Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:31])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH3:30])[N:17]=2)[CH2:9]1.[CH:32]([CH:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1)([CH3:34])[CH3:33]>>[CH2:29]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:21][CH:20]=2)[C:16]([NH:15][CH2:14][C:13]([NH:12][CH:10]2[CH2:9][N:8]([CH:38]3[CH2:39][CH2:40][CH:35]([CH:32]([CH3:34])[CH3:33])[CH2:36][CH2:37]3)[CH2:11]2)=[O:31])=[N:17]1)[CH3:30]
Reactant: CC(C)C1CCC(=O)CC1
Reactant: CCn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCC(=O)NC2CN(C3CCC(C(C)C)CC3)C2)c2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-ethyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in Example 67, Step A) and 4-isopropyl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([OH:25])[CH3:24])[CH3:20].[H-].[Na+]>>[CH2:19]([O:21][C:22](=[O:26])[C@@H:23]([O:25][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1)[CH3:24])[CH3:20]
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CCOC(=O)[C@H](C)O
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)[C@H](C)Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1

Procedure:
The subtitle compound was prepared according to the procedure outlined in example 1 step iii) using 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (product of example 1 step ii) (0.77 g), TIM (15 mL), 2-hydroxy-(2S)-propanoic acid ethyl ester (0.40 mL) and 60% sodium hydride (0.14 g) to give the subtitle compound as a clear, colourless oil. Yield: 1 g
Reaction SMILES: [C:1]1(=[O:11])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[C:3](=O)[O:2]1.[N+:12]([C:15]1[CH:16]=[C:17]([CH2:21]C(O)=O)[CH:18]=[CH:19][CH:20]=1)([O-:14])=[O:13].C([O-])(=O)C.[Na+]>C(O)C>[N+:12]([C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[CH:21]=[C:3]1[C:4]2[CH2:5][CH2:6][CH2:7][CH2:8][C:9]=2[C:1](=[O:11])[O:2]1)([O-:14])=[O:13]
Reactant: O=C1OC(=O)C2=C1CCCC2
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1OC(=Cc2cccc([N+](=O)[O-])c2)C2=C1CCCC2
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
4,5,6,7-Tetrahydro-isobenzofuran-1,3-dione (1) (2.50 g, 16.4 mmol) and 3-nitro phenyl acetic acid (2.72 g, 15.0 mmol) were heated in the presence of sodium acetate (60.0 mg, 0.750 mmol) to 240° C. using a ‘Wood's Alloy’ bath. Once the reaction had reached 240° C. an additional amount of sodium acetate (60.1 mg, 0.750 mmol) was added. The reaction mixture was then heated for a further 45 minutes and then cooled to 80° C. Ethanol (20 ml) was added to the thick gum and the mixture slurried for 30 minutes. The resulting suspension was cooled to ambient temperature and filtered. The solid was further washed with additional cold ethanol (2×5 ml) and dried to afford the desired product as a mixture of geometric isomers. Main peak in LC-MS, (2.48 g) and was taken through crude; m/z (LC-MS, ESP), RT=4.48 mins (no ionization observed).
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH2:10].C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([CH:39]=[CH:40][C:41]=1[CH3:42])[CH2:22][N:23]1[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)=[CH:26][C:25]([C:36](Cl)=[O:37])=[N:24]1>C(Cl)Cl>[CH3:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH:4]1[NH:10][C:36]([C:25]1[CH:26]=[C:27]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[N:23]([CH2:22][C:21]2[CH:39]=[CH:40][C:41]([CH3:42])=[C:19]([Cl:18])[CH:20]=2)[N:24]=1)=[O:37]
Reactant: CC1CCCC(C)C1N
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C(=O)NC3C(C)CCCC3C)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Yield: 32.8 %

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 36 from 0.605 g of 2,6-dimethylcyclohexylamine hydrochloride, 1 ml of triethylamine in 15 ml of DCM and 1.5 g of the compound obtained in step A of EXAMPLE 36 in 15 ml of DCM. 0.6 g of the expected product is obtained; m.p.=59.9° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6](=O)[CH2:7][C:8](=O)[C:9]([O:11][CH3:12])=[O:10].Cl.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24]>CO>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[CH:7][C:8]([C:9]([O:11][CH3:12])=[O:10])=[N:24]1
Reactant: NNc1ccccc1Cl
Reactant: COC(=O)C(=O)CC(=O)c1ccco1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cc(-c2ccco2)n(-c2ccccc2Cl)n1
Temperature: 0 °C
Yield: 79.3 %

