Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=2)[CH2:9][CH2:8][CH2:7]1.[OH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[C:15]2[C:10]([CH2:9][CH2:8][CH2:7][N:6]2[CH2:5][C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([CH2:24][OH:23])=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[CH:11][CH:12]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1ccc2c(c1)N(Cc1cccc(Br)c1)CCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: OCc1ccc(-c2cccc(CN3CCCc4ccc(C(F)(F)F)cc43)c2)cc1
Temperature: 80 °C

Procedure:
Under a nitrogen atmosphere, a solution of 1-(3-bromo-benzyl)-7-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (2.36 g, 6.37 mmol), 4-(hydroxymethyl)phenyl boronic acid (1.07 g, 7.01 mmol), and 2 M Na2CO3 (7 mL, 12.7 mmol) in 16 mL of toluene and 4 mL ethanol (0.3 M) was treated with tetrakistriphenylphosphine palladium (Pd(Ph3)4) (0.37 g, 0.32 mmol) and heated to 80° C. for 2 hours. After cooling to room temperature the solution was extracted with ethyl acetate, dried over MgSO4, and concentrated. Purification by flash chromatography (30% ethyl acetate in heptane) provided [3′-(7-trifluoromethyl-3,4-dihydro-2H-quinolin-1-ylmethyl)-biphenyl-4-yl]-methanol. 1H NMR (CDCl3, 300 MHz) δ 7.49-7.32 (m, 6 H), 7.16-7.13 (m, 2 H), 6.95 (d, J=8.4 Hz, 1 H), 6.73-6.60 (m, 2 H), 4.66 (s, 2 H), 4.48 (s, 2 H), 3.30 (t, J=5.7 Hz, 2 H), 2.76 (t, J=6.3 Hz, 2 H), 1.98-1.90 (m, 2 H); ESI-LCMS m/z calcd for C24H22F3NO: 397.4; found 398.7 (M+1)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:13]([OH:15])=[O:14]>CC(O)=O.[Pd]>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[C:13]([OH:15])=[O:14]
Reactant: COc1ccc2ccccc2c1C(=O)O
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1C(=O)O)CCCC2
Reaction time: 23 h
Yield: 36.9 %

Procedure:
A mixture of 2-methoxy-1-naphthalenecarboxylic acid (1.0 g, 4.95 mmol) and 10% Pd/C (0.3 g) in HOAc (25 mL) was hydrogenated on Parr apparatus at 60° C. and 50 psi for 23 h. After filtration through diatomaceous earth, the solvent was removed under reduced pressure, and water was added. The solid was filtered and washed with water to give product as a yellow solid (0.377 g, 37%). 1H NMR (DMSO-d6) δ 12.81 (s, 1H), 7.05 (d, 1H), 6.83 (d, 1H), 3.68 (s, 3H), 2.66 (s, 2H), 2.59 (s, 2H), 1.69 (m, 4H); MS m/z 205 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Br:9])=[CH:4][N:3]=1.[NH3:10]>>[Br:9][C:5]1[C:6]([NH2:10])=[N:7][C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: N
Reactant: Clc1ncc(Br)c(Cl)n1
Product: Nc1nc(Cl)ncc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2,4-Dichloro-5-bromopyrimidine (200 g, 0.88 mol) is added slowly to NH3 (1000 ml, 7 M in MeOH) while the reaction mixture is kept below 10° C. The reaction mixture is stirred at rt for 2 h, heated to 60° C. for 2 h, and then cooled again to rt and stirred for 55 h. It is concentrated under reduced pressure, and the residue is suspended in H2O (500 ml). The aqueous layer is extracted with EtOAc (3×) and the combined organic layers are dried over MgSO4, filtered, and concentrated under reduced pressure to yield the title compound as a white solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)=[N:7][C:6]=1Br)=[O:4].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:6]1[N:7]=[C:8]([N:10]2[C:14]3[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=3[N:12]=[CH:11]2)[S:9][C:5]=1[C:3]([OH:2])=[O:4]
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)cc32)nc1Br
Product: COc1cc2ncn(-c3nc(-c4ccccc4Cl)c(C(=O)O)s3)c2cc1OC
Yield: 46.2 %

