Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][N:13]([C:16]2[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:26])[CH:17]=2)[C:12]1=[O:27])(C(C)(C)C)(C)C>C(O)(=O)C>[OH:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][N:13]([C:16]2[S:20][C:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:18]([CH3:26])[CH:17]=2)[C:12]1=[O:27]
Reactant: CCOC(=O)c1sc(N2CCN(CCO[Si](C)(C)C(C)(C)C)C2=O)cc1C
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(N2CCN(CCO)C2=O)cc1C
Temperature: 25 °C
Yield: 78 %

Procedure:
Ethyl 5-(3-(2-(tert-butyldimethylsilyloxy)ethyl)-2-oxoimidazolidin-1-yl)-3-methylthiophene-2-carboxylate (1.09 g 2.63 mmol) in acetic acid (10 mL) was stirred at 40° C. for 64 h. The reaction mixture was allowed to cool to ambient temperature and concentrated in vacuo. The residue was purified by column chromatography eluted with ethyl acetate and then with 5% methanol in dichloromethane to afford the title compound as a colorless solid in 78% yield (0.62 g): 1H NMR (300 MHz, CDCl3) δ 6.15 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.89-3.82 (m, 4H), 3.74-3.67 (m, 2H), 3.49-3.44 (m, 2H), 2.49 (s, 3H), 2.34 (t, J=5.3 Hz, 1H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 299.2 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([O:9][CH3:14])=[O:8])=[O:4]
Reactant: NCC(=O)NCC(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)CNC(=O)CN
Reaction time: 8 h

Procedure:
2.5 g (19 mmoles) of Gly-Gly-OH was suspended in 25 mL of dry methanol. Two equivalents of thionyl chloride were added, and the suspension stirred to dissolution. The mixture was allowed to sit at room temperature overnight. The solvent was removed under vacuum, the residue taken up in a minimum of methanol, and anhydrous ether added to effect crystallization. Yield 3.2 g (92%). M.P. 146°-146° C. 1H-NMR (DMSO) 3.6 (s, 3H OMe), 3.8 and 3.9 (d, 2H, Gly α-H's).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:19]2[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:5]=[C:6]([F:18])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1.C1C=C([O:36]O)C(C(O)=O)=C(C(O)=O)C=1>CO>[F:18][C:6]1[CH:5]=[C:4]([N:19]2[CH2:23][C@@H:22]([CH2:24][NH+:25]([O-:36])[C:26](=[O:28])[CH3:27])[O:21][C:20]2=[O:29])[CH:3]=[C:2]([F:1])[C:7]=1[N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][OH:16])[CH2:10][CH2:9]1
Reactant: O=C(O)c1cccc(OO)c1C(=O)O
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Solvent: CO
Product: CC(=O)[NH+]([O-])C[C@@H]1CN(c2cc(F)c(N3CCN(C(=O)CO)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
(S)-N-[[3-[3,5-Difluoro-4-[4-(hydroxyacetyl)-1-piperazinyl]-phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide (VIII-A, R1═COCH3, R2═H, X1═X2═F) (0.13 g) is dissolved in 5 mL of methanol. Monoperoxyphthalic acid, magnesium salt hexahydrate (80% pure, 0.2 g) is added and the resulting suspension is stirred at 25° C. for 72 hours. An additional 0.2 g of monoperoxyphthalic acid is added and the reaction is stirred an additional 48 hours. The reaction mixture is filtered and the filtrate is concentrated to afford a light-yellow oil. This material is chromatographed on silica gel using 20% methanol (saturated with ammonia) in chloroform as eluent to afford 55 mg of the N-oxide.
Reaction SMILES: C(O)(C)(C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:40]([CH2:41][OH:42])=[C:39]([CH:43]([CH3:45])[CH3:44])[CH:38]=[C:37]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:36]=2)=[CH:31][CH:30]=1>CC#N.C(Cl)Cl.CCOCC>[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:40]([CH:41]=[O:42])=[C:39]([CH:43]([CH3:45])[CH3:44])[CH:38]=[C:37]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[N:36]=2)=[CH:31][CH:30]=1
Reactant: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CC#N
Solvent: CC(C)(C)O
Solvent: CCOCC
Product: CC(C)c1cc(-c2ccccc2)nc(-c2ccc(F)cc2)c1C=O
Reaction time: 0.25 h
Yield: 92 %