Procedure:
A stirred solution compound 5 (10.0 g, 50 mmol) and (2-chlorophenyl)hydrazine hydrochloride (10.0 g, 56 mmol) in methanol 80 mL was heated to reflux for 6 h. On cooling to 0° C., solid crashed out, filtered and washed with cold methanol to afford the title compound 6 (12.0 g, 80.0%) which was used for further reaction.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:9][C:10]2[C:11](=[C:13]([C:17]([OH:19])=O)[CH:14]=[CH:15][CH:16]=2)[N:12]=1.[ClH:20].C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:44][C@H:45]1[CH:50]2[CH2:51][CH2:52][N:47]([CH2:48][CH2:49]2)[CH2:46]1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[ClH:20].[N:47]12[CH2:52][CH2:51][CH:50]([CH2:49][CH2:48]1)[C@H:45]([NH:44][C:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:10]3[O:9][C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[OH:1])=[N:12][C:11]=13)=[O:19])[CH2:46]2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3O)nc12
Reactant: N[C@@H]1CN2CCC1CC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1CN2CCC1CC2)c1cccc2oc(-c3ccccc3O)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.3 %

Procedure:
A mixture of 2-(2-hydroxyphenyl)benzoxazole-4-carboxylic acid (50 mg, 0.2 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (75 mg, 0.4 mmol), 1-hydroxybenzotriazole (57 mg, 0.4 mmol) and (S)-(−)-3-aminoquinuclidine dihydrochloride (39 mg, 0.2 mmol) in DMF (5 mL) was stirred at room temperature for 10 min, then triethylamine (0.08 mL, 0.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with ethyl acetate (50 mL), and then treated with a saturated solution of sodium bicarbonate. The organic layer was isolated and the aqueous layer was further extracted with ethyl acetate (2×50 mL). The combined organics were washed with water (2×25 mL), brine (2×25 mL), dried (Na2SO4), filtered and concentrated. The crude material was purified by semi-preparative HPLC to afford the desired product (49 mg, 68%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H), 8.37 (d, J=6.7 Hz, 1H), 8.22 (dd, J=7.8, 1.0 Hz, 1H), 8.10 (dd, J=7.9, 1.6 Hz, 1H), 7.77 (dd, J=8.1, 0.9 Hz, 1H), 7.55-7.50 (m, 2H), 7.16 (dd, J=8.6, 0.6 Hz, 1H), 7.08 (t, J=7.0 Hz, 1H), 4.40-4.30 (m, 1H), 3.63-3.55 (m, 1H), 3.22-3.20 (m, 1H), 3.07-2.90 (m, 3H), 2.87-2.80 (m, 1H), 2.22-2.17 (m, 1H), 2.02-1.92 (m, 1H), 1.85-1.78 (m, 2H), 1.73-1.65 (m, 1H); MS (ESI+) m/z 364 (M+H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)=[O:3].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:13]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=1[O:11][CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1cc(C(C)=O)ccc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 5 h
Yield: 98.6 %

Procedure:
A mixture of 4-hydroxy-3-methoxyacetophenone (40 g, 240 mmol), benzyl bromide (34.1 mL, 260 mmol) and potassium carbonate (50.0 g, 360 mmol) in DMF (800 mL) was stirred at 40° C. for 5 hours. The reaction was cooled to room temperature and poured into a mixture of ice and water (2000 mL). The solid was collected by filtration, washed with water and dried in vacuo to give the title compound as a white solid (60.66 g, 98%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10][C:9]1=[O:15])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)N[C@H]1CC[C@@H](O[Si](C(C)(C)C)(C)C)CNC1=O)(C)(C)C.[CH2:41]([O:48][C:49](=[O:52])[CH2:50]Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.ClCC1C=CC=CN=1>>[CH2:41]([O:48][C:49](=[O:52])[CH2:50][N:10]1[CH2:11][CH2:12][CH2:13][CH2:14][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:16])[C:9]1=[O:15])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCCNC1=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CNC1=O
Agent: ClCc1ccccn1
Product: CC(C)(C)OC(=O)N[C@H]1CCCCN(CC(=O)OCc2ccccc2)C1=O

Procedure:
Following the procedure of example 1h) except ((S)-2-oxo-azepan-3-yl)-carbamic acid tert-butyl ester is substituted for [(3S,6R)-6-(tert-butyl-dimethyl-silanyloxy)-2-oxo-azepan-3-yl]-carbamic acid tert-butyl ester and bromo-acetic acid benzyl ester is substituted for 2-chloromethyl-pyridine and one equivalent of KN(Si(CH3)3)2 base to give ((S)-3-tert-butoxycarbonylamino-2-oxo-azepan-1-yl)-acetic acid benzyl ester. Removal of the Boc group by procedure 2d) gives ((S)-3-amino-2-oxo-azepan-1-yl)-acetic acid benzyl ester.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1>[Pd].C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([OH:12])[CH:7]=1
Reactant: COC(=O)/C=C/c1cccc(O)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)CCc1cccc(O)c1
Reaction time: 4 h

