Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([C:15]([OH:17])=O)[CH2:5]1)(=[O:3])[CH3:2].O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:30][NH:31][CH3:32].C(N=C=NCCCN(C)C)C>O1CCCC1.O.C(OCC)(=O)C>[C:1]([CH:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C@H:6]([C:15](=[O:17])[N:31]([CH3:32])[CH3:30])[CH2:5]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1C(=O)O
Reactant: CNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC(=O)N1CC(C(C)=O)C[C@H]1C(=O)N(C)C
Reaction time: 2 h
Yield: 42.5 %

Procedure:
To a solution of (2S)-4-acetyl-1-allyloxycarbonylpyrrolidine-2-carboxylic acid (23.27 g) in tetrahydrofuran (230 ml) were added in turn 1-hydroxybenzotriazole hydrate (13.7 g), dimethylamine hydrochloride (8.27 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (18.5 ml) at 0° C. After 2 hours, the reaction mixture was poured into a mixture of ethyl acetate and water, the organic layer was separated, washed twice with saturated aqueous layer hydrogen carbonate and brine in turn. The solvent was dried over magnesium sulfate and removed in vacuo. The residue was chromatographed on silica gel (600 ml) eluting with a mixture of dichloromethane and acetone (6:1→4:1) to give (2S)-4-acetyl-1-allyloxycarbonyl-2-dimethylcarbamoylpyrrolidine (11 g).
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].O.[F:6][C:7]([F:20])([F:19])[C:8]1[CH:9]=[C:10]([CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[NH2:11]>C(Cl)(Cl)Cl>[F:6][C:7]([F:19])([F:20])[C:8]1[CH:9]=[C:10]([N:11]=[C:1]=[S:2])[CH:12]=[C:13]([C:15]([F:16])([F:18])[F:17])[CH:14]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cc(N=C=S)cc(C(F)(F)F)c1
Reaction time: 0.25 h

Procedure:
0.052 Mol of thiophosgene were mixed with 60 ml of water and were stirred for 15 minutes. 0.040 Mol of 3,5-bistrifluoromethylaniline were dropped with 30 ml chloroform, and the mixture was stirred for 2 hours at 15° C. The organic solution was washed with HCl 2M, dried and the solvent was removed under vacuum to obtain 3,5-bistrifluoromethylphenylisothiocyanate as a yellow-red oil, that was used as crude product.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([O:24][C:25]([C:27]1[N:28]2[CH:31]([S:32][CH2:33][C:34]=1[CH:35](Cl)[CH:36]=O)[CH:30]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:29]2=[O:47])=[O:26])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCCC1.C(O)C.C(OCC)(=O)C>[NH:7]([C:8]1[S:9][C:35]([C:34]2[CH2:33][S:32][CH:31]3[N:28]([C:29](=[O:47])[CH:30]3[NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:27]=2[C:25]([O:24][CH:11]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:26])=[CH:36][N:10]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=S)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(Cl)C=O)CSC12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(Nc4ccccc4)s3)CSC12