Procedure:
In a similar manner as described for Example 26, 4-bromo-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid methyl ester (40 mg, 0.1 mmol) and 2-chlorophenylboronic acid (23.5 mg, 0.15 mmol) gave 4-(2-Chloro-phenyl)-2-(5,6-dimethoxy-benzoimidazol-1-yl)-thiazole-5-carboxylic acid (19.2 mg, 46%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.63 (br.s., 1 H); 8.82 (s, 1 H); 7.73 (s, 1 H); 7.59-7.65 (m, 2 H); 7.51 (td, 1 H); 7.46 (d, 1H); 7.39 (s, 1 H); 3.85 (s, 3 H); 3.81 (s, 3 H). MS m/z 416 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:11]([N+:21]([O-])=O)=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[CH:14]=[CH:13]2>CCO.[Pd]>[NH2:21][C:11]1[C:10]([O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:4][C:3]=2[O:2][CH3:1])=[CH:19][CH:18]=[C:17]2[C:12]=1[CH:13]=[CH:14][C:15](=[O:20])[NH:16]2
Reactant: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(=O)ccc3c2[N+](=O)[O-])c(OC)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1ccc(Oc2ccc3[nH]c(=O)ccc3c2N)c(OC)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pd/C (30 mg) was added to 25.2 (250 mg) in EtOH (15 mL). The mixture was stirred under hydrogen at room temperature for 6 h. The catalyst was removed by filtration through celite. The filtrate was concentrated under vacuum to give 25.3. MS ESI (pos.) m/z: 369.1 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[OH:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Br:21][CH:22](Br)[CH3:23]>CN(C)C=O>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:6]=1[O:14][CH2:23][CH2:22][Br:21])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc([N+](=O)[O-])ccc1O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc([N+](=O)[O-])ccc1OCCBr
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 55.2 %

Procedure:
A portion (9.6 g, 0.049 mol) of the 2-acetamido-4-nitrophenol produced in (1) above and potassium carbonate (33.86 g, 0.245 mol) were dissolved in dimethylformamide (100 ml), followed by heating at 70° C., addition of dibromoethane (21 ml, 0.245 mol) and stirring for 20 min. Thereafter, the reaction solution was filtered to remove the insoluble matter and the solvent was evaporated, with the residue being thereafter diluted with sodium bicarbonate and subjected to two extractions with ethyl acetate. The organic extracts were dried with sodium sulfate and the solvent was evaporated, with the resulting residue being purified by being subjected to column chromatography on silica gel using, as an eluent, ethyl acetate containing n-hexane (50%) to yield the end compound 1-(2-acetamido-4-nitrophenoxy)-2-bromoethane (8.2 g) as a pale yellow solid mass.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH:7]2[CH2:12][CH2:11][N:10](C(OCC3C=CC=CC=3)=O)[CH2:9][CH2:8]2)[CH2:3]1.C1CC=CCC=1>CO.[Pd]>[NH:10]1[CH2:11][CH2:12][CH:7]([N:4]2[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]2)[CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)N1CCC(N2CC[C@H](O)C2)CC1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CO
Product: O[C@H]1CCN(C2CCNCC2)C1
Temperature: 80 °C
Yield: 90.1 %

