Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([O:11]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:14][CH2:15][CH2:16][OH:17]>O>[CH2:1]([N:8]1[CH2:9][C@@H:10]([OH:11])[C@H:12]([NH:14][CH2:15][CH2:16][OH:17])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCO
Reactant: c1ccc(CN2CC3OC3C2)cc1
Solvent: O
Product: OCCN[C@@H]1CN(Cc2ccccc2)C[C@H]1O

Procedure:
40 g (0.22 mol) of 3-benzyl-6-oxa-3-azabicyclo[3.1.0]hexane are heated under reflux with 42 g (0.68 mol) of 2-aminoethanol in 450 ml of water overnight. The solution is extracted once with tert.-butyl methyl ether and the aqueous phase is concentrated. The residue is distilled.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[C:9]1(=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[H][H]>C(O)C.[Pd]>[CH:9]1([NH:1][C@@H:2]([CH:3]([CH3:5])[CH3:4])[C:6]([OH:8])=[O:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=C1CCCCC1
Reactant: [H][H]
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)[C@H](NC1CCCCC1)C(=O)O
Yield: 75.1 %

Procedure:
A mixture of L-valine (29.29 g, 250 mmol), and cyclohexanone (51.8 mL, 500 mmol, Aldrich Inc, Milwaukee, Wis.) was agitated in an atmosphere of hydrogen (pressure, 23.4-51.1 psi) at room temperature in 370 mL ethanol in the presence of Pd/C (20%, 3 g) until the absorption of hydrogen had ceased. The mixture was filtered, and this ethanolic filtrate was set aside, then the filter cake washed with 450 mL 1 M HCl. The ethanolic filtrate was concentrated to dryness and the residue dissolved in the aqueous filtrate above, which was treated with concentrated aqueous sodium hydroxide (29.8%) to adjust the pH to 5.5. The white solid precipitated out which was isolated via filtration, washed with two 150 mL portions of ethanol and dried under vacuum to give 37.4 g (70%) of the pure titled compound as a white solid; mp >300° C. APCI-MS m/z 200.2 (MH+).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:34])([F:33])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:32][CH2:31][C:19]3([CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]3)[CH2:18][CH2:17]2)[CH:13]=[CH:12][N:11]=1>C(Cl)Cl>[F:34][C:9]([F:8])([F:33])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:17][CH2:18][C:19]3([CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:31][CH2:32]2)[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc(C(F)(F)F)c3)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(N2CCC3(CCNC3)CC2)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TFA (1.5 ml) is added to a solution of tert-butyl 8-(2-(trifluoromethyl)pyridin-4-yl)-2,8-diazaspiro[4.5]decane-2-carboxylate (0.64 mmol, 1.0 eq.) in methylene chloride (5 ml) at 0° C. and the reaction mixture is stirred at 25° C. for 1 h. When the reaction was complete, the solvent was removed in vacuo in order to obtain the desired amine (AMN-26).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9](Cl)[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([NH2:6])=O.[OH:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21].[B:23]1([OH:33])[C:27]2[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:26]=2[CH2:25][O:24]1>>[OH:33][B:23]1[C:27]2[CH:28]=[CH:29][C:30]([O:32][C:9]3[CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]([C:4]#[N:6])=[C:2]([O:16][CH2:17][CH2:18][CH2:19][C:20](=[O:22])[CH3:21])[N:10]=3)=[CH:31][C:26]=2[CH2:25][O:24]1
Reactant: CC(=O)CCCO
Reactant: NC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: OB1OCc2cc(O)ccc21
Product: CC(=O)CCCOc1nc(Oc2ccc3c(c2)COB3O)cc(C(F)(F)F)c1C#N