Procedure:
N-Phenylthiourea (3.34 g) is added to a solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-3-(1-chloro-2-oxoethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (a mixture of the epimers of the chloroaldehyde) (10.3 g) in a mixture of tetrahydrofuran (100 cc) and ethanol (40 cc), and the reaction mixture is then heated at the reflux temperature for 135 minutes. It is diluted with ethyl acetate (250 cc) and a half-saturated sodium bicarbonate solution (500 cc). The organic layer is washed with a half-saturated sodium chloride solution (250 cc) and then dried over magnesium sulphate and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue obtained is chromatographed on a column (height: 30 cm; diameter: 7 cm) of silica gel (0.04-0.06 mm), elution being carried out under a pressure of 0.7 bar (70 kPa) with a 70:30 (by volume) mixture of cyclohexane and ethyl acetate. After 1.5 liters of eluate have been collected, 100 cc fractions are collected and fractions 20 and 21 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 30° C. The residue is triturated with isopropyl ether (30 cc). 3-(2-Anilino-thiazol-5-yl)-2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene (2.7 g) is obtained in the form of a yellow solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@@H:5]([CH2:7][OH:8])[NH2:6].Cl[C:11](Cl)([O:13]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[O:13]=[C:11]1[NH:6][C@@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][O:8]1
Reactant: COC(=O)[C@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)[C@H]1COC(=O)N1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a suspension of D-serine methyl ester hydrochloride (25.0 g, 160.7 mmol) in tetrahydrofuran (150 mL), a solution of triphosgene (47.68 g, 160.7 mmol) in tetrahydrofuran (100 mL) was added at 0° C. and the mixture was stirred at 80° C. for 2 hours. The volatiles were evaporated under vacuum and the residue was subjected to flash column silica gel chromatography using 5% methanol in chloroform. Yield: 17.5 g (75%). 1H NMR (400 MHz, DMSO-d6) δ: 3.69 (s, 3H), 4.32-4.33 (m, 1H), 4.32-4.33 (m, 2H), 8.22 (s, 1H).
Reaction SMILES: [C:1]([CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[CH3:6])([OH:3])=O.C(Cl)(=O)C(Cl)=O.[C:24]1([C@@H:30]([CH2:32][OH:33])[NH2:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.Cl>ClCCl.CN(C)C=O>[OH:33][CH2:32][C@@H:30]([NH:31][C:1]([CH2:4][CH:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)[CH3:6])=[O:3])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCOC(=O)c1ccc(C(C)CC(=O)O)cc1
Reactant: N[C@H](CO)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(C(C)CC(=O)N[C@H](CO)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 4-(2-carboxy-1-methylethyl)benzoate (J. I. DeGraw et al. J. Med. Chem. 1986, 29, 1056) (3.54 g, 15 mmol) in dichloromethane (100 mL) cooled in an ice bath was added oxalyl chloride (3.9 mL, 45 mmol). Dimethylformamide (0.1 mL) was added and the mixture stirred at room temperature for 2 hours, then concentrated under reduced pressure. The residual acid chloride was dissolved in dichloromethane (60 mL) and added to an ice-cooled mixture of (S)-2-phenylglycinol (2.72 g, 20 mmol) and triethylamine (6.3 mL, 45 mmol) in dichloromethane (60 mL) over 30 minutes. The reaction mixture was stirred at room temperature for 1 hour. 2N Hydrochloric acid was added, the organic phase was separated, then washed with water, dried (anhydrous magnesium sulfate) and evaporated. The diastereomeric products were separated by flash chromatography with elution by ethyl acetate, then ethyl acetate-methanol (9:1). There were obtained an earlier eluting (SS) diastereomer (P14a); TLC (silica gel; ethyl acetate) Rf 0.36; MS (ES+ve): [M+H]+ at m/z 356 (C21H25NO4 requires [M+H]+ at m/z 356); and a later eluting (RS) diastereomer (P14b); TLC (silica gel; ethyl acetate) Rf 0.19; MS (ES+ve): [M+H]+ at m/z 356 (C21H25NO4 requires [M+H]+ at m/z 356).
Reaction SMILES: [C:1]([N:6]1[CH2:10][CH2:9][O:8][C:7]1=[O:11])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.FC(F)(F)S(O)(=O)=O.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[C:13]1([NH:12][CH:3]([CH3:4])[CH2:2][C:1]([N:6]2[CH2:10][CH2:9][O:8][C:7]2=[O:11])=[O:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C/C=C/C(=O)N1CCOC1=O
Reactant: Nc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CC(CC(=O)N1CCOC1=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.6 %

Procedure:
A solution of 3-crotonoyl-1,3-oxazolidin-2-one (47 mg, 0.3 mmol) and Pd((R)-binap)(H2O)2(OTf)2 (8.0 mg, 0.0075 mmol) in toluene (1.5 ml) in a stream of nitrogen was cooled to 0° C., and aniline (42 mg, 0.45 mmol) was added. To the solution was dropwise added trifluoromethanesulfonic acid (63 μL, 0.45 mmol), and the resulting mixture was stirred at room temperature for 24 hours. When no starting material was detected, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated and purified by a silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective 3-(3-phenylaminobutyryl)-oxazolidin-2-one (66 mg, 89% yield). The enantiomeric excess ratio was determined to be 94%. e.e. by a liquid chromatography with an optical isomer separating column (column: AD-H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26](Br)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:1][O:2][C:3](=[O:32])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:25]5[C:26]([C:33]6[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=6)=[N:27][CH:28]=[CH:29][CH:30]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5Br)ccc(F)c43)ccc21
Reactant: OB(O)c1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5cccnc5-c5ccccc5)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-(2-bromo-pyridin-3-yl)-7-fluoro-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and phenylboronic acid following a procedure analogous to that described in Step 1 of Intermediate 56. LC (method 9): tR=1.15 min; Mass spectrum (ESI+): m/z=496 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.C(N(CC)C(C)C)(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[O:12][CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13]
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc([N+](=O)[O-])cc1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc([N+](=O)[O-])cc1OCOCC[Si](C)(C)C
Reaction time: 1.5 h

