Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:15]=[C:14]([CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].Br[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[CH:35]=[C:34]([Cl:36])[CH:33]=[CH:32][C:31]2=[O:37])=[N:28][CH:29]=1>CN(C=O)C>[Cl:36][C:34]1[CH:33]=[CH:32][C:31](=[O:37])[N:30]([C:27]2[CH:26]=[CH:25][C:24]([CH2:23][O:7][C:8]3[CH:15]=[C:14]([CH2:16][N:17]4[CH:21]=[CH:20][N:19]=[CH:18]4)[CH:13]=[CH:12][C:9]=3[C:10]#[N:11])=[CH:29][N:28]=2)[CH:35]=1
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cn1
Reactant: N#Cc1ccc(Cn2ccnc2)cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccnc2)cc1OCc1ccc(-n2cc(Cl)ccc2=O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (0.123 g, 0.376 mmol) was added to a solution of 2-hydroxy-4-imidazol-1-ylmethyl-benzonitrile (as described in Example 4, Step F) (0.050 g, 0.25 mmol) and 5′-bromomethyl-5-chloro-[1,2′]bipyridinyl-2-one (Step H) (0.079 g, 0.263 mmol) in anhydrous DMF (5 mL) and stirred at ambient temperature overnight. The reaction mixture was partitioned between EtOAc and aqueous saturated NaHCO3 solution, the organic layer separated, washed with H2O, brine and dried (MgSO4). Filtration and concentration to dryness gave the title compound after chromatography (silica gel, 1-4% CH3OH/CH2Cl2). FAB MS 418 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.Cl.[CH3:33][NH2:34]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][NH:34][CH3:33])=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: CN
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Agent: Cl
Product: CNCc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and methylamine hydrochloride (32.7 mg; 0.48 mmol) to give Example 129 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.76-8.73 (2H, m), 7.97-7.87 (3H, m), 7.76-7.69 (1H, m), 7.64-7.49 (6H, m), 3.76 (2H, s), 2.31 (3H, s). LC/MS (Method C): 428 (M+H)+. HPLC (Method E) Rt 2.14 min (Purity: 98.9%).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:16]1[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=1[NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=1)[C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[S:12]([CH3:15])(=[O:14])=[O:13].[C:34](N1C=CN=C1)(N1C=CN=C1)=[O:35].C(N(CC)CC)C>C(#N)C>[O:35]=[C:34]1[NH:2][CH:3]([C:4]2[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=2[S:12]([CH3:15])(=[O:14])=[O:13])[C:16]2[C:21](=[O:22])[CH2:20][CH2:19][CH2:18][C:17]=2[N:23]1[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:31])[F:32])[CH:25]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C(N)C1=C(Nc2cccc(C(F)(F)F)c2)CCCC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2cccc(C(F)(F)F)c2)C2=C1C(=O)CCC2
Temperature: 25 °C

Procedure:
To a solution of 4-{amino-[6-oxo-2-(3-trifluoromethyl-phenylamino)-cyclohex-1-enyl]-methyl}-3-methanesulfonyl-benzonitrile hydrochloride (INTERMEDIATE 17, 529 mg, 0.95 mmol) in acetonitrile (5.0 mL) is added 1,1′-carbonyldiimidazole (192 mg, 1.19 mmol) and triethylamine (33 μL, 0.24 mmol). After stirring at room temperature over night, the reaction mixture is concentrated under reduced pressure. The residue is treated with water and the precipitate is filtered off, washed with water and dried. Yield: 468 mg. ESI mass spectrum: [M+H]+=490; Retention time HPLC: 0.57 min (X012_S01).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11]1[CH:19]=[C:18]2[C:14]([CH2:15][C:16](=[O:20])[NH:17]2)=[CH:13][CH:12]=1.[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=O)[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:21]1([CH2:26][CH2:27][NH:28][C:29]([C:31]2[C:35]([CH3:36])=[C:34]([CH:37]=[C:15]3[C:14]4[C:18](=[CH:19][C:11]([C:4]5[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=5[O:2][CH3:1])=[CH:12][CH:13]=4)[NH:17][C:16]3=[O:20])[NH:33][C:32]=2[CH3:39])=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COc1ccc(-c2ccc3c(c2)NC(=O)C3)c(OC)c1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCN1CCCC1
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3=Cc2[nH]c(C)c(C(=O)NCCN3CCCC3)c2C)c(OC)c1
Yield: 30.7 %

