Procedure:
Potassium cyanide (0.0082 g, 0.125 mmol) and acetone cyanohydrin (0.031 ml, 0.336 mmol) were added to a solution of 4-[(E)-3-(3,5-Dichloro-phenyl)-4,4,4-trifluoro-but-2-enoyl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.0600 g, 0.111 mmol) in toluene (3.0 ml). To this vigorously stirred suspension was added antracen-9-yl-methyl quininium chloride (0.0153 g, 0.028 mmol). The reaction mixture was stirred at 90 C for 4 days. After this time water was added and the reaction mixture was extracted with dichloromethane (3×). The crude product was purified by flash chromatography (0% to 25% ethyl acetate in cyclohexane) to afford 4-[(R)-3-Cyano-3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-butyryl]-2-methyl-N-[(2,2,2-trifluoro-ethylcarbamoyl)-methyl]-benzamide (0.020 g, 32%) as a light yellow solid. Chiral HPLC analysis (Chiralpack AS-RH, acetonitrile:water:methanol=45:5:50, 1 ml/min, retention time 8.70 minutes (major enantiomer), 11.30 minutes (minor enantiomer) indicated that the reaction proceeded with 94% enantioselectivity.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35](O)=[O:36])=[CH:27][CH:26]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:24][C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([C:35]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19][C:20]([F:23])([F:22])[F:21])[CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=2)[OH:4])=[O:36])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: O
Product: O=C(NC(Cc1cccc(SC(F)(F)F)c1)C(O)c1ccc(F)cc1)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-{3-[(trifluoromethyl)thio]phenyl}propan-1-ol (450 mg, 1.51 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (287 mg, 1.51 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (435 mg, 2.27 mmol) and 1-hydroxybenzotriazole hydrate (231 mg, 1.51 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1-ethyl acetate). Recrystallization from ethyl acetate-hexane gave the objective substance (447 mg, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=O)[NH:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.CO.Cl>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[CH2:6][NH:8][CH2:9]2
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Brc1ccc2c(c1)CNC2
Temperature: 0 °C
Yield: 38.3 %

Procedure:
280 ml of 1M Borane-THF complex was added dropwise to a stirred solution of 4-bromophthalimide (20.85 g; 92.2 mmol) in anhydrous THF (200 ml) at 0° C. then heated at reflux overnight. The reaction was cooled to 0° C. then treated cautiously with methanol (100 ml) followed by 2M HCl (100 ml) then heated at reflux for 3 hours. The reaction mixture was cooled and the organics evaporated. The aqueous was diluted with water (100 ml) the extracted with DCM (×3). The aqueous was basified with 2M NaOH then extracted with DCM (×3). The combined DCM extracts were dried (MgSO4), filtered and evaporated to give 6.99 g of 5-bromo-2,3-dihydro-1H-isoindole as a dark brown gummy solid. 1H NMR (DMSO-d6) 7.45 (1H, s), 7.36 (1H, d), 7.20 (1H, d), 4.05 (4H, s).
Reaction SMILES: C=O.[O:3]=[C:4]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:21][CH2:20]1)[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][CH2:17][NH:16][CH2:15]2)[CH:13]=1)=[O:8].[C:36](O)(=O)C.N>O.[Zn]>[O:3]=[C:4]([N:19]1[CH2:24][CH2:23][CH:22]([O:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=2)[CH2:21][CH2:20]1)[CH2:5][NH:6][C:7]([C:9]1[N:10]=[N:11][N:12]([CH:14]2[CH2:18][CH2:17][N:16]([CH3:36])[CH2:15]2)[CH:13]=1)=[O:8]
Reactant: CC(=O)O
Reactant: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1cn(C2CCNC2)nn1
Agent: C=O
Agent: N
Agent: [Zn]
Solvent: O
Product: CN1CCC(n2cc(C(=O)NCC(=O)N3CCC(Oc4cccc(C(F)(F)F)c4)CC3)nn2)C1
Reaction time: 0.08 h
Yield: 122.1 %

