Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[Cl:28][C:29]1[CH:30]=[C:31]([N:35]2[C:39]([C:40]([F:43])([F:42])[F:41])=[C:38]([C:44]([OH:46])=O)[CH:37]=[N:36]2)[CH:32]=[CH:33][CH:34]=1.[F:47][C:48]([F:58])([F:57])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52][NH2:53].C(N(CC)CC)C>O1CCCC1>[F:47][C:48]([F:57])([F:58])[C:49]1[CH:50]=[C:51]([CH:54]=[CH:55][CH:56]=1)[CH2:52][NH:53][C:44]([C:38]1[CH:37]=[N:36][N:35]([C:31]2[CH:32]=[CH:33][CH:34]=[C:29]([Cl:28])[CH:30]=2)[C:39]=1[C:40]([F:41])([F:42])[F:43])=[O:46]
Reactant: O=C(O)c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Reactant: NCc1cccc(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1cnn(-c2cccc(Cl)c2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (0.083 g; 0.189 mmol) was added to a solution of 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid (0.050 g; 0.172 mmol), 3-trifluoromethyl benzylamine (0.030 g; 0.206 mmol) and triethylamine (0.072 mL; 0.516 mmol) in tetrahydrofuran (10 mL). The reaction mixture was stirred at room temperature for 4 h, concentrated and the crude product purified by column chromatography on silica gel to give 1-(3-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid 3-trifluoromethyl-benzylamide. LCMS m/z=448.8 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[F:15])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.C([Li])CCC.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1.CCCCCC>[F:15][C:14]1[CH:13]=[CH:12][C:4]([CH2:5][N:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)=[CH:3][C:2]=1[C:24](=[O:26])[CH3:25]
Reactant: Fc1ccc(CN2CCOCC2)cc1Br
Reactant: CON(C)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1cc(CN2CCOCC2)ccc1F
Temperature: -75 °C
Reaction time: 1 h
Yield: 64.1 %

Procedure:
4-(3-Bromo-4-fluorobenzyl)morpholine (Preparation 1, 35.5 g) is dissolved in THF (400 mL) and cooled to −75° C. A solution of n-butyllithium in hexane (2.5 M, 57.0 mL) is added via addition funnel, maintaining the temperature below −68° C. A solution of N-methoxy-N-methylacetamide (16.0 g) in THF (50 mL) is added via addition funnel, maintaining the temperature below −65° C. The reaction is stirred at −75° C. for 1 h and allowed to warm to rt overnight. The reaction is quenched with 1 N HCl (150 mL) and poured into ethyl acetate (400 mL). The aqueous layer is separated, made basic with sat. aq. NaHCO3, and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed with sat. NaHCO3 (2×100 mL) and brine (50 mL). The combined aqueous washes are back-extracted with ethyl acetate (100 mL). The organic layers are combined, dried (Na2SO4), and concentrated in vacuo to a yellow oil. The crude product is distilled (135° C., 0.3 Torr) to afford 19.7 g (64%) of the title compound as a clear, colorless oil. Physical characteristics: B.p. 135° C. (0.3 Torr); 1H NMR (300 MHz, DMSO-d6) δ 7.72, 7.61-7.56, 7.31, 3.56, 3.48, 2.58, 2.34; IR (liq.) 1996, 1979, 1919, 1688, 1612, 1492, 1417, 1361, 1291, 1281, 1212, 1118, 865 cm−1; MS (ESI+) m/z 238 (M+H)+. Anal. Calcd for C13H16FNO2: C, 65.81; H, 6.80; N, 5.90. Found: C, 65.43; H, 6.75; N, 5.84.
Reaction SMILES: CC1(C)COB([C:8]2[CH:9]=[CH:10][C:11]([F:23])=[C:12]([C:14]3[CH:22]=[N:21][CH:20]=[CH:19][C:15]=3[C:16]([NH2:18])=[O:17])[CH:13]=2)OC1.Br[C:26]1[N:30]2[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:37])[CH3:36])=[N:34][C:29]2=[N:28][CH:27]=1>>[F:23][C:11]1[CH:10]=[CH:9][C:8]([C:26]2[N:30]3[CH:31]=[CH:32][C:33]([C:35]([OH:38])([CH3:36])[CH3:37])=[N:34][C:29]3=[N:28][CH:27]=2)=[CH:13][C:12]=1[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([NH2:18])=[O:17]
Reactant: CC1(C)COB(c2ccc(F)c(-c3cnccc3C(N)=O)c2)OC1
Reactant: CC(C)(O)c1ccn2c(Br)cnc2n1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4cnccc4C(N)=O)c3)cnc2n1

