Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=O)[CH2:11][CH2:10]2)=[N:7][CH:8]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.[NH2:33][C:34]1[CH:43]=[C:42]2[C:37]([CH:38]=[CH:39][CH:40]=[N:41]2)=[CH:36][CH:35]=1>ClCCCl.CN(C=O)C>[N:41]1[C:42]2[C:37](=[CH:36][CH:35]=[C:34]([NH:33][C:15]([CH:12]3[CH2:11][CH2:10][N:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:8][N:7]=4)[CH2:14][CH2:13]3)=[O:17])[CH:43]=2)[CH:38]=[CH:39][CH:40]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: O=C(O)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1ccc2cccnc2c1)C1CCN(c2ccc(C(F)(F)F)cn2)CC1
Temperature: 25 °C

Procedure:
1-(5-Trifluoromethylpyrid-2-yl)-piperidine-4-carboxylic acid (D101) (100 mg, 0.36 mmol) was treated with oxalyl chloride (63 ul, 0.72 mmol) and catalytic DMF in 1,2-dichloroethane (3.5 ml) at 60° C. for 0.75 h. On cooling to room temperature the solvent was removed in vacuo and the residue was dissolved in DCM (2 ml). Triethylamine (30 ul, 0.2 mmol) and 7-aminoquinoline (D55) (27 mg, 0.19 mmol) were added and the reaction stirred at room temperature until complete by tlc. The resultant precipitate was collected by filtration to give the title compound as an off-white solid. MS(ES): MH+ 401, M-H+ 399.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3OCCO3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1.Cl.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1
Reactant: C1CCNCC1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(C2OCCO2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-N5 -[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (106 mg) in tetrahydrofuran (2 ml) was stirred with 2N hydrochloric acid (0.2 ml) for 1/2 h at room temperature. The mixture was treated with piperidine (0.5 ml), stirred at room temperature for 1 h, and then treated with sodium borohydride (75 mg). After a further 1 h, the mixture was diluted with water, and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo. The resulting oil was crystallised from a mixture of benzene and cyclohexane to yield the title compound (60 mg) m.p. 93°-4°. TLC silica (methanol:ammonia 80:1) Rf 0.5.
Reaction SMILES: B.C1COCC1.Br[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([Cl:22])=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=1)=[O:10].Cl.[N-:24]=[N+:25]=[N-:26].[Na+].[I-].[Na+]>C1COCC1>[N:24]([CH2:8][C@@H:9]([C:11]1[CH:12]=[CH:13][C:14]([Cl:22])=[C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=1)[OH:10])=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)Nc1cc(C(=O)CBr)ccc1Cl
Agent: B
Agent: Cl
Agent: [I-]
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CN=[N+]=[N-])ccc1Cl
Reaction time: 0.5 h
Yield: 64 %

Procedure:
R-2-Methyl-CBS-oxazaborolidine (1.0 M in THF, 2 mL, 2 mmol) in 50 mL of THF was added slowly to a stirred solution of borane-THF complex (1.0 M in THF, 12 mL, 12 mmol) at room temperature. The mixture was stirred for 30 minutes and then N-(5-bromoacetyl-2-chloro-phenyl)-methanesulfonamide (which was obtained in Example 24) (2.80 g, 8.6 mmol) in 50 ml of THF was added dropwise. Upon stirring over night hydrochloride (1.0 M solution in diethyl ether) was added until the pH was ˜1. After stirring for one hour the reaction mixture was partitioned between ethyl acetate and water. The organic phase was dried over MgSO4 and concentrated. The residue was then dissolved in 50 mL of DMSO. To the solution sodium azide (2.93 g, 45 mmol) and sodium iodide (3 g, 20 mmol) were added. After stirring at room temperature for 3 days the reaction was quenched with water, extracted with diethyl ether. The organic layer was dried over MgSO4 and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate and hexanes to give the title compound as a white solid (1.6 g, 64%); 1H NMR (300 MHz, CDCl3) δ 2.60(d, J=5.9 Hz, 1 H), 3.06(s, 3 H), 3.45–3.50(m, 2 H), 4.85–4.95(m, 1 H), 6.84(brs, 1 H), 7.22(dd, J=8.3, 2.0 Hz, 1 H), 7.44(d, J=8.3 Hz, 1 H), 7.65 (d, J=2.0 Hz, 1 H); MS (ES) m/z: 288.9 ((M−H)−, 100%); HRMS Calcd. for C9H12ClN4O3S(M+): 290.0241. Found: 290.0228.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34](O)=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:39]=[CH:38][C:21]([CH2:22][N:23]2[C:31]3[C:26](=[CH:27][C:28](/[C:32](/[CH3:37])=[CH:33]/[C:34]([NH:1][C:2]4[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=4[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:35])=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2Cc2ccc(F)cc2)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2Cc2ccc(F)cc2)c1