Procedure:
6-(2,4-Dimethoxyphenyl)-1,3-dihydroindol-2-one (51 mg, 0.19 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-pyrrolidin-1-ylethyl)amide (50 mg) to give 30 mg (31%) of the title compound as an orange solid.
Reaction SMILES: [Br:1][C:2]1[O:10][C:9]2[CH:8]=[CH:7][N:6]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[NH:16][N:15]=[CH:14]4)[C:5](=[O:20])[C:4]=2[CH:3]=1.Br[CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][N:16]1[C:17]2[C:13](=[CH:12][C:11]([N:6]3[CH:7]=[CH:8][C:9]4[O:10][C:2]([Br:1])=[CH:3][C:4]=4[C:5]3=[O:20])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: O=c1c2cc(Br)oc2ccn1-c1ccc2[nH]ncc2c1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cn1ncc2cc(-n3ccc4oc(Br)cc4c3=O)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.1 %

Procedure:
To a solution of 2-bromo-5-(1H-indazol-5-yl)furo[3,2-c]pyridin-4(5H)-one (1.13 g, 3.41 mmol) in DMSO (10.5 mL) was added methyl bromoacetate (0.64 mL, 6.8 mmol) and Cs2CO3 (4.44 g, 13.6 mmol). The reaction mixture was stirred at ambient temperature for 18 h; then additional methyl bromoacetate (0.30 mL) was added. After 3 h, additional methyl bromoacetate (0.30 mL) was added. The reaction mixture was stirred for 3.5 h and then the reaction mixture was diluted with H2O (50 mL) and extracted with CH2Cl2 (4×25 mL). The extracts were washed with brine (3×25 mL), dried (Na2SO4) and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/MTBE, 4:1) yielded the title compound (0.77 g, 56%) as a light yellow solid: 1H NMR (500 MHz, CDCl3) δ 8.10 (s, 1H), 7.73 (s, 1H), 7.43 (s, 2H), 7.30 (d, J=7.5 Hz, 1H), 6.97 (s, 1H), 6.60 (d, J=7.0 Hz, 1H), 5.21 (s, 2H), 3.77 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]([CH2:10][CH3:11])=[CH:5][O:6][CH2:7][CH2:8][OH:9]>CO.[C].[Pd]>[CH3:1][O:2][C:3](=[O:12])[CH:4]([CH2:10][CH3:11])[CH2:5][O:6][CH2:7][CH2:8][OH:9]
Reactant: CCC(=COCCO)C(=O)OC
Agent: [Pd]
Solvent: CO
Product: CCC(COCCO)C(=O)OC

Procedure:
28 g 3-(2-hydroxyethoxy)-2-ethyl-acrylic acid methyl ester was hydrogenated in 100 ml methanol in the presence of 2 g 5% palladium-carbon catalyst at atmospheric pressure. 24 g 3-(2-hydroxyethoxy)-2-ethyl-propionic acid methyl ester boiling at 104°-107° C./0.1 torr (84% yield) was recovered from the filtered hydrogenation mixture after evaporation of the solvent and vacuum distillation and identified by its carbon content of 54.35% (54.54% calculated for C8H16O4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[I:11]N1C(=O)CCC1=O.C(OCC)(=O)C>CC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C1CCC(=O)N1I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: Brc1cnc2[nH]cc(I)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
5-Bromo-1H-pyrrolo[2,3-b]pyridine (5 g, 25 mmol) was dissolved in anhydrous acetone (75 ml) and added N-iodo succinimide (6.18 g, 27.5 mmol) under nitrogen atmosphere and stirred at RT for 2 h. The reaction was monitored by TLC (10% Ethyl acetate in hexane). The reaction mixture was cooled to RT and filtered, washed with cold acetone (50 ml) and dried under vacuum to afford 7.05 g (87% yield) of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)O)=[O:5])[CH3:2].[NH2:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([Br:23])[N:9]([CH:20]([CH3:22])[CH3:21])[C:10]=1[CH:11]([NH:24][C:25]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:26]=1[C:27]#[N:28])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: CCOC(=O)c1nc(Br)n(C(C)C)c1C(O)c1ccc(Cl)cc1
Product: CCOC(=O)c1nc(Br)n(C(C)C)c1C(Nc1cc(Cl)ccc1C#N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The title compound was prepared in analogy to the procedure described for step E2 but using intermediate B and 2-amino-4-chlorobenzonitrile. The reaction mixture was stirred at rt for 20 h. The mixture was extracted with HCl 1M and with a saturated aqueous NaHCO3 solution. The organic layers were dried (Na2SO4), filtered and concentrated. The product was triturated in Et2O, the suspension was filtered and the solid was dried in HV. tR: 1.36 min (LC-MS 2); ESI-MS: 535.2/537.2/539.1 [M+H]+ (LC-MS 2).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH2:11][CH3:12])[CH:3]=1.[CH:13](O)([CH3:15])[CH3:14]>>[CH2:11]([C:4]1[CH:3]=[C:2]([Br:1])[CH:10]=[CH:9][C:5]=1[C:6]([O:8][CH:13]([CH3:15])[CH3:14])=[O:7])[CH3:12]
Reactant: CC(C)O
Reactant: CCc1cc(Br)ccc1C(=O)O
Product: CCc1cc(Br)ccc1C(=O)OC(C)C

