Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-:27][Si](C)(C)C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2C2C=CC=CC=2)C2CCCCC2)CCCCC1>[NH2:27][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(Br)cc2)CC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2ccc(N)cc2)CC1
Temperature: 65 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
A sealed tube was charged with tert-butyl 4-(4-bromophenyl)-4-methylpiperidine-1-carboxylate (286) (2.6 g, 7.37 mmol), (dicyclohexylphosphino)biphenyl (65 mg, 0.18 mmol), Pd2(dba)3 (68 mg, 0.074 mmol) and LiHMDS (1M, 14.7 mL, 14.7 mmol) in anhydrous THF (15 mL). The resulting mixture was purged with N2 stream and stirred in 65° C. bath for overnight. After being cooled to RT, the mixture was diluted with water (10 mL) and extracted with DCM (5 mL×3). The combined organic layers were washed with brine, dried, concentrated in vacuo, and subjected to silica flash column chromatography using 0 to 30% EtOAc in PE to afford tert-butyl 4-(4-aminophenyl)-4-methylpiperidine-1-carboxylate (287) (750 mg, 36%) as a white solid. Proton NMR (CDCl3): δ 7.13 (2H, d, J=8.5 Hz), 6.69 (2H, d, J=8.5 Hz), 3.67-3.57 (2H, m), 3.54-3.44 (2H, m), 3.43-3.33 (2H, m), 2.03 (2H, s), 1.67-1.61 (2H, m), 1.47 (9H, s), 1.22 (3H, s) ppm.
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:13]1([CH2:19][CH2:20][CH2:21]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>>[CH3:1][C:2]([CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCCCc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(CCCc1ccccc1)C(=O)OCC
Yield: 79.3 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-methylmalonate (3.48 g), 3-phenylpropyl bromide (3.98 g) and sodium hydride (55% suspension in oil, 0.96 g) and the reaction mixture was treated to afford the desired compound (4.63 g) as a syrup.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][C:10]([C:20](=[O:28])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:9][N:8]=1)(=O)=O.[C:31]([C:33]1([OH:41])[CH:38]2[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]2)[CH2:34]1)#[CH:32].C(N(CC)CC)C.N>CN(C)C=O>[CH2:13]([C:12]1[C:7]([C:32]#[C:31][C:33]2([OH:41])[CH:38]3[CH2:39][CH2:40][N:35]([CH2:36][CH2:37]3)[CH2:34]2)=[N:8][CH:9]=[C:10]([C:20](=[O:28])[NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:11]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C#CC1(O)CN2CCC1CC2
Reactant: O=C(Nc1ccccc1)c1cnc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)c1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(C#CC2(O)CN3CCC2CC3)c(Cc2ccccc2)c1
Reaction time: 3 h

Procedure:
150 mg of 3-benzyl-5-(N-phenylcarbamoyl)-2-pyridyl trifluoromethanesulfonate, 60 mg of 3-ethynyl-3-quinuclidinol, 50 mg of tetrakis (triphenylphosphine)palladium(0), 10 mg of cuprous iodide and 0.15 ml of triethylamine were added to 2 ml of N,N-dimethylformamide, followed by stirring for 3 hours in an oil bath kept at 50° C. After cooling as it was, aqueous ammonia was added thereto and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to NH-silica gel column chromatography, to synthesize 90 mg of the target compound.
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3].Cl[Si:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:28][Si:27]([CH3:30])([CH3:29])[O:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3]
Reactant: C[Si](C)(C)Cl
Reactant: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O)[C@H]1[C@@H](C)C(=S)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]1[C@@H](C)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (content, 90.6%; 14.7 g) was dissolved in dry toluene (60 ml), and chlorotrimethylsilane (7.8 g) and triethylamine (7.8 g) were added thereto under ice-cooling, followed by stirring at room temperature for 40 minutes. The reaction mixture was diluted with toluene (300 ml), washed with 2% sodium bicarbonate solution (300 ml) and aqueous sodium chloride (300 ml×2) and dried over magnesium sulfate to give (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (16.35 g; yield, 90%).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:12]=[N:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[CH2:15]([O:14][N:13]=[CH:12][C:5]1([C:3]([OH:4])=[O:2])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)C1(C=NOCc2ccccc2)CCCCCC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1(C=NOCc2ccccc2)CCCCCC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-cycloheptanecarboxylic acid methyl ester (5.2 g, 18 mmol) and lithium hydroxide monohydrate (7.56 g, 180 mmol) in THF (80 mL) and water (40 mL) was stirred at 60° C., for 24 h. The THF was removed in vacuo and the reaction mixture was acidified to pH 4 with 6N aqueous HCl and was extracted with dichloromethane (50 μL×5). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound (4.44 g, 90%). MH+276.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=O)[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[CH3:28][S:29]([NH2:32])(=[O:31])=[O:30].C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([NH:32][S:29]([CH3:28])(=[O:31])=[O:30])=[O:27])[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C(=O)O)c2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C(=O)NS(C)(=O)=O)c2)c1

