Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)(=[O:16])=[O:15])[C@H:10]([CH3:29])[CH2:9]2)=[C:4]([C:30]([F:33])([F:32])[F:31])[CH:3]=1.[CH3:34][CH:35]=O.CC(O)=O.[BH3-]C#N.[Na+]>CO>[CH2:34]([N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([S:14]([N:11]3[CH2:12][CH2:13][N:8]([C:5]4[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=4[C:30]([F:31])([F:33])[F:32])[CH2:9][C@H:10]3[CH3:29])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=2)[CH2:24][CH2:25]1)[CH3:35]
Reactant: C[C@@H]1CN(c2ccc(F)cc2C(F)(F)F)CCN1S(=O)(=O)c1cccc(N2CCNCC2)c1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCN1CCN(c2cccc(S(=O)(=O)N3CCN(c4ccc(F)cc4C(F)(F)F)C[C@H]3C)c2)CC1
Yield: 91.3 %

Procedure:
To a solution of (2R)-4-[4-fluoro-2-(trifluoromethyl)phenyl]-2-methyl-1-[(3-piperazin-1-ylphenyl)sulfonyl]piperazine (120 mg, 0.247 mmol) in MeOH (2 mL) was added CH3CHO (12 mg, 0.27 mmol), HOAc (17.7 μL, 0.3 mmol) and NaBH3CN (8 mg, 0.125 mmol) at room temperature. The resultant mixture was stirred till disappearance of starting material as monitored by LCMS. The solvent was removed. The crude product was purified by SiO2 column eluted with DCM/MeOH to give the desired product as a light yellow solid (116 mg, 100%). HRMS: calcd for C24H30F4N4O2S+H+, 515.20983. found (ESI-FTMS, [M+H]1+), 515.20891.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:12][O:11]2)[CH:5]=[CH:4][CH:3]=1.[CH2:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][NH:14]1>CCO>[Br:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]([OH:11])[CH2:12][N:14]2[CH2:15][CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc2c(c1)CCNC2
Reactant: Brc1cccc(NCC2CO2)n1
Solvent: CCO
Product: OC(CNc1cccc(Br)n1)CN1CCc2ccccc2C1
Temperature: 80 °C
Reaction time: 16 h
Yield: 6.7 %

Procedure:
To a stirred mixture of 6-bromo-N-(oxiran-2-ylmethyl)pyridin-2-amine (1.33 g, 5.81 mmol) in EtOH (100 mL) was added 1,2,3,4-tetrahydroisoquinoline (773 mg, 5.81 mmol). The mixture was stirred at 80° C. for 16 hours. The reaction mixture was concentrated and the residue was purified column to afford the desired compound (140 mg). LCMS (m/z): 362.1/363.1 [M+H]+/[M+2H]+
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:20][CH:19]=2)=[O:16])=[O:8])[N:3]=[CH:2]1.[CH:32](=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[NH:1]1[CH:5]=[C:4]([CH2:6][C:7]([N:9]2[CH2:14][CH2:13][N:12]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:11][C@H:10]2[C:15]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:22][CH:23]=2)=[O:16])=[O:8])[N:3]=[CH:2]1
Reactant: O=Cc1ccccc1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CNCCN1C(=O)Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1CN(Cc2ccccc2)CCN1C(=O)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.7 %

Procedure:
Step (b) A flask was charged with (S)-1-(2-(1H-imidazol-4-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide (107 mg, 0.252 mmol), benzaldehyde (0.154 mL, 1.51 mmol), methanol (10 mL) and sodium triacetoxyborohydride (534 mg, 2.52 mmol). The reaction mixture was stirred at ambient temperature for 30 minutes and then diluted with deionized water (15 mL). The mixture was washed with ethylene chloride (20 mL) and the aqueous layer was basified with 2N sodium hydroxide (40 mL) and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give Compound 175 (S)-1-(2-(1H-imidazol-4-yl)acetyl)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)piperazine-2-carboxamide (41 mg, 32% yield), as an off-white solid. 1H-NMR (400 MHz, CDCl3): 10.23 (s, 1H), 7.63-7.18 (m, 8H), 7.02-6.82 (m, 7H), 5.42 (s, 1H), 4.02-3.90 (m, 1H), 3.88-3.80 (m, 1H), 3.78-3.61 (m, 2H), 3.58-3.34 (m, 2H), 3.08-2.97 (m, 1H), 2.78-2.64 (m 1H), 2.28-2.18 (m, 1H), 2.11-2.00 (m, 1H). MS (EI) for C29H28FN5O3. found 514.3 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][NH:6]1)=[O:4].C(N(CC)CC)C.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][N:6]1[C:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:4]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1C[C@@H](O)CN1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.3 %