Procedure:
334 mg of compound 30 was obtained in a similar manner to those described in the Examples 1 and 2 using 654 mg of ethyl 4-(2-aminophenoxy)butyrate and 454 mg of 3-[1-(4-fluorobenzyl)indol-5-yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.
Reaction SMILES: [Br:1][C:2]([CH3:7])([CH3:6])[C:3](Br)=[O:4].Cl.[CH2:9]([O:16][NH2:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CCOC(C)=O>[Br:1][C:2]([CH3:7])([CH3:6])[C:3]([NH:17][O:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:4]
Reactant: CC(C)(Br)C(=O)Br
Reactant: NOCc1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(Br)C(=O)NOCc1ccccc1
Yield: 87 %

Procedure:
Prepared in 87% yield (3.53 g, 11.3 mmol) from the reaction of 2-bromo-2-methylpropanoyl bromide (3.0 g, 13 mmol) with O-benzylhydroxylamine hydrochloride (2.13 g, 13 mmol) via general procedure A. Rf=0.58 (3:1, hexanes:EtOAc); mp=88.6-91.1° C.; 1H-NMR (500 MHz, CDCl3): δ 9.05 (br s, 1H), 7.45-7.34 (m, 5H), 4.94 (s, 2H), and 1.93 (s, 6H); 13C-NMR (126 MHz, CDCl3): δ 169.7, 134.9, 129.6, 129.1, 128.8, 78.4, 59.5, and 32.6; FT-IR (neat) 3195 (br), 3034, 2954, 2890, 1652 (s), 1505, 1469, 1454, 1112, 1032, 1004 cm-1. HRESI-MS: calcd □ for C11H18BrN2O2 (M+NH4)+ 289.0546, observed 289.0543.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>>[C:1]1([CH2:7][C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([Cl:19])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccccc1Cc1ccccc1

Procedure:
A mixture of 5.0 g of 2-(phenylmethyl) benzoic acid in 5.0 ml of thionyl chloride is heated on a steam bath for 1 hour. The volatiles are evaporated in vacuo to give 5.74 g of the desired product as an oil. M+ =227 as methyl ester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2([OH:26])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][CH:3]=1.C[O:28][C:29](=[O:52])[C@H:30]([C@@H:49]([CH3:51])O)[NH:31]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O.OS(O)(=O)=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[C:13]2([O:26][C@H:49]([CH3:51])[C@@H:30]([C:29]([OH:52])=[O:28])[NH2:31])[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:6][CH:7]=1
Reactant: COC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)[C@@H](C)O
Reactant: OC1(c2sccc2-c2ccc(F)cc2)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](OC1(c2sccc2-c2ccc(F)cc2)c2ccccc2-c2ccccc21)[C@H](N)C(=O)O

Procedure:
from 9-[3-(4-fluorophenyl)thien-2-yl]-9H-fluoren-9-ol (Example 3v) and Nα -(9-fluorenylmethoxycarbonyl)-L-threonine methyl ester following method A, using trifluoroacetic acid as catalyst in place of H2SO4 ;
Reaction SMILES: Br.[Cl:2][C:3]1[CH:4]=[C:5]([C:10]2[O:11][C:12](=[CH:17][Br:18])[C:13]([CH3:16])([CH3:15])[N:14]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1.S(=O)(=O)(O)[OH:20]>O>[Br:18][CH2:17][C:12](=[O:11])[C:13]([NH:14][C:10](=[O:20])[C:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[C:7]([Cl:9])[CH:6]=1)([CH3:16])[CH3:15]
Reactant: CC1(C)N=C(c2cc(Cl)cc(Cl)c2)OC1=CBr
Reactant: O=S(=O)(O)O
Agent: Br
Solvent: O
Product: CC(C)(NC(=O)c1cc(Cl)cc(Cl)c1)C(=O)CBr
Temperature: 50 °C

