Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.C(OC(=O)C[C@@H](N)C(N[C@H](C(=O)NC)C(C)(C)C)=O)C1C=CC=CC=1.FC(F)(F)C(O)=O.[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([NH2:64])[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CO[CH:68]1[CH:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:84]=[CH:83][C:82]([C:85]#[N:86])=[CH:81][CH:80]=3)=[CH:75][CH:74]=2)[CH2:71][CH:70](OC)O1>ClCCCl>[CH2:40]([O:47][C:48](=[O:65])[CH2:49][C@@H:50]([N:64]1[CH:70]=[CH:71][C:72]([C:73]2[CH:78]=[CH:77][C:76]([C:79]3[CH:80]=[CH:81][C:82]([C:85]#[N:86])=[CH:83][CH:84]=3)=[CH:75][CH:74]=2)=[CH:68]1)[C:51]([NH:53][C@@H:54]([CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)[CH2:55][OH:56])=[O:52])[C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@H](CO)Cc1ccccc1
Reactant: COC1CC(c2ccc(-c3ccc(C#N)cc3)cc2)C(OC)O1
Agent: CNC(=O)[C@@H](NC(=O)[C@H](N)CC(=O)OCc1ccccc1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: N#Cc1ccc(-c2ccc(-c3ccn([C@H](CC(=O)OCc4ccccc4)C(=O)N[C@H](CO)Cc4ccccc4)c3)cc2)cc1
Temperature: 87.5 °C
Yield: 39.1 %

Procedure:
As described in Example 1(b) for the preparation of 3(R)-amino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester trifluroacetate salt, crude 3(R)-amino-N-(l(S)-benzyl-2-hydroxyethyl)succinamic acid benzyl ester trifluoroacetate salt (prepared as described in Example 1(a); 0.876 mmol) was condensed with 4'-(2,5-dimethoxytetrahydrofuran-3-yl)-biphenyl-4-carbonitrile (326 mg, 1.05 mmol) in 1,2-dichloroethane (5 mL). The solution was heated at 85-90° C. for 5 hours, allowed to cool, and evaporated to give a brown oil which was purified via flash column chromatography with 1% HOAc/30% d, EtOAc/hex as eluant. HOAc was removed via azeotrope with n-heptane layers to provide 200 mg (39%) of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-[3-(4'-cyanobiphenyl-4-yl)-1H-pyrrol-1-yl]succinamic acid benzyl ester as a pale yellow powder, mp 149-50° C. 1H NMR (CDCl3): ∂ 7.74 (s, 4H), 7.59 (d, 4H, J=4.1 Hz), 7.32-7.18 (m, 10H), 7.05 (bm, 2H), 6.94 (t, 1H, J=2.2 Hz), 6.64 (t, 1H, 2.5 Hz), 6.58 (bm, 1H), 5.48 (d, 1H, J=7.8 Hz), 5.10 (d, 2H, J=3.1 Hz), 5.00 (dd, 1H, J=5.0, 9.3 Hz), 4.46-4.32 (m, 2H), 4.22-4.12 (m, 1H), 3.41 (dd, 1H, J=5.3, 17.1 Hz), 3.04 (dd, 1H, J=9.1, 17.1 Hz), 2.70-2.63 (m, 2H). IR: 3389, 3030, 2948, 2225, 1735, 1665, 1603, 1528, 1495 cm-1. HRFABMS: Calculated for C37H33N3O4Cs (MH+Cs+): 716.1525. Found: 716.1503. Anal. Calculated for C37H33N3O4.0.4 CH2Cl2 : C, 72.73; H, 5.52; N, 6.80. Found: C, 72.67, H, 5.53; N, 6.81.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].F[C:8]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[CH:20][C:9]=1[C:10]([NH:12][C:13]1[CH:18]=[CH:17][NH:16][C:15](=[O:19])[CH:14]=1)=[O:11].[F:28][C:29]([F:39])([F:38])[O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=1>CN(C=O)C>[O:19]=[C:15]1[CH:14]=[C:13]([NH:12][C:10](=[O:11])[C:9]2[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:8]=2[O:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][C:29]([F:28])([F:38])[F:39])=[CH:32][CH:33]=2)[CH:18]=[CH:17][NH:16]1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C(Nc1cc[nH]c(=O)c1)c1ccc(C(F)(F)F)cc1Oc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Cs2CO3 (651.6 mg, 2 mmol) was added to a solution of 2-fluoro-N-(2-oxo-1,2-dihydropyridin-4-yl)-4-(trifluoromethyl)benzamide (60.0 mg, 0.2 mmol) and 4-(trifluoromethoxy)phenol (259.1 μL, 2 mmol) in DMF (1 mL) and the reaction was stirred at 100° C. for 1 hour. The reaction was filtered and purified by reverse phase HPLC using a gradient of acetonitrile in water (10-99%) and HCl as a modifier to yield N-(2-oxo-1,2-dihydropyridin-4-yl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (79) (25.7 mg, 28%). ESI-MS m/z calc. 458.07. found 459.5 (M+1)+; Retention time: 1.80 minutes (3 minutes run)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(O[C:10](=[O:26])[C:11]1[C:16](C)=[CH:15][CH:14]=[CH:13][C:12]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C.