Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]S(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)=[O:35].N12CCCN=C1CCCCC2.Cl>CN(C)C(=O)C.C(OC)(C)(C)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]2[C:8](=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=2)[NH:14][C:33]=1[C:34](=[O:35])[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1)[CH3:2]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1NS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: COC(C)(C)C
Product: CCOC(=O)Cc1c(C(=O)c2ccc(Cl)cc2)[nH]c2cc(Cl)ccc12
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
To a solution of 3-[4-chloro-2-(toluene-4-sulfonylamino)-phenyl]-acrylic acid ethyl ester (3.00 g, 7.90 mmol) in N,N-dimethylacetamide (15.0 ml) was added potassium carbonate (2.18 g, 15.8 mmol) and 2-bromo-4′-chloroacetophenone (2.03 g, 8.69 mmol). The reaction was stirred 30 minutes and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.54 ml, 23.7 mmol) was added. The reaction mixture was stirred one hour, poured into 1N hydrochloric acid (30 ml) and extracted with methyl t-butyl ether (2×30 ml). The organic extracts were dried with magnesium sulfate, filtered, and concentrated to provide a solid which was slurried in a mixture of methyl t-butyl ether and hexanes to afford [6-chloro-2-(4-chloro-benzoyl)-1H-indol-3-yl]-acetic acid ethyl ester (2.42 g, 81%). mp=186-188° C. 1H NMR (300 MHz, CDCl3) d 1.27 (t, 2, J=7.1), 3.80 (s, 2), 4.11 (q, 2, J=7.1), 7.15 (ddd, 1, J=8.5, 1.7, 0.5), 7.28-7.30 (m, 1), 7.48 (d, J=8.3), 7.54-7.57 (m, 1), 7.77 (d, 2, J=8.3), 9.16 (bs, 1). 13C NMR (75 MHz, CDCl3) d 15.42, 32.29, 62.45, 113.27, 117.60, 122.99, 123.23, 127.85, 130.12, 131.77, 133.61, 137.86, 138.13, 140.10, 172.45, 188.25. IR 3305, 1732, 1618, 1323 cm−1. Analysis calculated for C19H15Cl2NO3: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.70; H, 3.97; N, 3.71.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:5]([O:7]C(C)(C)C)=[O:6]>Cl.O1CCOCC1>[CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH:12][CH2:13][C:14]([CH3:15])([CH3:17])[CH3:16])[C:5]([OH:7])=[O:6]
Reactant: CC(C)C[C@H](NCC(C)(C)C)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C[C@H](NCC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.022 g, 4.57 mmol) and pivalaldehyde (0.502 mL, 4.57 mmol) were combined in dichloromethane (25 mL). Acetic acid (1.0 mL) was added. The reaction was stirred at room temperature for 5 minutes, then PS-cyanoborohydride (3.90 g, 9.14 mmol) was added. The reaction was stirred at room temperature overnight, then filtered and the solvent was removed in vacuo. The crude material was diluted with dichloromethane and basified using saturated aqueous sodium bicarbonate to give (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 3.04 (t, J=7.4, 1H), 2.40 (d, J=11.1, 1H), 2.09 (d, J=11.1, 1H), 1.86-1.70 (m, 1H), 1.46 (s, 10H), 1.40 (t, J=7.2, 3H), 0.95-0.89 (m, 6H), 0.89 (s, 9H), (S)-tert-butyl 4-methyl-2-(neopentylamino)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(neopentylamino)pentanoic acid: 1H NMR (300 MHz, DMSO-d6) δ ppm 8.89-8.37 (m, 1H), 8.34-8.03 (m, 1H), 3.82 (t, J=6.5, 1H), 2.88 (d, J=12.3, 1H), 2.62 (d, J=12.2, 1H), 1.83-1.67 (m, 2H), 1.67-1.56 (m, 1H), 1.00 (s, 9H), 0.97-0.88 (m, 6H).