Procedure:
This compound was prepared from 2,6-dichloro-4-(trifluoromethyl)nicotinamide, 5-hydroxypentan-2-one, and benzo[c][1,2]oxaborole-1,5(3H)-diol in a similar manner to that of D230. 1H-NMR (400 MHz, DMSO-d6) δ (ppm) 1.85-1.88 (m, 2H), 1.93 (s, 3H), 2.95-2.99 (t, J=4.9 Hz, 2H), 3.91-3.94 (t, J=5.4 Hz, 2H), 5.01 (s, 2H), 7.21 (dd, J=6.0, 1.5 Hz, 1H), 7.3 (s, 1H), 7.64 (s, 1H), 7.81 (d, J=6.0 Hz, 1H), 9.26 (s, 1H).
Reaction SMILES: O.[OH-].[Li+].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14](=[O:34])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[C:25]([O:27]C)=[O:26])=[CH:20][CH:19]=3)[N:16]=2)=[CH:7][CH:6]=1>O1CCOCC1.O>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C:14](=[O:34])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]([CH:29]4[CH2:33][CH2:32][CH2:31][CH2:30]4)[C:25]([OH:27])=[O:26])=[CH:20][CH:19]=3)[N:16]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(c1ccc(CN2N=C(c3ccc(Cl)cc3)OCC2=O)cc1)C1CCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)C(c1ccc(CN2N=C(c3ccc(Cl)cc3)OCC2=O)cc1)C1CCCC1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
86 mg (2.04 mmol) of lithium hydroxide monohydrate were added to a solution of 450 mg (1.02 mmol) of methyl (4-{[2-(4-chlorophenyl)-5-oxo-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl]methyl}phenyl)(cyclopentyl)acetate in 10 ml of dioxane and 10 ml of water, and the mixture was stirred at 80° C. for 12 h. After removal of the dioxane under reduced pressure, the aqueous phase was adjusted to pH 2 using 1 M hydrochloric acid, which resulted in the flocculation of the product. The solution was filtered and the filter residue was dried under reduced pressure. This gave 373 mg (0.87 mmol, 86% of theory) of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.ClC(Cl)(O[C:35](=[O:41])OC(Cl)(Cl)Cl)Cl.[CH2:43]([N:45]([CH2:49][CH3:50])[CH2:46][CH2:47][NH2:48])[CH3:44]>C(Cl)(Cl)Cl.O>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:35]([NH:48][CH2:47][CH2:46][N:45]([CH2:49][CH3:50])[CH2:43][CH3:44])=[O:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CCN
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 22.4 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (100 mg) was dissolved in chloroform (10 ml) and triethylamine (1 ml) to prepare a solution. A solution of triphosgene (139 mg) in chloroform was then added to the solution, and the mixture was stirred at room temperature for 10 min. Next, N1,N1-diethyl-1,2-ethanediamine (52 mg) was added thereto, and the mixture was further stirred at room temperature for one hr. Water was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by concentration. The residue was purified on a column using chloroform/methanol to give the title compound (32 mg, yield 22%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]=[C:9]=[O:10].[CH3:11][C:12]1[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:31])([F:30])[F:29])=[N:14][NH:15][C:16]=1[CH3:17].Cl>C(OCC)(=O)C>[CH3:7][NH:8][C:9]([N:15]1[C:16]([CH3:17])=[C:12]([CH3:11])[C:13]([O:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][C:20]=2[C:28]([F:29])([F:30])[F:31])=[N:14]1)=[O:10]
Reactant: CN=C=O
Reactant: Cc1[nH]nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CNC(=O)n1nc(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)c(C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.9 %

Procedure:
Potassium carbonate (0.50 g, 3.6 mmol) and methyl isocyanate (0.17 g, 3.0 mmol) were added to a solution of 4,5-dimethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole (1.08 g, 3.6 mmol) in ethyl acetate (20 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with diethyl ether (20 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/3), to give a white solid of N-methyl-4,5-dimethyl-3-(4-nitro-2-trifluoromethylphenyloxy)pyrazole-1-carboxamide (0.88 g, yield: 81.9%). mp: 113-115° C.; 1H-NMR (CDCl3, TMS, ppm): δ 1.88 (s, 3H), 2.57 (s, 3H), 2.94 (d, J=5.0 Hz, 3H), 6.70-6.95 (m, 1H), 7.44 (d, J=9.2 Hz, 1H), 8.39 (dd, J=2.7 and 9.2 Hz, 1H), 8.60 (d, J=2.7 Hz, 1H).
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:16][C:17]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=1[O:28][CH3:29].[NH2:30][C:31]([NH2:33])=[O:32].Cl>C(O)C>[OH:16][C:17]1[C:24]([N+:25]([O-:27])=[O:26])=[CH:23][C:20]([CH:21]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:33][C:31](=[O:32])[NH:30]2)=[CH:19][C:18]=1[O:28][CH3:29]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: NC(N)=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCO
Product: COc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Yield: 41 %