Procedure:
A cloudy solution of 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylic acid (100 mg, 0.222 mmol), methanesulfonamide (24.3 mg, 0.256 mmol), DMAP (5.4 mg, 0.044 mmol), EDC (59.7 mg, 0.311 mmol), and triethylamine (0.043 mL, 0.31 mmol) in DMF (4 mL) was stirred for 14 hours at room temperature. The reaction mixture was purified directly via reverse phase HPLC (CH3CN:H2O with 0.1% TFA) to give 3′-methyl-N-(methylsulfonyl)-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxamide. MS ESI calc'd. for C20H18F3N4O3S [M+H]+ 451, found 451. 1H NMR (500 MHz, DMSO-d6) δ 12.26 (s, 1H), 10.26 (s, 1H), 8.82 (d, J=4.9 Hz, 1H), 8.18 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=7.8 Hz, 1H), 7.87 (d, J=7.9 Hz, 1H), 7.61 (t, J=7.8 Hz, 1H), 7.57 (s, 1H), 7.26 (d, J=5.0 Hz, 1H), 7.24 (s, 1H), 3.39 (s, 3H), 2.38 (s, 3H).
Reaction SMILES: [CH3:1][N:2](C(OC(C)(C)C)=O)[C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[NH2:18][CH:19]([CH2:24][CH:25]=[CH2:26])[CH2:20][C:21]([O-:23])=[O:22].C(O)(C(F)(F)F)=O>O>[CH3:1][NH:2][C@H:3]([C:8]([OH:10])=[O:9])[CH2:4][CH:5]([CH3:7])[CH3:6].[NH2:18][CH:19]([CH2:24][CH:25]=[CH2:26])[CH2:20][C:21]([O-:23])=[O:22]
Reactant: CC(C)C[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Agent: C=CCC(N)CC(=O)[O-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](CC(C)C)C(=O)O
Reaction time: 0.5 h

Procedure:
Methyl N-(t-butoxycarbonyl)leucine-3-amino-5-hexenoate (10 g) was treated with 90% TFA in water(100 ml). The mixture was stirred for 30 min and the TFA and water were then removed by evaporation. The residue was purified by preparative HPLC on a C18 silica column eluting with acetonitrile/water/0.1% TFA to give a gummy solid on evaporation of appropriate fractions. This was dissolved in ethyl acetate (50 ml) and washed twice with saturated sodium bicarbonate solution(10 ml), once with saturated brine(10 ml), dried (MgSO4) and evaporated to give 1.6 g of a single diastereoisomer of methyl leucine-3-amino-5-hexenate as a pale blue oil. HPLC Dynamax 60A C18 column; acetonitrile/water/0.1%TFA 10-70% over 20 min Rt 10.7 min; 1H NMR (DMSO-d6, 300 MHz, ppm): 0.9(6H, m), 1.4-1.5 (2H, m), 1.5-1.7 (1H, m), 2.1-2.3(2H, m), 2.3-2.5(2H, m), 3.5 (3H, s), 3.6-3.7(1H, m), 4.1-4.2(1H, m), 4.4-4.6 (2H, b), 5.0-5.1 (2H, dd), 5.6-5.8 (1H, m), 8.4 (1H, d): m/Z 257 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12].ClCC(C1C=CC=CC=1)=O.[NH2:27][C:28]1[N:29]=[CH:30][NH:31][C:32]=1[C:33]#[N:34]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:29]2[CH:30]=[N:31][C:32]([C:33]#[N:34])=[C:28]2[N:27]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1Cl
Reactant: N#Cc1[nH]cnc1N
Agent: O=C(CCl)c1ccccc1
Product: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccccc3Cl)nc12
Yield: 17 %

