Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](SC)=[N:19][C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH3:28])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[NH2:30][C@H:31]([CH2:34][CH3:35])[CH2:32][OH:33]>CS(C)=O>[CH3:1][O:2][C:3](=[O:29])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20]([NH:30][CH:31]([CH2:32][OH:33])[CH2:34][CH3:35])=[N:19][C:18](=[O:25])[N:17]([CH2:26][CH2:27][CH3:28])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2
Reactant: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Reactant: CC[C@@H](N)CO
Solvent: CS(C)=O
Product: CCCn1c(=O)nc(NC(CC)CO)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 150 °C
Reaction time: 3 h

Procedure:
3-[4-(6-Methylsulfanyl-2-oxo-3-propyl-3,7-dihydro-2H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (105 mg) was dissolved in 2 mL of DMSO along with an appropriate amino alcohol (e.g., 160 uL of (R)-2-amino-1-butanol for compound 3). The reaction mixture was stirred at 150° C. for 3 h. It was then cooled to rt and purified by preparative HPLC to afford 50 mg of the titled compound.
Reaction SMILES: N1C=CC=CC=1.[Si:7]([N:14]1[CH:17]([CH2:18][CH:19]([OH:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=2)=[O:22])[CH2:16][C:15]1=[O:35])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].CC(O)C>C(Cl)Cl.[O-2].[O-2].[O-2].[Cr+6]>[Si:7]([N:14]1[CH:17]([CH2:18][C:19](=[O:34])[CH2:20][C:21]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=2)=[O:22])[CH2:16][C:15]1=[O:35])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: [Cr+6]
Agent: [O-2]
Solvent: ClCCl
Solvent: CC(C)O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)N1C(=O)CC1CC(=O)CC(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
Anhydrous chromium trioxide (16.88 g 169 mmol) is added to a solution of anhydrous pyridine (27.3 ml, 338 mmol) in anhydrous methylene chloride (470 ml). The resulting mixture is stirred at room temperature for 30 minutes and then treated with a solution of N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-hydroxypropyl]-azetidin-2-one (8.92 g, 21.1 mmol) in methylene chloride (80 ml). The reaction mixture is stirred an additional 15 minutes at room temperature and then treated with 2-propanol (6.75 ml). The methylene chloride phase is decanted from the dark, tary residue and evaporated under vacuum. The residue from this operation is triturated with diethyl ether (350 ml) and filtered through a pad of magnesium sulfate which is washed with additional ether (150 ml). The ethereal filtrate is washed with water (200 ml), 5% aqueous sodium bicarbonate (200 ml) and brine, dried with magnesium sulfate, filtered, evaporated under vacuum, and stripped with toluene to afford the crude product (5.99 g) as an amber oil. Chromatigraphy on a silica gel column using 3:2 petroleum ether-ethyl acetate as eluting solvent yields N-(t-butyldimethylsilyl)-4-[3-(p-nitrobenzyloxycarbonyl)--2-oxopropyl]-azetidin-2-one (5.17 g, 58%) as a pale yellow, viscous oil which solidifies. Trituration with diethyl ether gives the product as small, white crystals: mp 65°-66.5°, IR (CH2Cl2) 1732, 1522, and 1350 cm-1, NMR (CDCl3) δ0.20 (s,3,CH3), 0.23 (s,3,CH3), 0.93 (s,9,C(CH3)3), 2.58 (dd,1,J=2.7 and 15.7, H3β), 2.72 (dd,1, J=9.4 and 18.2, CH2COCH2CO2), 3.19 (dd,1,J=4.0 and 18.2, CH2COCH2CO2), 3.35 (dd,1,J=5.3 and 15.7,H3β), 3.55 (s,2, COCH2CO2), 3.90 (m,1,H4), 5.30 (s,2,CH2Ar), 7.55 and 8.25 (two d, 4,J=8.5, ArH); MS m/e 405 (M+ -15), 363 (M+ -57), 321 (363-42) and 136.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:13][CH2:12][CH:11]([C:14](N)=[O:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC(C(OCC)=O)CC1.C1(C(C2C=CC=CC=2)N2CCC(C(OCC)=O)CC2)C=CC=CC=1>>[C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)C1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCOC(=O)C1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: CCOC(=O)C1CCNCC1
