Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[CH:35][C:36](Br)=[N:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:36]1[CH:35]=[CH:34][C:33]([C:32]([F:41])([F:40])[F:31])=[CH:38][N:37]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(C(F)(F)F)cn2)c1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (˜0.5 mmol) was used in Procedure A with 5-trifluoromethyl-2-bromopyridine (113 mg, 0.5 mmol). Purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to yield N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white foam: TLC Rf=0.30 (15% ethyl acetate/hexanes); MS (Q1) 460 (M)+.
Reaction SMILES: NC1C=CC2N([CH:22]([CH2:27][CH2:28][CH3:29])[CH2:23][C:24]([OH:26])=[O:25])C(=O)N(CC3C4C(=CC=CC=4C)N(C)C=3)C=2C=1.[Si](N=C=O)(C)(C)C.C(=O)(O)[O-].[Na+].[CH2:44]1COC[CH2:45]1>>[CH2:44]([O:26][C:24](=[O:25])[CH2:23][CH2:22][CH2:27][CH2:28][CH3:29])[CH3:45]
Reactant: C1CCOC1
Reactant: CCCC(CC(=O)O)n1c(=O)n(Cc2cn(C)c3cccc(C)c23)c2cc(N)ccc21
Agent: C[Si](C)(C)N=C=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 3-[5-Amino-3-(1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-2,3-dihydro-benzoimidazol-1-yl]hexanoic acid: ethyl ester (50 mg, 0.111 mmol) in THF (30 ml) was added TMS isocynate (1.73 mg, 15 mmol). The solution was stirred at RT for 3 hours. The reaction was checked by LCMS. To the reaction mixture an aqeous solution of Sodium bicarbonate (60 ml) was added. The resulting mixture, stirred for another 30 minutes, was then extracted with Ethyl Acetate. The organic layer, dried over MgSO4, was filtered and evaporated to dryness to give a dark residue. The residue was purified by prep TLC, eluded with 10% methanol in Dichloromethane to give 10 mg (18%) of 3-[3-1,4-Dimethyl-1H-indol-3-ylmethyl)-2-oxo-5-ureido-2,3-dihydro-benzoimidazol-1-yl]hexanoic acid ethyl ester. LCMS (ESMS): m/z 491.58 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:8]=[C:9]2[O:13][CH:12]([CH3:14])[CH2:11][C:10]=12)=[O:4].COC(C1C=C(O)C2CC(C)OC=2C=1)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=2)[C:8]2[CH2:11][CH:12]([CH3:14])[O:13][C:9]=2[CH:10]=1)=[O:4]
Reactant: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)cc2c1CC(C)O2
Agent: COC(=O)c1cc(O)c2c(c1)OC(C)C2
Product: COC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2c(c1)OC(C)C2

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1f, from 4-hydroxy-2-methyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (10c) (58 mg, 0.29 mmol). Purification by column chromatography eluting with 15-25% EtOAc in hexanes gave a pale yellow solid (65 mg, 64% yield). 1H NMR (400 MHz, CDCl3) δ 7.90-7.93 (m, 2 H) 7.23-7.26 (m, 2 H) 7.10 (s, 1 H) 7.07 (s, 1 H) 4.98-5.07 (m, 1 H) 3.89 (s, 3 H) 3.21 (dd, J=16.67, 8.84 Hz, 1 H) 3.07 (s, 3 H) 2.70 (dd, J=16.55, 7.45 Hz, 1 H) 1.48 (d, J=6.32 Hz, 3 H); LCMS for C18H18O6S m/z 385.10 (M+Na)+.
Reaction SMILES: OC1C(C)=C(O)C=CC=1C=O.O1C=CCCC1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:35][C:36]1[C:37]([O:51]C2CCCCO2)=[C:38]([CH:41]=[CH:42][C:43]=1[O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][O:46]1)[CH:39]=[O:40]>>[OH:51][C:37]1[C:36]([CH3:35])=[C:43]([O:44][CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][O:46]2)[CH:42]=[CH:41][C:38]=1[CH:39]=[O:40]
Reactant: Cc1c(OC2CCCCO2)ccc(C=O)c1OC1CCCCO1
Agent: C1=COCCC1
Agent: Cc1c(O)ccc(C=O)c1O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: Cc1c(OC2CCCCO2)ccc(C=O)c1O

