Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][NH:26][C:27]([C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1)=[O:28]>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:33]4[CH:34]=[C:29]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH:26][CH3:25])=[O:28])[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: CNC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)c1
Temperature: 120 °C
Yield: 4.2 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL CEM test tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 3-(methylcarbamoyl)phenylboronic acid (18.6 mg, 0.104 mmol). The mixture was heated in a microwave reactor at 120° C. for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC and preparative HPLC to give pure 3-(2′-amino-1′-methyl-5′-oxo-2-phenyl-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)-N-methylbenzamide (0.96 mg, 4%). 1H-NMR (CDCl3): 2.36 (d, 1H), 2.57 (t, 1H), 2.73 (s, 3H), 2.97 (s, 3H), 5.87 (d, 1H), 7.11 (m, 2H), 7.45 (m, 8H), 7.51 (m, 1H), 7.60 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.CO[C:12](=N)[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=1.O.Cl>CO>[CH3:24][O:23][C:17]1[CH:16]=[C:15](/[CH:14]=[CH:13]/[C:12]2[NH:8][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[N:7]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH3:22]
Reactant: Nc1ccccc1N
Reactant: COC(=N)C=Cc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(/C=C/c2nc3ccccc3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of 1,2-phenylenediamine (0.63 g; 5.8 mmol) and methyl-(3,4-dimethoxy)-cinnamoimidate hydrochloride (1.5 g; 5.8 mmol) in methanol (35 mL) was stirred at ambient temperature for 18 hours. The methanol solution was concentrated to dryness. The residue was recrystallized from MeOH-Diethyl Ether to obtain 1.3 g (67% yield) of the title compound as a mono-hydrochloride, hydrate, yellow solid, m.p. 248° C. dec. Anal. Calcd. for C17H16N2O2 HCl H2O: C, 60.98, H, 5.12; N, 8.37. Found: C, 60.78; H, 5.12; N, 8.45. Mass Spectrum: (EI; M+) m/z 280..1H-NMR (DMSO-d6; 400 MHz) δ15.2 (broad s, 1H), 8.18-8.2 (d, 1H), 7.76-7.8 (m, 2H), 7.45-7.54 (m, 2H), 7.32 (d 1H), 7.2-7.3 (m, 3H), 7.08-7.12 (d, 1H), 3.83 (s, 3H), 3.86 ppm (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH2:6])=[C:4]([OH:10])[CH:3]=1.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13].O>C(Cl)Cl>[CH3:1][C:2]1[C:8]([CH3:9])=[CH:7][C:5]([NH:6][C:12](=[O:13])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([OH:10])[CH:3]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(N)c(O)cc1C
Solvent: ClCCl
Solvent: O
Product: Cc1cc(O)c(NC(=O)Oc2ccccc2)cc1C
Reaction time: 2 h
Yield: 92 %

Procedure:
To 4,5-dimethyl-2-hydroxyaniline(6.80 g, 0.05 mole), methylene chloride(100 ml) was added and then phenyl chloroformate(8.0 g, 0.05 mole) was added slowly. After stirring for 2 hours, addition of water(150 ml), extraction with methylene chloride and column chromatography gave the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([NH2:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OCC)(=[O:18])C.C=O.[OH-].[K+]>CCCCCC>[OH:18][CH2:16][NH:14][C:12](=[O:13])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: CCOC(C)=O
Reactant: NC(=O)CCC(=O)OCc1ccccc1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCCCCC
Product: O=C(CCC(=O)OCc1ccccc1)NCO
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To astirred solution of 20.7 g. (0.10 mole) of benzylsuccinamate in 150 ml. ethyl acetate at 25°C. is added 3.0 g. of paraformaldehyde and 1 ml. of a 20% (by weight) solution of ethanolic potassium hydroxide. After stirring at 25°C. for 20 hours, hexane is added to the cloudpoint and the mixture is cooled at 5°C. for 24 hours. Solvents are decanted off and the residue is washed with 25 ml. hexane to give benzyl N-hydroxymethylsuccinamate.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[C:14]([N+:16]([O-])=O)[CH:13]=[C:12]([CH3:19])[C:3]=1[O:4][CH2:5][CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:16][C:14]1[CH:13]=[C:12]([CH3:19])[C:3]([O:4][CH2:5][CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:2]([CH3:1])[CH:15]=1
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1OCCN1CCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cc(N)cc(C)c1OCCN1CCCC1