Procedure:
Reaction of 1-(2-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (251 mg, 1.0 mmol), prepared from commercially available 2-chloro-acetophenone according to general procedure A, and 4-amino-5-cyano-1H-imidazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as a yellow solid (55 mg, 17%). MS (ISP) 323.1 [(M+H)+]; mp 180° C.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[C:12]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:12][O:10][C:1](=[O:11])[C@@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)[C@H](O)c1ccccc1
Solvent: CO
Product: COC(=O)[C@H](O)c1ccccc1

Procedure:
Into methanol (20 ml) were added (R)-mandelic acid (5.0 g) and p-toluenesulfonic acid (0.1 g), and the resulting mixture was heated under reflux for 2 hours. The reaction mixture was cooled, then neutralized, and concentrated. Ethyl acetate and water were added to the resulting residue, and the organic layer was collected by layer separation. The organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was removed by filtration, and the solvent was distilled off from the filtrate to obtain a colorless oily compound mentioned above (5.35 g, 97.9%).
Reaction SMILES: C([O:4][C:5]1[C:6]([CH3:24])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:23])([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:9][CH2:8]2)(=O)C.[OH-].[Na+]>C(O)C.O>[OH:4][C:5]1[C:6]([CH3:24])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:23])([CH2:17][C:18]([OH:20])=[O:19])[CH2:9][CH2:8]2
Reactant: CCOC(=O)CC1(C)CCc2c(C)c(OC(C)=O)c(C)c(C)c2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(CC(=O)O)O2
Temperature: 25 °C
Reaction time: 7 h
Yield: 70.8 %

Procedure:
A solution of ethyl 6-acetoxy-2,5,7,8-tetramethylchroman-2-acetate (36.5 g, ~108 mmol) and 50% aqueous sodium hydroxide (110 mL) in a mixture of ethanol (500 mL) and water (500 mL) was stirred at ambient temperature for 7 h. The reaction mixture was extracted with hexane (2×200 mL). The pH of the resulting solution was adjusted to ~2 with concentrated hydrochloric acid. Water (~200 mL) was added and the reaction mixture was cooled in an ice/water bath. Crystallization was induced by scratching with a glass rod and the solid that formed was collected by filtration. The solid was recrystallized from an ethanol/water mixture to give 20.2 g (70.9% yield) of the desired product as a tan solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.Cl.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CCOCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOCC
Product: Brc1ccc(OCCN2CCOCC2)cc1

Procedure:
The first step is a Williamson ether synthesis between 4-bromophenol (131 g) and N-chloroethylmorpholine (1 as the HCl salt; 141 g) using K2CO3 powder (3 to 3.5 equivalents) as the base and having acetonitrile as the solvent. The ingredients were mixed and stirred at reflux overnight with high conversion (96.3-99.1%). After dilution with dichloromethane and heptane, the reaction mixture was filtered and evaporated to give the desired product 2 in essentially a quantitative yield (216 g). Note that with similar substrates (e.g., 4-bromo-3-fluorophenol), conversions (even with extensive heating) were not always so high (e.g., 59.9-98.3%). Both the alkyl chloride and the K2CO3 are preferably purchased from Aldrich. If continued heating does not drive reaction to completion, unreacted bromophenol can readily be removed by dissolving the crude reaction mixture in 4 parts toluene and washing out the phenol with 4 parts 15% aqueous NaOH.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>C1COCC1.C(OCC)(=O)C>[O:14]1[CH2:15][CH2:16][N:11]([C:2]2[S:3][CH:4]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:6]=2)[CH2:12][CH2:13]1
Reactant: C1COCCN1
Reactant: COC(=O)c1csc(Br)n1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1csc(N2CCOCC2)n1
Yield: 93.4 %