Procedure:
A mixture of 2-methoxy-5-nitrophenol (10 g, 59.1 mmol) in dichloromethane (150 mL) was treated with 2-(trimethylsilyl)ethoxymethyl chloride (10.5 mL, 59.3 mmol) and N,N-diisopropylethylamine (11.3 mL, 64.9 mmol) at room temperature and stirred for 1.5 hours. The reaction mixture was then concentrated under vacuum, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered, and concentrated under vacuum to provide the desired product.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]([OH:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH:22]=[CH:23][C:3]=12.N.[H][H]>C1(C)C=CC=CC=1.[Pt]=O>[OH:1][C:2]1[C:11]([CH:12]([OH:15])[CH2:13][CH3:14])=[C:10]2[C:5]([C:6]([CH2:17][CH2:18][CH3:19])=[CH:7][C:8](=[O:16])[O:9]2)=[C:4]2[O:20][C:21]([CH3:25])([CH3:24])[CH2:22][CH2:23][C:3]=12
Reactant: CCCc1cc(=O)oc2c(C(O)CC)c(O)c3c(c12)OC(C)(C)C=C3
Reactant: [H][H]
Agent: O=[Pt]
Agent: N
Solvent: Cc1ccccc1
Product: CCCc1cc(=O)oc2c(C(O)CC)c(O)c3c(c12)OC(C)(C)CC3
Yield: 62.7 %

Procedure:
A mixture of 5-hydroxy-6-(1-hydroxypropyl)-2,2-dimethyl-10-propyl-2H-pyrano[2,3-f]chromen-8-one (11a) (400 mg, 1.16 mmol) and platinum oxide poisoned with ammonia (100 mg) in toluene (50 mL) was hydrogenated under atmospheric pressure of hydrogen at ambient temperature for 2 hours. Column chromatography on silica gel eluted with 30% ethyl acetate in hexanes and subsequent crystallization from 20% acetone in hexanes provided 252 mg of 12a (63% yield). 1H NMR (CDCl3): 1.02 (t, J=7.5 Hz, 3H), 1.22 (t, J=7.5 Hz, 3H), 1.41 (s, 6H), 1.62 (m, 2H), 1.82 (t, J=6.5 Hz, 2H), 2.75 (t, J=6.5 Hz, 2H), 2.91 (m, 4H), 3.78 (s, 3H), 6.01 (s, 1H); 13C NMR (CDCl3): 7.97, 13.84, 17.20, 23.19, 26.66, 31.33, 38.48, 38.99, 62.14, 76.35, 106.14, 110.66, 112.48, 116.55, 151.24, 153.50, 157.51, 157.92, 159.92, 203.40; IR: 1724, 1704 cm−1; MS (ACPI+): 359 (M+1); Anal. Calcd. for C21H26O5: C 70.37, H 7.31; Found: C 70.15, H 7.28.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([O:12]C(=O)C)=[CH:8][CH:7]=1)(=[O:4])[CH:2]=[CH2:3].C[O-].[Na+]>CO>[OH:12][C:9]1[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:4])[CH:2]=[CH2:3])=[CH:11][CH:10]=1
Reactant: C=CC(=O)Nc1ccc(OC(C)=O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: C=CC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To 2 (200 mg, 0.98 mmol) in 1.5 ml of MeOH in a 5 ml screw-capped vial is added 1.0 ml of 0.5 M of sodium methoxide in MeOH. The mixture is stirred at ambient temperature, and the reaction is complete in 10 min. The mixture is neutralized by addition of cation exchange resin (Dowex, 50W×8, H+) (moist pH paper). The resin is removed by filtration and washed with MeOH. The combined filtrate and wash is concentrated by rotary evaporation to yield an off-white solid (152 mg, 95%), ESI-MS (M+H)+: 164.2. 1H-NMR (acetone-d6), δ 9.15 (1H, br, NH), 7.59 (2H, d, J=9.0 Hz, NHCCH), 6.82 (2H, d, J=9.0 Hz, NHCCHCH), 6.52˜6.35 (2H, m, COCHCHH (anti to each other)), 5.70 (1H, dd, J=9.8 and 2.2 Hz, COCHCHH (syn to COCH)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[C:17]([F:22])[CH:16]=1.C[Al](C)C.C1(C)C=CC=CC=1>CC1C=CC=CC=1C>[Br:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:10](=[NH:11])[C:9]([C:3]2[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=2[Cl:8])([CH3:13])[CH3:12])=[C:17]([F:22])[CH:16]=1
Reactant: CC(C)(C#N)c1c(Cl)cccc1Cl
Reactant: Nc1ccc(Br)cc1F
Agent: C[Al](C)C
Solvent: Cc1ccccc1C
Solvent: Cc1ccccc1
Product: CC(C)(C(=N)Nc1ccc(Br)cc1F)c1c(Cl)cccc1Cl
Temperature: 100 °C
Yield: 46.6 %