Procedure:
3-[5-(5,5-Dimethyl-[1,3,2]dioxaborinan-2-yl)-2-fluorophenyl]isonicotinamide (100 mg, 0.41 mmol) was coupled to 2-(3-bromoimidazo[1,2-α]pyrimidin-7-yl)propan-2-ol (106 mg, 0.41 mmol) using the method in Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 8% methanol then trituration with diethyl ether gave 3-{2-fluoro-5-[7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyrimidin-3-yl]phenyl}isonicotinamide as a white solid: δH (400 MHz, CDCl3) 1.58 (6H, s), 4.42 (1H, s), 5.68 (1H, s), 5.82 (1H, s), 7.08 (1H, d, J 7), 7.36 (1H, t, J 7), 7.57-7.61 (3H, m), 7.86 (1H, s), 8.71 (1H, d, J 7), 8.74 (1H, s), 8.78 (1H, d, J 5); m/z (ES+) 392 (M++H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])([CH3:4])([CH3:3])[CH3:2].Br[C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][CH:33]=1)[C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:24]>>[C:1]([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[C:17][C:20]1[CH:33]=[CH:32][CH:31]=[C:22]([C:23]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[O:24])[CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: O=C(c1cccc(Br)c1)N1CCOCC1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1cccc(C(=O)N2CCOCC2)c1

Procedure:
Following the general method as outlined in Intermediate 20, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-(3-bromobenzoyl)morpholine (Intermediate 178), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]1([NH:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([O:15]CC)=[O:14])[N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].O.Cl>C1COCC1>[C:1]1([NH:7][C:8]2[O:9][CH:10]=[C:11]([C:13]([OH:15])=[O:14])[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1coc(Nc2ccccc2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1coc(Nc2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of ethyl 2-(phenylamino)oxazole-4-carboxylate (1.64 g, 6.94 mmol) and lithiumhydroxide (332 mg, 13.88 mmol) in THF (23 ml)/water (11.5 ml) was stirred at rt for 4 hours. The reaction mixture was acidified with 2 N HCl and extracted with EA (2 x). The combined organic phases were dried over Na2SO4, filtered and evaporated under reduced pressure to afford the title product. HPLC/MS (Method G): RtG=1.41 min, MS (Method D) [M+H]+=204.9.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>CN(C=O)C>[C:17]([O:21][C:22]([N:24]1[CH2:28][CH2:27][CH2:26][C@@H:25]1[CH2:29][O:14][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][CH:12]=1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 0.25 h
Yield: 64.8 %