Procedure:
Using General Esterification Procedure A; 4-bromo-2-ethyl-benzoic acid (2.25 g, 9.9 mmols) was combined with isopropyl alcohol to give the title compound as a colorless oil after column chromatography (2% EtOAc-hexanes).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:37])[CH:10]([NH:19][C:20]([O:22]CC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:38](Cl)(=O)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][C:9](=[O:37])[CH:10]([NH:19][C:20](=[O:22])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCCCC(=O)Cl
Reactant: C=CCOC(=O)CCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCOC(=O)CCC(NC(=O)CCCCCCCCC)C(=O)OCc1ccccc1
Temperature: 22 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
The Fmoc protective group was subsequently removed by exposure to DMAP and the free amine was acylated in situ with decanoyl chloride to give 2-Decanoylamino-pentanedioic acid 5-allyl ester 1-benzyl ester (7) in 63% yield as follows. To a suspension of 1 g (2.0 mmol) of 6 in 10 mL of CH2Cl2 was added 1 g (8.2 mmol) of DMAP. The reaction mixture was stirred at 22° C. for 24 h, treated with 0.62 mL (3.0 mmol) of decanoyl chloride, stirred for 2 h at 22° C., and extracted with saturated sodium bicarbonate solution (2×10 mL). The organic layer was dried (Na2SO4), evaporated to dryness, and the residue was chromatographed on SiO2 (Hexanes/EtOAc, 5:1) to give 548 mg (63%) of 7 as a viscous oil: IR (neat) 3293, 3063, 2924, 2855, 1740, 1649, 1534, 1453, 1379, 1175, 986, 930 cm-1 ; 1H NMR δ 7.26 (s, 5 H), 6.68 (d, I H, J=7.8 Hz), 5.85-5.75 (m, 1 H), 5.22 (d, 1 H, J=17.3 Hz), 5.14 (d, 1 H, J=10.4 Hz), 5.08 (s, 2 H), 4.63-4.57 (m, 1 H), 4.48 (d, 2 H, J=5.6 Hz), 2.38-2.28 (m, 2 H), 2.2-2.1 (m, 3 H), 2.0-1.9 (m, 1 H), 1.55 (t, 2 H, J=6.9 Hz), 1.20 (bs, 12 H), 0.82 (t, 3 H, J=5.9 Hz); 13C NMR δ 173.0, 172.1, 171.6, 135.0, 131.7, 128.2, 128.1, 127.8, 117.9, 66.8, 64.9, 51.3, 36.0, 31.6, 29.9, 29.1, 29.0, 26.8, 25.3, 22.3, 13.8; MS (El) m/z (relative intensity) 431 (12), 319 (21), 296 (51), 142 (100), 124 (31), 91 (91); HRMS (El) m/z calculated for C25H37NO5 : 431.2672, found: 431.2673.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH2:19][CH3:20])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:19][CH3:20])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCC[C@@H](O)[C@H](CC)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 6 (600 mg, 2.24 mmol) and 1-bromohexadecane (1.37 mL, 4.49 mmol), alcohol 59 was obtained as a colorless oil (775 mg, 70% yield).
Reaction SMILES: O=[C:2]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:9]([O:11]C)=O.[Br:13][C:14]1[CH:19]=[CH:18][N:17]=[C:16]([NH2:20])[CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[Br:13][C:14]1[CH:19]=[CH:18][N:17]2[C:9](=[O:11])[C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:2]=3[N:20]=[C:16]2[CH:15]=1
Reactant: COC(=O)C1CCCCCC1=O
Reactant: Nc1cc(Br)ccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1c2c(nc3cc(Br)ccn13)CCCCC2
Temperature: 85 °C
Reaction time: 5 h
Yield: 69.4 %