Procedure:
2-(2,6-Dichlorophenyl)-2-methylpropanenitrile (20 g, 93 mmol) and 4-bromo-2-fluoroaniline (28.4 g, 149 mmol) were dissolved in anhydrous o-xylene (200 mL) and heated to 100° C. under N2. Trimethylaluminum (2 M) in toluene (140 mL, 280 mmol) was added drop-wise (˜0.9 mL per minute) over 2.5 hours while the reaction mixture was stirred at 100° C. After addition, the reaction mixture was stirred at 100° C. for 30 minutes, and then cooled to −5° C. The reaction mixture was very carefully quenched with potassium sodium tartrate (20 g in 100 mL water) (Caution: gas and heat formation). The reaction mixture was filtered through Celite 545. The filtrate was washed with 1N HCl (4×70 mL). The aqueous was neutralized with 2N NaOH and extracted with EtOAc (4×100 mL). The organics were combined, washed with brine, dried with Na2SO4, and concentrated on a rotary evaporator to afford 24 g of crude product. The crude product was recrystallized with 72 mL of MTBE and 240 mL of hexane to give N-(4-bromo-2-fluorophenyl)-2-(2,6-dichlorophenyl)-2-methylpropanimidamide (17.5 g, 43.3 mmol, 46.4% yield) as a white solid (purity: 99%). 1H-NMR (MeOD, 400 MHz) δ 7.42 (d, 2H, J=8.0 Hz), 7.30 (m, 2H), 7.16 (t, 1H, J=8.0 Hz), 6.93 (t, 1H, J=8.0 Hz), 2.11 (s, 6H); 13C-NMR (DMSO-d6, 100 MHz) δ 166.5, 156.1, 153.7, 140.6, 138.5, 135.9, 131.4, 128.6, 128.0, 125.7, 119.5, 112.9, 50.0, 29.2; MS m/e 403.09 (M+H+); HPLC (XBridge 5μ C18 4.6×50 mm, 4 mL/min, Solvent A: 10% MeOH/water with 0.2% H3PO4, Solvent B: 90% MeOH/water with 0.2% H3PO4, gradient with 0-100% B over 4 minutes): 2.32 minutes.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][N:13]3C(OC(C)(C)C)=O)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24]>C(Cl)Cl>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][CH2:12][NH:13]3)=[CH:9][CH:8]=2)=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccncc3)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1cc(-c2ccc3c(c2)NCC3)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a 100 ml flask was added tert-butyl 6-(pyridin-4-yl)indoline-1-carboxylate 50.B (202 mg, 0.68), 10 ml of CH2Cl2, and 5 ml of TFA. The reaction was stirred at room temperature for 2 hours at which time the solvent was removed to give 6-(pyridin-4-yl)indoline TFA salt 50.0 as a light yellow solid (300 mg, 100% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([OH:26])[CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[N:12][O:13][CH2:14][CH2:15][O:16][C:17]2[CH:25]=[CH:24][C:20]([C:21]([OH:23])=[O:22])=[C:19]([O:26][CH2:33][C:32]3[CH:31]=[CH:30][C:29]([C:28]([F:27])([F:37])[F:38])=[CH:36][CH:35]=3)[CH:18]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(C=NOCCOc2ccc(C(=O)O)c(O)c2)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Product: CC(C)(C)c1ccc(C=NOCCOc2ccc(C(=O)O)c(OCc3ccc(C(F)(F)F)cc3)c2)cc1