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]([N+:28]([O-:30])=[O:29])=[C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:20]=2)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:31](Br)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[OH-].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH2:31]([N:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:19]1[CH:20]=[C:15]([N:12]2[CH2:11][CH2:10][N:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:14][CH2:13]2)[CH:16]=[CH:17][C:18]=1[N+:28]([O-:30])=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(Nc3ccccc3)c2)CC1
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)N1CCN(c2ccc([N+](=O)[O-])c(N(Cc3ccccc3)c3ccccc3)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
A suspension of 5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (1.0 g, 2.5 mmol), benzylbromide (0.3 ml, 2.5 mmol), potassium hydroxide (0.18 g, 3.2 mmol) and tetra-butyl ammonium iodide (0.05 g, 0.25 mmol) in 40 ml toluene was stirred at room temperature overnight. The red solids were filtered to get N-benzyl-5-(4-benzoylpiperazin-1-yl)-2-nitro-N-phenylbenzenamine (1.1 g, 90%). 1H NMR (500 MHz, DMSO-d6) δ (ppm) 3.40-3.58 (m, br, 8H), 4.94 (s, 2H), 6.30 (d, J=8.0 Hz, 2H), 6.73 (t, J=7.2 Hz, 1H), 6.88 (d, J=9.2 Hz, 2H), 7.09-7.48 (m, 12H), 7.98 (d, J=8.9 Hz, 1H).
Reaction SMILES: O=O.C(NC(C)C)(C)C.C([Li])CCC.[C:15]([O:19][C:20](=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)([CH3:18])([CH3:17])[CH3:16].BrC[CH2:32][CH:33]([CH3:39])[CH2:34][C:35]([F:38])([F:37])[F:36].[Cl-].[NH4+]>C1COCC1.CCCCCC.C(OCC)(=O)C.C1CCCCC1.C(OCC)(=O)C>[F:36][C:35]([F:38])([F:37])[CH2:34][CH:33]([CH3:39])[CH2:32][CH:21]([C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1)[C:20]([O:19][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:29]
Reactant: CC(CCBr)CC(F)(F)F
Reactant: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Agent: O=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(C(CC(C)CC(F)(F)F)C(=O)OC(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Under exclusion of oxygen, 0.44 ml (3.2 mmol) of diisopropylamine was initially charged in 4 ml of THF, the mixture was cooled to −78° C. and 1.28 ml (3.2 mmol) of a 2.5 M solution of n-butyllithium in hexane were added slowly. The reaction solution was then warmed to −10° C. and stirred at this temperature for 10 min. The reaction solution was then once more cooled to −78° C., and 500 mg (2.32 mmol) of tert-butyl(4-methylphenyl)acetate, dissolved in 6 ml of THF, were added slowly. The reaction solution was then slowly warmed to −30° C. and then once more cooled to −78° C. Once this temperature had been reached, 596 mg (2.91 mmol) of 5-bromo-1,1,1-trifluoro-3-methylpentane were slowly added dropwise. After the addition had ended, the solution was slowly warmed to room temperature and stirred overnight. After TLC check (mobile phase cyclohexane/ethyl acetate 10:1), saturated ammonium chloride solution was added and the mixture was taken up in ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate. After filtration, the solvent was removed under reduced pressure. The crude product was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 20:1). This gave 490 mg (1.48 mmol, 61% of theory) of a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][C:23]([CH3:28])=[CH:22]2.[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:33]1[CH2:34][CH2:35][N:30]([CH3:29])[CH2:31][CH2:32]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][C:23]([CH3:28])=[CH:22]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CN1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OC[C@H](O)CN1CCN(C)CC1
Temperature: 70 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
A mixture of (2R)-6-methoxy-4-(2-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (300 mg, 0.79 mmol), and 1-methylpiperazine (0.26 ml, 2.38 mmol) in DMF (10 ml) was stirred at 70° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, dichloromethane/methanol/0.88 ammonia (100/8/1) and evaporated in vacuo to give (2R)-7-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (344 mg, 91%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:10])=[N:5][C:6]([CH3:9])=[CH:7][N:8]=1.[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19](Cl)(=[O:21])=[O:20]>N1C=CC=CC=1>[Cl:11][C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=1[S:19]([NH:10][C:4]1[C:3]([O:2][CH3:1])=[N:8][CH:7]=[C:6]([CH3:9])[N:5]=1)(=[O:21])=[O:20]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Reactant: COc1ncc(C)nc1N