Procedure:
By following Example 2 procedure, 10.0 g of 2,4-Dihydroxy-3-methylbenzaldehyde was reacted with 48.3 g of 3,4-dihydro-2H-pyran in the presence of 1.6 g of pyridinium para-toluenesulfonate to get 15.0 g of crude title product. Formation of 3-methyl-2,4-bis(tetrahydro-2H-pyran-2-yloxy)benzaldehyde was not noticed either by GC or TLC of the crude sample. Crude product was purified by column chromatography to get the title compound as white solid. DSC: 58.2° C. (peak). IR (KBr): 3125, 2946, 2870, 2747, 1645, 1623, 1585, 1494, 1431, 1388, 1356, 1327, 1288, 1246, 1204, 1181, 1121, 1091, 1036, 1022, 955, 921, 895, 872, 799, 758, 712, and 642 cm−1. 1H-NMR (CDCl3, 400 MHz): δ 11.49 (s, 1H, exch. with D2O, OH), 9.72 (s, 1H, CHO), 7.33 (d, J=8.8 Hz, 1H, H-6), 6.78 (d, J=8.8 Hz, 1H, H-5), 5.58 (t, J=2.8 Hz, 1H, OCHO), 3.81 (dt, J=2.8 Hz, 11.2 Hz, 1H, CH2O), 3.61-3.66 (m, 1H, CH2O), 2.15 (s, 3H, ArCH3), 2.00-2.05 (m, 1H, CH2CHO), 1.89-1.93 (m, 2H, CH2CHO and CH2CH2CHO), 1.62-1.75 (m, 3H, OCH2CH2CH2). 13C NMR (CDCl3, 100 MHz): δ 194.80 (CHO), 161.62 (C-4), 161.20 (C-2), 132.71 (C-6), 115.47 (C-1), 114.05 (C-3), 106.17 (C-5), 95.67 (OCHO), 61.89 (C-6′), 30.00 (C-2′), 24.97 (C-5′), 18.36 (C-4′), 7.38 (ArCH3). Mass (EI-MS): 236.24 (M), 235.10 (M−1).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([CH:10]=[O:11])[CH2:3]1.[CH3:13][Mg]Br>C1COCC1>[CH3:9][C:6]1([CH3:8])[CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3][CH:4]([CH:10]([OH:11])[CH3:13])[CH2:5]1
Reactant: CC1(C)CC(C=O)CC(C)(C)C1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(O)C1CC(C)(C)CC(C)(C)C1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
The crude 3,3,5,5-Tetramethyl-cyclohexanecarboxaldehyde (650 mg, 3.8 mmol) was treated with methylmagnesium bromide (4.5 mmol, 1.2 eq) in THF (20 mL) at 0° C., and allowing to warm to RT following a method analogous to General Procedure I to produce 1-(3,3,5,5-tetramethyl-cyclohexyl)-ethanol (400 mg) after quenching the reaction at 0° C. with 2N HCl, extraction of the product with EtOAc, and evaporation of the solvent under vacuum. The crude material was used without purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:28]4[CH:27]=[CH:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=4)[CH2:32][CH2:33]3)[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=CCCc1cc(-c2ccc(F)cc2)n(-c2ccccc2)n1
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(-c4ccccc4)n3)CC2)cc1

Procedure:
80 mg (58%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-fluorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (80 mg, 0.272 mmol), 1-(4-methoxyphenyl)piperazine (72 mg, 0.272 mmol), DIPEA (0.071 mL, 0.408 mmol) and NaBH(OAc)3 (173 mg, 0.816 mmol).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[C:15]([Cl:25])[CH:14]=3)[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:26]([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27]>>[Cl:25][C:15]1[CH:14]=[C:13]([CH:18]=[CH:17][C:16]=1[O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[CH2:12][N:9]1[C:10](=[O:11])[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:26]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[O:27])[C:7]=2[CH2:8]1
Reactant: O=C1c2ccnc(Cl)c2CN1Cc1ccc(OCC(F)(F)F)c(Cl)c1
Reactant: O=COc1ccccc1
Product: O=C(Oc1ccccc1)c1nccc2c1CN(Cc1ccc(OCC(F)(F)F)c(Cl)c1)C2=O
Yield: 49 %

