Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C@@H:3]1[C:7]([OH:9])=[O:8].[C:10](Cl)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11]>O1CCOCC1.C([O-])(O)=O.[Na+]>[C:10]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[C@H:3]1[C:7]([OH:9])=[O:8])([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@H]1NCC[C@@H]1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1[C@@H](O)CCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 58 %

Procedure:
To a stirred and cooled suspension of trans-3-hydroxy-(L)-proline (2.00 g, 15.3 mmol, 1.00 eq.) in 1,4-dioxane (110 mL) and aq. NaHCO3 (5% w/v, 55 mL) was added slowly a solution of Fmoc-Cl (4.02 g, 15.56 mmol, 1.02 eq.) in dioxane (50 mL). The reaction mixture was kept at 4° C. for 4 h, allowed to warm to room temperature, and stirred for another 6 h to afford a clear, colorless solution. Most of the dioxane was evaporated in vacuo (45° C. bath temperature), and the resultant solution was extracted with diethyl ether (2×100 mL) to remove excess Fmoc-Cl. The aqueous layer was acidified to pH 2-3 with 1 M HCl to afford a cloudy solution, which was extracted with EtOAc (4×100 mL). The combined organic layers were dried (MgSO4), filtered, evaporated in vacuo and co-evaporated twice with CH2Cl2. Drying under vacuum afforded the product as an off-white, microcrystalline solid (3.10 g, expected 5.39 g, yield 58%). Spectroscopic data were in agreement with the literature (Taylor, Hardre et al. 2005).
Reaction SMILES: [N+:1](=[CH2:3])=[N-:2].CC1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[CH3:18][O:19][C:20](=[O:25])[C:21](Br)=[CH:22][CH3:23].C(O)(=O)C>C(OCC)C>[CH3:23][C:22]1[CH:3]=[N:1][NH:2][C:21]=1[C:20]([O:19][CH3:18])=[O:25]
Reactant: CC=C(Br)C(=O)OC
Reactant: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1[nH]ncc1C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of diazomethane (nominally 0.68 g—generated from DIAZALD® (5 g) in diethyl ether (45 ml)) at −78° C. was added a solution of E/Z methyl-2-bromo-2-butenoate (3.58 g) (available from Fluka) in diethyl ether (15 ml), dropwise, over 15 min. The mixture was maintained at −78° C. for 1 h then allowed to warm to 20° C. with stirring overnight. Acetic acid (1 ml) was added to destroy excess diazomethane and the mixture evaporated under reduced pressure. The residue was co-evaporated with toluene. Purification of the residue by column chromatography on silica gel eluting with ethyl acetate:cyclohexane (1:1) gave the title compound (1.12 g) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].[NH:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:14]1[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Reactant: OCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(N2CCC(CCO)CC2)c(C)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 95.7 %

Procedure:
To 1-fluoro-2-methyl-5-(methyloxy)-4-nitrobenzene (Example 113, Step B) (21.5 g, 116 mmol) in DMSO (100 mL) was added 2-(4-piperidinyl)ethanol (15 g, 116 mmol) and K2CO3 (48.1 g, 348 mmol). The reaction was heated in a sealed tube at 80° C. overnight. The reaction mixture was cooled to rt and poured into H2O. The resultant solid was filtered, air dried, dissolved in DCM, dried (Na2SO4), filtered, and rotovapped down to give the title compound of Step F (32.6 g, 111 mmol, 95%). 1H NMR (400 MHz, DMSO-d6) δ 7.71 (s, 1H), 6.63 (s, 1H), 4.33 (t, J=5.0 Hz, 1H), 3.85 (s, 3H), 3.39-3.49 (m, 2H), 3.23 (d, J=12.2 Hz, 2H), 2.65 (t, J=11.3 Hz, 2H), 2.14 (s, 3H), 1.72 (d, J=11.4 Hz, 2H), 1.46-1.61 (m, 1H), 1.39 (q, J=6.6 Hz, 2H), 1.25 (qd, J=12.0, 3.4 Hz, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([O:35][C:36]1[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>C(Cl)Cl.C(#N)C>[CH2:28]([O:35][C:36]1[CH:37]=[CH:38][C:39]([C:40]([O:27][C:24]2[CH:23]=[CH:22][C:21]([CH2:20][C@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])=[CH:26][CH:25]=2)=[O:41])=[CH:43][CH:44]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCOc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Product: CCCCCCCOc1ccc(C(=O)Oc2ccc(C[C@H](NC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)cc2)cc1
Reaction time: 8 h
Yield: 92.6 %