Product: OCC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
Step 1): In a similar manner to that of Preparation 1, but replacing isonipecotamide and 1-diphenylmethylpiperidine-4-carboxamide with ethyl isonipecotate and ethyl 1-diphenylmethyl-4-piperidinecarboxylate respectively, 1-diphenylmethyl-4-hydroxymethylpiperidine was prepared.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.[NH2:16][C:17]1[C:22]2[O:23][CH2:24][O:25][C:21]=2[C:20]([C:26]#[C:27][C:28]([CH3:31])([OH:30])[CH3:29])=[CH:19][C:18]=1[Cl:32].Cl[C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1>CN(C=O)C.[Cl-].[NH4+]>[Cl:32][C:18]1[CH:19]=[C:20]([C:26]#[C:27][C:28]([CH3:29])([OH:30])[CH3:31])[C:21]2[O:25][CH2:24][O:23][C:22]=2[C:17]=1[NH:16][C:34]1[C:43]2[C:38](=[CH:39][C:40]([O:46][CH3:47])=[C:41]([O:44][CH3:45])[CH:42]=2)[N:37]=[CH:36][N:35]=1
Reactant: CC(C)(O)C#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3c(Cl)cc(C#CC(C)(C)O)c4c3OCO4)c2cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.8 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (1.5 ml) in tetrahydrofuran (1.0M, 1.5 mmol) was added over 5 min. to a stirred mixture of 4-(7-amino-6-chloro-1,3-benzodioxol-4yl)-2-methylbut-3-yn-2-ol (0.186 g) and 4-chloro-6,7-dimethoxyquinazoline (0.150 g) in DMF (6.5 ml) cooled to 0° C. under a nitrogen atmosphere. The mixture was stirred for 1 hr at ambient temperature. The reaction mixture was diluted with saturated aqueous ammonium chloride (70 ml) and extracted with ethyl acetate (3×30 ml). The organic extracts were washed with brine (20 ml), dried over sodium sulphate and then evaporated. The residue was purified by column chromatography on silica using increasingly polar mixtures of ethyl acetate and isohexane as eluent. There was thus obtained the title compound as a solid (0.150 g). NMR Spectrum: (DMSOd6) 1.47 (s, 6H), 3.90 (s, 3H), 3.91 (s, 3H), 5.50 (s, 1H), 6.13 (s, 2H), 7.04 (s, 1H), 7.17 (s, 1H), 7.80 (s, 1H), 8.31 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 442 and 444.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.[CH3:16][CH2:17][SH:18].[C:19]([N:26]1[CH2:33][CH2:32][CH2:31][C@@H:27]1[C:28]([OH:30])=[O:29])([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:17]([S:18][O:30][C:28](=[O:29])[C@H:27]1[CH2:31][CH2:32][CH2:33][N:26]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C(=O)O
Reactant: CCS
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCSOC(=O)[C@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
To a solution of DCC (2.55 g, 12.4 mmol), DMAP (100 mg), and EtSH (0.71 g, 11.1 mmol) in DCM was added dropwise a solution of (2R)-N-BOC-proline (3.00 g, 9.52 mmol) in DCM (30 mL). The reaction mixture was stirred at rt for 30 min, and filtered though Celite. The filtrate was dried over MgSO4 and concentrated in vacuo, and the residue was purified by column chomatography (EtOAc/Hex=1/4) to give the title compound (2.34 g, 95.2%).