Procedure:
10% Palladium on carbon (0.31 g) was added to a solution of trans-3-(3-hydroxyphenyl)acrylic acid methyl ester (31.0 g, 17.4 mmol) (prepared as described in Example 6A) in ethyl acetate (30 mL) at room temperature under a nitrogen atmosphere. The mixture was hydrogenated under a balloon pressure for 4 hours. The catalyst was filtered, and the filtrate was concentrated to dryness. Crude 3-(3-hydroxyphenyl)propionic acid methyl ester (3.16 g) was directly used in the next step.
Reaction SMILES: C(O[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=2)[CH:9]=[C:8]([CH3:19])[N:7]=1)=[O:5])C.[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][N:22]=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:4]([C:6]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[C:14]([Cl:18])[CH:13]=3)[CH:9]=[C:8]([CH3:19])[N:7]=2)=[O:5])=[N:22][CH:23]=1
Reactant: CCOC(=O)c1cc(-c2ccnc(Cl)c2)cc(C)n1
Reactant: Nc1ccc(Cl)cn1
Product: Cc1cc(-c2ccnc(Cl)c2)cc(C(=O)Nc2ccc(Cl)cn2)n1

Procedure:
The title compound, was prepared from 2′-Chloro-6-methyl-[4,4′]bipyridinyl-2-carboxylic acid ethyl ester in accordance with the general method of example 26, step 6 using 2-amino-5chloropyridine instead of 3-chloroaniline to yield the final compound as a white crystalline, MS (ISP): m/e=359.0, 361.1 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=4)[N:26]=3)[C:22]([Cl:40])=[CH:21][N:20]=2)[CH2:14][CH2:13]1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:40][C:22]1[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[CH:34]=3)[N:26]=2)=[CH:24][C:19]([NH:18][C@H:15]2[CH2:14][CH2:13][C@H:12]([NH:11][CH2:10][CH2:9][OH:8])[CH2:17][CH2:16]2)=[N:20][CH:21]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OCCN[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a scintillation vial containing N2′-(trans-4-(2-(tert-butyldimethylsilyloxy)ethylamino)cyclohexyl)-5′-chloro-N6-(3-fluorobenzyl)-2,4′-bipyridine-2′,6-diamine from step 1) was added THF (0.300 ml) and TBAF (0.160 ml, 0.319 mmol). The homogenous reaction mixture was capped, and stirred at ambient temperature for 3 hours. The reaction mixture was concentrated and purified by reverse phase preparative HPLC to yield 2-(trans-4-(5′-chloro-6-(3-fluorobenzylamino)-2,4′-bipyridin-2′-yl-amino)cyclohexylamino)ethanol (2.2 mg, 9%). LCMS (m/z): 470.3 (MH retention time=0.58 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.31-1.46 (m, 2H) 1.51-1.67 (m, 1H) 2.21 (d, J=10.56 Hz, 2H) 3.11-3.20 (m, 2H) 3.66-3.77 (m, 1H) 3.77-3.83 (m, 1H) 4.62 (s, 1H) 6.74 (s, 1H) 6.78-6.84 (m, 1H) 6.87-6.92 (m, 1H) 6.96-7.03 (m, 1H) 7.08-7.14 (m, 1H) 7.15-7.21 (m, 1H) 7.31-7.38 (m, 1H) 7.68-7.76 (m, 1H) 8.02 (s, 1H).
Reaction SMILES: [CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][NH:5]1)[CH2:2][CH3:3].Br[CH2:11][CH2:12][CH2:13][C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+].C(Cl)Cl.CO>C(#N)C.[Cl-].[Na+].O>[CH2:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[CH2:11][CH2:12][CH2:13][C:14]#[N:15])[CH2:2][CH3:3]
Reactant: CCCC1CCCCN1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: CCCC1CCCCN1CCCC#N
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
A mixture of 2-propylpiperidine (550 mg, 4.3 mmol), 4-bromobutyronitrile (430 mg, 3.0 mmol) and potassium carbonate (550 mg, 4.0 mmol) in acetonitrile (5 mL) was stirred at rt for 12 h., followed by addition of a saturated brine (25 mL). The reaction mixture was extracted with ethyl acetate (3×25 mL) and the combined organic phases were dried (MgSO4) and evaporated to dryness to produce crude 8. The crude product was subjected to CC [eluent: CH2Cl2: MeOH (99: 1)] to give pure 8 (0.48 g, 83%); LC-MS [M+H]+ 194 (cald. 194.2).
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([O:24][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])([CH3:27])[CH3:26])[CH:18]=2)[CH2:12]1)=O)C1C=CC=CC=1.[C:33]([OH:42])(=[O:41])[C@H:34]([C@@H:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35]>[Pd].C(O)C>[C:33]([OH:42])(=[O:41])[C@H:34]([C@@H:36]([C:38]([OH:40])=[O:39])[OH:37])[OH:35].[CH2:31]([O:30][C:28](=[O:29])[C:25]([CH3:27])([O:24][C:19]1[CH:18]=[C:17]([CH:13]2[CH2:14][CH2:15][CH2:16][NH:11][CH2:12]2)[CH:22]=[CH:21][C:20]=1[CH3:23])[CH3:26])[CH3:32]
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)OCc3ccccc3)C2)ccc1C
Agent: [Pd]
Agent: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCNC2)ccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.5 %