Procedure:
Prepared using General Procedure 3: To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-hydroxyphenyl)propanoate (5.57 g, 15.0 mmol) and TEA (6.27 mL, 45.0 mmol) in DCM (15 mL) and acetonitrile (30 mL) was added 4-(heptyloxy)benzoyl chloride (3.78 mL, 15.75 mmol) dropwise. After stirring overnight, the mixture was quenched with saturated aqueous NaHCO3 (50 mL). The organic layer was dried over MgSO4, and concentrated. The product was purified by chromatography (EA/hexanes) to afford 8.19 g (93%) of (S)-4-(2-(((benzyloxy)carbonyl)amino)-3-(tert-butoxy)-3-oxopropyl)phenyl 4-(heptyloxy)benzoate INT-4. LCMS-ESI (m/z) calculated for C35H43NO7: 589; no mass ion observed, tR=5.26 min (Method 3). 1H NMR (400 MHz, CDCl3) δ 8.17-8.08 (m, 2H), 7.41-7.28 (m, 5H), 7.19 (d, J=8.4 Hz, 2H), 7.15-7.07 (m, 2H), 7.01-6.91 (m, 2H), 5.35-5.23 (m, 1H), 5.17-5.04 (m, 2H), 4.54 (dd, J=13.9, 6.1 Hz, 1H), 4.04 (t, J=6.6 Hz, 2H), 3.10 (d, J=5.9 Hz, 2H), 1.91-1.76 (m, 2H), 1.47 (ddd, J=15.2, 8.9, 6.7 Hz, 2H), 1.43-1.36 (m, 10H), 1.36-1.30 (m, 5H), 0.90 (t, J=6.9 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH2:17])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[CH:24]1([C:28](O)=[O:29])[CH2:27][CH2:26][CH2:25]1>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C:14]([NH:17][C:28]([CH:24]2[CH2:27][CH2:26][CH2:25]2)=[O:29])([CH3:16])[CH3:15])[N:5]=[C:4]([CH3:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=C(O)C1CCC1
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)NC(=O)C3CCC3)c2c1N

Procedure:
Prepared as in Example Da from ethyl 4-amino-5-(2-amino-2-methylpropoxy)-2-methylquinoline-3-carboxylate (Example Db) and cyclobutanecarboxylic acid as an off-white solid (61%). MS 400 (MH+).
Reaction SMILES: C([NH:4][NH:5][C:6]([N:8]1[N:12]=[C:11]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[F:20])[S:10][C:9]1([CH2:27][O:28][CH2:29][O:30][CH3:31])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])(=O)C.CCN(C(C)C)C(C)C.O=P(Cl)(Cl)Cl.Cl[CH:47](Cl)[CH3:48]>>[F:20][C:14]1[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:13]=1[C:11]1[S:10][C:9]([CH2:27][O:28][CH2:29][O:30][CH3:31])([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:8]([C:6]2[O:7][C:47]([CH3:48])=[N:4][N:5]=2)[N:12]=1
Reactant: COCOCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=O)NNC(C)=O
Reactant: CC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCOCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nnc(C)o1
Reaction time: 0.5 h
Yield: 38 %