Procedure:
37% Aqueous formaldehyde (12 mg, 0.4 mmol) solution was added to a stirred solution of 1-pyrrolidin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide (100 mg, 0.15 mmol) in a mixture of acetic acid (37.62 mg, 0.62 mmol) and H2O (0.5 mL) and stirring was continued at ambient temperature for 5 minutes. To the above mixture was added, Zinc powder (39.23 mg, 0.6 mmol) and stirring was continued at ambient temperature for 1 hr. The reaction mixture was cooled, basified with aqueous ammonia solution and extracted with DCM. The organic layer thus collected was dried over sodium sulfate and concentrated under reduced pressure to afford 88 mg (88% Yield) of 1-(1-methyl-pyrrolidin-3-yl)-1H-[1,2,3]triazole-4-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 481.2. 1H NMR (300 MHz, DMSO-d6): δ 11.2-11.0 (b, 1H), 8.85 (s, 1H), 8.4 (s, 1H), 7.5 (t, 1H), 7.3 (t, 3H), 5.51 (b, 1H), 4.7 (m, 2H), 4.4 (d, 2H), 3.8 (m, 1H), 3.7 (m, 2H), 3.4 (m, 2H), 2.9 (s, 3H), 2.5 (m, 2H), 2.0 (m, 2H), 1.7-1.5 (m, 2H).
Reaction SMILES: [Na].COC([C:6]1[C:7]2[N:8]([CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[N:14]=2)[CH:9]=[CH:10][N:11]=1)=O.[CH3:22][CH:23]([OH:25])[CH3:24]>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[N:14]=[C:7]3[C:6]([O:25][CH:23]([CH3:24])[CH3:22])=[N:11][CH:10]=[CH:9][N:8]3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: CC(C)O
Reactant: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Agent: [Na]
Product: CC(C)Oc1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Yield: 70 %

Procedure:
A mixture of anhydrous IPA (25 mL) and sodium (0.4 g, 17.4 mmol) was heated at reflux until the sodium was consumed. The reaction mixture was cooled to ambient temperature and the 8-chloro-2-(4-fluorophenyl)-imidazo[1,2-a]pyrazine (prepared from general procedure B using 3-chloropyrazin-2-ylamine and 2-bromo-1-(4-fluorophenyl)-ethanone; 2.0 g, 8 mmol) was added. The reaction mixture was heated at reflux for about 2 h, cooled to ambient temperature, and partitioned between EtOAc and water. The layers were separated and the organic phase was dried over MgSO4, filtered, and evaporated. The resulting solid was triturated with heptane to afford 1.52 g (70%) of the title compound: LC/MS (Table 1, Method g) Rt=2.78 min; MS m/z: 272.2 (M+H)+.
Reaction SMILES: [Br:1][CH:2]([P:13]([O:19][CH:20]([CH3:22])[CH3:21])(=[O:18])[O:14][CH:15]([CH3:17])[CH3:16])P(OC(C)C)(=O)OC(C)C.[H-].[Na+].[Cl:25][C:26]1[CH:33]=[C:32]([F:34])[C:31]([C:35]2[C:39]([Cl:40])=[C:38]([O:41][CH:42]([F:44])[F:43])[N:37]([CH3:45])[N:36]=2)=[CH:30][C:27]=1[CH:28]=O>>[Br:1][C:2]([P:13](=[O:18])([O:14][CH:15]([CH3:16])[CH3:17])[O:19][CH:20]([CH3:21])[CH3:22])=[CH:28][C:27]1[CH:30]=[C:31]([C:35]2[C:39]([Cl:40])=[C:38]([O:41][CH:42]([F:43])[F:44])[N:37]([CH3:45])[N:36]=2)[C:32]([F:34])=[CH:33][C:26]=1[Cl:25]
Reactant: CC(C)OP(=O)(OC(C)C)C(Br)P(=O)(OC(C)C)OC(C)C
Reactant: Cn1nc(-c2cc(C=O)c(Cl)cc2F)c(Cl)c1OC(F)F
Agent: [H-]
Agent: [Na+]
Product: CC(C)OP(=O)(OC(C)C)C(Br)=Cc1cc(-c2nn(C)c(OC(F)F)c2Cl)c(F)cc1Cl
Yield: 21.5 %

Procedure:
Following the procedure described in Example 40 and using 3.4 g (8 mmol) of tetraisopropyl bromomethanediphosphonate, 0.2 g (8 mmol) of sodium hydride and 1.6 g (4 mmol) of 2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorobenzaldehyde, a crude product is obtained whose silica gel chromatography first revealed 0.5 g of diisopropyl 1-bromo-2-[2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl]vinylphosphonate followed by 0.4 g of diisopropyl 2-[2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl]ethynylphosphonate.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].O>CC#N>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[O:11][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)CBr
Reactant: OCCCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)COc1cccc(CCCO)c1
Temperature: 60 °C
Reaction time: 7 h