Procedure:
A 250 mL Parr bottle was charged with 0.27 g of 10% palladium on carbon (50% water) and covered with 20 mL ethanol. 3-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-4-methyl-phenyl]-piperidine-1-carboxylic acid benzyl ester (1.36 g, 3.09 mmol) was dissolved in 50 mL ethanol and added to the catalyst suspension. The reaction was hydrogenated at 50 psi for 2 h. The catalyst was filtered through a celite plug. The filter cake was washed with 150 mL ethanol and the filtrated concentrated under reduced pressure. The resultant oil was taken up in 20 mL hot ethanol to which was added D-tartaric acid (464 mg, 3.09 mmol) in 10 mL hot ethanol. The solution was allowed to stir 24 h at ambient temperature. The white crystalline precipitate was collected by filtration to yield 978 mg (69%) of 2-methyl-2-(2-methyl-5-piperidin-3-yl-phenoxy)-propionic acid ethyl ester D-tartaric acid salt as a white crystalline solid.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[C:17]([C:35]2[O:39][C:38]([C:40]3[CH:55]=[CH:54][C:43]([CH2:44][N:45](C)[C:46](=O)OC(C)(C)C)=[CH:42][CH:41]=3)=[N:37][N:36]=2)=[N:18][C:19]([C:22]2[CH:27]=[CH:26][C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])=[CH:24][C:23]=2[F:34])=[CH:20][N:21]=1)=O)(C)(C)C>C(Cl)Cl>[F:34][C:23]1[CH:24]=[C:25]([S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH:26]=[CH:27][C:22]=1[C:19]1[N:18]=[C:17]([C:35]2[O:39][C:38]([C:40]3[CH:41]=[CH:42][C:43]([CH2:44][NH:45][CH3:46])=[CH:54][CH:55]=3)=[N:37][N:36]=2)[C:16]([NH2:15])=[N:21][CH:20]=1
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3nnc(-c4ccc(CN(C)C(=O)OC(C)(C)C)cc4)o3)n2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1ccc(-c2nnc(-c3nc(-c4ccc(S(=O)(=O)C(C)C)cc4F)cnc3N)o2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a solution of tert-butyl 4-(5-(3-bis(tert-butoxycarbonyl)amino-6-(2-fluoro-4-(isopropylsulfonyl)phenyl)pyrazin-2-yl)-1,3,4-oxadiazol-2-yl)benzyl(methyl)carbamate (114 mg, 0.1456 mmol) in CH2Cl2 (5 mL). The reaction was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue azeotroped with CH2Cl2 (×2) and ether (×2). The material was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 μM, 100 Å column, gradient 10%-95% B (solvent A: 0.05% TFA in water; solvent B: CH3CN) over 16 minutes at 25 mL/min]. The product fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (43.5 mg, 62% yield); 1H NMR (400.0 MHz, DMSO) d 1.23 (d, 6H), 2.29 (s, 3H), 3.58 (m, 1H), 3.76 (s, 2H), 7.60 (d, 2H), 7.88 (d, 2H), 8.00 (br s, 2H), 8.10 (d, 2H), 8.32 (t, 1H) and 8.80 (s, 1H) ppm; MS (ES+) 483.3
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([OH:19])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)CCl.Cl.[NH2:25][C@H:26]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CN(C=O)C.CCN(C(C)C)C(C)C.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[C@H:26]([NH:25][C:11](=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:34][CH2:33]2)=[CH:36][CH:37]=1
Reactant: N[C@@H](C(=O)N1CCC(c2ccc(Cl)cc2)CC1)C1CCCCC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(N[C@@H](C(=O)N1CCC(c2ccc(Cl)cc2)CC1)C1CCCCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A reaction tube was charged with HOBt (8 mg), benzoic acid (7 mg) and EDC (11 mg) in DMF (0.6 mL) and then allowed to agitate at rt. for 15 min. After this time, a solution of (R)-2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-2-cyclohexylethanone hydrochloride (16 mg) in DIEA (38 μL) and DMF (187 μL) was added. Upon completion of addition, the reaction mixture and was shaken overnight at rt. At the conclusion of this period, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 178. MS found: (M+H)+=440.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:16][C@H:15]3[CH2:17][CH2:18][OH:19])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][C:29](O)=[CH:28][C:27]=2[O:33][CH3:34])[CH2:23][CH2:22][CH2:21]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1(C)C=CC=CC=1>[N:20]1([C:24](=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:19][CH2:18][CH2:17][C@@H:15]3[CH2:16][C@@H:14]3[CH:11]3[CH2:12][CH2:13][N:8]([C:5]4[N:6]=[CH:7][C:2]([Cl:1])=[CH:3][N:4]=4)[CH2:9][CH2:10]3)=[CH:28][C:27]=2[O:33][CH3:34])[CH2:23][CH2:22][CH2:21]1
Reactant: COc1cc(O)ccc1CC(=O)N1CCC1
Reactant: OCC[C@@H]1C[C@@H]1C1CCN(c2ncc(Cl)cn2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)ccc1CC(=O)N1CCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethanol (75 mg, 0.266 mmol) was dissolved in toluene (1 ml) and 1-(azetidin-1-yl)-2-(4-hydroxy-2-methoxyphenyl)ethanone (59 mg, 0.069 mmol), triphenylphosphine (105 mg, 0.399 mmol), and DIAD (78 μl, 0.399 mmol) added and the mixture stirred at RT overnight. The mixture was concentrated in vacuo and the residue purified by column chromatography using a Biotage RP C18 cartridge (30 g) using a gradient eluant of 0-100% water:acetonitrile+0.1% TFA to afford the title compound. LC/MS (m/z): 485 (M+H)+. GPR119 Human EC50: 7.1 nM.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:31]([CH3:33])[CH3:32])([CH:28]([CH3:30])[CH3:29])[O:16][Si:17]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[O:18][CH2:19]2)[C@@H:12]1[OH:34].[C:35]([O-])([O-])=O.[Cs+].[Cs+].CI>CN(C=O)C>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:21][C@H:20]2[C@@H:13]([O:14][Si:15]([CH:28]([CH3:30])[CH3:29])([CH:31]([CH3:33])[CH3:32])[O:16][Si:17]([CH:25]([CH3:26])[CH3:27])([CH:22]([CH3:23])[CH3:24])[O:18][CH2:19]2)[C@@H:12]1[O:34][CH3:35]
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2O[C@@H](n3cnc4c(Cl)ncnc43)[C@@H](O)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: CO[C@H]1[C@@H]2O[Si](C(C)C)(C(C)C)O[Si](C(C)C)(C(C)C)OC[C@H]2O[C@H]1n1cnc2c(Cl)ncnc21
Reaction time: 3 h
Yield: 71.4 %