Procedure:
To a mixture of N′-acetyl-5-(2,5-difluorophenyl)-2-((methoxymethoxy)methyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbohydrazide (0.221 g, 0.491 mmol) and DIEA (0.634 g, 4.91 mmol) in dichloroethane (10 mL) was added POCl3 (0.376 g, 2.45 mmol). After stirring for 30 minutes, the mixture was partitioned between dichloromethane (10 mL) and saturated NaHCO3 (5 mL). The organic layer was extracted with dichloromethane (10 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, and chromatographed (20:1 to 10:1 hexanes/ethyl acetate) to provide the final product (0.080 g, 38%). MS ESI (+) m/z 433 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.68 (m, 1H), 7.54 (d, 2H, J=7 Hz), 7.35 (m, 3H), 7.10 (m, 2H), 4.90 (d, 1H, J=11 Hz), 4.74 (m, 2H), 4.52 (d, 1H, J=11 Hz), 3.37 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[C:24](Cl)(=[O:26])[CH3:25].[NH4+].[Cl-]>C1COCC1>[C:24]([N:8]1[C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:11][O:10][C:9]1=[O:12])(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(=O)N1C(=O)OC[C@H]1c1ccccc1
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a stirred suspension of 5.000 g (4R)-(−)-4-phenyl-2-oxazolidinone (30.03 mmol) in 100 mL THF, were added 21.0 mL n-butyllithium in hexane (1.5 M, 31.53 mmol, 1.05 eq) at 0° C. within 10 min. The resulting colorless solution was stirred for additional 50 min at 0° C. 2.57 mL acetyl chloride (36.04 mmol, 1.2 eq) were then added within 1 min. After 3.5 h the reaction was stopped by addition of 25 mL saturated aqueous NH4Cl and the mixture was extracted with 75 mL ethyl acetate. The organic phase was washed with 50 mL saturated aqueous NaHCO3 and with 50 mL brine. The solution was dried for 30 minutes over 5 g Na2SO4 and filtered. The filter cake was washed with 10 mL ethyl acetate. After removal of solvent in a rotary evaporator (40° C., 18 mbar), the crude product was obtained as white crystals (6.13 g, 100% w/w; HPLC purity 88.3% area). Further purification was achieved by dissolving in 10.6 mL ethyl acetate at reflux temperature and subsequent dropwise addition of 26.6 mL heptane. The resulting suspension was allowed to slowly cool down to 5° C. and after standing overnight, the precipitate was collected by filtration. After washing with 3 mL heptane, the title compound was obtained as white crystals (5.26 g, 25.6 mmol, 85% by weight) and in high purity (HPLC purity 96.6% area).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>O1CCCC1>[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)=[O:24]
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc2[nH]ccc2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2[nH]ccc2c1)c1ccco1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 50.4 %

Procedure:
To a solution of 2.09 gm (15.8 mMol) 5-amino-1H-indole in 20 mL tetrahydrofuran were added 2.6 mL (18.97 mMol) triethylamine and the solution was cooled in an ice bath. To the reaction mixture were then added dropwise 1.71 ml (17.4 mMol) 2-furoyl chloride. When this addition was complete the cooling bath was removed and the reaction mixture was stirred 1.5 hours at ambient temperature. At this point the reaction was diluted with water and extracted well with ethyl acetate. The organic solutions were combined and washed sequentially with water, 2N sodium hydroxide, water and saturated aqueous sodium chloride. The remaining organics were then dried over sodium sulfate and concentrated under reduced pressure to give a dark purple solid. The solid was subjected to flash chromatography, eluting with a gradient of dichloromethane containing 0-2% methanol. The recovered solid was crystallized from ethyl acetate to give 1.8 gm (50.3%) of 5-(2-furoyl)amino-1H-indole as pale purple crystals.
Reaction SMILES: [C:1]1([CH3:28])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[CH:23]([CH2:24][C:25](O)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]2=3)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[ClH:29].Cl.[NH:31]1[CH2:35][CH2:34][N:33]=[C:32]1[C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][NH2:44])=[CH:38][CH:37]=1>>[ClH:29].[NH:33]1[CH2:34][CH2:35][N:31]=[C:32]1[C:36]1[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][NH:44][C:25](=[O:26])[CH2:24][CH:23]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]2[S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:28])=[CH:6][CH:5]=2)(=[O:9])=[O:8])=[CH:40][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)O)cc1
Reactant: NCCc1ccc(C2=NCCN2)cc1
Agent: Cl
Product: Cc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2CC(=O)NCCc2ccc(C3=NCCN3)cc2)cc1