Procedure:
t-Butanol (175 mg, 2.35 mmol) was added to a stirring solution of Dess-Martin periodinane (1.005 gm, 2.37 mmol) in dry CH3CN (15 ml). After 15 minutes, a solution of 2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinemethanol (582 mg, 1.81 mmol) in CH3CN (9 ml) and CH2Cl2 (3 ml) was added to the mixture and stirring was continued for 40 minutes. The mixture was diluted with Et2O and quenched with 1N NaOH (25 ml). After 25 minutes of rapid mixing, the biphasic mixture was separated and the aqueous layer was extracted with Et2O. The combined organic layers were washed in succession with 1N NaOH, H2O, and brine, then dried (Na2SO4), filtered and stripped to yield a solid residue. The residue was chromatographed (Merck SiO2, 30% hexane in CH2 Cl2) to give 2-(4-fluorophenyl)-4-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde as a white solid (532 mg, 92%). An analytical sample was obtained by recrystallization from a minimum amount of hot hexane.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH2:14][C:13]([CH2:15][C:16]#[N:17])=[C:12]([CH2:18][Br:19])[CH2:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([S:7]([N:10]2[CH2:11][C:12]([CH2:18][Br:19])=[C:13]([CH2:15][CH2:16][NH2:17])[CH2:14]2)(=[O:9])=[O:8])=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CC#N)C2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)N2CC(CBr)=C(CCN)C2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 49.4 %

Procedure:
4 g of N-(p-toluenesulfonyl)-3-(bromomethyl)-4-(cyanomethyl)-3-pyrroline, prepared in Preparation 6, was dissolved in 100 ml of ethyl ether. The solution was slowly added to the suspension of 1 g of lithium aluminum hydride (LAH) in 20 ml of ethyl ether, and heated with refluxing for 3 hours. The reaction mixture was cooled by ice water. After adding 3 ml of water, it was stirred for 30 minutes and filtered off. The filtrate was concentrated. 2 g of the title compound was obtained (yield 49%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[N:4]([CH3:14])[C:3]=1[C:15]([O:17]C)=O.[NH2:19][C:20]1[C:21](=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:12])(=[O:13])[N:4]([CH3:14])[C:3]=1[C:15]([NH:19][C:20]1[C:21](=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:17]
Reactant: COC(=O)C1=C(O)c2ccccc2S(=O)(=O)N1C
Reactant: Nc1cccccc1=O
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2cccccc2=O)=C(O)c2ccccc2S1(=O)=O
Reaction time: 15 h
Yield: 17 %

Procedure:
A solution of methyl 4-hydroxy-2-methyl-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (3.0 g) and 2-amino-2,4,6-cycloheptatrien-1-one (1.6 g) in xylene (100 ml) is refluxed for 8 hours. The reaction mixture is then allowed to stand at room temperature for 15 hours. The crystals that have separated out are collected by filtration, washed with toluene and recrystallized from dimethylformamide to give 4-hydroxy-2-methyl-N-(1-oxo-2,4,6-cycloheptatrien-2-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide (0.68 g), m.p. 259°-261° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:19]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:21]=1)[CH2:6][NH:7][C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9].[CH3:28]N(C)C=O.CI.O>[Cl-].[Na+].O.C(Cl)Cl>[F:25][C:22]([F:24])([F:23])[C:20]1[CH:19]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:21]=1)[CH2:6][N:7]([CH3:28])[C:8]([C:10]1[C:15]([Br:16])=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9]
Reactant: CSc1ncc(Br)c(C(=O)NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: ClCCl
Product: CSc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
To a solution of 4.40 g (9.28 mmol) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid 3,5-bis-trifluoromethyl-benzylamide in 50 ml N,N-dimethylformamide 0.48 g (12.06 mmol) sodiumhydride (60% dispersion in mineral oil) was added and the reaction mixture stirred for 1 hr. After the addition of 0.92 ml (14.85 mmol) methyl iodide at 0°, the reaction mixture was stirred for 3 hrs. at RT. The reaction mixture was distributed between 100 ml H2O, 100 ml brine and 100 ml CH2Cl2. The phases were separated, the aqueous layer washed twice with 100 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) to give 3.50 g (77%) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][C@H:8]([CH2:12][CH:13]=[CH2:14])[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.O[CH2:21][C@H:22]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH2:12]([C@@H:8]([CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:15])[C:9]([O:11][CH2:21][C@H:22]([NH:29][C:30](=[O:35])[CH2:31][CH2:32][CH:33]=[CH2:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:10])[CH:13]=[CH2:14]
Reactant: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)O
Reactant: C=CCCC(=O)N[C@@H](CO)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C=CCCC(=O)N[C@@H](COC(=O)[C@@H](CC=C)CC(=O)OC(C)(C)C)c1ccccc1
Reaction time: 16 h