Procedure:
A mixture of methyl 2-oxocycloheptanecarboxylate (2 g, 11.8 mmol) and 4-bromopyridin-2-amine (2.04 g, 11.8 mmol), and PPA (5 mL) in 1,2-dichloroethane (10 mL) was stirred at 85° C. for 5 h. The reaction mixture was cooled to ambient temperature. A chilled saturated sodium carbonate solution was added to adjust pH to 8. The resulting mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with brine and dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography to produce 2.4 g of the desired product. MS (ESI): 293 (MH+).
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH:15]2[CH2:20][NH:19][CH2:18][C:17]3[CH:21]=[CH:22][S:23][C:16]2=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([O-])(=O)/C=C/C([O-])=O>>[CH2:1]([N:19]1[CH2:20][CH:15]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:16]2[S:23][CH:22]=[CH:21][C:17]=2[CH2:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(C2CNCc3ccsc32)cc1
Reactant: ClCc1ccccc1
Agent: O=C([O-])/C=C/C(=O)[O-]
Product: c1ccc(CN2Cc3ccsc3C(c3ccccc3)C2)cc1
Yield: 34 %

Procedure:
Benzyl chloride is condensed with 7-phenyl-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (Example 4), according to the procedure of Example 8. Fumarate: M.p. = 200° C; yield: 34%.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([OH:12])=O)[CH:6]=[CH:7][CH:8]=1.CC1(C)C(C)(C)[O:19][B:18]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)[O:17]1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C(=O)C>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[C:5]([CH2:9][C:10]([NH:29][C:26]2[N:27]=[CH:28][C:23]([B:18]([OH:19])[OH:17])=[CH:24][CH:25]=2)=[O:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1ccc(B(O)O)cn1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A 250 mL round-bottomed flask was charged with 2-(3-(trifluoromethyl)phenyl)acetic acid (2.319 g, 11.36 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (2.5 g, 11.36 mmol), 1-ethyl-3-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (2.178 g, 11.36 mmol), 1-hydroxybenzotriazole hydrate (1.740 g, 11.36 mmol), N-methylmorpholine (5.00 mL, 45.4 mmol) and N,N-dimethylacetamide (50 mL). The reaction was stirred at 50 °C. for 16 hours. The reaction was then quenched by the addition of ethyl acetate (50 mL) and water (50 mL). The layers were separated, and the organic was Washed with water (3×50 mL) and brine (1×50 mL). The organic was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by reverse-phase HPLC using a 15% water (0.1% trifluoroacetic acid) to 95% acetonitrile (0.1% trifluoroacetic acid) gradient to give the boronic acid as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.88 (s, 2 H), 7.54-7.66 (m, 3 H), 7.72 (s, 1 H), 7.96 (d, J=8.5 Hz, 1 H), 8.12 (dd, J=1.7 and 8.1 Hz, 1 H), 8.4 (br s, 1 H), 10.94 (s, 1 H).
Reaction SMILES: [CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O)[CH3:2].[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:1]([C:3]1[C:10]([C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[C:18]([C:26]([F:28])([F:29])[F:27])[CH:17]=3)=[N:13][CH:12]=2)=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][N:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1)[CH3:2]
Reactant: O=C(O)C1CNC1
Reactant: CCc1c(C=O)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCc1c(CN2CC(C(=O)O)C2)cccc1-c1cnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.4 %

Procedure:
To a solution of 2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}benzaldehyde (D72) (60 mg), 3-azetidinecarboxylic acid (28.9 mg) and acetic acid (0.1 mL) in dichloromethane (DCM) (3 mL) stirred under nitrogen at room temperature for 1 h was added sodium triacetoxyborohydride (60.6 mg) in one charge. The reaction was stirred at room temperature overnight. The mixture was partitioned with DCM and water, washed with saturated brine and the organic phase was dried and evaporated, the residue was purified by Mass Directed AutoPrep to afford 1-[(2-ethyl-3-{2-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}phenyl)methyl]-3-azetidinecarboxylic acid (E31) (14 mg). δH (DMSO-d6, 400 MHz): 1.06 (3H, t), 1.33 (6H, d), 2.73 (2H, m), 3.22 (5H, m), 3.63 (2H, s), 4.89 (1H, m), 7.26 (2H, m), 7.39 (1H, d), 7.45 (1H, d), 7.84 (1H, s), 8.15 (2H, m). δF (DMSO-d6, 376 MHz): −61.3. MS (ES): C26H27F3N2O3S requires 504. found 505.1 (M+H+).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=2[F:26])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=3[F:26])[CH2:9]2)[O:7][NH:30]1
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](c2cc(F)c(F)cc2F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1c1cc(F)c(F)cc1F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 59.2 %