Procedure:
To a suspension of (6aR,8R,9S,9aS)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropyltetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-9-ol (300 mg, 0.57 mmol) and Cs2CO3 (1.86 g, 5.7 mmol) in DMF (5.7 mL) at 0° C. was added MeI (350 μL, 5.7 mmol) dropwise. The suspension was stirred for 3 hours, quenched with saturated aqueous NH4Cl and CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography (0 to 20% EtOAc/hexanes) to afford 221 mg (71%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.I>C(O)(=O)C.[Cl-].[Na+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CC=C(c1ccccc1)c1ccc(Br)cc1
Agent: I
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(O)CCC(c1ccccc1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 4-(4-bromophenyl)-4-phenylbut-3-enoic acid (5.0 g., 0.0157 mole) in glacial acetic acid (50 ml.) was treated with 56.9% aqueous hydriodic acid (22.5 ml.) and red phosphorus (4.5 g.) and the resulting mixture stirred at reflux for 16 hours. The reaction mixture was then cooled to room temperature, diluted with saturated aqueous sodium chloride solution (250 ml.) and extracted with methylene chloride (250 ml.). The extract was washed with saturated aqueous sodium chloride solution (2×100 ml.), dried (MgSO4) and evaporated under vacuum to the desired butanoic acid derivative, which was used in the next step without further purification (5 g., oil, ca. 99% yield).