Reaction SMILES: C([Mg]Cl)(C)C.Br[C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[C:10]2[C:27]([F:30])([F:29])[F:28].[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[N:44]([CH3:45])[CH:43]=[N:42][CH:41]=2)=[O:39])=[CH:34][CH:33]=1>C1COCC1>[Cl:31][C:32]1[CH:33]=[CH:34][C:35]([C:38]([C:40]2[N:44]([CH3:45])[CH:43]=[N:42][CH:41]=2)([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[C:12]([C:17]([F:20])([F:19])[F:18])[C:11]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:10]3[C:27]([F:28])([F:30])[F:29])[OH:39])=[CH:36][CH:37]=1
Reactant: FC(F)(F)c1nc2ccc(Br)cc2c(C(F)(F)F)c1-c1ccccc1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(C(F)(F)F)c(-c3ccccc3)c(C(F)(F)F)c2c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
Isopropylmagnesium chloride (2.0 M in THF, 0.532 mL, 1.06 mmol) was added dropwise to a solution of 6-iodo-3-phenyl-2,4-bis(trifluoromethyl)quinoline (474 mg, 1.01 mmol, Intermediate 8, step d) in THF (1 mL) at −78° C. under an argon atmosphere. The mixture was stirred at −78° C. for 5 min, then was removed from the cold bath and was stirred for 15 min. Neat (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (246 mg, 1.12 mmol, Intermediate 18, step b) was added followed by 1 mL THF to aid stirring of the thick mixture. The mixture was stirred at room temperature overnight. The reaction was quenched by addition of saturated aqueous NH4Cl and extracted with EtOAc (three times). The organic phase was dried (Na2SO4), filtered, and concentrated. The residue was purified by flash column chromatography (silica gel, gradient 0-3% MeOH-DCM) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 8.36 (d, J=1.71 Hz, 1H), 8.29 (d, J=8.80 Hz, 1H), 7.89 (dd, J=1.59, 8.93 Hz, 1H), 7.41-7.52 (m, 3H), 7.38 (s, 1H), 7.32-7.37 (m, 4H), 7.28-7.31 (m, 2H), 6.43 (s, 1H), 3.40 (s, 3H); MS m/e 562.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([OH:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O.[CH3:44][O:45][CH2:46][CH:47](O)[CH3:48]>C1COCC1.O>[CH3:44][O:45][CH2:46][CH:47]([O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]2)[CH3:48]
Reactant: Cc1ccc2cccc(O)c2n1
Reactant: COCC(C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)Oc1cccc2ccc(C)nc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.8 %

Procedure:
To 2-methylquinolin-8-ol (1.0 g, 6.28 mmol) in THF (5 mL) was added PPh3 (6.92 g, 26.4 mmol), DEAD (1.58 ml, 10.1 mmol) and 1-methoxypropan-2-ol (0.736 g, 8.17 mmol). The reaction was stirred for 24 hours at ambient temperature and then water was added. The aqueous phase was extracted with DCM and the combined organic phases dried over MgSO4, filtered and purified by reverse chromatography (SP4, 40M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 8-(1-methoxypropan-2-yloxy)-2-methylquinoline (1.0 g, 68.8% yield) as a clear liquid