Procedure:
A solution of 2-chloro-9-methoxybenzo[h]-5,6-dihydroquinazoline (50 mg, 0.20 mmol) and 1-[2-(4-amino-2,6-dimethylphenoxy)ethyl]pyrrolidine (47 mg, 0.20 mmol) in ethoxyethanol (2 ml) was treated with hydrogen chloride (0.2 ml of 1.0M HCl in diethyl ether, 0.20 mmol). The resulting mixture was heated at reflux for 6 h, then allowed to cool to room temperature. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate, the organic phase dried (MgSO4) and evaporated. The residue was subjected to column chromatography (3-6% methanol-dichloromethane) to afford the title compound as an off-white solid (37 mg) m.p. 123-126°. δH(d6DMSO) 9.28 (1H, s), 8.36 (1H, s), 7.76 (1H, d, J 2.8 Hz), 7.51 (2H, s), 7.26 (1H, d, J 8.3 Hz), 7.01 (1H, dd, J 8.3, 2.8 Hz), 3.85 (3H, s), 3.82 (2H, m), 3.31-2.60 (1H, m), 2.23 (6H, s) and 1.73 (4H, m). 1-[2-(4-amino-2,6-dimethylphenoxy)ethyl]pyrrolidine was prepared by treating a degassed stirring solution of 1-[2-(2,6-dimethyl-4-nitrophenoxy)ethyl]pyrrolidine (824 mg, 3.12 mmol) in ethanol (8 ml) with ammonium formate (590 mg, 9.36 mmol) and 10% palladium on charcoal (100 mg) for 8 h. The mixture was filtered through Celite® and evaporated. The residue was subjected to column chromatography (2-6% methanoldichloromethane) to afford the desired product (489 mg) as a pale yellow oil. 8H (CDCl3) 6.33 (2H, s), 3.84 (2H, t, J 6.3 Hz), 3.38 (2H, br s), 2.90 (2H, t, J 6.3 Hz), 2.65 (4H, m), 2.20 (6H, s) and 1.83 (4H, m). MS (ES+) 235 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:14])=[O:13])[CH:10]=1)[N:7]([CH2:20][O:21][CH3:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2.[H-].[Na+].[CH3:30]N(C)C=O.CI>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N:11]([CH3:30])[S:12]([C:15]3[S:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:14])[CH:10]=1)[N:7]([CH2:20][O:21][CH3:22])[C:6]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:5]2
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cc2cc(F)cc(NS(=O)(=O)c3cccs3)c2n1COC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2cc(F)cc(N(C)S(=O)(=O)c3cccs3)c2n1COC
Temperature: 4 °C
Reaction time: 0.5 h
Yield: 43 %

Procedure:
A mixture of ethyl 5-fluoro-1-(methoxymethyl)-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.45 g), 60% sodium hydride (52 mg) and N,N-dimethylformamide (10 mL) was stirred at 4° C. for 30 min. Methyl iodide (0.095 mL) was added to the solution, and the mixture was stirred at room temperature for 2 days. The reaction solution was diluted with ethyl acetate, washed with aqueous citric acid solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:9-2:8) to give the title compound (0.20 g, yield 43%) as colorless prism crystals.
Reaction SMILES: CO[C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4].COC(C1ON=C(OC[C:35]2[C:36]([C:41]3C=CC=CN=3)=[N:37]OC=2C)C=1)=O.C(N)(C)C>>[CH:36]([NH:37][C:3]([C:5]1[S:9][N:8]=[C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:6]=1)=[O:4])([CH3:41])[CH3:35]
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)ns1
Reactant: COC(=O)c1cc(OCc2c(-c3ccccn3)noc2C)no1
Solvent: CC(C)N
Product: Cc1onc(-c2ccccc2)c1COc1cc(C(=O)NC(C)C)sn1
Yield: 68 %