Procedure:
Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate (1.888 g, 4.87 mmol) was dissolved in MeOH (18 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.195 g, 4.87 mmol) dissolved in water (1.800 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.299 mL, 4.87 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h 20 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (24 mL, 144.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow oil. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 5-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. A mixture of cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)piperidine-1-carboxylate and trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2,4,5-trifluorophenyl)-piperidine-1-carboxylate (1.027 g, 59%) was obtained as white solid after freeze drying. MS m/z 357 (M+H)+
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][NH:2]1.[BH3-][C:15]#N.[Na+].C=O.Cl>CO.O>[CH3:15][N:2]1[CH2:3][CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: [BH3-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN1CCc2c([nH]c3ccccc23)C1
Reaction time: 2 h
Yield: 94.6 %

Procedure:
2,3,4,9-Tetrahydro-1H-β-carboline (0.50 g, 2.9 mmol) and NaCNBH3 (0.44 g, 7.0 mmol) were added to a round bottomed flask, dissolved in MeOH (35 mL), and treated with 3.23 mL of a 27% solution of formaldehyde in water. This mixture was stirred for 2 h, after which, 2N HCl (50 mL) was added, followed by stirring for 15 min. The mixture was taken to pH=11 by addition of concentrated, aqueous NaOH and extracted with methylene chloride (3×30 mL). The combined organic layers were washed with brine, dried (Na2SO4), and concentrated. The product was purified by MPCC (0-10% gradient of MeOH in CH2Cl2), giving the title compound (511 mg, 95%) as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.39 (d, 1H, J=7.7 Hz), 7.27 (d, 1H, J=8.0 Hz), 7.05 (t, 1H, J=7.5 Hz), 6.96 (t, 1H, J=7.7 Hz), 3.68 (s, 2H), 2.86 (m, 4H), 2.53 (s, 3H). 13C NMR APT (100 MHz, CD3OD): δ 136.1 (up), 131.7 (up), 127.2 (up), 121.2 (down), 119.2 (down), 117.9 (down), 110.8 (down), 107.8 (up), 53.0
Reaction SMILES: [C:1]1([C:12]([OH:14])=O)[CH:2]=[CH:3][CH:4]=[C:5]2[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=12.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([CH2:56][C:57]([F:63])([F:62])[C:58]([F:61])([F:60])[F:59])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C.C(=O)([O-])O.[Na+].O.[Cl-].[Na+].O>[F:63][C:57]([F:62])([C:58]([F:59])([F:61])[F:60])[CH2:56][C:53]1[CH:54]=[CH:55][C:50]([CH2:49][CH:39]([NH:38][C:12]([C:1]2[CH:2]=[CH:3][CH:4]=[C:5]3[CH2:11][CH2:10][CH2:9][CH:8]=[CH:7][C:6]=23)=[O:14])[CH:40]([C:42]2[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=2)[OH:41])=[CH:51][CH:52]=1
Reactant: O=C(O)c1cccc2c1C=CCCC2
Reactant: NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(NC(Cc1ccc(CC(F)(F)C(F)(F)F)cc1)C(O)c1cccc(Cl)c1)c1cccc2c1C=CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxylic acid (151 mg, 0.801 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (154 g, 0.801 mmol) and 1-hydroxybenzotriazole monohydrate (123 mg, 0.801 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(2,2,3,3,3-pentafluoropropyl)phenyl]-1-propanol (0.30 g, 0.763 mmol) was finally added. The mixture was stirred at room temperature, overnight. The mixture was diluted with ethyl acetate, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The mixture was filtered using a glass filter filled with silica gel, and the filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-[(1RS,2SR)-1-[4-(2,2,3,3,3-pentafluoropropyl)benzyl]-2-(3-chlorophenyl)-2-hydroxyethyl]-6,7-dihydro-5H-benzo[a]cycloheptene-1-carboxamide (0.284 g, 66%) as colorless crystals.