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][C:13]1[N:14]=[CH:15][O:16][C:17]=1C(O)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH3:12][C:13]1[N:14]=[CH:15][O:16][C:17]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Cc1ncoc1C(=O)O
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ncoc1-c1ccc(CC(=O)O)cc1
Reaction time: 3 h
Yield: 24 %

Procedure:
To a solution of 3.00 g (14.0 mmol) 4-bromophenyl acetic acid in 25.0 ml DMF was added 3.60 g (27.9 mmol) 4-methyl-1,3-oxazole-5-carboxylic acid, 6.80 g (20.9 mmol) cesium carbonate, 4.1 g (14.0 mmol) tetrabutyl ammonium chloride monohydrate, and 0.400 g (0.700 mmol) bis(tri-t-butylphosphine)palladium(0). After 3.00 h at 140° C., the reaction mixture was diluted with CH2Cl2, washed with 10% citric acid, washed twice with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by preparative HPLC (5->95% CH3CN/H2O over 20 min, 0.05% added TFA, C18 50×150 mm) afforded 0.730 g (24%) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid. 1H NMR (CD3OD, 400 MHz) δ 8.14 (s, 1H); 7.61 (d, 2H, J=8.32 Hz); 7.41 (d, 2H, J=8.33 Hz); 3.65 (s, 2H); 2.41 (s, 3H). ESMS+1 for C12H11NO3: 218.1. To a solution of 0.725 g (3.34 mmol) [4-(4-methyl-1,3-oxazol-5-yl)phenyl]acetic acid in 7.00 ml CH2Cl2 was added 0.978 g (3.34 mmol) 2-[(1R)-1-ammonioethyl]-5-(2,2,2-trifluoroethoxy)pyridinium dichloride, 0.591 g (4.34 mmol) HOAT, 0.832 g (4.34 mmol) EDC, and 1.75 mL (10.0 mmol) DIEA. After 24.0 h at room temperature, the reaction mixture was diluted with CH2Cl2, washed three times with water, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (1×14 cm silica gel, linear gradient 20-100% EtOAc:hexane) afforded 0.720 g (51.4%) 2-[4-(4-methyl-1,3-oxazol-5-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) δ 8.22 (d, 1H, J=2.38 Hz); 7.83 (s, 1H); 7.59 (dd, 2H, J=1.83 Hz, 6.59 Hz); 7.36 (d, 2H, J=8.42 Hz); 7.22 (m, 2H); 6.72 (br d, 1H, J=7.51 Hz); 5.12 (m, 1H); 4.38 (q, 2H, J=8.06 Hz); 3.62 (s, 2H); 2.45 (s, 3H); 1.41 (d, 3H, J=6.78). HRMS (ES) exact mass calcd for C21H20F3N3O3: 420.1540, Found: 420.1530.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[C:6]1(=[O:16])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][CH2:8][NH:7]1.C(OC(=O)C)C>OS(O)(=O)=O.CCCCCC>[N+:1]([C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][NH:7][C:6]2=[O:16])=[CH:11][CH:12]=1)([O-:4])=[O:2]
Reactant: O=C1NCCc2ccccc21
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1NCCc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
KNO3 (348 mg, 3.7414 mmol) was added to a solution of 3,4-dihydro-2H-isoquinolin-1-one (I-23b: 500 mg, 3.4013 mmol) in concentrated H2SO4 (10.2 mL) at 0° C. and the resulting mixture was stirred at room temperature for 3 hours. The reaction was monitored by TLC (80% ethylacetate in hexane). The reaction mixture was quenched in chilled water and extracted with ethylacetate. The organic layer was washed with brine solution, dried over Na2SO4 and concentrated. The concentrate was crystallized from diethyl ether to afford 400 mg of the product (61.2% yield).