Procedure:
As described for example 14e, 3-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-isothiazole-5-carboxylic acid methyl ester (100 mg, 0.3 mmol), instead of 3-(5-methyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-isoxazole-5-carboxylic acid methyl ester, was converted, using isopropyl amine (21 mg, 0.36 mmol), to the title compound (74 mg, 68%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol=1:0 to 9:1). MS: m/e=358.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]#[N:17])=[C:12]2[C:7]([C:8](=[O:18])[CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].Cl>C1COCC1>[CH2:1]([N:5]1[C:14](=[O:15])[C:13]([C:16]#[N:17])=[C:12]2[C:7]([CH:8]([OH:18])[CH2:9][CH2:10][CH2:11]2)=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc2c(c(C#N)c1=O)CCCC2=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCn1cc2c(c(C#N)c1=O)CCCC2O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
2-Butyl-3,8-dioxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-011) (10 mg, 0.04 mmol) was dissolved in THF (1 mL), and to the reaction mixture was added sodium borohydride (2.1 mg, 0.056 mmol), and the reaction mixture was stirred at room temperature for 10 min. To the reaction mixture was added diluted hydrochloric acid (1 mol/L, 3 mL), and the reaction mixture was extracted with ethyl acetate (10 mL), washed with brine (5 mL), dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. The obtained crystalloid residue was recrystallized from methylene chloride to give 2-butyl-8-hydroxy-3-oxo-2,3,5,6,7,8-hexahydroisoquinoline-4-carbonitrile (7-013) (7.4 mg, 75%) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11](OS(C(F)(F)F)(=O)=O)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1.[CH3:24][C:25]1([CH3:39])[C:29]([CH3:31])([CH3:30])[O:28][B:27]([C:32]2[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][CH:33]=2)[O:26]1.CS(C)=O>O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:12]=[C:11]([NH:36][C:35]3[CH:34]=[CH:33][C:32]([B:27]4[O:28][C:29]([CH3:31])([CH3:30])[C:25]([CH3:39])([CH3:24])[O:26]4)=[CH:38][CH:37]=3)[C:10]([CH2:21][CH3:22])=[C:9]([CH3:23])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1OS(=O)(=O)C(F)(F)F
Solvent: O
Solvent: CS(C)=O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 23 %

Procedure:
A 18-mL vial was charged with [2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (39 mg, 0.1 mmole) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22 mg, 0.1 mmol) and DMSO (0.5 ml). The resulting mixture was stirred under Ar for 3.5 hr. After cooling to room temperature, water was added to the mixture (5 ml). The precipitate was collected by filtration and the crude product was purified by chromatography on silica gel using hexane/DCM (4:1) followed by 2% of methanol in DCM as eluent to afford the title compound, containing impurities, which was forward to the next step without any further purification (10.3 mg, 23% yield).
Reaction SMILES: [F:1][CH:2]1[CH2:7][N:6]([C:8]([C:10]2[N:11]=[C:12]([CH3:21])[S:13][C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:9])[CH:5]([CH2:22][NH:23]C(=O)OC(C)(C)C)[CH2:4][CH2:3]1>C(Cl)Cl>[NH2:23][CH2:22][CH:5]1[CH2:4][CH2:3][CH:2]([F:1])[CH2:7][N:6]1[C:8]([C:10]1[N:11]=[C:12]([CH3:21])[S:13][C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:9]
Reactant: Cc1nc(C(=O)N2CC(F)CCC2CNC(=O)OC(C)(C)C)c(-c2ccccc2)s1
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CC(F)CCC2CN)c(-c2ccccc2)s1
Yield: 42 %

Procedure:
The above described tert-butyl (5-fluoro-1-(2-methyl-5-phenylthiazole-4-carbonyl)piperidin-2-yl)methylcarbamate was stirred in CH2Cl2 (5 mL) and TFA (5 mL) overnight and concentrated in vacuo. The resulting residue was taken in EtOAc and washed with saturated NaHCO3. EtOAc layer was separated, dried with MgSO4 and concentrated in vacuo to afford desired (2-(aminomethyl)-5-fluoropiperidin-1-yl)(2-methyl-5-phenylthiazol-4-yl)methanone in 42% yield over two steps.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@@H:9]([CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O)[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2].[CH3:38][NH2:39]>CCO>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C@@H:9]([CH2:25][NH:39][CH3:38])[CH2:10][C@H:11]1[CH2:15][O:14][C:13]([CH3:17])([CH3:16])[N:12]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](CCC(=O)OC(C)(C)C)C[C@H]2COC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reactant: CN
Solvent: CCO
Product: CNC[C@H](CCC(=O)OC(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 70 °C
Yield: 95 %