Procedure:
The title compound was prepared as a white solid from 4-{2-[({[4-(tert-butyl)phenyl]methylidene}amino)oxy]-ethoxy}-2-hydroxybenzoic acid and 4-trifluromethyl benzyl bromide using a procedure similar to that of step 1 of example 6 followed by a procedure similar to that of step 3 of example 1. mp=164.1-164.8° C.; mass spectrum (+APCI, M+H) m/z 516. 1H NMR (400 MHz, DMSO-d6); δ 12.30 (s, 1H), 8.24 (s, 1H), 7.72 (m, 5H), 7.53 (d, 2H), 7.42 (d, 2H), 6.75 (d, 1H), 6.63 (dd, 1H), 5.29 (s, 2H), 4.41 (t, 2H), 4.3 (t, 2H), 1.25 (s, 9H). Elemental analysis: Calcd. for C28H28F3NO5: C, 65.24; H, 5.47; N, 2.72, Found: C, 63.30; H, 5.21; N, 2.68.
Reaction SMILES: [O:1]1[CH:8]2[CH:2]1[CH:3]=[C:4]([CH3:12])[C:5](=[O:11])[CH2:6][C:7]2([CH3:10])[CH3:9].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=1>O1CCCC1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[OH:1][CH:8]1[C:7]([CH3:10])([CH3:9])[CH2:6][C:5](=[O:11])[C:4]([CH3:12])=[CH:3][CH:2]1[O:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(CO)cc1
Reactant: CC1=CC2OC2C(C)(C)CC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCOC1
Product: COc1ccc(COC2C=C(C)C(=O)CC(C)(C)C2O)cc1
Yield: 51 %

Procedure:
To a solution of eucarvone-4,5-oxide, i.e. 4,5-epoxy-2,6,6-trimethyl-2-cyclohepten-1-one (50 g, 0.3M), in tetrahydrofuran (150 ml), 4-methoxybenzyl alcohol (55 g, 0.4M) and p-toluenesulfonic acid (2 g) were added, and it was heated under reflux for eight hours, concentrated, and then purified by silica gel column chromatography using hexane-ethyl acetate (10:1) as an eluent to obtain 46.7 g (50%) of 5-hydroxy-4-(4-methoxybenzyloxy)-2,6,6-trimethyl-2-cyclohepten-1-one (AUM09) as a light yellow oily product.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][C:18]2[N:22]([CH3:23])[C:21](=[O:24])[N:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=3)[N:19]=2)=[CH:11][CH:10]=1)([CH3:7])[CH3:6])C>C(O)C.[OH-].[Na+]>[C:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][N:20]2[C:21](=[O:24])[N:22]([CH3:23])[C:18]([CH2:17][CH2:16][CH2:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:36])=[O:3])=[CH:14][CH:13]=3)=[N:19]2)=[CH:27][CH:28]=1)([CH3:33])([CH3:34])[CH3:35]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCCc2nn(Cc3ccc(C(C)(C)C)cc3)c(=O)n2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(CCCc2ccc(OC(C)(C)C(=O)O)cc2)nn(Cc2ccc(C(C)(C)C)cc2)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.5 %