Procedure:
To a solution of (S)-2-(2-tert-butoxy-2-oxoethyl)pent-4-enoic acid (684 mg, 3.19 mmol) in DMF (25 mL) cooled in an ice/water bath was added EDC (612 mg, 3.19 mmol) and the resulting solution was stirred for 30 min. (R)-N-(2-hydroxy-1-phenylethyl)pent-4-enamide (700 mg, 3.19 mmol), iPr2NEt (1.77 mL, 9.58 mmol), and DMAP (39.0 mg, 0.319 mmol) were subsequently added and the reaction mixture was stirred 16 h at which point LC-MS analysis indicated the presence of both starting material and desired product. The reaction mixture was diluted with saturated NH4Cl and EtOAc and the layers separated. The aqueous layer was extracted 2× with EtOAc and the combined organic extracts were washed with 1 N HCl and brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified using silica gel chromatography (MeOH/CH2Cl2 gradient) to yield 340 mg of product as a colorless oil in 26% yield. LRMS (M+Na)+: 438.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][C:14]1[C:15]2[CH:22]=[C:21]([N+:23]([O-])=O)[CH:20]=[CH:19][C:16]=2[S:17][CH:18]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-].[Na+]>C(O)C>[NH2:23][C:21]1[CH:20]=[CH:19][C:16]2[S:17][CH:18]=[C:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:15]=2[CH:22]=1
Reactant: COC(=O)c1ccc(Cc2csc3ccc([N+](=O)[O-])cc23)c(OC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1ccc(Cc2csc3ccc(N)cc23)c(OC)c1
Yield: 54.6 %

Procedure:
Stannous chloride dihydrate (0.38 g.) was added to a stirred solution of (I) (0.12 g.) in ethanol (5 ml.), under an atmosphere of nitrogen. The mixture was heated under reflux for 2 hours. The cooled mixture was basified with saturated aqueous sodium bicarbonate (15 ml.) and extracted with ethyl acetate (2×25 ml.). The extracts were dried (MgSO4) and evaporated. The residual oil was purified by flash chromatography on silica gel (50 ml.), eluting with 3:7 v/v ethyl acetate:hexane to give methyl 4-(5-aminobenzo[b]thien-3-ylmethyl)-3-methoxybenzoate (H) (0.06 g., 54%) as an oil; NMR (80 MHz, DMSO-d6): 3.84 (s, 3H, OCH3), 3.91 (s,3H, OCH3), 4.03(s,2H, CH2 --Ar), 5.0(br s,2H, NH2), 6.80(m,2H), 7.14(m,2H), 7.52(m,3H).
Reaction SMILES: [CH:1]([C:3]1[NH:7][C:6]([CH3:8])=[C:5]([C:9]([OH:11])=O)[C:4]=1[CH3:12])=[O:2].[CH2:13]([N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:16][CH3:17])[CH3:14]>>[CH2:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH2:19][CH2:20][NH:21][C:9]([C:5]1[C:4]([CH3:12])=[C:3]([CH:1]=[O:2])[NH:7][C:6]=1[CH3:8])=[O:11])[CH3:14]
Reactant: CCN(CC)CCCN
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)O
Product: CCN(CC)CCCNC(=O)c1c(C)[nH]c(C=O)c1C
Yield: 63.8 %