[C:27](OCC)(=[O:29])C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOCC>[CH2:19]([O:18][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]([O:29][CH3:27])[C:11]=1[CH2:10][OH:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1c(C)cccc1OCc1ccccc1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: COc1cccc(OCc2ccccc2)c1CO
Yield: 100 %

Procedure:
In a nitrogen stream, to a suspension of lithium aluminum hydride (0.82 g, 21.50 mmol) in ether (30 mL), a solution of 2-benzyloxy-6-methyl-benzoic acid ethyl ester (4.47 g, 16.54 mmol) in ether (15 mL) was added at room temperature over 10 minutes. The reaction mixture was stirred under heating to reflux for one hour. Ethyl acetate (2 mL) was added dropwise to the reaction mixture under cooling with ice, and then a saturated Rochelle salt aqueous solution (20 mL) was added thereto dropwise and the mixture was stirred at room temperature for one hour. The reaction mixture was subjected to Celite filtration. To the filtrate was added a saturated Rochelle salt aqueous solution (10 mL) and the mixture was extracted with ether. The organic layer was washed with a saturated sodium chloride aqueous solution and dried (anhydrous sodium sulfate), and then the solvent was distilled under reduced pressure. The obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:4)] to obtain the title compound (3.84 g, 100%).
Reaction SMILES: [H-].[Na+].[C:3]([C@@H:7]([C@H:9]([C:11]([O:13][CH3:14])=[O:12])[OH:10])[OH:8])([O:5][CH3:6])=[O:4].Br[CH2:16][C:17]([CH3:19])=[CH2:18]>CN(C=O)C>[CH3:16][C:17](=[CH2:18])[CH2:19][O:10][C@H:9]([C@@H:7]([O:8][CH2:18][C:17]([CH3:19])=[CH2:16])[C:3]([O:5][CH3:6])=[O:4])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](O)[C@@H](O)C(=O)OC
Reactant: C=C(C)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(C)CO[C@@H](C(=O)OC)[C@@H](OCC(=C)C)C(=O)OC
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a cooled (−10° C.) suspension of NaH (60% dispersion in mineral oil, 6.73 g, 168 mmol) in DMF (240 mL) was added dropwise a solution of (+)-dimethyl L-tartrate (15.0 g, 84.0 mmol) in DMF (40 mL) over a period of 30 min. After the addition was complete, the mixture was stirred for another 30 min at −10° C., and then 3-bromo-2-methylpropene (25.5 mL, 253 mmol) was added while maintaining the reaction temperature below 0° C. The mixture was stirred for 1.5 h at −10° C., quenched with H2O and saturated aqueous sodium chloride (NaCl, brine), and extracted with EtOAc. The phases were separated and the aqueous phase was further extracted with EtOAc. The combined organic phases were washed with brine, dried over magnesium sulfate (MgSO4), filtered, and concentrated to yield a yellow oil. Purification by flash chromatography (SiO2, hexanes/EtOAc gradient) yielded the title compound as a colorless oil (17.05 g, 71%): IR (neat) 2953, 1758, 1435, 1270, 1203, 1106 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.92-4.86 (m, 4H), 4.37 (s, 2H), 4.19 (d, J=12.3 Hz, 2H), 3.82 (d, J=12.3 Hz, 2H), 3.77 (s, 6H), 1.68 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 169.84, 141.04, 114.10, 78.60, 75.66, 52.22, 19.52; HRMS-ESI (m/z) [M]+ calcd for C14H22O6, 286.1416; found, 286.1417.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([S:11][C:12]([S:15][C:16]2[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([O:26][CH2:27][CH2:28][CH:29]3[CH:33]([CH2:34][CH2:35][OH:36])[O:32]C(OCC)[O:30]3)=[C:18]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:17]=2)([CH3:14])[CH3:13])[CH:8]=[C:7]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:6]=1[OH:48])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.O>CO>[C:40]([C:18]1[CH:17]=[C:16]([S:15][C:12]([S:11][C:9]2[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([OH:48])=[C:7]([C:44]([CH3:47])([CH3:46])[CH3:45])[CH:8]=2)([CH3:14])[CH3:13])[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]=1[O:26][CH2:27][CH2:28][CH:29]([OH:30])[CH:33]([OH:32])[CH2:34][CH2:35][OH:36])([CH3:43])([CH3:42])[CH3:41]