Procedure:
Phenylmethyl 4-[(3S)-3-hydroxy-1-pyrrolidinyl]-1-piperidinecarboxylate (1.33 g, 4.37 mmol) was dissolved in methanol (11.65 ml) and 1,4-cyclohexadiene (2.91 ml) was added. The mixture was flushed with nitrogen and palladium on carbon (10%) (0.023 g, 0.218 mmol) was added. The reaction mixture was heated in an 80° C. oil bath at reflux for 1 h. The mixture was filtered through Celite®, washed with MeOH, and the filtrate was concentrated to afford (3S)-1-(4-piperidinyl)-3-pyrrolidinol (0.670 g, 81% yield). MS (m/z) 171.0 (M+H+).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([CH2:9][NH:10][C:11](=O)[CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:7][CH:6]=1.C(O)(=O)C>O1CCCC1>[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][CH:14]([OH:17])[CH2:15][CH3:16])=[CH:19][CH:20]=1
Reactant: CCC(O)CCC(=O)NCc1ccc(OC)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCC(O)CCCNCc1ccc(OC)cc1
Temperature: 22.5 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (121 gal, 458 L) and sodium borohydride (22.154 kg, 585.6 moles) were charged to a clean and dry nitrogen purged 500 gallon glass lined tank. The suspension was allowed to stir for 30 minutes at 20-25° C. then 4-hydroxyhexanoic acid 4-methoxy-benzylamide (45.75 kg, 182 moles) was added as a solid. After 30 minutes, the reaction was cooled to 5-10° C. and over a 4 to 8 hour period a solution of acetic acid (9.1 gallons, 34.4 L) in tetrahydrofuran (12 gal, 45.4 L) was added keeping the temperature at 0-10° C. A slight nitrogen bleed was kept on the tank to help remove the hydrogen. When the addition was complete the reaction was warmed to 20-25° C. and stirred for an hour. The temperature of the reaction was slowly increased to a gentle reflux (˜66° C.) and held there for 16 hours. The reaction was quenched by the addition of 1N HCl, keeping the temperature <25° C. Excess tetrahydrofuran was removed by atmospheric distillation. Ethyl acetate was added to the resulting aqueous solution to extract unreacted amide. The acidic aqueous was then brought to pH 11 to allow the product amine to be extracted into ethyl acetate and held for use in the next step. An aliquot of the ethyl acetate solution of product was worked up to project final yield and concentration. The yield for this large scale run was 55.0%, which was less than that achieved with small scale preparations (78.8%). The large scale procedure had 12.8% unreduced amide starting material after the quench which accounted in part for the lower yield.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[NH:7][C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2.[H-].[Li+].Br[CH2:16][CH:17]=[CH2:18]>CN(C)C=O>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[N:7]([CH2:18][CH:17]=[CH2:16])[C:6](=[O:12])[CH:5]=[CH:4][C:3]1=2
Reactant: C=CCBr
Reactant: O=C1CCCc2[nH]c(=O)ccc21
Agent: [H-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=CCn1c2c(ccc1=O)C(=O)CCC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 63 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-5-oxo-2(1H)-quinolinone (20.0 g), lithium hydride (1.57 g), and dimethylformamide (800 ml) was stirred for 3 hrs at 25° C., under nitrogen. 3-Bromopropene (15.5 g) was added and the mixture was stirred for an additional eighteen hrs. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated. The residue was triturated with petroleum ether to afford 15.7 g (63%) of 5,6,7,8-tetrahydro-5-oxo-1-(2-propenyl)-2(1H)-quinolinone.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][NH:14][C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][O:19][CH2:20][CH:21]([C:38]([O-:40])=[O:39])[CH2:22][C:23](=O)[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:25].C1CCC(N=C=NC2CCCCC2)CC1.C(OCC)(=O)C>ClCCl>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:16][O:15][N:14]([C:23]2([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=3)=[O:25])[CH2:22][CH:21]([CH2:20][O:19][CH3:18])[C:38](=[O:39])[O:40]2)[C:13]1=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCC(CC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)[O-]
Reactant: O=C(N[C@H]1CONC1=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCC1CC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@H](NC(=O)OCc3ccccc3)C2=O)OC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.6 %