Procedure:
To a solution of 4-phenoxyphenol (200 mg, 1.07 mmol) in DMF (3 mL) at 0-5° C. was added 60% NaH (75 mg, 1.875 mmol) at 0-5° C. The reaction mixture was stirred at rt for 15 min at 0-5° C. A solution of (R)-2-(Toluene-4-sulfonyloxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (382 mg, 1.074 mmol) in DMF (2 mL) was added to the above mixture at 0-5° C. The reaction mixture was warmed to rt and then heated at 90° C. for 15 h. The mixture was concentrated, diluted with saturated aq NaHCO3 and extracted with ethyl acetate. The aqueous layer was re-extracted with ethylacetate. The combined organic layers were dried over anhy. MgSO4 and the solvent was removed in vacuo to obtain the crude mixture, which was purified by silica gel flash chromatography to obtain the title product (256 mg, 64%); MS; m/z 370 (M+H) LCMS (UV)>90%.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:30]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:42]=[C:41]([F:43])[CH:40]=[CH:39][C:30]=1[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][N:36]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:35][CH2:34]1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Reactant: Fc1ccc(CCN2CCNCC2)c(F)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(CCc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(2,4-difluorophenethyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. To the residue, acetonitrile is added and the solution is stirred at 60° C. for 0.5 h. The solution is then cooled to RT, and the resulting solids are collected by filtration to give 7-(2-(4-(2,4-difluorophenethyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=493.2). 1H NMR (CDCl3, 400 MHz) δ 2.55 (m, 10 H), 2.78 (t, 4H, J=6.8 Hz), 4.28 (t, 2H, J=6.8 Hz), 5.67 (s, 2H), 6.58 (d, 1H, J=3.6 Hz), 6.73-6.80 (m, 3H), 6.97 (m, 1H), 7.15 (m, 1H), 7.24 (m, 1H), 7.61 (s, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:20]2[CH:19]=[CH:18][C:17]([S:14]([C:6]3([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][CH3:13])[CH2:8][CH2:7]3)(=[O:15])=[O:16])=[CH:22][CH:21]=2)=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(CC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN1CCC(C(=O)O)(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CC1

Procedure:
4-[4-(4-Chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid was prepared starting from 4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-1-ethyl-piperidine-4-carboxylic acid ethyl ester (3.02 g, 6.7 mmol) dissolved in THF:methanol (3: 1150 ml) and 10 N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.8 g (65%); white solid; mp 184° C.; MS: 423.9 (M+H)+
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)C=CC=CC=1.[OH-].[Na+].[ClH:22].C1(C2NC(C)=C(C([Cl:36])C)N=2)C=CC=CC=1>C(O)C.O>[ClH:36].[ClH:22].[ClH:36].[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: Cc1[nH]c(-c2ccccc2)nc1C(C)Cl
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C1CNCCN1
Temperature: 25 °C
Yield: 55 %

Procedure:
14 Grams (0.052 mol) of N-(diphenylmethyl)piperazine and 6 grams (0.15 mol) of sodium hydroxide were dissolved in 180 ml of a mixture of ethanol :water 60:40. The mixture was heated to reflux, then 2-phenyl-4-(1-chloroethyl)-5-methylimidazole hydrochloride in 180 milliliters of ethanol:water 60:40 were added dropwise. After 4 to 5 hours under reflux, the reaction mixture was allowed to cool to room temperature. The oil that separated was washed twice with water, then dissolved in ether and hydrochloric acid was added. The precipitate was recrystallized from ethanol to give 1-diphenylmethyl-4- 1-(2-phenyl-5-methyl-1H-imidazol-4-yl)ethyl!piperazine trihydrochloride (55% yield), which melted at 215° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[C:19](Cl)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]>C(Cl)Cl>[C:19]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21]
Reactant: NCCCOc1ccncc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCCOc1ccncc1
Yield: 77.3 %