Procedure:
N- (1',1'-dimethylpropynyl)-3,5-dichlorobenzamide (40 gm, 0.156 m) was dissolved in methylene chloride (600 ml) and bromine (25 gm, 0.156 m) in methylene chloride (100 ml) was added gradually with stirring at room temperature. After the complete addition of the bromine, the mixture was stirred for another 15 minutes and diluted with hexane (500 ml). The yellowish-white precipitate which formed was filtered and dried to yield 58 gm of 2-(3',5'-dichlorophenyl)-4,4-dimethyl-5-bromomethylenoxazoline hydrobromide. The oxazoline hydrobromide (55 gm, 0.13 m) was added to concentrated sulfuric acid (200 ml) and stirred to obtain a clear solution. Water (20 ml) was added and the mixture heated at about 50° C. for about 24 hours. The mixture was then poured into ice water (about 2000 ml) and the white precipitate which formed was filtered and dried. Recrystallization from isopropanol, ether and hexane (1:1:2) yielded 21 gm of pure product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.Cl[CH2:13]CCl.S(Cl)(Cl)=O.CN(C=O)C>CO>[CH3:13][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=1[F:11]
Reactant: ClCCCl
Reactant: O=C(O)c1ccc(Br)cc1F
Solvent: CO
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Br)cc1F

Procedure:
4-Bromo-2-fluorobenzoic acid (10 g, 0.04 mol) was suspended in 1,2-dichloroethane (60 mL, 0.8 mol) to which was added thionyl chloride (10 mL, 0.1 mol) followed by a drop of DMF. The mixture was heated to reflux for 1 hour. Excess thionyl chloride and 1,2-dichloroethane were stripped off and the crude product was treated with methanol (50 mL) and heated to reflux for an hour. The mixture was concentrated to dryness, dissolved in dichloromethane, treated with cold sat. sodium bicarbonate solution. The organic layer was dried, then concentrated under vacuum to obtain the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)[CH:7]=1)=[O:4].[NH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CC#N>[N:22]1([CH2:2][C:3]([NH:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[CH:21]=[N:20][C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=3)[CH:7]=2)=[O:4])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1
Reactant: O=C(CCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=C(CN1CCNCC1)Nc1cccc(-c2cnc3ccccc3n2)c1
Yield: 39.4 %

Procedure:
A slurry of 2-chloro-N-(3-quinoxalin-2-ylphenyl)acetamide (100 mg, 0.336 mmol) and piperazine (58 mg, 0.672 mmol) in MeCN (5 mL) was heated at reflux for 48 hrs. The resulting precipitate was filtrated, washed with MeCN (10 mL) and submitted to preparative LCMS to afford 2-(piperazin-1-yl)-N-(3-(quinoxalin-2-yl)phenyl)acetamide (46 mg, 39% yield). LCMS calculated for C20H21N5O (M+H): 348.42. found 348. 1H-NMR (DMSO-d6, 400 Mhz) δH: 9.92 (1H, br.), 9.52 (1H, s), 8.55 (1H, m), 8.13-8.20 (2H, m), 8.05-8.08 (1H, m), 7.82-7.98 (3H, m), 7.55-7.60 (1H, m), 3.25-3.40 (NH and 6H, br.), 2.80-2.88 (4H, br.).
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[C:22]2[S:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16](N)[CH:15]=1.N([O-])=O.[Na+].[I-:28].[K+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[Br:13][C:14]1[C:22]2[S:21][N:20]=[CH:19][C:18]=2[CH:17]=[C:16]([I:28])[CH:15]=1
Reactant: Nc1cc(Br)c2sncc2c1
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: O
Solvent: CC#N
Product: Brc1cc(I)cc2cnsc12
Temperature: 12.5 °C
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
To a solution of p-toluenesulfonic acid monohydrate (1.36 g, 7.2 mmol) in acetonitrile (8.5 mL) was added 7-bromo-benzo[d]isothiazol-5-ylamine (400 mg, 1.74 mmol). The resulting suspension was cooled to 10 to 15° C. and a solution of sodium nitrite (331 mg, 4.8 mmol) and potassium iodide (996 mg, 6 mmol) in water (1.5 mL) was added gradually. The reaction mixture was stirred for 10 min and then allowed to come to RT and stirred for 16 h. The reaction mixture was treated with water (5 mL) and aqueous 1.0 N sodium bicarbonate solution (15 mL), and aqueous 2.0 N sodium thiosulfate solution (10 mL). The precipitate was collected by filtration and the purified by column chromatography (25% ethyl acetate:hexanes) to afford 300 mg (50%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 8.9 (s, 1H), 8.37 (d, J=1.2 Hz, 1H), 7.91 (d, J=1.5 Hz, 1H).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[CH3:7][C:8](Br)(C)[C:9](OCC=C)=O.C(OCC)(=O)C>[Cu]Br.C(#N)C>[CH3:7][CH2:8][CH2:9][CH2:6][O:5][C:1]([CH:2]=[CH2:3])=[O:4]
Reactant: C=CCOC(=O)C(C)(C)Br
Reactant: C=CC(=O)OC
Agent: [Cu]Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CC(=O)OCCCC
Temperature: 80 °C