Procedure:
5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3.0 g, 17.9 mmol) reacted with diethylamino propylamine (2.57 g, 19.7 mmol) to give 3.19 g (64%) of 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-diethylamino-propyl)-amide.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>O1CCCC1>[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])=[CH:28][CH:27]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-fluorophenyl isocyanate (0.139 ml, 1.22 mmol), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 265 mg (85.2%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([SH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([O:11][C:12](=[O:19])[CH:13]=[C:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[CH3:10]>N1CCCCC1>[CH2:9]([O:11][C:12](=[O:19])[CH2:13][C:14]([S:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:18])[CH2:15][CH2:16][CH3:17])[CH3:10]
Reactant: SCc1ccccc1
Reactant: CCCC(C)=CC(=O)OCC
Solvent: C1CCNCC1
Product: CCCC(C)(CC(=O)OCC)SCc1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 62.1 g (0.5 mol) of benzyl mercaptan and 78.1 g (0.5 mol) of (rac)-3-methyl-2-hexenoic acid ethyl ester of step (a) in 100 ml of piperidine was heated at reflux until complete reaction was observed (48 h), and cooled to room temperature. Then the excess of piperidine was distilled off at reduced pressure (0.04 mbar, 26-33° C.). The residue, 96.5 g (68%) of (rac)-3-benzylsulfanyl-3-methyl-hexanoic acid ethyl ester, was of good purity and was directly used in the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([CH:10]([CH3:12])[CH3:11])[C:3]=1[OH:13].O[C:15]1C=C(C(C)C)C=C(O)C=1C.C1(C)CC(=O)C(C(C)C)C(=O)C1.C(OC(OCC)OCC)C.OS(O)(=O)=O>CCO.[Cl-].[Ti+4].[Cl-].[Cl-].[Cl-]>[CH:10]([C:4]1[C:3]2[O:13][CH:15]=[N:1][C:2]=2[C:7]([CH3:8])=[CH:6][C:5]=1[OH:9])([CH3:11])[CH3:12]
Reactant: Cc1cc(O)c(C(C)C)c(O)c1N
Reactant: Cc1c(O)cc(C(C)C)cc1O
Agent: [Ti+4]
Agent: CC1CC(=O)C(C(C)C)C(=O)C1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOC(OCC)OCC
Product: Cc1cc(O)c(C(C)C)c2ocnc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a flask charged with 4-amino-2-isopropyl-5-methyl-benzene-1,3-diol (450 mg, 2.5 mmol) (Treibs and Albrecht, “The dihydroxycymenes. IV. Isocymorcin (3,5-dihydroxycymene) from 3,5-menthanedione by dehydrogenation and total synthesis,” Journal fuer Praktische Chemie (1961), 13, 291-305), purged with argon, and cooled to 0° C. was sequentially added triethylorthoformate (0.7 mL, 4.2 mmol), EtOH (4 mL), and a 10% v/v solution of H2SO4 in EtOH (40 μL). The reaction was allowed to warm to room temperature slowly, stirred overnight, quenched with saturated NaHCO3, and concentrated. The residue was partitioned between water and methylene chloride. The combined organic phases were dried with Na2SO4 and concentrated to provide 510 mg of 7-isopropyl-4-methyl-benzooxazol-6-ol.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[CH:12]=1.[CH3:14][O:15]C=O>C1COCC1>[Br:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([Br:13])[C:12]=1[CH:14]=[O:15]
Reactant: Brc1cncc(Br)c1
Reactant: COC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1c(Br)cncc1Br
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of diusopropylamine (6.6 mL, 46.43 mmol) in THF (40 mL) at 0° C. was treated with n-butyllithium in hexanes (2.50 M solution, 18.6 mL, 46.43 mmol) over 15 minutes, stirred at 0° C. for 30 minutes, diluted with THF (200 mL), cooled to −78° C., treated with 3,5-dibromopyridine (10 g, 42.21 mmol) in THF (110 mL) over 95 minutes, stirred at −78° C. for 30 minutes, treated dropwise with methylformate (5.2 mL, 84.42 nunol), stirred at −78° C. for 2 hours, transferred to ice-cold saturated NaHCO3 solution, stirred for 15 minutes, and extracted with diethyl ether. The extract was washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel with 10% acetone/hexane to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:3]=12.C1(O)C=CC=CC=1.[CH3:24][N:25]([CH2:27][CH2:28][NH2:29])[CH3:26]>CCOCC>[CH3:24][N:25]([CH3:26])[CH2:27][CH2:28][NH:29][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[C:12]([CH3:16])([CH3:15])[O:13][CH2:14][C:3]=12
Reactant: CN(C)CCN
Reactant: CC1(C)OCc2c1nc1ccccc1c2Cl
Solvent: CCOCC
Solvent: Oc1ccccc1
Product: CN(C)CCNc1c2c(nc3ccccc13)C(C)(C)OC2

Procedure:
A mixture of the starting material of formula I, 9-chloro-1,3-dihydro-3,3-dimethylfuro[3,4-b]quinoline (8.0 g, described in Example 31), phenol (15g) and the amine of formula H--Y--X, dimethylaminoethylamine (9.8 g), is heated at 150° C. for 18 hours under an atmosphere of nitrogen. Ether is added and the reaction is washed with 10% sodium hydroxide solution. The organic phase is extracted with 6 N hydrochloric acid and the aqueous phase is washed with ether. The aqueous phase is basified with 10% sodium hydroxide and extracted with ether. The organic extract is washed with water, dried, evaporated and crystallized from ethyl acetate to yield the title compound, mp 126°-127° C. The corresponding hydrochloride salt of the title compound is crystallized from ethanol, mp 182°-190° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[CH:7]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH2:14][C:15]2[CH:23]=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)[S:32]([C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)(=[O:34])=[O:33])[CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc3c(c2)OCO3)c1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2ccc3c(c2)OCO3)S(=O)(=O)c2ccc(F)cc2)c1