Procedure:
In 2 ml of dichloromethane were dissolved 121 mg of (4S)-4-benzyloxycarbonylamino-3-isoxazolidinone and 200 mg of the Compound (78) obtained in Example 78. To the solution was added a solution of 137 mg of DCC in 1 ml of dichloromethane. The solution was stirred at room temperature for 2 hours. To the reaction solution was added ethyl acetate. The crystals which separated out were filtered off, and the filtrate was washed with water and dried (MgSO4). The solvent was evaporated off, and the residue was subjected to a silica gel column chromatography, followed by elution with hexane-ethyl acetate (2:1) to give 216 mg of the subject Compound (80) as a pale yellow oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17]([C:19]2[S:26][C:25]([CH3:27])=[C:24]3[C:20]=2[CH2:21][C@H:22]2[C:28]([CH3:30])([CH3:29])[C@H:23]23)=[O:18])[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][OH:12].CCN(C(C)C)C(C)C.[CH3:40][S:41](Cl)(=[O:43])=[O:42]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17](=[O:18])[C:19]2[S:26][C:25]([CH3:27])=[C:24]3[C:20]=2[CH2:21][C@H:22]2[C:28]([CH3:30])([CH3:29])[C@H:23]23)[CH:5]=[C:6]([O:13][CH3:14])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][O:12][S:41]([CH3:40])(=[O:43])=[O:42]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCO
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(Cl)c1OCCCOS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 471.3 %

Procedure:
To a solution of 3-[3-chloro-4-(3-hydroxy-propoxy)-5-methoxy-phenyl]-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (430 mg, 0.958 mmol) in DCM (20 mL) and DIPEA (0.262 mL, 1.53 mmol) is added methane sulfonylchloride (0.090 mL, 1.15 mmol) at 0° C. The reaction mixture is stirred at 0° C. for 30 min. The reaction mixture is diluted with DCM, washed with 0.1 N aq. NaOH followed by 10% aq. citric acid solution, dried over MgSO4 and evaporated to give methanesulfonic acid 3-{2-chloro-6-methoxy-4-[3-oxo-3-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propyl]-phenoxy}-propyl ester (2.38 g) as a brown oil; LC-MS: tR=1.14 min, [M+1]+=527.23.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:5][CH:4]=1>ClCCl.O=[Mn]=O>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:20]2[CH:21]=[CH:22][C:23]([CH:26]=[O:27])=[CH:24][CH:25]=2)[C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[C:12]([O:18][CH3:19])[CH:11]=2)=[CH:5][CH:4]=1)=[O:1]
Reactant: COc1cc(N(c2ccc(CO)cc2)c2ccc(CO)cc2)ccc1CO
Agent: O=[Mn]=O
Solvent: ClCCl
Product: COc1cc(N(c2ccc(C=O)cc2)c2ccc(C=O)cc2)ccc1C=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 94 %

Procedure:
MnO2 (40 mg, 444 μmol) is added to a solution of compound 8 (27 mg, 74 μmol) in dichloromethane (2 ml). The suspension obtained is stirred for 48 hours at room temperature and then it is filtered. The solid obtained is washed with dichloromethane. The mother liquors are then concentrated to give 25 mg of compound 9 in the form of a yellow solid (yield: 91%).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]([C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21])[C:8](=NOC)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:25])[CH:3]=1.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[NH:37][NH2:38]>>[Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:17]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:38][N:37]([C:29]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:28]=3[Cl:27])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:25])[CH:3]=1
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Reactant: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)OCC
Agent: Cl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(Br)cc1F
Yield: 54 %

Procedure:
By the procedure of Example 1, Step G, ethyl 3-(4-bromo-2-fluorobenzyl)-2-methoxyimino-4-oxooctanoate (from Step A) was reacted with 2-chloro-5-nitrophenylhydrazine hydrochloride. The crude product was flash chromatographed twice on silica gel (first column: gradient elution with 0.5-2% MeOH in CH2Cl2 ; second column: gradient elution with 5-20% EtOAc in hexane) to give a 54% yield of the title compound as an orange oil; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 538, 540 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.86 (t, J=7.3 Hz, 3H), 1.02 (t, J=7.1 Hz, 3H), 1.32 (m, 2H), 1.55 (m, 2H, partially obscured by H2O peak), 2.57 (t, J=7.8 Hz, 2H), 4.10 (s, 2H, superimposed on q, J=7.2 Hz, 2H), 6.82 (dd, J≈8, 8 Hz, 1H), 7.16 (d, J≈8 Hz, 1H), 7.23 (m, 1H, partially obscured by CHCl3 peak), 7.65 (d, J=8.8 Hz, 1H), 8.25 (dd, J=8.8, 2.6 Hz, 1H), 8.33 (d, J=2.6 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([C:8](=[O:13])[C:9]([F:12])([F:11])[F:10])[CH:7]=1.[N-:15]=[N+]=[N-].[Na+].O.[O-]S([O-])(=O)=O.[Na+].[Na+]>CS(C)=O.CCOC(C)=O>[NH2:15][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8](=[O:13])[C:9]([F:12])([F:11])[F:10]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1cc(Br)ccc1F)C(F)(F)F
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Nc1ccc(Br)cc1C(=O)C(F)(F)F
Temperature: 25 °C