Procedure:
To a 30 mL pyrex tube were added methyl acrylate (5 mL, 4.78 g, 55.5 mmole), allyl 2-methyl-2-bromopropionate(0.354 mL, 460 mg, 2.2 mmole), copper (I) bromide (318 mg, 2.22 mmole), 2,21-bipyridyl (1.04 g, 6.66 mmole), ethyl acetate (4 mL) and acetonitrile (1 mL). The mixture was degassed by three freeze-pump-thaw cycles and then sealed. The mixture was heated to 80° C. for 3 hours and then after cooling to ambient temperature, the mixture was diluted with ethyl acetate (20 mL). An insoluble precipitate was filtered off and the filtrate was washed twice with dil. HCl and once with NaCl solution. The organic layer was dried over Na2SO4 and concentrated under reduced pressure to yield a poly(butyl acrylate) having an alkenyl group at one end and a bromine atom at the other end (3.93 g, 75%). The molecular weight and the molecular weight distribution of the polymer were found to be 2700 and 1.48, respectively, by GPC analysis (based on polystyrene standard). The number of alkenyl groups introduced into the polymer was 0.81 based on 1H NMR analysis.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH:4]([CH3:23])[CH2:3]1.[O:24]1[C:33]2[CH:32]=[C:31]([CH:34]=O)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.CO>[O:24]1[C:33]2[CH:32]=[C:31]([CH2:34][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH:4]([CH3:23])[CH2:3]3)[N:30]=[CH:29][C:28]=2[O:27][CH2:26][CH2:25]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: CC1CC(N)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CO
Product: CC1CC(NCc2cc3c(cn2)OCCO3)CCN1CCn1c(=O)ccc2c(F)cc(F)cc21
Temperature: 0 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
A solution of 1-[2-(4-amino-2-methylpiperidin-1-yl)ethyl]-5,7-difluoroquinolin-2(1H)-one (Intermediate 213, crude, 220 mg, 0.69 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (114 mg, 0.69 mmol) in dry dichloroethane/methanol (4 mL, 4:1) was heated over 3 Å molecular sieves at 80° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (299 mg, 1.38 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 hours and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (20 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to pH˜10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (4×20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (17:3) gave 195 mg (69%) of the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:16][C:17]([F:33])([F:32])[C:18]1[O:22][N:21]=[C:20]([C:23]2[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=2)[C:26](O)=[O:27])[N:19]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([CH2:13][CH2:14][NH:15][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:20]4[N:19]=[C:18]([C:17]([F:33])([F:32])[F:16])[O:22][N:21]=4)[CH:24]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCCc1csc(-c2ccc(Cl)cc2)n1
Product: O=C(NCCc1csc(-c2ccc(Cl)cc2)n1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 22 %

Procedure:
This compound was synthesized from 2-(2-(4-chlorophenyl)thiazol-4-yl)ethanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (40 mg, yield 22%). 1H NMR (400 MHz, CDCl3) δ 8.53 (t, J=1.5 Hz, 1H), 8.27-8.25 (dt, J=7.8 Hz, 1.3 Hz, 1H), 8.09-8.07 (dt, J=7.8 Hz, 1.4 Hz, 1H), 7.89-7.87 (m, 2H), 7.68 (m, 1H), 7.62 (t, J=7.8 Hz, 1H), 7.36-7.34 (m, 2H), 7.09 (s, 1H), 3.92-3.87 (m, 2H), 3.16 (t, J=6.0 Hz, 2H). MS (ESI) m/z: Calculated for C21H14ClF3N4O2S: 478.05. found: 479.0 (M+H)+.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.C(OCC)(=O)C>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[C:2]1[S:3][CH:4]=[CH:5][N:6]=1
Reactant: OB(O)c1cccs1
Reactant: Brc1nccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: c1csc(-c2nccs2)c1
Temperature: 25 °C
Yield: 64.5 %