Reactant: CCOC1OC(CCO)C(CCOc2c(C(C)(C)C)cc(SC(C)(C)Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc2C(C)(C)C)O1
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(Sc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1)Sc1cc(C(C)(C)C)c(OCCC(O)C(O)CCO)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
2,6-Di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-{2-[2-ethoxy-5-(2-hydroxy-ethyl)-[1,3]dioxo-lan-4-yl]-ethoxy}-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenol (Ex-13D, 4.0 g, 5.7 mmol) was dissolved in methanol (60 mL). Acetic acid (2.8 mL) and water (2.8 mL) were added and the resultant mixture was stirred at reflux for 3 h. The reaction mixture was concentrated under reduced pressure and the residue was diluted with water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate and concentrated to an off-white foam. The residue was dissolved in methanol (60 mL) and potassium carbonate (1.6 g) was added. The mixture was stirred at room temperature for 1.5 h and concentrated under reduced pressure and the residue was diluted with water (100 mL). The solution was extracted with dichloromethane (3×100 mL), dried over sodium sulfate, and concentrated to a white foam. Following silica gel chromatography (2:1 ethyl acetate:hexanes) gave 2.2 g (65%) of 6-{2,6-di-tert-butyl-4-[1-(3,5-di-tert-butyl-4-hydroxy-phenylsulfanyl)-1-methyl-ethylsulfanyl]-phenoxy}-hexane-1,3,4-triol as a white solid, mp 75–77° C. 1H-NMR (300 MHz, CDCl3) δ7.54 (s, 2H), 7.45 (s, 2H), 5.36 (s, 1H), 3.92–3.99 (m, 4H), 3.78 (brs, 2H), 2.99 (d, 1H, J=3.8 Hz, 2.78 (d, 1H, J=3.8 Hz), 2.15 (t, 1H, J=4.6 Hz), 2.02–2.11 (m, 2H), 1.83–1.85 (m, 2H), 1.43–1.44 (m, 42H). HRMS (ESI) calcd for C37H60O5S2 (M+Na), 671.3780; found, 671.3775. Anal. calcd. for C37H60O5S2: C, 68.47, H, 9.32, S, 9.88; Found: C, 68.62, H, 9.49, S, 9.59.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:30])[C:11](=[O:29])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[C:14]([F:28])[CH:13]=2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:38][C:39]([CH3:44])([CH3:43])[CH2:40][CH:41]=O.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:30])[C:11](=[O:29])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:25]([CH2:41][CH2:40][C:39]([CH3:44])([CH3:43])[CH3:38])[CH2:26][CH2:27]3)=[C:14]([F:28])[CH:13]=2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)CC=O
Reactant: CN(C(=O)c1ccc(OCCCN2CCNCC2)c(F)c1)c1ccc(Cl)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CO
Product: CN(C(=O)c1ccc(OCCCN2CCN(CCC(C)(C)C)CC2)c(F)c1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
N-(4-Chloro-phenyl)-3-fluoro-N-methyl-4-(3-piperazin-1-yl-propoxy)-benzamide dihydrochloride from Example E71.2 (184 mg, 0.4 mmol) was dissolved in methanol (4.95 ml) and triethylamine (0.167 ml, 1.2 mmol). Acetic acid (0.05 ml) then 3,3-dimethylbutyraldehyde (46 mg, 0.44 mmol) were added and the mixture was stirred for 1 h at room temperature. Sodium cyanoborohydride (31 mg, 0.5 mmol) was added and the mixture was stirred for 20 h at room temperature then concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; 10% methanol:90% dichloromethane) to give a white foam identified as the title compound (77 mg, 37%).