Procedure:
To a solution of 700 mg (4.60 mmol) of 4-(3-aminopropyloxy)pyridine and 0.77 ml (5.52 mmol) of triethylamine in 30 ml of methylene chloride, 0.57 ml (4.63 mmol) of pivaloyl chloride was added under ice-cooling with stirring. The mixture was stirred at room temperature for 1.5 hours. The reaction mixture was washed successively with a saturated aqueous solution of sodium bicarbonate and brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 840 mg of the desired compound (yield: 77.3%, colorless crystals).
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([N:6]1[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]([I:15])=[CH:7]1)[CH3:5].[BH4-].[Li+].C1COCC1>CCO>[I:15][C:8]1[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][C:14]=2[N:6]([CH:4]([CH3:5])[CH2:3][OH:2])[CH:7]=1
Reactant: COC(=O)C(C)n1cc(I)c2cnccc21
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(CO)n1cc(I)c2cnccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
To a solution of 2-(3-iodo-pyrrolo[3,2-c]pyridine-1-yl)-propionic acid methyl ester (Preparation 57, 18.1 g, 54.8 mmol) in EtOH (300 mL) was added 2M lithium borohydride solution in THF (63.1 mL, 126 mol) at 0° C. The reaction was stirred at this temperature for 30 minutes before warming to room temperature for 18 hours. The reaction was quenched by the addition of water (300 mL) at 0° C. with stirring for 1 hour. The EtOH was removed in vacuo and the resulting residue diluted further with water (600 mL) followed by extraction into 5% MeOH in DCM (250 mL). The organic layer was collected, dried over MgSO4 and concentrated in vacuo. The residue was purified using silica gel column chromatography eluting with 0-5% MeOH in DCM to afford the title compound (12 g, 73%).
Reaction SMILES: C([Li])CCC.[CH:6]1[C:19]2[NH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.Br[CH2:21][CH2:22][O:23][CH2:24][CH2:25][O:26][CH3:27]>C1COCC1>[CH3:27][O:26][CH2:25][CH2:24][O:23][CH2:22][CH2:21][N:18]1[C:19]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:11][C:12]2[C:17]1=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: c1ccc2c(c1)Nc1ccccc1O2
Reactant: COCCOCCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCOCCN1c2ccccc2Oc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.2 %