Solvent: c1ccncc1
Product: COc1ncc(C)nc1NS(=O)(=O)c1cccc(Cl)c1Cl
Yield: 56.7 %

Procedure:
A solution of 3-methoxy-6-methyl-2-pyrazinamine (Example 194a) (0.050 g) and 2,3-dichlorobenzenesulphonyl chloride (0.098 g) in pyridine (0.3 mL) was stirred at room temperature for 18 h. Solvent was evaporated to give a residue which was purified by chromatography on silica gel eluting with dichloromethane/ethyl acetate/acetic acid (200:4:1) giving the title compound as a pale orange solid (0.071 g).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].C(N(CC)C(C)C)(C)C.C([O:23][C:24](=O)[CH:25]=[C:26]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)[CH2:27]Br)C>C(#N)C>[CH3:2][O:3][C:4](=[O:11])[C@@H:5]([N:6]1[CH2:27][C:26]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)=[CH:25][C:24]1=[O:23])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: CCOC(=O)C=C(CBr)Oc1cccc(C(F)(F)F)c1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2cccc(C(F)(F)F)c2)=CC1=O
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
A mixture of (L)-leucine methyl ester hydrochloride (0.79 g, 4.34 mmol) in acetonitrile (9.5 mL) was treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol). After addition was complete, the mixture was stirred at 60° C. for 1 h. At this time, the reaction was cooled to 25° C., treated with N,N-diisopropylethylamine (0.70 mL, 4.26 mmol) and acetonitrile (9.5 mL) and then heated to 80° C. Upon reaching 80° C., the reaction was treated with a solution of 4-bromo-3-(3-trifluoromethyl-phenoxy)-but-2-enoic acid ethyl ester (1.40 g, 3.96 mmol) in acetonitrile (9.5 mL). After the addition was complete the reaction mixture was heated to 100° C. and stirred overnight. At this time, the reaction mixture was cooled to 25° C. and concentrated in vacuo. The residue was diluted with dichloromethane (100 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a saturated aqueous sodium bicarbonate solution (1×100 mL), a saturated aqueous sodium chloride solution (1×100 mL), dried over magnesium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 15-50% ethyl acetate/hexanes) afforded (S)-4-methyl-2-[2-oxo-4-(3-trifluoromethyl-phenoxy)-2,5-dihydro-pyrrol-1-yl]-pentanoic acid methyl ester (0.86 g, 59%) as a light, brown solid: HR-ES-MS m/z calculated for C18H20NO4F3 [M+H]+ 372.1417, observed 372.1418; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.88 (d, J=6.6 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.29-1.55 (m, 1H), 1.56-1.68 (m, 1H), 1.73-1.90 (m, 1H), 3.66 (s, 3H), 4.19 (d, J=18.1 Hz, 1H), 4.26 (d, J=18.1 Hz, 1H), 4.75 (dd, J=11.4, 4.6 Hz, 1H), 4.95 (s, 1H), 7.64-7.78 (m, 4H).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][N:32]2[CH2:35][CH:34]([OH:36])[CH2:33]2)=[C:13]([CH:30]=1)[CH2:14][NH:15][C:16](=[O:29])[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1CN1CC(O)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1cc(Cl)ccc1CN1CC(O)C1)[C@@H]1CCCN1
Yield: 35.2 %

Procedure:
TFA (3 mL) was added to a stirred solution of N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-1-(tert-butoxycarbonyl)-L-prolinamide (210 mg, 0.49 mmol) in CH2Cl2 (6 mL) at 0° C. After 90 min the solution was concentrated and the residue was partitioned between CH2Cl2 and 10% NaHCO3. The aqueous layer was saturated with NaCl and then extracted with more CH2Cl2. The combined organic layers were washed with brine, dried over (Na2SO4) and then evaporated. The reside was purified by chromatography on silica (ammonia saturated CHCl3/MeOH, 93:7) to give N-{5-chloro-2-[(3-hydroxyazetidin-1-yl)methyl]benzyl}-L-prolinamide (55.8 mg) as a glass: 1H NMR (CDCl3, 400 MHz) δ 1.71 (m, 2H), 1.93 (m, 1H), 2.16 (m, 1H), 2.92 (m, 2H), 3.05 (m, 2H), 3.39 (m, 2H), 3.61 (dd, J=12.3, 20.7 Hz, 2H), 3.72 (dd, J=6.4, 8.6 Hz, 2H), 4.28-4.46 (m, 3H), 7.12 (d, J=8.1 Hz), 7.19 (dd, J=2.2, 8.1 Hz), 7.36 (d, J=2.0 Hz, 1H), 9.09 (br s, 1H).