Procedure:
(S)-tert-butyl 4-((R)-5-tert-butoxy-5-oxo-2-(tosyloxymethyl)pentyl)-2,2-dimethyloxazolidine-3-carboxylate (300 mg, 0.55 mmol) was dissolved in 30% MeNH2 in EtOH (60 mL), the solution was heated to 70° C. for 2 h in a pressure sealed vessel. After cooling to rt, the solvent was removed under reduced pressure to give (S)-tert-butyl 4-((R)-5-tert-butoxy-2-((methylamino)methyl)-5-oxopentyl)-2,2-dimethyloxazolidine-3-carboxylate (212 mg, 95%). MS ESI +ve m/z 401 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1.B(Cl)([C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1)[C@H]1[C@H](C)[C@@H]2C(C)(C)[C@@H](C2)C1.[Cl-].[Na+]>C1(C)C=CC=CC=1.CCCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([OH:26])[CH2:9][CH2:10][CH2:11][C:12]([N:14]2[CH:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:17][O:16][C:15]2=[O:25])=[O:13])=[CH:4][CH:3]=1
Reactant: O=C(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccc(F)cc1
Agent: C[C@@H]1[C@H]2C[C@@H](C[C@H]1B(Cl)[C@@H]1C[C@@H]3C[C@H]([C@H]1C)C3(C)C)C2(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: O=C(CCC[C@H](O)c1ccc(F)cc1)N1C(=O)OCC1c1ccccc1
Reaction time: 15 h
Yield: 96 %

Procedure:
3-[5-(4-fluorophenyl)-1,5-dioxopentyl]-4-phenyl-2-oxazolidinone (100 gm) is dissolved in toluene (750 ml), the mixture of (−)-β-chlorodiisopinocampheylborane ((−)-DIP chloride) in heptane (545 ml, 1.5M) and toluene (750 ml) is added at 0° C. to 5° C. for 1 hour. The reaction mixture is stirred for 15 hours at 25° C. to 30° C. and 340 ml of 10% sodium chloride is then added at the same temperature. The layers are separated and the organic layer is washed with 5% sodium bicarbonate (300 ml), 1N sulfuric acid (300 ml), and 10% sodium chloride (300 ml). Then the organic layer is dried on sodium sulfate to give 3-[(5S)-5-(4-fluorophenyl)-5-hydroxy-1-oxopentyl]-4-phenyl-2-oxazolidinone in 96% yield.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH:10]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:11][CH:10]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(NCc3ccccc3)C(C)C2)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CC(CNc2ccccc2)CCC1NCc1ccccc1

Procedure:
A mixture comprising toluene-4-sulfonic acid 4-benzylamino-3-methyl-cyclohexylmethyl ester (350 mg, 0.90 mmol), aniline (126, mg, 1.35 mmol) and potassium carbonate (250 mg, 1.80 mmol) in MeCN (1 mL) is heated using microwave radiation at 180° C. for 1 hour. The reaction mixture is partitioned between DCM and water and passed through a phase separator. The solvent is removed in vacuo and purification of the crude residue by chromatography on silica eluting with iso-hexane: EtOAc (25:1 increasing to 10:1) affords the title compound. [MH+ 309.34].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[C:20]([CH3:27])[C:21]([C:24](O)=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[CH3:36][NH:37][CH3:38]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]4[CH:19]=[C:20]([CH3:27])[C:21]([C:24]([N:37]([CH3:38])[CH3:36])=[O:25])=[N:22][CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: Cc1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cnc1C(=O)O
Reactant: CNC
Agent: Cl
Product: Cc1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)CC3)cnc1C(=O)N(C)C