Procedure:
A solution of methyl 2-bromothiazole-4-carboxylate (0.20 g, 0.901 mmol) in THF (10 mL) was treated with morpholine (0.17 mL, 1.94 mmol) and refluxed for 18 h. The reaction was then diluted with ethyl acetate and washed with sat. NaHCO3 (1×), brine (1×) and dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (2.5×10 cm, 50% AcOEt/CH2Cl2) to give the title material (0.192 g, 92%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ ppm: 7.44 (s, 1H) 3.82 (s, 3H) 3.75 (m, 4H) 3.45 (m, 4H).
Reaction SMILES: B#B.[Br:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][C:5]=1[CH3:13].O.[OH-].[Na+]>C1COCC1>[Br:3][C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][C:5]=1[CH3:13]
Reactant: Cc1cc(C(=O)O)ccc1Br
Agent: B#B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(CO)ccc1Br
Reaction time: 5 h
Yield: 63.1 %

Procedure:
Diborane in THF (1M; 220 ml) was added dropwise to a solution of 4-bromo-3-methylbenzoic acid (20.0 g) in THF (100 ml) at room temperature under nitrogen. The solution was stirred for 5 h, treated cautiously with water (20 ml) and aqueous sodium hydroxide (2N; 200 ml) and extracted with ether (3×100 ml). The dried extract was evaporated to give the title compound as a colourless oil (11.8 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([C@@H:35]([O:37]C(=O)C)[CH3:36])=[O:34]>>[OH:37][C@@H:35]([CH3:36])[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:34]
Reactant: N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Product: C[C@H](O)C(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A157) and acetic acid (S)-1-chlorocarbonyl-ethyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:34]([NH2:36])=[O:35])[CH2:33][CH2:32][C:27]4(OCC[O:28]4)[CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.Cl>C1COCC1.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3([C:34]([NH2:36])=[O:35])[CH2:25][CH2:26][C:27](=[O:28])[CH2:32][CH2:33]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(N)=O)CCC4(CC3)OCCO4)s2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(C(N)=O)CCC(=O)CC3)s2)c1
Temperature: 23 °C
Reaction time: 6 h
Yield: 74.8 %

Procedure:
To a suspension of 8-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decane-8-carboxamide (700 mg, 1.35 mmol) in anhydrous THF (2 ml) and was added concentrated HCl (5.53 ml, 67.4 mmol). The resulting dark yellow solution was stirred at 23° C. for 6 h. The mixture was diluted with saturated aqueous NaHCO3 (80 ml) and extracted with EtOAc (2×70 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude oil was triturated with hexanes and diethyl ether which afforded 1-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]-4-oxocyclohexanecarboxamide (683 mg, 1.01 mmol, 74.6%) as an tan solid. MS APCI: [M+H]+ m/z 476.1.
Reaction SMILES: [NH:1]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:2]([C:26](O)=O)[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH2:51]([C:56]1[CH:57]=[C:58]([NH2:63])[C:59]([NH2:62])=[CH:60][CH:61]=1)[C:52]([CH3:55])([CH3:54])[CH3:53].C(O)(=O)C>C(#N)C>[CH2:51]([C:56]1[CH:61]=[CH:60][C:59]2[NH:62][C:26]([C@@H:2]([NH:1][C:29](=[O:30])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:3][C:4](=[O:25])[NH:5][C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:63][C:58]=2[CH:57]=1)[C:52]([CH3:55])([CH3:54])[CH3:53]
Reactant: CC(C)(C)Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CC(C)(C)Cc1ccc2[nH]c([C@H](CC(=O)NC(c3ccccc3)(c3ccccc3)c3ccccc3)NC(=O)OC(C)(C)C)nc2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 92.2 %