Procedure:
A solution of 1-(5-bromo-2-fluorophenyl)-2,2,2-trifluoroethanone (6.67 g, 24.6 mmol, Intermediate 8, step a) in DMSO (6.2 mL) was treated with NaN3 (1.76 g, 27.0 mmol) and stirred under air (lightly capped) at 95° C. for 1 hour. The brownish-red opaque reaction was then cooled to room temperature on an ice bath, diluted with EtOAc (49 mL), treated with SnCl2-dihydrate (6.66 g, 29.5 mmol) in several portions over ˜30 sec followed by water (1.33 mL, 73.8 mmol), and the mixture was stirred at room temperature for 30 min. The reddish solution with heavy off-white particulates was then treated with anhydrous Na2SO4 (˜6 g; ˜40 mmol; ˜400 mmol water capacity) and stirred vigorously for a few minutes. The mixture was then filtered over a bed of Celite®, and the cloudy orange filtrate was dry load flash chromatographed (˜60 g silica gel) with a heptane to 50% DCM/heptane gradient to provide the title compound as an orange oil that crystallized upon standing.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>ClCCl>[CH3:16][S:17]([O:8][CH2:7][C@H:2]1[CH2:3][O:4][CH2:5][CH2:6][O:1]1)(=[O:19])=[O:18]
Reactant: OC[C@H]1COCCO1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1COCCO1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A round bottomed flask was charged with (2S)-1,4-dioxan-2-ylmethanol (115 mg, 0.973 mmol), triethylamine (0.204 mL, 1.46 mmol), and 5 mL of dichloromethane then cooled to −10° C. Methanesulfonyl chloride (91 μL, 1.17 mmol) was added by syringe and the solution was stirred for 30 minutes at −10° C. The solution was diluted in dichloromethane, washed with 1 M HCl, and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were washed with saturated aquoues sodium bicarbonate (2×) and brine, then dried over sodium sulfate and concentrated to afford (2R)-1,4-dioxan-2-ylmethyl methanesulfonate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[C:14](=O)[C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:7][CH2:6]2.C([SiH](CC)CC)C.[ClH:26]>FC(F)(F)C(O)=O.O>[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:15](=[CH:16][CH:17]=1)[CH2:14][C:8]1([CH2:13][CH2:12][CH2:11][CH2:10][NH:9]1)[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC1(CCCCN1)C2=O
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCC1(CCCCN1)C2
Reaction time: 1 h

Procedure:
In 30 ml of trifluoroacetic acid was dissolved 6.57 g of 3,4-dihydro-6-methoxyspiro[naphthalene -2(1H),2'-piperidin]-1-one followed by addition of 8.5 ml of triethylsilane and the mixture was stirred for 1 hour. This reaction mixture was poured portionwise in water and after addition of 1N-hydrochloric acid, washed with hexane. The aqueous layer was made basic with 1N-aqueous sodium hydroxide solution and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate and filtered and the solvent was then distilled off. The residue was treated with 7.0 ml of 4N-methanolic HCl to give a solid. This solid was recrystallized from methanol-ether to provide 5.09 g of white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH:20]([O:22][CH3:23])[CH2:19][CH2:18][CH:17]2[CH2:24]O)=[O:15])[CH:5]=[CH:6][CH:7]=1.[C:26]1(=[O:36])[NH:30][C:29](=[O:31])[C:28]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:27]12>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH:20]([O:22][CH3:23])[CH2:19][CH2:18][CH:17]2[CH2:24][N:30]2[C:26](=[O:36])[C:27]3[C:28](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:29]2=[O:31])=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COC1CCC(CO)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1
Product: COC1CCC(CN2C(=O)c3ccccc3C2=O)N(C(=O)c2nc(C)sc2-c2cccc(F)c2)C1