Procedure:
2-Bromothiazole (15.0 g) and 2-thiopheneboronic acid (14.0 g) were dissolved in dimethoxyethane (150 ml). To the mixture was added bis(triphenyl)phosphine palladium(II)dichloride (3.2 g) and 2M sodium carbonate (137 ml), and the mixture was refluxed under argon atmosphere for 2 hours. The mixture was cooled to room temperature, and the reaction solution was diluted with ethyl acetate, and washed with water. The organic layer was collected, dried over sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=96:4) to give 2-(2-thienyl)thiazole (9.87 g) as oil. APCI-Mass m/z 168 (M+H)
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([C:19]2([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20]2)=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:19]1([C:16]2[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=2)[CH2:23][CH2:22][O:21][CH2:20]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C2(CN)CCOC2)cn1
Product: Cc1ncc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCOC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and (3-(2-methylpyrimidin-5-yl)tetrahydrofuran-3-yl)methanamine. LCMS (MH+): m/z=366.0, tR (minutes, Method E)=0.45
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:15][OH:16])[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[H-].[Na+].CS(O[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]([N:33]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]4[CH:50]=[CH:49][C:48]([CH:51]5[CH2:53][CH2:52]5)=[CH:47][CH:46]=4)=[C:39]([O:54][CH3:55])[CH:38]=3)[CH2:34]2)=[O:32])[CH:26]=1)(=O)=O.O>CN(C=O)C>[CH:51]1([C:48]2[CH:49]=[CH:50][C:45]([CH2:44][O:43][C:40]3[CH:41]=[CH:42][C:37]([CH:35]4[CH2:34][N:33]([C:31]([C:27]5[CH:26]=[C:25]([CH2:24][O:16][CH2:15][C:3]6([CH2:2][OH:1])[CH2:4][O:5][CH:6]([C:9]7[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=7)[O:7][CH2:8]6)[CH:30]=[CH:29][N:28]=5)=[O:32])[CH2:36]4)=[CH:38][C:39]=3[O:54][CH3:55])=[CH:46][CH:47]=2)[CH2:53][CH2:52]1
Reactant: COc1cc(C2CN(C(=O)c3cc(COS(C)(=O)=O)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Reactant: OCC1(CO)COC(c2ccccc2)OC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C2CN(C(=O)c3cc(COCC4(CO)COC(c5ccccc5)OC4)ccn3)C2)ccc1OCc1ccc(C2CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (5-hydroxymethyl-2-phenyl-[1,3]dioxan-5-yl)methanol (0.66 g) in DMF (10 mL) was added NaH (0.12 g). The mixture was stirred at RT for 1 hr. To the mixture was added 2-{3-[4-(4-cyclopropylbenzyloxy)-3-methoxyphenyl]azetidine-1-carbonyl}pyridin-4-ylmethyl methanesulfonate (0.7 g) prepared in Example 1 (7). The reaction mixture was stirred at RT for 1 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then dried over MgSO4. The solvent was removed under reduced pressure to give the crude title compound.
Reaction SMILES: C([O:8][C:9](=[O:26])[CH2:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21]C)=[O:19])C1C=CC=CC=1>CO.[Pd]>[CH3:21][O:20][C:18](=[O:19])[CH2:17][CH2:16][CH2:15][O:14][C:13]1[CH:12]=[C:11]([CH2:10][C:9]([OH:26])=[O:8])[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)CCCOc1cccc(CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCOc1cccc(CC(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.7 %

Procedure:
The mixture of ethyl 4-(3-(2-(benzyloxy)-2-oxoethyl)phenoxy)butanoate (2.05 g, 5.77 mmol) and Pd/C (0.207 g) in methanol was stirred at room temperature under H2 overnight. The mixture was filtered and the filtrate was concentrated under reduce pressure. The residue was washed with ether, filtrated and dried to obtain 2-(3-(4-methoxy-4-oxobutoxy)phenyl)acetic acid (compound 0202-35) (1 g, 66%): LCMS: 267 [M+1]+.
Reaction SMILES: [C:1]([CH:9]1[C:14](=O)[CH2:13][CH2:12][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[NH2:23][NH2:24]>C(O)C>[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[C:9]3[CH2:10][N:11]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:13][C:14]=3[NH:24][N:23]=2)=[CH:3][CH:4]=1
Reactant: NN
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)c2ccncc2)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccncc3)c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a mixture of tert-butyl 3-isonicotinoyl-4-oxopiperidine-1-carboxylate (7.4 g, 24.3 mmol) and TEA (10.15 ml) in ethanol was added hydrazine (3.65 ml, 73 mmol). The reaction mixture was stirred at room temperature for overnight. The solvent was removed under vacuum and DCM (50 ml) was added, followed by water (50 ml). The organic layer was collected, washed with brine and dried over sodium sulfate. Removal of solvent gave the desired product (7 g). LC-MS found 301.2 (M+H)