Procedure:
A mixture of 1,2-diphenylethanone (300 mg, 1.53 mmol), 4-hydroxy-3-methoxy-5-nitrobenzaldehyde (301 mg, 1.53 mmol), urea (275 mg, 4.587 mmol), and concentrated HCl (0.3 mL) in ethanol (10 mL) was refluxed for 80 h. After being cooled down to room temperature, the mixture was evaporated. The residue was purified by HPLC to give Compound 9 (262 mg, yield 41.1%). 1H NMR (DMSO-d6 400 MHz): δ 10.45 (s, 1H), 8.73 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 7.27-7.25 (m, 3H), 7.23-7.21 (m, 3H), 7.06-7.00 (m, 3H), 6.83 (d, J=6.8 Hz, 2H), 5.2 (d, J=2.4 Hz, 1H), 3.80 (s, 3H); MS (ESI): m/z 417.9 [M+1]+.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[NH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.C(O)C>C(OCC)C>[N:14]1([C:2]2[S:3][C:4]3[C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:5]=3[N:6]=2)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: C1CCNCC1
Reactant: O=C(O)c1cccc2nc(Br)sc12
Solvent: CCOCC
Solvent: CCO
Product: O=C(O)c1cccc2nc(N3CCCCC3)sc12
Temperature: 72.5 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
A mixture of ethyl ester of 2-bromobenzothiazole-7-carboxylic acid (572 mg, 2.00 mmol), piperidine (5 ml) and ethanol (1 ml) was stirred at 70-75° C. for 2.5 hrs. Diethyl ether (15 ml) was added to the mixture at room temperature and the precipitates were filtered off and washed with diethyl ether. The filtrate and washings were combined and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform) to give ethyl ester of 2-piperidinobenzothiazole-7-carboxylic acid (526 mg, 90%) as pale orange crystals.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:5]2[O:11][CH2:10][CH2:9][O:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=2)O1.C(Cl)Cl.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[O:15]1[CH2:16][CH2:17][N:12]([C:4]2[C:5]3[O:11][CH2:10][CH2:9][O:8][C:6]=3[N:7]=[C:2]([C:26]3[CH:27]=[N:28][C:29]([NH2:32])=[N:30][CH:31]=3)[N:3]=2)[CH2:13][CH2:14]1
Reactant: Clc1nc2c(c(N3CCOCC3)n1)OCCO2
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ncc(-c2nc3c(c(N4CCOCC4)n2)OCCO3)cn1
Temperature: 100 °C

Procedure:
A mixture of 2-chloro-4-morpholin-4-yl-6,7-dihydro-[1,4]dioxino[2,3-d]pyrimidine (114 mg, 0.44 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (196 mg, 0.88 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) and cesium carbonate (430 mg, 1.32 mmol) in dioxane (5 mL) and water (0.5 mL) was degassed and then heated at 100° C. for 2 hours. Further 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyrimidin-2-ylamine (100 mg, 0.44 mmol), PdCl2dppf.DCM (36 mg, 0.04 mmol) were added and the mixture heated at 100° C. for a further 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with methanol and the product eluted with 2M ammonia in methanol. The basic fractions were combined and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-10% methanol in DCM) then triturated with diethyl ether affording 101 (37 mg, 27%). LCMS: RT=2.75 min, [M+H]+=317. 1H NMR (400 MHz, DMSO): δ 8.90 (2H, s), 7.01 (2H, s), 4.42-4.36 (2H, m), 4.25-4.18 (2H, m), 3.70 (8H, s).
Reaction SMILES: Cl[CH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[F:14])([OH:6])[CH2:4]Cl.C(=O)(O)[O-].[Na+].[CH2:20]([NH2:22])[CH3:21].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O1CCCC1.C(OCC)(=O)C>[Cl:13][C:9]1[C:8]([F:14])=[C:7]([C:3]2([OH:6])[CH2:4][N:22]([CH2:20][CH3:21])[CH2:2]2)[CH:12]=[CH:11][CH:10]=1
Reactant: OC(CCl)(CCl)c1cccc(Cl)c1F
Reactant: CCN
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN1CC(O)(c2cccc(Cl)c2F)C1
Temperature: 120 °C
Yield: 35 %