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[CH2:6][CH2:5]1.O>CO.CO.C1(C)C=CC=CC=1>[CH3:3][C:4]1([CH3:15])[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]([OH:14])[CH2:6][CH2:5]1
Reactant: CC1(C)CCC(=O)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)CCC(O)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of sodium borohydride (3.5 g, 93 mmoles) in dry methanol (50 ml) at 0° C. under a nitrogen atmosphere was added a solution of 4,4-dimethyl-1-tetralone (10 g, 57.4mmoles) in dry methanol:toluene (1:3) dropwise over a 45 minute period. After this time the mixture was allowed to warm to room temperature, and then two volumes of water were added. After stirring for 1 hour, the organic layer was separated, dried over magnesium sulfate, filtered, and evaporated under reduced pressure to leave a light yellow oil. This was purified by silica gel column chromatography eluting with ethyl acetate:hexane (1:9) to give 1,2,3,4-tetrahydro-4,4-dimethyl-1-naphthol as a colorless oil. (9.89 g, 98%).
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]2[CH2:8][CH2:9][N:10]3[CH:21]=[CH:20][CH:19]=[C:11]3[C:12](=[CH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1)([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:23]=[CH:22][C:7]2[CH2:8][CH2:9][N:10]3[CH:21]=[CH:20][CH:19]=[C:11]3[C:12](=[CH:13][CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: CN(C)CCC=C1c2cc([N+](=O)[O-])ccc2CCn2cccc21
Agent: [Pd]
Solvent: CO
Product: CN(C)CCC=C1c2cc(N)ccc2CCn2cccc21

Procedure:
A mixture of 9-nitro-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine (2.0 g.), 0.2 g. of 10% Pd/C and 350 ml. of methanol is hydrogenated until the theoretical amount of hydrogen is absorbed. The mixture is filtered and the filtrate is evaporated to dryness to yield 9-amino-11-(3-dimethylaminopropylidene)-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].[Cl:23][C:24]1[CH:25]=[C:26]([N:31]=[C:32]=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30].C(N(C(C)C)CC)(C)C>N1C=CC=CC=1>[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]([NH:2][CH2:3][C:4]2[CH:12]=[CH:11][CH:10]=[C:9]3[C:5]=2[C:6](=[O:22])[N:7]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:8]3=[O:13])=[O:33])[CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)Nc4ccc(Cl)c(Cl)c4)c3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 78.9 %

Procedure:
A mixture of 4-aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.50 g, 1.6 mmol), 3,4-dichlorophenyl isocyanate (0.29 g, 1.6 mmol), and diisopropylethylamine (0.40 g, 3.1 mmol) in 10 mL pyridine was warmed to 40° C. with stirring under N2, and the resulting solution was stirred at the same temperature for 2 hours. The mixture was cooled, and the solvent was evaporated under vacuum. The residue was chromatographed using a methylene chloride-methanol gradient, eluting with 97:3 methylene chloride-methanol, to provide 0.60 g of the product in 82% yield: mp 241-243° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.54-2.64 (m, 2H), 2.84-2.97 (m, 1H), 4.71 (d, J=6.0 Hz, 2H), 5.17 (dd, J=12.5 Hz, d=5.4 Hz, 1H), 6.92 (t, J=6.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.75-7.88 (m, 4H), 9.15 (s, 1H), 11.15 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.8, 48.9, 117.8, 118.8, 121.9, 122.4, 127.2, 130.4, 130.9, 131.6, 133.7, 134.8, 139.9, 140.5, 154.9, 167.0, 167.6, 169.8, 172.8; Anal. calcd. for C21H16Cl2N4O5.0.25H2O: C, 52.57; H, 3.47; N, 11.68. Found: C, 52.78; H, 3.41; N, 11.37.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].[CH2:10]([O:17][CH2:18][CH2:19]Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O1CCCC1>[CH2:10]([O:17][CH2:18][CH2:19][CH2:8][C:4]1[CH:5]=[C:6]([CH3:7])[N:1]=[C:2]([CH3:9])[CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Cc1cc(C)nc(C)c1
Reactant: BrCCOCc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(CCCOCc2ccccc2)cc(C)n1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Collidine (1), (5 g, 41.3 mmol) in dry tetrahydrofuran was added dropwise and the mixture was stirred for 60 min at -40° C. To this stirred mixture 1-benzoxy-2-bromethane (Tetrahedron Lett. 28, 2639-42, 1979) (8.24 g, 39.2 mmol) dissolved in dry tetrahydrofuran (20 ml) was added dropwise during 30 min and the reaction mixture was stirred overnight.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[C:26]([C:28](O)=[O:29])[N:27]=1>>[NH2:22][C:23]1[S:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=2)=[C:26]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])[N:27]=1
Reactant: Nc1nc(C(=O)O)c(-c2cccc(F)c2)s1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with 2-amino-5-(3-fluoro-phenyl)-thiazole-4-carboxylic acid.