Procedure:
Into a solution of 1 (10 g, 55 mmol) in anhydrous CHCl3 (100 mL) was added triethylamine (19 mL, 138 mmol) and triphenylmethyl chloride (14.5 g, 52 mmol). The mixture was stirred at RT for 3 d before concentrating and redissolving in EtOAc. The solution was washed sequentially with 10% aq. citric acid, water, and brine before drying over MgSO4 and concentrating under reduced pressure to give 2 (20 g, 100%) as a yellow solid.
Reaction SMILES: C(Cl)(Cl)=O.ClC(OCC)=O.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2C(=O)O[C:28](=[O:29])[C:27]3=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=[C:26]23)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:26]([NH:25][C:22]2[CH:23]=[CH:24][C:19]([O:18][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:20][CH:21]=2)=[C:27]([CH:33]=1)[C:28]([N:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1)=[O:29]
Reactant: C1CCNCC1
Reactant: COc1ccc2c(c1)c(=O)oc(=O)n2-c1ccc(OCc2ccccc2)cc1
Agent: CCOC(=O)Cl
Agent: O=C(Cl)Cl
Product: COc1ccc(Nc2ccc(OCc3ccccc3)cc2)c(C(=O)N2CCCCC2)c1

Procedure:
It is contemplated that the foregoing product by reaction with phosgene or ethyl chloroformate can be converted to N-(4-methoxy-2-methylphenyl)isatoic anhydride [VIII; R=H, R"=2--CH3, OR°=4--OCH3 ], and the latter reacted with piperidine to give 1-[2-(4-methoxy-2-methylphenylamino)benzoyl]piperidine [IX; R=H, R"=2--CH3, N=Z=1-piperidinyl, OR°=4--OCH3 ] which can be de-etherified with boron tribromide to yield 1-[2-(4-hydroxy-2-methylphenylamino)benzoyl]piperidine [I; R and R'=H, R"=2--CH3, N=Z=1-piperidinyl, OH at 4-position].
Reaction SMILES: [C:1]([C:9]1[N:10]2[C:14](=[CH:15][CH:16]=1)[CH:13]([C:17](N(C)C1C=CC=CC=1)=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:27].[Na+].CO>O>[CH:5]1[CH:6]=[CH:7][C:2]([C:1]([C:9]2[N:10]3[CH2:11][CH2:12][CH:13]([C:17]([OH:18])=[O:27])[C:14]3=[CH:15][CH:16]=2)=[O:8])=[CH:3][CH:4]=1
Reactant: [OH-]
Reactant: CN(C(=O)C1CCn2c(C(=O)c3ccccc3)ccc21)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(c1ccccc1)c1ccc2n1CCC2C(=O)O
Temperature: 25 °C
Yield: 83.4 %