Reaction SMILES: [O:1]([C:8]1[C:9]2[NH:16][C:15](/[CH:17]=[CH:18]/[CH2:19][OH:20])=[CH:14][C:10]=2[N:11]=[CH:12][N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1.C(OCC)(=O)C>[C:28]([O:20][CH2:19]/[CH:18]=[CH:17]/[C:15]1[NH:16][C:9]2[C:8]([O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:13][CH:12]=[N:11][C:10]=2[CH:14]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(OC/C=C/c1cc2ncnc(Oc3ccccc3)c2[nH]1)c1ccccc1

Procedure:
(2E)-3-(4-Phenoxy-5H-pyrrolo[3,2-d]pyrimidin-6-yl)-2-propen-1-ol (1.0 g) was suspended in tetrahydrofuran (20 mL), and triethylamine (0.651 mL) and benzoyl chloride (0.86 mL) were sequentially added under ice-cooling. The mixture was stirred under ice-cooling for 2 hrs, diluted with ethyl acetate (200 mL) and washed with water (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by basic silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→0:100) to give the title compound (1.08 g) as crystals.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C@H:29]4[CH2:33][CH2:32][N:31]([CH3:34])[C:30]4=[O:35])[CH:27]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])=[C:9](Cl)[CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1>[Pd].C1COCC1.C(O)C>[N:1]1([C:5]([C:7]2[CH:37]=[CH:36][C:10]([O:11][C:12]3[CH:13]=[C:14]([CH:25]=[C:26]([O:28][C@H:29]4[CH2:33][CH2:32][N:31]([CH3:34])[C:30]4=[O:35])[CH:27]=3)[C:15]([NH:17][C:18]3[CH:23]=[N:22][C:21]([CH3:24])=[CH:20][N:19]=3)=[O:16])=[CH:9][CH:8]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3Cl)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cnc(NC(=O)c2cc(Oc3ccc(C(=O)N4CCC4)cc3)cc(O[C@H]3CCN(C)C3=O)c2)cn1
Yield: 88.8 %

Procedure:
A solution of 3-[4-(azetidine-1-carbonyl)-2-chloro-phenoxy]-5-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-N-(5-methylpyrazin-2-yl)benzamide (Intermediate 22) (120 mg, 0.22 mmol) and 10% palladium on carbon (20 mg, catalytic) in THF (5 mL) and ethanol (5 mL) was stirred under an atmosphere of hydrogen for 16 hours. The palladium on carbon was removed by filtration and the filtrate evaporated under reduced pressure. The residue was dissolved in ethyl acetate (30 mL), washed with water (10 mL), brine (10 mL), dried (MgSO4), filtered and evaporated under reduced pressure to give product (98 mg, 89%). 1H NMR δ (300 MHz, CDCl3) 2.12-2.26 (m, 1H), 2.36 (quintet, 2H), 2.52-2.67 (m, 4H), 2.94 (s, 3H), 3.35-3.57 (m, 2H), 4.19-4.42 (m, 4H), 4.93 (t, 1H), 6.93 (s, 1H), 7.03 (d, 2H), 7.20 (s, 1H), 7.42 (s, 1H), 7.66 (d, 2H), 8.15 (s, 1H), 8.54 (s, 1H), 9.52 (s, 1H); m/z 502 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][C:11](=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C(OCC)C>[CH2:1]([N:8]1[CH2:14][CH2:13][CH2:12][CH:11]([OH:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCN(Cc2ccccc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: OC1CCCN(Cc2ccccc2)CC1
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of 1-benzyl-4-azepanone (610 mg, 3.00 mmol) in diethyl ether (8 ml) was added to a suspension of lithium aluminum hydride (57 mg, 1.50 mmol) in diethyl ether (5 ml) at 0° C. and stirred for 1 hour. Water (0.057 ml), a 2N-aqueous sodium hydroxide solution (0.114 ml) and then water (0.171 ml) were added to the reaction mixture, and the resulting mixture was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate 1/1, chloroform/methanol=30/1) to obtain 1-benzyl-4-azepanol (516 mg, 84%).