Procedure:
The title compound was prepared from [5-(toluene-4-sulfonyl)-5,6-dihydro-phenanthridin-6-yl]-acetic acid and 2-[4-(4,5-dihydro-1H-imidazol-2-yl)-phenyl]-ethylamine dihydrochloride (Reference Example 2) according to the method described in Example 1e. MS (EI) 565.7 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])C.C1CCN2C(=NCCC2)CC1>CO>[CH3:1][O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][OH:16])[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5]
Reactant: CCOC(=O)c1cc2ccc(CO)cc2s1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)c1cc2ccc(CO)cc2s1
Reaction time: 48 h

Procedure:
A solution of 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (9.45 g, 40.0 mmol) and DBU (6.00 mL, 40.1 mmol) in anhydrous MeOH (200 mL) was allowed to stir for 2 d. After concentration, the residue was dissolved in EtOAc (800 mL) and washed with 1N HCl, water, saturated NaHCO3 and brine. The organic layer was dried, filtered and the filtrate was concentrated and dried to give 6-hydroxymethyl-benzo[b]thiophene-2-carboxylic acid methyl ester as off white solid. 1H NMR (CDCl3, 200 MHz) δ 8.03 (d, J=0.6 Hz, 1H), 7.90-7.80 (m, 2H), 7.39 (dd, J=8.0, 1.4 Hz, 1H), 4.83 (s, 2H), 3.94 (s, 3H), 1.98 (brs, 1H). MS (EI): cal'd 223.0 (MH+), exp 223.1 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([CH3:13])=[CH:9]2)([CH3:3])[CH3:2].[CH3:14]N(C=O)C.[H-].[Na+].IC>CCOCC>[CH:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11]([CH3:14])[C:10]([CH3:13])=[CH:9]2)([CH3:3])[CH3:2]
Reactant: Cc1cc2cccc(C(C)C)c2[nH]1
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CI
Product: Cc1cc2cccc(C(C)C)c2n1C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 7-isopropyl-2-methyl-1H-indole (0.75 g, 4.33 mmol) and DMF (2 mL) is added 60% NaH (0.19 g, 4.76 mmol). After 30 minutes iodomethane (0.30 mL, 4.76 mmol) is added and the solution stirred for 1 hour. The solution is diluted with Et2O (30 mL), washed with water (2×20 mL), brine (20 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO (2%-5% EtOAc gradient) to furnish the title compound (0.33 g, 1.76 mmol, 41%). 1H NMR (CDCl3), δ 1.42 (d, J=6.5 Hz, 6H), 2.43 (s, 3H), 3.84-3.91 (m, 1H), 6.24-6.27 (m, 1H), 3.93 (s, 1H), 6.29 (s, 1H), 7.01-7.14 (m, 1H), 7.38 (d, J=7.5 Hz, 1H) ppm. LC/MS (m/z): calcd. for C13H17N (M+H)+: 188.2. found: 188.1.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH2:8][O:9][CH3:10])[CH:7]=1.B([C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)(O)O.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:9][CH2:8][C:6]1[CH:7]=[C:2]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1
Reactant: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Reactant: COCc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COCc1cncc(-c2ccc(C(C)(C)C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
3-bromo-5-(methoxymethyl)pyridine (example 32b) (4.8 g, 23.56 mmol), 2-(4-boronophenyl)-2-methylpropanoic acid (example 21b) (5.4 g, 25.92 mmol) and K2CO3 (6.5 g, 47.12 mmol) were mixed in DME (60 mL) and 15 ml of water (15 mL). The mixture was degassed for 30 minutes and Pd(PPh3)4 (0.55 g, 0.47 mmol) was added. The reaction mixture was heated to reflux for 16 hr then cooled to room temperature, and evaporated under reduced pressure. The residue was diluted with aqueous NaOH (0.5 N, 60 mL) and stirred for 30 min., and the solution extracted with ether (20 mL×3). The aqueous phase was cooled to 0° C., acidified with 2 N HCl to PH=5˜6, then extracted with EtOAc. The organic phase was washed successively with water and brine, dried over MgSO4, filtered and evaporated. The residue was triturated with hexane, filtered and evaporated to give 5.9 g of 2-(4-(5-(methoxymethyl)pyridine-3-yl)phenyl)-2-methylpropanoic acid as a light brown solid in 88% yield. 1H NMR (400 MHz, CDCl3): δ 1.66 (s, 6H), 3.44 (s, 3H), 4.54 (s, 2H), 7.54-7.56 (d, 4H), 7.92 (s, 1H), 8.56 (s, 1H), 8.76 (s, 1H). MS (M+H, 286).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].[H-].[Na+].[CH2:10]([O:12][C:13](=[O:16])[CH2:14][CH3:15])[CH3:11]>C1COCC1>[CH2:10]([O:12][C:13](=[O:16])[C@@H:14]([N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7])[CH3:15])[CH3:11]
Reactant: CCOC(=O)CC
Reactant: O=c1cccc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](C)n1ccccc1=O
Reaction time: 0.17 h
Yield: 46.7 %