Procedure:
A mixture of 1,3-dichloro-2-(3-chloro-2-fluorophenyl)propan-2-ol (0.88 g, 3.42 mmol), sodium bicarbonate (0.92 g, 10.95 mmol) and ethylamine in tetrahydrofurane (2.0 M, 1.82 ml, 3.64 mmol) in acetonitrile (15 ml) was heated at 120° C. for 30 min under microwave irradiation. Additional ethylamine in tetrahydrofurane (2.0 M, 0.91 ml, 1.82 mmol was added and the mixture was heated at 120° C. for 30 min under microwave irradiation. Aqueous sodium carbonate (50 ml, 10%) and ethyl acetate (50 ml) was added and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (50 ml), the pooled organic phase was dried (MgSO4) and evaporated. The crude product was purified by flash column chromatography on silica gel (ethyl acetate/isooctane, 1:4 to 1:1) to give the title compound (0.28 g, 35%). The amine was converted to the fumaric acid salt and recrystallized from ethanol/diethyl ether/diisopropyl ether: M.p. 172-173° C. MS m/z (relative intensity, 70 eV) 229 (M+, 1), 172 (29), 157 (56), 109 (41), 58 (bp).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH:11]([CH3:20])[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)=[CH:6][CH:5]=1.[C:21](Cl)(=O)[CH2:22][CH3:23].C([O-])(=O)C.[NH4+:30].CC(O)=O>ClCCl.CO.[OH-].[Na+]>[CH2:22]([C:21]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=2)[C:11]([CH3:20])=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:30]=1)[CH3:23]
Reactant: CCC(=O)Cl
Reactant: [NH4+]
Reactant: CC(Nc1ccc(CCO)cc1)C(=O)c1ccccc1
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc(-c2ccccc2)c(C)n1-c1ccc(CCO)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a stirred solution of 2-{[4-(2-hydroxyethyl)phenyl]amino}-1-phenyl-1-propanone (step 1 in EXAMPLE 3, 1.2 g, 4.5 mmol) in dichloromethane (10 mL) was added propionyl chloride (1.0 mL, 11.1 mmol) at ambient temperature. After 1 h, the reaction mixture was partitioned between ethyl acetate (30 mL) and water (10 mL). The aqueous phase was extracted with ethyl acetate (3×30 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. To the residue was added ammonium acetate (7.7 g, 100 mmol) and AcOH (15 mL) and the mixture was heated at 100° C. for 10 h. After cooling, the mixture was diluted with MeOH and basified with 4N NaOH aq. at 0° C. After 30 min, volatile components were removed under reduced pressure. The aqueous phase was extracted with dichloromethane (4×20 mL) and the combined organic phase was dried (MgSO4) and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with hexane/ethyl acetate (gradient elution from 1:1 to 1:2) to afford 0.32 g (23%) of the title compound as brown amorphous: 1H-NMR (CDCl3)δ1.19 (3H, t, J=7.5 Hz), 2.16 (3H, s), 2.57 (3H, q, J=7.5 Hz), 2.97 (2H, t, J=6.4 Hz), 3.96 (2H, t, J=6.4 Hz), 7.19-7.26 (3H, m), 7.38-7.43 (4H, m), 7.79 (2H, dd, J=7.1, 1.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH3:11])=[CH:4][CH:3]=1.[C:13](OCC)(=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15].[O-]CC.[Na+]>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10](=[O:12])[CH2:11][C:13](=[O:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)C=Cc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)C(=O)CC(=O)C=Cc1ccc(Cl)cc1

Procedure:
A solution of 4-(4-chlorophenyl)-3-buten-2-one (27.1 g) and diethyl oxalate (21.9 g) in dry diethyl ether (200 ml) was added dropwise over 15 minutes to a stirred suspension of sodium ethoxide (3.45 g of sodium dissolved in absolute ethanol and excess ethanol evaporated off) in dry diethyl ether (400 ml) cooled to 5°-10° C. by an ice bath. A yellow solid began to precipitate after 5 minutes.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].Br[C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN1CCCC1=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][N:19]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)cn2)CC1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 57.7 %

Procedure:
Sodium hydride (0.20 g, 60% dispersion in mineral oil) was added to a solution of-4-hydroxypiperidine-1-car-boxylic-acid-tert-butyl ester (0.92 g) in anhydrous 1-methyl-2-pyrrolidinone (5 μl), precooled in ice. After stirring for 30 minutes under nitrogen, 2,5-dibromopyridine (1.0 g) was added. The reaction mixture was then stirred for two hours at room temperature before heating to 70° C. for four hours. The resultant dark mixture was poured onto ice (200 ml) containing 2% citric acid (20 ml), and was extracted with diethyl ether (3×15 ml). The aqueous phase was then basified to pH 13 with solid sodium hydroxide, and extracted with diethyl ether (2×15 ml). The combined organics were washed with water (3×20 ml), saturated brine (20 ml) and dried over anhydrous sodium sulfate and evaporated to give the title compound as a light brown oil (0.87 g, 58%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][OH:44])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[OH:8][C@:9]1([C:21]2[S:22][C:23]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[N:38]=[C:37]([C:39]([F:41])([F:42])[F:40])[CH:36]=[CH:35][N:34]=4)[CH:29]=[C:28]([CH2:43][O:44][S:46]([CH3:45])(=[O:48])=[O:47])[CH:27]=3)=[CH:24][N:25]=2)[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH3:18])=[O:16])[C:11]([CH3:20])([CH3:19])[CH2:10]1
Reactant: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(CO)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H]1CC[C@](O)(c2ncc(-c3cc(COS(C)(=O)=O)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Temperature: 23 °C
Reaction time: 120 h
Yield: 88.5 %