Reaction SMILES: COC(=O)[C@@H](N[C:19]([C:21]1[CH:22]=[C:23]([C:28]2[CH:33]=[CH:32][C:31](F)=C(Cl)C=2)[CH:24]=[CH:25][C:26]=1[OH:27])=[O:20])CC1C=CC(C2C=CC=CC=2)=CC=1.[CH3:37][O:38][C:39](=[O:50])[C@@H:40]([NH2:49])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=1>>[CH3:37][O:38][C:39](=[O:50])[C@@:40]([NH2:49])([C:19]([C:21]1[C:26]([OH:27])=[CH:25][C:24]2[C:23](=[CH:28][CH:33]=[CH:32][CH:31]=2)[CH:22]=1)=[O:20])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([Br:48])=[CH:44][CH:43]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O
Reactant: COC(=O)[C@@H](N)Cc1ccc(Br)cc1
Product: COC(=O)[C@](N)(Cc1ccc(Br)cc1)C(=O)c1cc2ccccc2cc1O

Procedure:
1.0 g (2.5 mmol) of resin-bound naphthoic acid obtained in Example 1 was reacted with 1.95 g (7.5 mmol) of (2S)-Amino-3-(4-bromophenyl)-propionic acid methyl ester as described in the general procedure A to give resin-bound 2-(S)-(3-Hydroxy-naphthalene-2-carbonyl)-amino-3-(4-bromophenyl)-propionic acid methyl ester.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[F:29][C:30]([F:44])([F:43])[C:31]1[CH:32]=[C:33]([CH:36]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:38]=1)[CH2:34][NH2:35]>O1CCCC1>[CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([NH:35][CH2:34][C:33]1[CH:36]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:38]=[C:31]([C:30]([F:29])([F:43])[F:44])[CH:32]=1)=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 48 %

Procedure:
To a solution of 255 mg (1.2 mmol) 2-benzylbenzoic acid in 1.5 ml tetrahydrofuran at 0° C. were added 195 mg (1.2 mmol) 1,1′-carbonyldiimidazole. After stirring for 2.5 h at room temperature, a solution of 243 mg (1.0 mmol) 3,5 bis(trifluoromethyl)benzylamine in 0.5 ml tetrahydrofuran was added and stirring was continued overnight. The solvent was removed in vacuo and the residue was purified by flash chromatography to give 210 mg (49%) of the title compound as white crystals.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[O:24][C:25]=3[CH3:26])[CH:15]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[O:18][N:17]=[C:16]([O:19][CH2:20][C:21]3[N:22]=[C:23]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)[O:24][C:25]=3[CH3:26])[CH:15]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2nn(C)cc2CC(=O)O)on1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
A mixture of methyl [1-methyl-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (701 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetic acid (547 mg, yield 81%), which was then recrystallized from acetone-hexane. melting point: 149–150° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)=[O:21].[BH4-].[Na+]>CO.C1COCC1>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[O:12][CH2:11][CH2:10][O:9]2)=[CH:4][C:3]=1[CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[CH:23]=1)[OH:21]
Reactant: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(=O)c1cccc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1ccc(C2(c3ccc(Cl)cc3)OCCO2)cc1C(O)c1cccc(Cl)c1
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
A mixture of [2-amino-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]phenyl](3-chlorophenyl)methanone (prepared as described in WO 98/49157) (0.088 mol) in methanol (300 ml) and THF (100 ml) was cooled on an ice bath. sodium tetrahydroborate (0.088 mol) was added portionwise. The mixture was stirred at a low temperature for 30 min, then hydrolized and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness. The product was used without further purification, yielding 36.6 g (100%) of 2-amino-α-(3-chlorophenyl)-5-[2-(4-chlorophenyl)-1,3-dioxolan-2-yl]-benzenemethanol (intermediate 9).