Procedure:
The title compound is prepared in 49% yield (180 mg, brown solid) from 4-chloro-2-(3-chloro-4-(2,2,2-trifluoroethoxy)benzyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (300 mg, 0.76 mmol, Intermediate-71) and phenyl formate (190 mg, 1.5 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH2:8][CH2:7]2)([O-:3])=[O:2].O=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.[Na]>C(O)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[CH2:8][CH2:7]2)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCN2
Agent: [Na]
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCc3cc([N+](=O)[O-])ccc32)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 122.9 %

Procedure:
5-Nitroindoline (12.18 mmol, 2 g) was stirred in acetic acid (50 mL) in an ice bath. tert-Butyl 4-oxopiperidine-1-carboxylate (14.62 mmol, 2.91 g) was added, followed by the portionwise addition of sodium triacetoxyhydroborate (18.27 mmol, 3.87 g). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated at reduced pressure. The resulting residue was taken up in ethyl acetate and washed with saturated sodium bicarbonate solution. The organic phase was concentrated at reduced pressure to afford the title compound (5.2 g).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([OH:26])[CH:22]=[CH:21][CH:20]=2)=[O:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][C:47]([CH3:51])([CH3:50])[CH2:48]O>C1COCC1>[CH3:13][O:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[C:23]([O:26][CH2:46][C:47]([CH3:51])([CH3:50])[CH3:48])[CH:22]=[CH:21][CH:20]=2)=[O:16]
Reactant: CC(C)(C)CO
Reactant: COC(=O)c1cc2c(O)cccc2[nH]1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc2c(OCC(C)(C)C)cccc2[nH]1
Reaction time: 20 h

Procedure:
DEAD (0.414 ml, 2.66 mmol) is slowly added to a solution of 4-Hydroxy-1H-indole-2-carboxylic acid methyl ester 75 (363 mg, 1.9 mmol), triphenylphosphine (698 mg, 2.66 mmol) and 2,2-Dimethyl-propan-1-ol (228 mg, 2.58 mmol) in 8 ml of THF. Stirring is continued for 20 hours and the solvent is then evaporated. The crude mixture is purified by chromatography on silicagel using cyclohexane/EtOAc (9/1).
Reaction SMILES: [CH:1]([C:4]1[CH:8]=[C:7]([CH2:9][NH2:10])[O:6][N:5]=1)([CH3:3])[CH3:2].C([N:19]=[C:20]=[S:21])(=O)C1C=CC=CC=1>CO.N>[CH:1]([C:4]1[CH:8]=[C:7]([CH2:9][NH:10][C:20]([NH2:19])=[S:21])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)c1cc(CN)on1
Agent: N
Solvent: CO
Product: CC(C)c1cc(CNC(N)=S)on1
Reaction time: 12 h
Yield: 91.9 %

Procedure:
The title compound was prepared in accordance with the general method described in Example 12(a) by using 1-(3-isopropyl-isoxazol-5-yl)methylamine (0.85 g, 6.06 mmol), benzoyl isothiocyanate (0.90 mL, 6.67 mmol) and ammonia in methanol (7 N, 30 mL) with the exception that the reaction time for amine with benzoyl isothiocyanate was 12 h and the reaction mixture in ammonia was stirred o.n. Work-up was done by concentrating the reaction mixture in vacuo and adding ethyl acetate (15 mL) and water (15 mL). The is organic layer was separated, dried over sodium sulfate, filtered and concentrated. The residue was triturated with diethyl ether (10 mL) and the solid was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (1.11 g, 91% yield), which was used in the next step without further purification. MS (ESI) m/z 200 (M+1).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[N:7][C:8]([Cl:12])=[C:9]([Br:11])[CH:10]=1)(=O)C.[OH-].[Na+]>C1COCC1>[Br:11][C:9]1[CH:10]=[C:5]([OH:4])[CH:6]=[N:7][C:8]=1[Cl:12]
Reactant: CC(=O)Oc1cnc(Cl)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Oc1cnc(Cl)c(Br)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of 5-bromo-6-chloropyridin-3-yl acetate (3.98 g, 15.89 mmol) in THF (20 mL) at 0° C. was added sodium hydroxide (20 mL, 50.0 mmol, 2.5 M in water). The reaction mixture was stirred at 0° C. for 45 min. The reaction mixture was partially concentrated and then taken to a pH of around 7 by adding acetic acid. The resulting precipitate was filtered and washed with water to give 5-bromo-6-chloropyridin-3-ol. MS (ESI, pos. ion) m/z: 207.9 and 209.9 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[Cl:11][C:8]1[N:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][CH:9]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(Cl)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(6-chloro-3-pyridyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (250 mg, 0.76 mmol) in ethyl acetate (10 ml) were added 3-phenylpropionyl chloride (168 ml, 1.13 mmol) and saturated aqueous sodium hydrogen carbonate (10 ml), 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 with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (302 mg, 86%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[OH-].[K+].[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(CC)CC)[CH:12]=1>O1CCCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C.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>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: CCB(CC)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1cncc(-c2cccnc2)c1
Yield: 33 %