Procedure:
To a solution of 3-(3-hydroxypropyl)phenol (100 g) in MeCN (750 mL) was added K2CO3 (109 g) at ambient temperature. Ethyl bromoacetate (87.4 mL) was added dropwise to the mixture at 0° C. over 30 minutes, and then the mixture was stirred at ambient temperature for 20 hours and at 60° C. for 7 hours. Water (800 mL) was added to the mixture at ambient temperature and the resulting mixture was extracted with EtOAc(1 L) two times. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to afford ethyl [3-(3-hydroxypropyl)phenoxy]acetate (121 g) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15](=O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].CCCCCC>C1(C)C=CC=CC=1>[C:31]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:13][CH2:14]2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: O=C(CCCCCCCCc1cccnc1)N1CCC(C=C(c2ccccc2)c2ccccc2)CC1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: C(=C(c1ccccc1)c1ccccc1)C1CCN(CCCCCCCCCc2cccnc2)CC1

Procedure:
The title compound was prepared in a manner similar to that employed for the compound of Example 16 starting with 6.5 g of 4-(2,2-diphenylethenyl)-1-[1-oxo-9-(3-pyridinyl)nonyl]piperidine and 7.7 mL of a 3.5M solution of sodium bis(2-methoxyethoxy)aluminum hydride in toluene. The analytically pure base was obtained from hexane, mp 51°-53° C. Analysis Calculated for C33H42N2 : C. 84.93; H, 9.07; N, 6.00. Found: C, 85.20; H, 9.00; N, 6.05. Evaporation of the hexane filtrates provided 5.9 g of crude product, which was dissolved in 25 mL of hot methanol and treated with 1.47 g of fumaric acid. The methanol was removed by distillation while adding acetone and the resulting solids were recovered and recrystallized from methanol/acetone to give 6.7 g (85%) of pure fumarate salt of 3-[9-[4-(2,2-diphenylethenyl)-1-piperidinyl]nonyl]pyridine, mp 125°-127° C. Analysis Calculated for C33H42N2.C4H4O4 : C, 76.26; H, 7.96; N, 4.81. Found: C, 76.54; H, 7.92; N, 4.90.
Reaction SMILES: Cl.[NH:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>CN(C=O)C>[C:28]([O:27][C:25](=[O:26])[CH2:24][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])([CH3:31])([CH3:30])[CH3:29]
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC[C@H]1C(=O)OCc1ccccc1
Reaction time: 71 h
Yield: 49.4 %

Procedure:
To a suspension of (S)-benzyl pyrrolidine-2-carboxylate hydrochloride (700 mg, 2.90 mmol) and K2CO3 (1201 mg, 8.69 mmol) in DMF (7 ml), t-butyl bromoacetate (0.535 ml, 3.62 mmol) is added. After stirring for 71 hours, aqueous K2CO3 (1.5 g of K2CO3/40 ml of H2O) is added to the reaction mixture. The products are extracted with EtOAc. The organic layer is washed twice with water and once with brine, dried over K2CO3, filtered, and concentrated to give (S)-benzyl 1-(2-tert-butoxy-2-oxoethyl)pyrrolidine-2-carboxylate (458 mg); HPLC retention time=1.38 minutes (condition D); MS (m+1)=320.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 9H) 1.81-2.03 (m, 3H) 2.13-2.14 (m, 1H) 2.82-2.88 (m, 1H) 3.13-3.17 (m, 1H) 3.46 (A of AB, J=17.3 Hz, 1H) 3.49 (B of AB, J=17.3 Hz, 1H) 3.73 (dd, J=8.8 and 4.8 Hz, 1H) 5.15 (A of AB, J=12.4 Hz, 1H) 5.17 (B of AB, J=12.4 Hz, 1H) 7.29-7.38 (m, 5H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[N:13]=[C:14]=[O:15])([CH3:3])[CH3:2].[NH2:16][C@H:17]([C:25]([OH:27])=O)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH2:28]([O:30][C:31]([CH:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32])[CH3:29]>>[CH2:18]([C@H:17]([NH:16][C:14]([NH:13][C:5]1[C:6]([CH:10]([CH3:11])[CH3:12])=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:2])[CH3:3])=[O:15])[C:25]([N:36]1[CH2:37][CH2:38][CH:33]([C:31]([O:30][CH2:28][CH3:29])=[O:32])[CH2:34][CH2:35]1)=[O:27])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)Nc2c(C(C)C)cccc2C(C)C)CC1

Procedure:
This compound was prepared in two steps from 2,6-diisopropylphenylisocyanate, (L)-phenylalanine, and 4-ethoxycarbonylpiperidine in the manner previously described in General Procedure A to give the desired urea amide product as a white solid. MS: 508 [M+H]+