Procedure:
The title compound of Step A was prepared following the method described in Step A of Examples 1 from 3-(3-{[(benzo[1,3]dioxol-5-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester, prepared in Step A of Example 15a, and 4-fluorobenzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.82 (m, 2H), 7.17 (m, 3H), 7.05 (d, 1H), 6.89 (d, 1H), 6.83 (s, 1H), 6.64 (d, 1H), 6.56 (s, 1H), 6.48 (m, 1H), 5.91 (s, 2H), 4.27 (s, 2H), 4.19 (s, 2H), 3.67 (s, 3H), 2.83 (t, 2H), 2.52 (t, 2H).
Reaction SMILES: C([O:3][C:4](=[O:36])[CH:5]([O:33][CH2:34][CH3:35])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:34]([O:33][CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)(=[O:24])=[O:25])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[C:4]([OH:36])=[O:3])[CH3:35]
Reactant: CCOC(=O)C(Cc1ccc(OCCc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)cc1)OCC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(Cc1ccc(OCCc2ccc(OS(=O)(=O)Cc3ccccc3)cc2)cc1)C(=O)O
Temperature: 25 °C
Yield: 92.6 %

Procedure:
2-Ethoxy-3-{4-[2-(4-phenylmethanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 30) (0.21 g; 0.41 mmol) was dissolved in tetrahydrofuran (4 ml) and lithium hydroxide (0.021 g; 0.48 mmol) dissolved in water (1 ml) was added dropwise. The resulting solution was stirred at room temperature over night and then acidified with hydrochloric acid (2M). Extraction with ethyl acetate, drying with magnesium sulfate and evaporation gave 0.184 g (92%) of 2-ethoxy-3-{4-[2-(4-phenylmethanesulfonyloxy-phenyl)ethoxy]phenyl}propanoic acid as an oil.
Reaction SMILES: [OH:1][C@:2]1([CH2:30][OH:31])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[C:32]1([N:38]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>N1C=CC=CC=1>[OH:1][C@:2]1([CH2:30][O:31][C:39](=[O:40])[N:38]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:12][Si:13]([C:26]([CH3:27])([CH3:28])[CH3:29])([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(CO)C2)(c1ccccc1)c1ccccc1
Solvent: c1ccncc1
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@](O)(COC(=O)N(c1ccccc1)c1ccccc1)C2)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 12 h
Yield: 64 %

Procedure:
A mixture of (2R)-2-hydroxy-2-hydroxymethyl-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.4 g) and N,N-diphenylcarbamoyl chloride (3 g) in pyridine (15 ml) was stirred at 100° C. for 12 hours, cooled to room temperature, and partitioned between ethyl acetate and 1N--HCl. The organic layer was washed with water, sat. NaHCO3, and brine. The dried solvent was evaporated in vacuo and the residue was purified by chromatography on silica gel to give (2R)-2-hydroxy-2-(N,N-diphenylcarbamoyloxymethyl)-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.3 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)(Cl)=O>C(#N)C>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CN1CCC(C(=O)NCc2nccnc2Cl)CC1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CN1CCC(c2ncc3c(Cl)nccn23)CC1
Temperature: 80 °C
Yield: 91.9 %

Procedure:
To a solution of N-((3-chloropyrazin-2-yl)methyl)-1-methylpiperidine-4-carboxamide (6.51 mmol, 1.75 g) in acetonitrile (10 ml) was added phosphorus oxychloride (65.1 mmol, 6.36 ml) and this solution was heated at 80° C. for four hours. The reaction mixture was concentrated in vacuo and coevaporated with toluene. The residue was cooled in an ice bath and quenched with 7N ammonia in methanol (50 ml) and dichloromethane (50 ml). The solids were removed by filtration and the filtrate was concentrated. To the residue dichloromethane (50 ml) and of 7N ammonia in methanol (1 ml) was added. After 10 minutes at room temperature the solids were removed by filtration and the filtrate was concentrated. To the residue dichloromethane (50 ml) was added. After 10 minutes at room temperature the solids were removed by filtration and the filtrate was concentrated to give 8-chloro-3-(1-methylpiperidin-4-yl)imidazo[1,5-a]pyrazine (1.5 g).