Procedure:
2-((1-(5-(3-Fluorophenyl)-2-methylthiazole-4-carbonyl)-5-methoxypiperidin-2-yl)methyl)isoindoline-1,3-dione was prepared according to general procedure I using (5-(3-fluorophenyl)-2-methylthiazol-4-yl)(2-(hydroxymethyl)-5-methoxypiperidin-1-yl)methanone and phthalimide.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].CN(C=O)C.[Br:18][CH2:19][C:20](Br)=[O:21]>O1CCOCC1>[Br:18][CH2:19][C:20]([NH:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:21]
Reactant: O=C(Br)CBr
Reactant: CCOC(=O)c1ccccc1N
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCOC(=O)c1ccccc1NC(=O)CBr
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A solution of ethyl 2-aminobenzoate (3.0 g, 18 mmol) in a mixture of anhydrous DMF (30 mL) and anhydrous dioxane (30 mL) in a 250 mL 3-necked round-bottomed flask equipped with a constant addition funnel (60 mL) was cooled to 0° C. using an ice-bath. Bromoacetyl bromide (3.68 g, 1.6 mL, 18 mmol) was added dropwise, keeping the internal temperature between 0° and 5° C. over a 1/2 h period. After the addition of the bromoacetyl bromide was completed, the solution was warmed to rt, stirred overnight, and then the solution was slowly poured into 500 mL of ice-water, causing a solid to precipitate. The precipitate was filtered, washed with water, and then dried in a vacuum dessicator overnight to afford 3.32 g (65%) of the title compound as a white solid, mp 65°-66° C.: 1H NMR (DMSO-d6) δ11.08 (s, 1H), 8.25 (dd, J=7.6, J=0.8, 1H), 7.95 (dd, J=8.0, J=1.2, 1H), 7.63 (t, J=8.4, 1H), 7.25 (dt, J=7.6, J=1.2, 1H), 4.33 (q, J=7.2, 2H), 4.23 (s, 2H), 1.33 (t, J=7.2, 3H); 13C NMR (DMSO-d6) δ166.82, 165.02, 138.86, 133.95, 130.62, 123.93, 121.11, 118.23, 61.30, 30.40, 13.99; MS (EI, m/z) 287 (M+).
Reaction SMILES: [C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([OH:18])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4].[CH3:20][O:21][CH2:22][CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:1](=[O:19])([O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])=[C:10]([O:18][CH2:23][CH2:22][O:21][CH3:20])[CH:9]=1)[O:2][C:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: COCCO
Reactant: CC(C)(C)OC(=O)Oc1ccc(C(C)(C)C)c(O)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCCOc1cc(OC(=O)OC(C)(C)C)ccc1C(C)(C)C
Temperature: 50 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a tetrahydrofuran (THF) (3 ml) solution of tert-butyl 4-tert-butyl-3-hydroxyphenyl carbonate (J. Org. Chem. 2001, 66, 3435) (266 mg, 1.0 mmol), 2-methoxy-ethanol (83 μL, 1.1 mmol) and triphenylphosphine (275 mg, 1.1 mmol) were added diethyl azodicarboxylate (DEAD) (165 μl, 1.1 mmol) and the mixture was stirred for 3 hours at 50° C. The solvent was removed under reduced pressure to give a residue, which was applied to a silica gel chromatography column and eluted with ethyl acetate/hexane=1/19 to furnish 0.23 g (71% yield) of the title compound as a yellow oil.