Reaction SMILES: C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H:29]([N:31]5[CH:36]=[C:35]([C:37](N)=O)[CH2:34][CH:33]=[CH:32]5)[C@H:28](O)[C@@H:27]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1.[Mg+2].[Cl-].[Cl-].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.C(#N)C>P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+]>[NH:31]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:27][CH:28]=2)[C:35]([CH3:37])=[CH:36]1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=P([O-])([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Microsomal incubations. Two mg microsomal protein was incubated with 0.4 mM 3MI and 4 mM NADPH in 0.05M sodium phosphate buffer (pH 7.4) containing 5 mM MgCl2 and 1 mM EDTA for 30 min at 37.degree. C. (production of metabolites was determined to be linear over a range of 10 to 40 min). Incubation volumes were 0.5 ml. Reactions were started by the addition of NADPH after 3-minute preincubation periods at 37° C., and stopped with 0.5 ml of ice-cold acetonitrile. Incubations of all 30 samples were run in duplicate and for control incubations NADPH was omitted. After the addition of acetonitrile the mixture was vortexed and centrifuged at 5000 rpm for 20 min. A 50 μl aliquot of the clear supernatant was analyzed by high-performance liquid chromatography (HPLC).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([O:37]C)=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[S:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]([C:24]4[O:25][C:26]([C:29]5[N:34]=[C:33]([C:35]([OH:37])=[O:36])[CH:32]=[CH:31][CH:30]=5)=[CH:27][N:28]=4)=[O:23])=[CH:16][CH:15]=3)=[CH:12][CH:13]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCSCC5)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCSCC5)cc4)cc3)o2)n1
Yield: 87.1 %

Procedure:
Methyl 6-(2-(3-(4′-(thiomorpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (105 mg, 0.199 mmol) was dissolved in THF/H2O (3:2, 15 mL) and LiOH (14 mg, 0.60 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 40 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4′-(thiomorpholinomethyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid (89 mg, 87%): 1H NMR (CDCl3, 600 MHz) δ 8.21 (d, 1H, J=6.9 Hz), 8.05-8.00 (m, 3H), 7.52 (d, 2H, J=8.1 Hz), 7.49 (d, 2H, J=8.1 Hz), 7.40 (d, 2H, J=8.0 Hz), 7.32 (d, 2H, J=8.0 Hz), 3.83 (s, 2H), 3.50 (t, 2H, J=7.5 Hz), 3.15 (t, 2H, J=7.5 Hz), 2.99 (s, 4H), 2.83-2.82 (m, 4H); 13C NMR (CDCl3, 150 MHz) δ 187.3, 157.4, 152.2, 149.6, 145.5, 140.7, 139.6, 138.9, 138.6, 130.4, 128.9, 128.0, 127.2, 127.1, 124.5, 123.2, 62.4, 54.2, 40.6, 29.3, 26.9; HR ESI-TOF m/z 514.1784 (M+H+, C29H27N3O4S, requires 514.1795).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([OH:15])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[N:29]1([C:34]2[CH:39]=[C:38]([CH2:40][NH2:41])[CH:37]=[C:36]([C:42]3[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=3)[N:35]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH3:17])[C:12](=[CH2:16])[C:13]([NH:41][CH2:40][C:38]2[CH:37]=[C:36]([C:42]3[CH:43]=[CH:44][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:46][CH:47]=3)[N:35]=[C:34]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)[CH:39]=2)=[O:15])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C=C(C(=O)O)N(C)S(=O)(=O)c1ccc(Cl)cc1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: C=C(C(=O)NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCCC2)c1)N(C)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 21.4 %

Procedure:
A solution of acid 4C (0.40 g, 1.45 mmol) in THF (20 mL) was added with DEPC (0.28 mL, 1.3 mol eq) and the mixture was stirred at room temperature several minutes. Then [2-pyrrolidin-1-yl-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27A (0.51 g, 1.1 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, water was added to the residue that is extracted with EtOAc (3×25 mL) and washed with brine (1×40 mL). The separated organic phase was dried over Na2SO4, evaporated to dryness and the residue was purified by flash chromatography (1:1 EtOAc:Petroleum ether) to afford a white solid (0.18 g) after crystallization from ethyl ether. Yield=22%, 1HNMR (DMSO, 200 MHz) δ 1.95 (m, 4H), 2.95 (s, 3H), 3.46 (m, 4H), 4.36 (d, 2H), 5.12 (s, 1H), 5.86 (s, 1H), 6.52 (s, 1H), 7.22 (s, 1H), 7.73 (d, 2H, JO 7.9), 7.82-7.79 (m, 5H), 8.26 (d, 2H, J=7.8), 8.85 (t, 1H); [M+1] 579.03 (C27H26ClF3N4O3S requires 578.13).