Procedure:
A mixture of 34.4 g (100 mmol) 5-benzoyl-N-methyl-N-phenyl-2,3-dihydro-1H-pyrrolizine-1-carboxamide, 25 g sodium hydroxide in 25 mL water, and 80 mL methanol was refluxed for 5 hours. The mixture was cooled to room temperature, stirred under nitrogen for sixteen hours, and then diluted with 80 mL of water. The mixture was extracted with toluene (2×50 mL), and the aqueous and organic phases were separated. The aqueous phase was acidified with 6 N hydrochloric acid (110 mL). The resulting precipitate was extracted several times with dichloromethane (1×150 mL), (1×75 mL), (1×50 mL). The combined extract was treated with FILTROL® (activated clay decolorizing agent) (4.5 g) for 30 minutes, filtered, and concentrated by atmospheric distillation. Hexane (190 mL) was added and the entire mixture allowed to cool to room temperature and then further cooled to 0° C. to −5° C. The product, 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid (ketorolac) was collected by filtration, washed with 100 mL of hexane/dichloromethane (7:3 v/v), and dried at 60° C. to 70° C. under vacuum, to yield ketorolac (21.3 g, 83.4% yield), mp 152° C. to 162° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:19]([O:21][P:22]([O-:26])[O:23][CH2:24][CH3:25])[CH3:20].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:12][O:11][C:9]([CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]1[CH:6]=[CH:7][C:2]([P:22](=[O:26])([O:23][CH2:24][CH3:25])[O:21][CH2:19][CH3:20])=[CH:3][CH:4]=1)=[O:10]
Reactant: CCOP([O-])OCC
Reactant: COC(=O)C(c1ccccc1)c1ccc(Br)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOP(=O)(OCC)c1ccc(C(C(=O)OC)c2ccccc2)cc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of compound Methyl 2-(4-bromophenyl)-2-phenylacetate, 14-d, (1.52 g, 5.0 mmol), diethylphosphite (2.42 g, 17.5 mmol) and triethylamine (3.13 g, 31 mmol) in toluene (20 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dicholoropalladium (100 mg). The mixture was allowed to stir overnight at 110° C. and filtrated. The solution was concentrated to afford the crude product which was purified by column chromatography to give compound 14-e as colorless oil (1.7 g, 94%). 1H NMR (300 MHz, CDCl3) δ1.29-1.35 (m, 6H), 3.73 (s, 3H), 4.10-4.13 (m, 4H), 5.03 (s, 1H), 7.23-7.40 (m, 7H), 7.69-7.77 (m, 2H). LC-MS: (M+H)+ 363.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13].[CH3:35][O-:36].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:35][O:36][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[S:12]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][S:23]([C:26]1[S:30][C:29]2[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=2[CH:27]=1)(=[O:25])=[O:24])(=[O:14])=[O:13]
Reactant: O=S(=O)(Nc1ccccc1NS(=O)(=O)c1cc(C(F)(F)F)ccc1Cl)c1cc2ccccc2s1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1ccc(C(F)(F)F)cc1S(=O)(=O)Nc1ccccc1NS(=O)(=O)c1cc2ccccc2s1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a solution of benzo[b]thiophene-2-sulfonic acid [2-(2-chloro-5-trifluoromethylbenzenesulfonylamino)phenyl]-amide (0.5 mmol) in dioxane (5 mL), solid sodium methoxide (2 mmol) was added in one portion and the resulting reaction mixture was then heated to reflux for ca. 4 h. After the completion of the reaction, the reaction mixture was cooled to RT and concentrated in vacuo. The residue obtained was redissolved in EtOAc (10 mL) and was washed with water (10 mL) and brine (10 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue obtained was purified by flash column chromatography eluting with DCM/EtOAc to obtain 204 mg of benzo[b]thiophene-2-sulfonic acid [2-(2-methoxy-5-trifluoromethyl-benzenesulfonylamino)phenyl]-amide. LC: Tr 1.20 min; MS: 544.1 (M+1)+.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([NH2:11])=[C:9]([C:12]([NH2:14])=[O:13])[C:8]([CH2:15][CH3:16])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][C:20]=1[O:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CCOC(C)=O>[CH:1]1([N:6]2[C:10]3=[N:11][C:23]([C:22]4[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[C:20]([O:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][O:33][CH2:32][CH2:31]5)[CH:21]=4)=[N:14][C:12](=[O:13])[C:9]3=[C:8]([CH2:15][CH3:16])[NH:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: COc1ccc(C=O)cc1OCCN1CCOCC1
Solvent: CCOC(C)=O
Product: CCc1[nH]n(C2CCCC2)c2nc(-c3ccc(OC)c(OCCN4CCOCC4)c3)nc(=O)c1-2
Temperature: 160 °C

Procedure:
A mixture of 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (1.25 g, 5.63 mmol), 4-methoxy-3-[2-(4-morpholinyl)ethoxy]benzaldehyde (1.64 g), and xylenes (12 ml) was heated at 160° C. overnight. Additional aldehyde (0.5 g) was added and the mixture was refluxed until complete, then cooled to room temperature. The solvent was stripped, the residue was slurried with EtOAc and the product was collected by filtration and combined with the product from a similar experimental run. The combined product was recrystallized from CH3CN to afford 1-cyclopentyl-3-ethyl-6-[4-methoxy-3-[2-(4-morpholinyl)ethoxy]phenyl]pyrazolo[3,4-d]pyrimidin-4-one, m.p. 205°-206° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([NH2:15])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:2].C[Al](C)C.[NH:22](/[C:26](/[CH3:32])=[CH:27]\[C:28](OC)=[O:29])[C:23]([CH3:25])=O>C(Cl)Cl>[CH2:16]([N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:11][C:12]([N:15]3[C:28](=[O:29])[CH:27]=[C:26]([CH3:32])[N:22]=[C:23]3[CH3:25])=[CH:13][N:14]=2)=[CH:6][CH:5]=1)[CH3:17]
Reactant: CCN(CC)c1ccc(-c2ncc(N)s2)cc1
Reactant: COC(=O)/C=C(/C)NC(C)=O
Agent: C[Al](C)C
Solvent: ClCCl
Product: CCN(CC)c1ccc(-c2ncc(-n3c(C)nc(C)cc3=O)s2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3 %