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 18 starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinolin-7-yl}-3-methylpyridine-2-carboxylic acid and dimethylamine hydrochloride. LCMS (M+H)+: m/z=487.3.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:32]1([N:38]=[C:39]=[O:40])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:39]([NH:38][CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:40])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: O=C=NC1CCCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: O=C(NC1CCCCC1)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.1 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and cyclohexyl isocyanate (32 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (91 mg, 75%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([O:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[CH:31]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1)([CH3:33])[CH3:32]>>[CH:31]([C:34]1[CH:39]=[CH:38][C:37]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([O:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:13][CH:12]=3)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:21][C:22]=2[CH3:28])=[CH:36][CH:35]=1)([CH3:33])[CH3:32]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Oc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)c1ccc(B(O)O)cc1
Product: Cc1cc(OC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)C)cc1

Procedure:
This compound is made in a manner substantially similar to Example 117 using isomer 1 of 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxy)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-isopropylphenylboronic acid as starting materials in step D. MS (ES): 502.2 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].C([O-])([O-])=O.[K+].[K+].[SH:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]>C(O)C>[O:4]=[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][S:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([OH:23])=[O:22]
Reactant: O=C(O)c1cccc(S)c1
Reactant: O=C(CBr)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(O)c1cccc(SCC(=O)c2ccccc2)c1
Yield: 120.3 %

Procedure:
To bromoacetophenone (250 mg, 1.16 mmole) and anhydrous K2CO3 (694 mg, 5.02 mmole) in ethanol, 193.6 mg (1.25 mmole) 3-mercaptobenzoic acid was added and the mixture refluxed overnight. The solvent was evaporated and water added to the solid residue. The basic aqueous solution was extracted with ethyl acetate to remove unreacted bromoacetophenone. The aqueous layer was acidified and extracted with ethyl acetate, dried, evaporated and the residue purified by flash chromatography using chloroform:methanol 95:5. Evaporation of the fractions resulted in a yellow powder (380 mg). M.S. m/s 271 (M−1)+. 1H NMR (DMSO) δ4.75 (2H, s, —CH2-), 7.39-7.7 (4H, m, 4×ArH), 7.75 (1H, d, ArH, J=5.61 Hz), 7.86 (1H, s, ArH), 8.02 (3H, d, ArH).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[OH:12])=[CH:5][CH:4]=[N:3]1>CCCCCC.C(O)C>[CH3:1][N:2]1[C:6]([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[OH:12])=[CH:5][CH:4]=[N:3]1
Reactant: Cn1nccc1[C@H]1CCC[C@@H]1O
Solvent: CCO
Solvent: CCCCCC
Product: Cn1nccc1[C@@H]1CCC[C@H]1O

Procedure:
The (1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentanol prepared in Example 8a was optically resolved with CHIRALPAK IC (Daicel Corp.; hexane/ethanol=8:2) to yield the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([O:5][C:6]1[CH:10]=[C:9]([CH2:11][S:12][CH3:13])[O:8][N:7]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[CH3:1][N:2]([CH3:14])[C:3]([O:5][C:6]1[CH:10]=[C:9]([CH2:11][S:12]([CH3:13])=[O:23])[O:8][N:7]=1)=[O:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(OC(=O)N(C)C)no1
Solvent: ClCCl
Product: CN(C)C(=O)Oc1cc(CS(C)=O)on1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
A solution of 757 mg of 3-dimethylcarbamoyloxy-5-methylthiomethylisoxazole in 5 ml of methylene chloride was added dropwise over a period of 30 minutes, with stirring, to an ice-cooled solution of 711 mg of m-chloroperbenzoic acid in 15 ml of methylene chloride. The mixture was then stirred for a further 30 minutes, after which it was filtered and the precipitate was washed with 2 ml of methylene chloride. The filtrate and the washings were combined, and then the solvent was removed by distillation, leaving a colourless, crystalline residue, which was recrystallized from diethyl ether, to give 700 mg (yield 86.1%) of 3-dimethylcarbamoyloxy-5-methylsulphinylmethylisoxazole, in the form of colourless needles melting at 84°-85° C.