Procedure:
To a solution of Boc-Asn(Trt)-OH (101 mg, 0.213 mmol) in acetonitrile (2.0 mL) cooled in an ice water bath was added 4-methylmorpholine (0.059 mL, 0.53 mmol) and isobutyl chloroformate (0.027 mL, 0.21 mmol). After stirring for 45 minutes 4-neopentylbenzene-1,2-diamine (Preparation 83, 34 mg, 0.19 mmol) was added and the mixture allowed to warm to room temperature. After stirring for 2.5 hours, the reaction mixture was concentrated in vacuo and acetic acid (1.0 mL, 18 mmol) was added. The reaction was stirred for 18 hours, concentrated in vacuo, redissolved in ethyl acetate, washed with water, aqueous saturated sodium hydrogen carbonate solution, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 0-100% ethyl acetate/hexanes gradient to afford the title compound (108 mg, 93%) as an off white solid that was taken directly on to the next step.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=1[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH:20]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([CH3:22])[CH3:21].O>CS(C)=O>[CH3:21][CH:20]([N:23]1[CH2:28][CH2:27][N:26]([C:2]2[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:10]([O-:12])=[O:11])=[CH:4][C:3]=2[CH3:13])[CH2:25][CH2:24]1)[CH3:22]
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: CC(C)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2CCN(C(C)C)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 86.3 %

Procedure:
To a solution of 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (1.3 g, 7.03 mmol) in dimethylsulfoxide was added potassium carbonate (1.9 g, 14.0 mmol) and isopropylpiperazine (2.0 mL, 14 mmol). The resulting suspension was warmed at 70° C. for 12 hours, poured into water, and extracted with diethyl ether. The ether layers were washed with aqueous saturated sodium chloride, dried over sodium sulfate, taken to a residue under reduced pressure, and purified by chromatography on SiO2 to afford 1-(1-methylethyl)-4-[2-methyl-5-(methyloxy)-4-nitrophenyl]piperazine (1.78 g, 86% yield) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm. 1.11 (d, J=6.60 Hz, 6 H), 2.24 (s, 3 H), 2.72 (s, 4 H), 2.79 (s, 1 H), 3.06 (s, 4 H), 3.93 (s, 3 H), 6.57 (s, 1 H), 7.81 (s, 1 H).
Reaction SMILES: O1C2C(=CC=CC=2)/C(=[N:11]/[OH:12])/CC1.[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:24][CH3:25])=[CH:20][CH:21]=2)[C:16]1=O)[CH3:14]>>[CH2:13]([CH:15]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:24][CH3:25])=[CH:20][CH:21]=2)[C:16]1=[N:11][OH:12])[CH3:14]
Reactant: CCC1Cc2ccc(OC)cc2C1=O
Reactant: O/N=C1\CCOc2ccccc21
Product: CCC1Cc2ccc(OC)cc2C1=NO

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 2-ethyl-6-methoxyindan-1-one and making non-critical variations provided the title compound as a oil: HRMS (FAB) calcd for C12H15NO2+H 206.1181, found 206.1175. Anal. Calcd for C12H15NO2: C, 70.22; H, 7.37; N, 6.82. Found: C, 69.90; H, 7.48; N, 6.64.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[N:22]=[C:23]([C:27]3[O:28][CH:29]=[CH:30][CH:31]=3)[O:24][C:25]=2[CH3:26])=[C:15]([O:32][CH3:33])[CH:14]=1)[C:6](OC)=[O:7])(=[O:3])[NH2:2].C1CCN2C(=NCCC2)CC1>C(Cl)(Cl)Cl>[O:28]1[CH:29]=[CH:30][CH:31]=[C:27]1[C:23]1[O:24][C:25]([CH3:26])=[C:21]([CH2:20][O:19][C:16]2[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][CH2:10][C@H:5]3[O:4][C:1](=[O:3])[NH:2][C:6]3=[O:7])=[CH:14][C:15]=2[O:32][CH3:33])[N:22]=1
Reactant: COC(=O)[C@@H](CCCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1)OC(N)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClC(Cl)Cl
Product: COc1cc(CCC[C@H]2OC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
To a solution of methyl (R)-(+)-2-carbamoyloxy-5-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]pentanoate (2.92 g) in chloroform (100 ml) was added dropwise, at temperature ranging from -5 to 0° C., 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (1.54 g). The mixture was stirred for one hour at the same temperature range. The reaction mixture was washed with 2N HCl and water, which was then dried (MgSO4) and concentrated to yield (R)-(+)-5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (2.46 g, 91%), which was recrystallized from acetone-isopropyl ether to give colorless needles, m.p.122-123° C. [α]D +39.4° (c=0. 495, CHCl3)