Procedure:
To a solution of 2-(4-(diethylamino)phenyl)thiazol-5-amine (0.45 g, 1.82 mmol) in CH2Cl2 (20 mL) was added trimethylaluminum (4.5 mL, 9.0 mmol, 2 M in toluene) dropwise at rt. The reaction mixture was stirred at rt for 1 h, followed by the addition of a solution of methyl 3-acetaminocrotonate ((315 mg, 2 mmol) in anhydrous CH2Cl2 (5 mL). The reaction mixture was stirred at rt for 3 days, then quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography to give the title compound as a yellow solid (22 mg, 3%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH:16]=O)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1.[NH2:18][CH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:14][CH2:15][CH2:16][NH:18][CH2:19][C@@H:20]3[CH2:24][N:23]([C:25]4[CH:26]=[CH:27][C:28]5[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=5[N:34]=4)[C:22](=[O:36])[CH2:21]3)[C:10](=[O:13])[CH:11]=[CH:12][C:6]2=[N:5][CH:4]=1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1cnc2ccc(=O)n(CCC=O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1cnc2ccc(=O)n(CCCNC[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10.9 %

Procedure:
To a solution of 3-(3-methoxy-6-oxopyrido[2,3-b]pyrazin-5 (6H)-yl)propanal (Reference Example 24, 120 mg, 0.515 mmol) in N,N-dimethylformamide (1.6 ml) were added 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 54, 175 mg, 0.66 mmol) and acetic acid (0.04 ml, 0.66 mmol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was cooled on ice, sodium triacetoxyborohydride (141 mg, 0.66 mmol) was added thereto and stirred overnight at room temperature. Two equivalents of sodium triacetoxyborohydride (282 mg, 1.32 mmol) were further added thereto and the reaction solution was stirred for 2 days. A sodium hydrogen carbonate aqueous solution was added to the reaction solution, which was then extracted with ethyl acetate and the obtained organic layer was washed with water and saturated sodium chloride solution. Subsequently, the organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The obtained crude product was purified by thin layer chromatography (dichloromethane/methanol) to yield 27 mg (11%) of the title compound.
Reaction SMILES: C[O:2][C:3](=[O:24])[C@@H:4]([N:9]1[CH2:13][C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[CH:11][C:10]1=[O:23])[CH2:5][CH:6]([CH3:8])[CH3:7].O.[OH-].[Li+].Cl>O1CCCC1.O>[CH3:22][O:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:12]2[CH2:13][N:9]([C@@H:4]([CH2:5][CH:6]([CH3:7])[CH3:8])[C:3]([OH:24])=[O:2])[C:10](=[O:23])[CH:11]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(OC)cc2)=CC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(OC2=CC(=O)N([C@@H](CC(C)C)C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 97.2 %

Procedure:
A mixture of (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.38 g, 1.16 mmol) in tetrahydrofuran (8.75 mL) and water (2.9 mL) was treated with lithium hydroxide monohydrate (59 mg, 1.40 mmol). The reaction was stirred at 25° C. for 2.5 h. At this time, the reaction was diluted with water (50 mL), acidified with a 2N aqueous hydrochloric acid solution and then was extracted with 10% methanol/dichloromethane (3×75 mL). The combined organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid (0.36 g, 99%) as a white solid: HR-ES-MS m/z calculated for C17H21NO5 [M+H]+ 320.1493, observed 320.1493. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.5 Hz, 3H), 0.92 (d, J=6.5 Hz, 3H), 1.34-1.54 (m, 1H), 1.54-1.68 (m, 1H), 1.68-1.86 (m, 1H), 3.77 (s, 3H), 4.10 (d, J=18.1 Hz, 1H), 4.22 (d, J=18.1 Hz, 1H), 4.62 (dd, J=11.5, 4.2 Hz, 1H), 4.75 (s, 1H), 7.00 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.1 Hz, 2H), 12.89 (br. s., 1H).
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[N:19][CH:18]=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>O1CCOCC1>[Cl:21][C:20]1[C:15]([N:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[N:16][CH:17]=[CH:18][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2Cl)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1nccnc1N1CCNCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Add 4 M HCl in 1,4-dioxane (10 mL) to 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid t-butyl ester (6.80 g, 22.76 mmol). Add 1,4-dioxane (40 mL) and subject the reaction to ultrasound then stir at room temperature under nitrogen for 3 hr. Add further HCl in 1,4-dioxane (40 mL) and stir for 1 hr. Add chloroform (400 mL), wash with 2 N sodium hydroxide (200 mL), saturated aqueous sodium chloride (100 mL), dry (magnesium sulfate) and concentrate to give 3′-chloro-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl as a yellow oil which crystallized on standing to give a solid (4.0 g, 88%). MS (m/z): 199.1 (M+1).
Reaction SMILES: COCN[C:5]([CH:7]1[CH2:11][S:10][CH2:9][N:8]1[C:12]([CH:14]1[CH2:18][S:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:13])=[O:6].[F:26][C:27](I)([F:32])[C:28]([F:31])([F:30])[F:29].C[Li].[Br-].[Li+]>C(OCC)C>[F:26][C:27]([F:32])([C:28]([F:31])([F:30])[F:29])[C:5]([CH:7]1[CH2:11][S:10][CH2:9][N:8]1[C:12]([CH:14]1[CH2:18][S:17][CH2:16][N:15]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:13])=[O:6]
Reactant: COCNC(=O)C1CSCN1C(=O)C1CSCN1C(=O)OC(C)(C)C
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CSCC1C(=O)N1CSCC1C(=O)C(F)(F)C(F)(F)F
Yield: 89.9 %