Procedure:
Butyllithium (1.6 M in hexane, 5 ml) was added dropwise to a stirring solution of 10H-phenoxazine (1.00 g, 5.46 mmol) in THF at −78° C. and continued the stirring for 1 h. To this mixture added 1-bromo-2(2-methoxyethoxy)ethane (1.5 ml, 11 mmol) dropwise and stirring continued for another 1 h at −78° C. The mixture was allowed to warm to RT and stirred overnight, after which the resultant dark orange solution was quenched with water. The aqueous phase was separated and extracted with dichloromethane. The combined organic phases were dried over magnesium sulfate and evaporated under reduced pressure. The crude mixture was purified by chromatography and Kugelrohr distillation to give the product as a pale yellow oil (1.11 g, 72%). Cyclic voltammetry of MEEP in a 0.1 M tetra-n-butylammonium hexafluorophosphate (TBAPF6) in acetonitrile solution shows a reversible redox couple at 0.26 V vs Fc+/Fc.
Reaction SMILES: [C:1]([C:4]1[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:7]([C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)[C:6](=[O:27])[C:5]=1O)(=O)[CH3:2].Cl.[CH:30]1([NH:33][NH2:34])[CH2:32][CH2:31]1>CCO.C1(C)C=CC=CC=1>[Cl:15][C:12]1[CH:11]=[CH:10][C:9]([CH:8]2[C:4]3[C:1]([CH3:2])=[N:34][N:33]([CH:30]4[CH2:32][CH2:31]4)[C:5]=3[C:6](=[O:27])[N:7]2[C:16]2[CH:17]=[C:18]([CH3:26])[C:19]3[N:20]([C:22]([CH3:25])=[N:23][N:24]=3)[CH:21]=2)=[CH:14][CH:13]=1
Reactant: NNC1CC1
Reactant: CC(=O)C1=C(O)C(=O)N(c2cc(C)c3nnc(C)n3c2)C1c1ccc(Cl)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: Cc1nn(C2CC2)c2c1C(c1ccc(Cl)cc1)N(c1cc(C)c3nnc(C)n3c1)C2=O
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 4-acetyl-5-(4-chlorophenyl)-1-(3,8-dimethyl-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-3-hydroxy-1H-pyrrol-2(5H)-one (Step 92.1) (630 mg, 1.588 mmol) and cyclopropylhydrazine hydrochloride (517 mg, 4.76 mmol) in EtOH (8 mL) and toluene (8 mL) was stirred for 2 hr at reflux. The reaction mixture was concentrated, diluted with CH2Cl2/saturated aq. NaHCO3 solution, and extracted with CH2Cl2. The combined organic layers were washed with water and brine, dried over Na2SO4 and evaporated. The crude material was purified by silica gel column chromatography (1% ammonia/5% MeOH/CH2Cl2) to afford the title product (412 mg, 0.952 mmol, 59.9% yield) as a yellow foam. tR: 0.95 min (LC-MS 2); ESI-MS: 433 [M+H]+ (LC-MS 2); Rf=0.28 (1% ammonia/5% MeOH/CH2Cl2); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.98-1.11 (m, 2H) 1.18-1.29 (m, 2H) 1.92 (s, 3H) 2.43 (s, 3H) 2.61 (s, 3H) 3.75-3.87 (m, 1H) 6.41 (s, 1H) 7.27-7.39 (m, 5H) 8.33-8.48 (m, 1H).
Reaction SMILES: [BH4-].[Na+].O1CCCC1.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:13]([C:15](O)=[O:16])[CH:14]=1.II>CO>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)=[C:13]([CH:14]=1)[CH2:15][OH:16]
Reactant: Nc1ccc(N2CCOCC2)c(C(=O)O)c1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(N2CCOCC2)c(CO)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A 50 mL two necked round bottom flask was fitted with a magnetic stirrer bar and a dropping funnel. A suspension of NaBH4 in tetrahydrofuran (100 mg, 2 4 mmol/10 mL) was added, followed by 5-amino-2-morpholinobenzenecarboxylic acid (222 mg, 1.0 mmol) in one portion. A reflux condenser was fitted and the reaction mixture was cooled to 0° C. under nitrogen atmosphere. A solution of iodine in tetrahydrofuran (250 mg, 1.0 mmol/15 mL) was added dropwise to the reaction mixture. After iodine addition was completed and gas evolution had ceased, the reaction mixture was heated at reflux for 6 hours and left stirring at room temperature overnight. Methanol was added slowly until the mixture became clear. The resulting solution stirred at room temperature for 30 minutes then solvent was removed under reduced pressure. The residue was dissolved in 20% KOH (30 mL), stirred for 4 hours and extracted with dichloromethane (3×30 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated to give 5-amino-2-morpholinobenzyl alcohol as an off-white solid (150 mg, 72% yield). 1H NMR (300 MHz, CDCl3) δ 7.05 (d, J=8.7 Hz, 1H), 6.59 (dd, J=8.4, 2.7 Hz, 1H), 6.49 (d, J=2.7 Hz, 1H), 5.51 (br s, 1H), 4.71 (s, 2H), 3.84 (t, J=5.1 Hz, 4H), 3.60 (br s, 2H), 2.91 (t, J=5.1 Hz, 4H). LC-ESI-MS (method B): rt 2.31 min.; m/z 209.2 [M+H]+.
Reaction SMILES: [N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)[CH:5]=NC=N1.N1C=[CH:35][CH:34]=[CH:33]1>>[N:1]1([C:6]2[O:10][C:9]3[C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:8]=3[C:7]=2[C:18](=[O:31])[C:19]2[CH:20]=[C:21]([O:29][CH3:30])[C:22]([O:27][CH3:28])=[C:23]([O:25][CH3:26])[CH:24]=2)[CH:35]=[CH:34][CH:33]=[CH:5]1
Reactant: COc1cc(C(=O)c2c(-n3cncn3)oc3c(O)c(OC)ccc23)cc(OC)c1OC
Reactant: c1cc[nH]c1
Product: COc1cc(C(=O)c2c(-n3cccc3)oc3c(O)c(OC)ccc23)cc(OC)c1OC