Reaction SMILES: [ClH:1].Cl.[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([O:28][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[CH2:24][CH2:23]3)[CH3:19])OCC[O:11]2)=[CH:6][CH:5]=1.Cl.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>CO>[ClH:35].[ClH:1].[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:11])[CH2:15][CH2:16][CH2:17][N:18]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][CH:25]([O:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)[CH2:26][CH2:27]2)[CH3:19])=[CH:8][CH:9]=1
Reactant: CN(CCCC1(c2ccc(F)cc2)OCCO1)CCN1CCC(Oc2cccc(Cl)c2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CO
Product: CN(CCCC(=O)c1ccc(F)cc1)CCN1CCC(Oc2cccc(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A solution prepared from 8.55 g (15.5 mmol) of 1-{2-{N-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-N-methylamino}ethyl}-4-(3-chlorophenoxy)piperidine dihydrochloride, 130 ml of methanol and 50 ml of 3N HCl was heated at reflux for 3 hours under nitrogen and allowed to cool to room temperature. The methanol was evaporated and the residue made basic with saturated sodium carbonate and extracted with ether. The ether extract was washed with saturated sodium chloride and dried over potassium carbonate. Filtration followed by evaporation of the solvent provided an oil. The yield of the dihydrochloride was 6.8 g (13.4 mmol, 86%). Recrystallization from ethanol/methanol provided analytically pure material.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27](=O)[CH2:28][CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH:15]2[CH2:24][CH2:23][C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[CH:20][CH:21]=3)[CH2:16]2)[CH2:27][CH2:28][CH3:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC=O
Reactant: COc1ccc2c(c1)CC(NC1CCN(Cc3ccccc3)CC1)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: CCCN(C1CCN(Cc2ccccc2)CC1)C1CCc2ccc(OC)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of (1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-amine from Step 1 and propionaldehyde (4.5 mL, 62.4 mmol) in dichloroethane (200 mL) under a nitrogen atmosphere was added sodium triacetoxyborohydride (24 g, 0.113 mol, 2 eq.) in a single portion. The reaction was stirred at room temperature for 24 h then concentrated in vacuo. The residue was partitioned between EtOAc (75 mL) and 5% aq. KOH (50 mL). The aqueous phase was extracted twice more with EtOAc (2×30 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated onto silica (10 g). This was placed on top of a flash column and eluted with 20% hexanes in acetone. The fractions containing product were pooled and concentrated to afford (1-benzyl-piperidin-4-yl)-(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amine as a clear oil (6.86 g).
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]=[C:11]([C:18](=O)[CH3:19])[C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][C:5]=12.C(=O)(O)[O-].[Na+].S(O)(O)(=O)=O.[CH3:31][O:32][C:33](=[NH:35])[NH2:34]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[O:2][N:3]=[C:4]2[C:9]([CH:10]3[C:11]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])=[C:18]([CH3:19])[NH:35][C:33]([O:32][CH3:31])=[N:34]3)=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CC(=O)C(=Cc1cccc2nonc12)C(=O)OC(C)C
Reactant: COC(=N)N
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC1=NC(c2cccc3nonc23)C(C(=O)OC(C)C)=C(C)N1
Temperature: 65 °C
Yield: 24.4 %

Procedure:
A mixture of 2-[(2,1,3-benzoxadiazol-4-yl)methylene]-3-oxobutanoic acid, 1-methylethyl ester (2.04 g, 7.43 mmol), sodium bicarbonate (1.87 g, 22.3 mmol) and O-methylisourea hydrogen sulfate (1.66 g, 9.66 mmol) in dimethylformamide (7.5 ml) was heated at 65° C. (oil bath) overnight under argon. The reaction was then diluted with ethyl acetate, washed several times with water, washed with saturated sodium chloride, dried (potassium carbonate), and evaporated. The residue was flash chromatographed over Merck silica gel (400 ml) eluting with 10% ethyl acetate/dichloromethane to give 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2-methoxy-6-methyl-5-pyrimidinecarboxylic acid, 1-methylethyl ester as a dark solid (0.60 g, 25%). TLC (10% ethyl acetate/dichloromethane) single spot, Rf =0.17.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:18])=[C:8]([C:10]2[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:9]=1)(=[O:3])[CH3:2].O.[Se](=O)=[O:21].C>O1CCOCC1>[F:18][C:7]1[CH:6]=[CH:5][C:4]([C:1](=[O:3])[CH:2]=[O:21])=[CH:9][C:8]=1[C:10]1[C:11]([C:16]#[N:17])=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=[Se]=O
Reactant: CC(=O)c1ccc(F)c(-c2ccccc2C#N)c1
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-c1cc(C(=O)C=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5′-Acetyl-2′-fluorobiphenyl-2-carbonitrile (0.31 g, 1.3 mmol) was suspended in 1,4-dioxane (4.75 ml) and water (0.25 ml) and warmed to 60° C. to solubilise the starting material. The solution was then cooled to ambient temperature, selenium dioxide (0.17 g, 1.55 mmol) added and the mixture heated under reflux for 2 h. The mixture was then allowed to cool to 60° C., activated charcoal (1 g) added and the mixture stirred for 30 min. The mixture was then allowed to cool to ambient temperature, filtered through a glass fibre filter paper and the solid washed with 1,4-dioxane (10 ml) and the filtrate evaporated to give crude 2′-fluoro-5′-(2-oxoacetyl)biphenyl-2-carbonitrile which was used without further purification in the next step.
Reaction SMILES: [C:1]([N:3]=[S:4]([C:7]1[C:8]([O:20][CH3:21])=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:10]([OH:12])=O)([CH3:6])=[O:5])#[N:2].[NH2:22][C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1.C(Cl)(=O)C(Cl)=O>N1C=CC=CC=1>[C:1]([N:3]=[S:4]([C:7]1[C:8]([O:20][CH3:21])=[C:9]([CH:13]=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[C:10]([NH:22][C:23]1[O:24][C:25]([CH3:28])=[N:26][N:27]=1)=[O:12])([CH3:6])=[O:5])#[N:2]
Reactant: Cc1nnc(N)o1
Reactant: COc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)(=O)=NC#N
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Product: COc1c(C(=O)Nc2nnc(C)o2)ccc(C(F)(F)F)c1S(C)(=O)=NC#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 2.8 %

Procedure:
350 mg (80% by weight; 0.869 mmol) of 3-(N-cyano-S-methylsulfonimidoyl)-2-methoxy-4-(trifluoromethyl)benzoic acid and 151 mg (1.52 mmol) of 2-amino-5-methyl-1,3,4-oxadiazole were initially charged in 10 ml of dry pyridine and cooled in an ice bath. 207 mg (1.63 mmol) of oxalyl chloride were added, and after 30 minutes the mixture was thawed to RT. The contents were stirred at RT for 2 h, and another 51.8 mg (0.408 mmol) of oxalyl chloride were then added. The mixture was then stirred at RT for 16 h. For work-up, the contents were freed from the solvent on a rotary evaporator and the residue was taken up in water and dichloromethane. After phase separation, the organic phase was freed from the solvent on a rotary evaporator and the residue was purified chromatographically under neutral conditions, which gave 9.80 mg of product.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[O:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O)[CH3:30].C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C4C=CC=CC=4)=C(C)C=3)=CN=2)CC1)=O)C>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:28])[NH:19][C:20]3[CH:21]=[C:22]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:29][CH3:30])[C:23]([CH3:26])=[CH:24][CH:25]=3)=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1ccccc1B(O)O
Reactant: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(-c4ccccc4)c(C)c3)cn2)CC1
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(-c4ccccc4OC)c3)cn2)CC1

Procedure:
5′-(2′-Methoxy-6-methyl-biphenyl-3-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester and 2-methoxylphenyl boronic acid following a method similar to the one described in the synthesis of 5′-(2-methyl-biphenyl-4-ylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester above. The product was isolated after silica gel column purification with 20-40% EtOAc in hexanes gradient. HRMS m/z calcd for C28H31N3O4 [M+H]+: 474.2388. Found: 474.2387.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH3:16])[N:11]([CH:17]2[CH2:19][CH2:18]2)[C:10]=1[C:20]([NH:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:21])C1C=CC=CC=1.[H][H]>C(O)C.CO.[Pd]>[CH:24]1([CH2:23][NH:22][C:20]([C:10]2[N:11]([CH:17]3[CH2:19][CH2:18]3)[C:12]([CH3:16])=[CH:13][C:14](=[O:15])[C:9]=2[OH:8])=[O:21])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: [H][H]
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NCC2CCCCC2)n1C1CC1
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: Cc1cc(=O)c(O)c(C(=O)NCC2CCCCC2)n1C1CC1
Temperature: 25 °C
Yield: 63 %

Procedure:
A mixture of 3-(benzyloxy)-N-(cyclohexylmethyl)-1-cyclopropyl-6-methyl-4-oxo-1,4-dihydropyridine-2-carboxamide (2.0 g, 4.8 mmol), Pd/C (10% wet, 0.45 g) in ethanol (150 mL) was hydrogenated in a Parr apparatus at 50 psi of hydrogen pressure for 16 h. The reaction mixture was filtered over a pad of Celite® and the Celite® was thoroughly washed with EtOH (25 mL). Evaporation of the solvent afforded a pale pink solid. The solid was dissolved in hot methanol, then cooled to RT as solid product precipitated out. The solid was collected by suction filtration. The mother liquor was concentrated in vacuo and the residual solid was again dissolved in hot methanol and cooled to RT to precipitate out the product, which was then collected. This process was repeated one more time. The three combined white solid fractions weighed 0.95 g (63% yield).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([CH3:27])[C:13]=3[NH:17][C:18](=[O:26])[CH2:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[N:8]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>ClCCl>[CH3:27][C:12]1[C:13]([NH:17][C:18](=[O:26])[CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:4]1[CH2:5][CH2:6][C@@H:2]([O:1][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:3]1)[CH:16]=[CH:15]2
Reactant: Cc1ccc2nc(N3CC[C@@H](O)C3)ccc2c1NC(=O)CC1CCCCC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(N3CC[C@@H](OS(C)(=O)=O)C3)ccc2c1NC(=O)CC1CCCCC1

Procedure:
Prepared according to the method of example 33(a), using N-[2-[(3R)-3-hydroxy-1-pyrrolidinyl]-6-methyl-5-quinolinyl]-cyclohexaneacetamide (Example 84) (0.545 g), methanesulfonyl chloride (0.23 mL), triethylamine (0.62 mL) and dichloromethane (20 mL) to afford the sub-title compound (0.4 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[Ti+3:13].O[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]O>>[CH3:1][CH:2]([CH3:4])[O-:3].[CH3:5][CH:6]([CH3:8])[O-:7].[CH3:9][CH:10]([CH3:12])[O-:11].[OH:3][Ti+3:13][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: OCCCCCCO
Reactant: [Ti+3]
Agent: CC(C)[O-]
Product: CCCCCC[Ti+3]O
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 200 %

Procedure:
0.1 moles of titanium-tri-isopropoxide (Tyzor TPT DuPont, Wilmington, Del.) and 0.1 moles of 6-hydroxy-1-hexanol were added to a 50 ml beaker and stirred at room temperature for 1 minute to form 0.1 mole of hydroxy-hexyl-titanium-tri-isopropoxide. The reaction mixture was heated to 70 degrees C. for 10 minutes to evaporate the isopropyl alcohol formed during the reaction.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:8]2([CH2:10][CH:9]2[C:11]([O:13]CC)=[O:12])[CH:6]2[CH2:7][CH:3]1[CH2:4][CH2:5]2.C1(C(OCC)=O)C2(CCCCC2)C1>>[CH3:1][C:2]1([CH3:16])[C:8]2([CH2:10][CH:9]2[C:11]([OH:13])=[O:12])[CH:6]2[CH2:7][CH:3]1[CH2:4][CH2:5]2
Reactant: CCOC(=O)C1CC12C1CCC(C1)C2(C)C
Agent: CCOC(=O)C1CC12CCCCC2
Product: CC1(C)C2CCC(C2)C12CC2C(=O)O

Procedure:
The title compound was prepared as described in Example 1B substituting the product from Example 30A for the product from Example 1A. MS m/z 194 (M)+.