Procedure:
To a stirred solution of 4-[[4-[(methoxymethylamino)carbonyl]-3-thiazolidinyl]carbonyl]-3-thiazolidine carboxylic acid, 1,1-dimethylethyl ester (compound from Example IIID; 0.33 g, 0.84 mmol) in ethyl ether (30 ml) under argon at -78° C. was added perfluoroethyl iodide (0.32 ml, 2.70 mmol) followed by methyl lithium.lithium bromide (1.57 ml, 2.36 mmol, 1.5M in ethyl ether). TLC indicated the reaction was complete. The reaction was poured into 100 ml ethyl ether containing 25 g silica gel. Residual amounts of product in the flask were dissolved in ethyl ether and added to the silica/ether solution. Subsequently, the organic phase was removed and the silica gel was washed with ethyl ether (2×100 ml). The combined organics were dried over magnesium and sodium sulfate and then filtered and evaporated to give an oily white foam (0.34 g). The material was then flash chromatographed on a 4×10 cm silica gel column eluting with 0.4 liter of ethyl acetate/hexane (30:70) followed by 0.5 liter of ethyl acetate/hexane (75:25). Product containing fractions were combined and concentrated to an oil (49 mg).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]1([C@@H:22]([CH2:24][OH:25])[NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(CC)CC)C>C(O)(C)C>[OH:25][CH2:24][C@@H:22]([NH:23][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: N[C@H](CO)c1ccccc1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: COc1cc2ncnc(N[C@H](CO)c3ccccc3)c2cc1OC
Yield: 70 %

Procedure:
A solution of 4-chloro-6,7-dimethoxyquinazoline (225 mg, 1 mmol), (S)-2-phenylglycinol (137.2 mg, 1 mmol) and triethylamine (304 mg, 3 mmol) in isopropanol (7 ml) was heated to reflux for about 8 h. Then the mixture was evaporated under vacuum to dryness and the residue purified by gradient elution chromatography on silica gel using as eluant dichloromethane/ethanol 2-6%. Thus pure title compound was obtained in 70% yield (228 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])=[CH:38][C:37]=1[CH3:51]>>[Si:41]([O:40][C:39]1[CH:48]=[C:49]([CH3:50])[C:36]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[C:10]3[C:6]=2[CH2:7][CH2:8][C@H:9]3[O:11][C:12]2[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=2)=[C:37]([CH3:51])[CH:38]=1)([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42]
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(O[Si](C)(C)C(C)(C)C)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzo-furan-3-yl)acetate and (4-bromo-3,5-dimethylphenoxy)(tert-butyl)dimethylsilane following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 4): tR=2.09 min; Mass spectrum (ESI+): m/z=599 [M+Na]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([O:8][CH:6]1[CH:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3][CH:2]([CH3:1])[CH2:7]1)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Reactant: O=C(Cl)c1ccccc1
Product: CC1CCC(C(C)C)C(OC(=O)c2ccccc2)C1

Procedure:
A solution of 1-menthol (1 gram) in benzoyl chloride (1 ml) was stirred at room temperature for 72 hours. This solution yielded menthyl benzoate of 89.5% purity. Further purification of this product through column chromatography resulted to increase in purity level to at least 98.8%. This fraction yielded colourless crystals and confirmed for purity by 1HNMR, 13CNMR, IR and Mass spectra.