Procedure:
2-(4-{3-[1-(4-t-Butylbenzyl)-4-methyl-5-oxo-4,5-dihydro-1H-[1,2,4]triazol-3-yl]-propyl}-phenoxy)-2-methyl-propionic acid ethyl ester (0.69 g, 1.39 mmol) was dissolved in ethanol (4 mL)), 1 N NaOH (4.75 mL) was added in one portion and the solution was stirred at ambient temperature overnight. The solution was concentrated to a hazy, colorless oil. This oil was partitioned between 1N HCl (5 mL) and ethyl acetate (5 mL). The aqueous layer was then reextracted with ethyl acetate (5 mL) and the organic layers combined, dried (MgSO4), filtered and concentrated in vacuo at 50° C. to afford the title compound as a clear oil (0.56 g, 86%): 1H NMR (DMSO-d6) δ 12.9 (br s, 1H), 7.31 (d, 2H, J=6 Hz), 7.14 (d, 2H, J=8 Hz), 7.05 (d, 2H, J=7 Hz), 6.73 (d, 2H, J=2 Hz), 4.77 (s, 2H), 3.09 (s, 3H), 2.53 (t, 2H, J=8 Hz), 2.49 (t, 2H, J=8 Hz), 1.81 (quint, 2 H, J=7 Hz), 1.46 (s, 6H), 1.22 (s, 9H); 13C NMR (DMSO-d6) δ 175.8, 154.14, 154.10, 150.5, 147.2, 135.2, 135.0, 129.7, 128.0, 125.9, 119.2, 79.0, 48.3, 34.9, 34.1, 31.8, 27.7, 27.6, 25.7, 25.1; IR (CHCl3) 2966, 1695, 1509, 1235 cm−1; Anal. Calcd. for C27H35N3O4: C, 69.65; H, 7.58; N, 9.02. Found: C, 69.30; H, 7.30; N, 8.96.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)[C:8](=[O:28])[CH2:7]2)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:16][CH2:17][N:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:20]1)[C:8](=[O:28])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2N1CCN1CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)CC(=O)N2CCN1CCN(Cc2ccccc2)CC1
Reaction time: 1 h

Procedure:
1,3-Dihydro-5-nitro-1-[2-[4-(phenylmethyl)-1-piperazinyl]ethyl]-2H-indol-2-one (200 mg) in ethanol (100 ml) containing 5% palladium on carbon (60 mg) was stirred under an atmosphere of hydrogen at STP for 1 hour. The catalyst was filtered off, the filtrate evaporated to dryness, and the residue purified by flash chromatography on silica gel.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.[CH:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=O>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][CH2:9][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cccnc1
Reactant: NCC1CCNCC1
Product: c1cncc(CNCC2CCNCC2)c1

Procedure:
4-Piperidylmethylamine and 3-formylpyridine were treated in the same manner as described in Reference example 2 to give N-(4-piperidylmethyl)-N-(3-pyridylmethyl)amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][NH:19][C:20]3[N:25]=[C:24]([O:26][C@@H:27]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28]4)[CH:23]=[CH:22][N:21]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.ClC1C=CN=C(NCC2N3C=C(Cl)C=CC3=NC=2C2C=CC(F)=CC=2)N=1.CN1CC[C@H](O)C1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:18][NH:19][C:20]3[N:25]=[C:24]([O:26][C@H:27]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28]4)[CH:23]=[CH:22][N:21]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[N:10]=2)[CH:7]=1
Reactant: CN1CC[C@@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1
Agent: CN1CC[C@H](O)C1
Agent: Fc1ccc(-c2nc3ccc(Cl)cn3c2CNc2nccc(Cl)n2)cc1
Product: CN1CC[C@H](Oc2ccnc(NCc3c(-c4ccc(F)cc4)nc4ccc(Cl)cn34)n2)C1

Procedure:
The title compound was prepared in the same fashion as that described for compound 183 from 4-chloro-N-((6-chloro-2-(4-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)pyrimidin-2-amine and (S)-1-methylpyrrolidin-3-ol. 1H-NMR (CDCl3, 400 MHz, δ) 8.20 (s, 1H), 7.65 (m, 1H), 7.50 (d, J=9.5 Hz, 1H), 9.10 (m, 3H), 5.93 (s, 1H), 5.34 (s, 1H), 4.93 (d, J=4.9 Hz, 2H), 2.75 (m, 4H), 2.33 (s, 3H), 2.25 (m, 2H), 1.95 (m, 1H) ppm; m/e 453 (M+H)+.