Procedure:
Triethylamine (0.200 ml, 1.434 mmol, 1.5 equiv) was added to a stirring solution of methyl (1S,4R)-4-hydroxy-4-{5-[3-(hydroxymethyl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]-1,3-thiazol-2-yl}-2,2-dimethylcyclohexanecarboxylate (513 mg, 0.956 mmol) in anhydrous dichloromethane (15 mL). The orange solution was cooled to 0° C. (water/ice) then charged with methanesulfonyl chloride (0.089 ml, 1.147 mmol, 1.2 equiv). The reaction mixture was allowed to slowly warm to 23° C. and stir for 5 d. The mixture was partitioned between methylene chloride (2×90 ml) and water (95 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to afford methyl (1S,4R)-4-hydroxy-2,2-dimethyl-4-[5-(3-{[(methylsulfonyl)oxy]methyl}-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylate (520 mg, 71%), as an orange-yellow oil. 1H NMR (500 MHz, CDCl3) δ 8.79 (bs, 1H), 8.66 (d, J=4.9 Hz, 1H), 7.95 (s, 1H), 7.85 (s, 1H), 7.61 (s, 1H), 7.23 (s, 1H), 7.06 (d, J=4.9 Hz, 1H), 4.59 (s, 1H), 3.90 (s, 2H), 3.69 (s, 3H), 3.01 (s, 2H), 2.38-2.25 (m, 2H), 2.01 (m, 3H), 1.95-1.77 (m, 4H), 1.35-1.20 (m, 6H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=O)[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[C:6]2[O:5]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>C(#N)C.C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][CH:4]1[CH2:18][N:17]([CH3:19])[C:16](=[S:22])[C:7]2=[N:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=[C:6]2[O:5]1
Reactant: CN1CC(CCCl)Oc2cc3ccccc3nc2C1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CN1CC(CCCl)Oc2cc3ccccc3nc2C1=S
Yield: 86.9 %

Procedure:
To 3.0 g (0.01 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methyl-1,4-oxazepino[6,7-b]-quinolin-5(4H)-one in 30 ml of acetonitrile was added 1.3 g (0.006 mole) of phosphorus pentasulfide. The mixture was stirred vigorously at reflux for 2 hr. After cooling, the reaction mixture was diluted with 60 ml of toluene and filtered. The residue on the filter paper was washed with 50 ml of additional toluene/acetonitrile, 3/1, V/V. The filtrate was washed with 3×50 ml saturated sodium carbonate (caution: gas evolved), dried over anhydrous sodium sulfate, filtered, treated with activated charcoal, filtered again and concentrated by rotary evaporation (90° C., 30 mm). The residual syrup was crystallized from isopropyl alcohol, yielding 1.6 g (52%) of yellow crystals, m.p. 114°-116° C.
Reaction SMILES: O.O.[OH-].[Li+].C[O:6][C:7](=[O:21])[CH2:8][C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=1>CO>[C:11]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][C:7]([OH:21])=[O:6])[CH:10]=1
Reactant: COC(=O)Cc1cccc(-c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Water (39 mL), followed by lithium hydroxide monohydrate (4.2 g, 101.5 mmol) were added to a solution of biphenyl-3-yl acetic acid methyl ester (11.43 g, 50.57 mmol) in methanol (265 mL). The mixture was stirred at ambient temperature for 2 h then the organics were removed under reduced pressure. The mixture was acidified with dilute hydrochloric acid (1M, 80 mL), extracted with chloroform (2×100 mL), dried (MgSO4) and evaporated under reduced pressure to afford biphenyl-3-yl acetic acid as a white solid, yield 10.6 g, (99%), analytical HPLC Rt=16.565 min, HPLC-MS (single main UV peak with Rt=7.91 min, 213.1 [M+H]+).