Procedure:
This material was prepared in a similar manner as 2-(1,2,4-triazol-1-yl)-7-hydroxy-3-(3,4,5-trimethoxybenzoyl)-6-methoxy-benzo[b]furan (entry 43, Table 1), above, using pyrrole in place of 1,2,4-triazole as the nucleophile. 1H NMR (300 MHz, CDCl3) δ 8.47 (d, 1H, J=1.21 Hz), 7.75 (d, 1H, J=1.20 Hz), 7.27 (d, 1H, J=8.60 Hz), 7.18 (d, 1H, J=8.66 Hz), 7.05 (s, 2H, benzoyl Hs), 3.94 (s, 3H, OMe), 3.74 (s, 6H, 2×OMe), 3.73 (s, 3H, OMe).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[CH:5]=[CH:6][C:7]([NH:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:12][CH:11]=1)=[O:8].B([O-])([O-])O[C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C>C1(C)C=CC=CC=1.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>[F:34][C:31]1[CH:32]=[CH:33][C:28]([C:2]2[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]([NH:9][C:10]2[CH:22]=[CH:21][C:13]([CH2:14][N:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(C=Cc1cccc(Br)c1)Nc1ccc(CN2CCCCC2)cc1
Reactant: [O-]B([O-])Oc1ccc(F)cc1
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: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: O=C(C=Cc1cccc(-c2ccc(F)cc2)c1)Nc1ccc(CN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.8 %

Procedure:
A suspension of 1-(4-(3-bromocinnamoylamino)-benzyl)piperidine (0.4 g), 4-fluorophenyl borate (0.14 g), 1M potassium carbonate (2 ml) and ethanol (1 ml) in toluene (5 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the suspension was added tetrakistriphenylphosphinepalladium (0.05 g), and the mixture was refluxed over night. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated sodium chloride solution, and dried with anhydrous magnesium sulfate. Under reduced pressure, the solvent was evaporated, and the residue was purified with silica gel column (methanol/triethylamine/ethyl acetate) to give crude crystals, which were recrystallized from ethyl acetate-hexane to give 1-(4-(3-(4-fluoro-phenyl)-cinnamoylamino)benzyl)piperidine (Compound 83) (0.35 g) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:4](=[O:13])[C:3]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][O:21][C:22]1[CH:51]=[CH:50][C:25]([CH2:26][O:27][C:28](=[O:49])[C@H:29]([N:36]2[CH2:40][C@H:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C@@H:38]([CH:47]=O)[CH2:37]2)[CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:24][CH:23]=1>>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28](=[O:49])[C@H:29]([N:36]2[CH2:40][C@H:39]([C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[C@@H:38]([CH2:47][N:10]3[CH2:9][CH2:8][CH:7]([N:5]4[C:4](=[O:13])[C:3]([C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)=[C:2]([CH3:1])[NH:6]4)[CH2:12][CH2:11]3)[CH2:37]2)[CH:30]2[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:50][CH:51]=1
Reactant: Cc1[nH]n(C2CCNCC2)c(=O)c1-c1ccccc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4[nH]c(C)c(-c5ccccc5)c4=O)CC3)[C@@H](c3ccccc3)C2)cc1
Yield: 91.3 %

Procedure:
When 0.070 g of 4-(5-methyl-4-phenyl-1H-pyrazol-3(2H)-on-2-yl)-piperidine and 0.043 g of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl ester were used in the procedure of Example 124, Step C, there was obtained 0.061 g of α-(R)-(3-(S)-((4-(5-methyl-4-phenyl-1H-pyrazol-3(2H)-on-2-yl)-piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl ester after chromatography on silica gel (20 mL column—elution with 3% MeOH in dichlormethane). ESI-MS 677.3 (M+H); TPLC A: 2.85 min.