Procedure:
Tetrakis(triphenylphosphine)palladium (915 mg; 0.75 mM) was added to a solution of 3,5-dibromopyridine (4.74 g, 20 mM) in 75 mL of tetrahydrofuran. After stirring for 5 minutes tetra-n-butylammonium bromide (483 mg; 1.5 mM), finely powdered potassium hydroxide (2.52 g; 45 mM) and 3-pyridyldiethylborane (2.2 g; 15 mM) were added and the resulting reaction mixture was heated to reflux for 2 hours. The reaction mixture was cooled, diluted with 100 mL of ethyl acetate and washed with 10×25 mL of saturated sodium chloride solution and dried over anhydrous magnesium sulfate. Solvent removal gave the crude product which was chromatographed on silica gel using ethyl acetate to give the desired product as a solid, boiling at 135°-6° C./~1 mm in 33% yield.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:16]2[C:21](Cl)=[CH:20][N:19]=[C:18]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=3[F:33])[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:34].[K+].C(P(C(C)(C)C)C1(C(C)C)CC(C(C)C)=CC(C(C)C)=C1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:34][C:21]3=[CH:20][N:19]=[C:18]([C:23]4[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][C:24]=4[F:33])[CH:17]=[C:16]3[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#Cc2cc(-c3ccc(S(C)(=O)=O)cc3F)ncc2Cl)CC1
Reactant: [OH-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C(C)(C)C)C(C)(C)C)C1
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(c2cc3cc(-c4ccc(S(C)(=O)=O)cc4F)ncc3o2)CC1
Temperature: 110 °C

Procedure:
A mixture of 4-[5-chloro-2-(2-fluoro-4-methanesulfonyl-phenyl)-pyridin-4-ylethynyl]-piperidine-1-carboxylic acid tert-butyl ester (208 mg), potassium hydroxide (70 mg), Pd2(dibenzylidenactone)3*CHCl3 complex (10 mg), and 2-di-tert-butylphosphino-2,4,6-triisopropylbiphenyl (14 mg) in a mixture of 1,4-dioxane (4 mL) and water (2 mL) is heated under an argon atmosphere in an oil bath at 110° C. for 1 h. The reaction mixture is mixed with water and extracted with ethyl acetate. The combined extracts are washed with brine, dried over MgSO4, and concentrated in vacuo. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1) to give the title compound. LC (method 7): tR=1.41 min; Mass spectrum (ESI+): m/z=475 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=3)[C:15]2=[O:29])=[CH:9][CH:8]=1)[CH3:2].[H][H]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][N:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=3)[C:15]2=[O:29])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc([N+](=O)[O-])cc3)c2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1ccc(Cn2cccc(-c3ccc(N)cc3)c2=O)cc1

Procedure:
3-{4-[3-(4-Nitrophenyl)-2-oxo-2H-pyridin-1-ylmethyl]phenyl}propionic acid ethyl ester (P7, 300 mg, 0.74 mmol) and palladium on charcoal (30 mg) were stirred at room temperature in ethanol (10 mL) under atmospheric pressure of hydrogen for 3 hours, then the reaction mixture was filtered through celite and concentrated. The crude oil was purified by chromatography on silica gel (50% v/v ethyl acetate in petroleum ether) to afford the title compound as an oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][N:24]2[C:28]3[CH:29]=[CH:30][C:31]([C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)=[CH:32][C:27]=3[S:26][C:25]2=[O:41])=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].C(N(CC)CC)C.Cl[C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51]>C(OCC)(=O)C>[C:33]([C:31]1[CH:30]=[CH:29][C:28]2[N:24]([CH2:23][CH2:22][O:21][C:18]3[CH:17]=[CH:16][C:15]([CH2:14][CH:9]([NH:8][C:50]([O:52][CH2:53][C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)=[O:51])[C:10]([O:12][CH3:13])=[O:11])=[CH:20][CH:19]=3)[C:25](=[O:41])[S:26][C:27]=2[CH:32]=1)(=[O:40])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: COC(=O)C(N)Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
1.5 g of the compound obtained in Step A of Example 12 are dissolved in 20 ml of ethyl acetate; 1.06 ml of triethylamine are then added and the temperature is lowered to 0° C. 0.725 ml of benzyl chloroformate are added and the mixture is allowed to return to ambient temperature and is stirred overnight.
Reaction SMILES: Cl.Cl.[OH:3][C@@H:4]1[CH2:11][N:10]([CH2:12][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][NH:18][CH:17]([CH3:21])[C:16]2=[O:22])[CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[Cl:23][C:24]1[CH:25]=[C:26]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:27]=[CH:28][C:29](O)=[O:30].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:23][C:24]1[CH:25]=[C:26](/[CH:27]=[CH:28]/[C:29]([N:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][CH2:12][N:10]3[CH2:9][CH2:8][C:5]4([CH2:6][CH2:7]4)[C@H:4]([OH:3])[CH2:11]3)[C:16](=[O:22])[CH:17]2[CH3:21])=[O:30])[CH:32]=[CH:33][C:34]=1[Cl:35]
Reactant: CC1NCCN(CCCN2CCC3(CC3)[C@H](O)C2)C1=O
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1C(=O)/C=C/c1ccc(Cl)c(Cl)c1
Reaction time: 1 h

Procedure:
To a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 25; 0.03 g, 0.2 mmol) in dichloromethane (1 ml) was added triethylamine (0.03 ml, 0.2 mmol) and acetic acid (0.02 ml, 0.4 mmol) followed by a solution of crude 2-methyl-3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (intermediate 14c; 0.06 g, 0.24 mmol) in dichloromethane (1 ml). Sodium triacetoxyborohydride (0.06 g, 0.26 mmol) was then added and the mixture stirred for 2 h, after which time the mixture was washed with saturated aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. The crude residue was then treated with HCl in dioxane (2 ml, 4 N) and stirred for 30 minutes after which time the reaction was concentrated to afford crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride as a white powder (0.1 g). To a solution of crude 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one dihydrochloride (0.03 g, 0.1 mmol) in N,N-dimethylformamide (0.8 ml) was added 3,4-dichlorocinnamic acid (0.2 g, 0.1 mmol), triethylamine (0.05 ml, 0.4 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluoro-phosphate (4 g, 0.1 mmol) and the reaction shaken for 1 h, after which time the reaction mixture was directly purified by preparative HPLC. This afforded the titled product as a colorless gum. MS (ISP)=480.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][C:8]2=[O:15])=[CH:4][CH:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)(C(F)(F)F)C(F)(F)F>[CH2:18]([N:25]=[C:13]([N:10]1[CH2:11][CH2:12][N:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[C:8](=[O:15])[CH2:9]1)[NH2:14])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: N#CN1CCN(Cc2ccc(F)cc2)C(=O)C1
Solvent: OC(C(F)(F)F)C(F)(F)F
Product: NC(=NCc1ccccc1)N1CCN(Cc2ccc(F)cc2)C(=O)C1

Procedure:
A solution of 4-(4-fluorobenzyl)-3-oxopiperazine-1-carbonitrile (0.56 g, 2.40 mmol) and benzylamine (0.53 mL, 4.80 mmol) in 1,1,1,3,3,3-hexafluoroisopropanol (10 mL) was heated to reflux overnight. The solvent was removed in vacuo and the residue was purified by prep HPLC on a C18 column eluting with a water/acetonitrile/TFA gradient. The pure fractions were concentrated to an oil. The oil was partitioned between aqueous sat. NH4Cl and chloroform. The layers were separated and the aqueous layer was extracted twice more with chloroform. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give an oil for the title compound. 1H NMR (400 MHz, d6 DMSO) before work-up δ 8.29 (t, 1H, J=5.5 Hz), 7.81 (bs, 2H), 7.29-7.40 (m, 7H), 7.19 (t, 2H, J=8.8 Hz), 4.56 (s, 2H), 4.45 (d, 2H, J=5.7 Hz), 4.15 (s, 2H), 3.67 (m, 2H), and 3.39 (m, 2H). ES MS (M+1)=341.3.