Procedure:
A stirred solution of 1H-Pyridin-2-one (500 mg, 5.26 mmol) in anhydrous THF (50 ml) at room temperature was treated portionwise with 60% NaH (231 mg, 5.78 mmol). The reaction mixture was kept for 10 min then added over 5 min to a solution of (R)-2-trifluoromethanesulfonyloxy)-propionic acid ethyl ester (1315 mg, 5.26 mmol) in anhydrous THF (2.5 ml) at room temperature. The resulting mixture was stirred for 2 h, then concentrated. The residue was dissolved in ethyl acetate, and the resulting solution was washed with ice cold dilute HCl. The organic layer was removed and the aqueous layer re-extracted with ethyl acetate. The combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (20% up to 80% ethyl acetate in hexane) to afford the title compound as a yellow oil (480 mg, 46%): [α]27D=−56.4° (c=0.275, CH2Cl2); 1H NMR (400 MHz CDCl3) δ 1.3 (3H, t), 1.65 (3H, d), 4.2 (2H, q), 5.6 (1H, q), 6.2 (1H, t), 6.4 (1H, d), 7.2-7.3 (2H, m).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[N:7]1[C:14](Cl)=[N:13][C:11]([Cl:12])=[N:10][C:8]=1Cl.[CH2:16]([NH:19][CH2:20][CH:21]=[CH2:22])[CH:17]=[CH2:18].[OH-].[Na+]>O1CCOCC1>[CH2:16]([N:19]([CH2:20][CH:21]=[CH2:22])[C:14]1[N:7]=[C:8]([N:19]([CH2:20][CH:21]=[CH2:22])[CH2:16][CH:17]=[CH2:18])[N:10]=[C:11]([Cl:12])[N:13]=1)[CH:17]=[CH2:18]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: C=CCNCC=C
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=CCN(CC=C)c1nc(Cl)nc(N(CC=C)CC=C)n1
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
After 21.2 g (0.20 mol) of sodium carbonate and 20.0 g (0.10 mol) of cyanuric chloride were added and dissolved into 140 g of 1,4-dioxane, 19.8 g (0.20 mol) of diallylamine was gradually added thereinto and further, 8.4 g (0.20 mol) of caustic soda was added thereinto. By generating the heat of reaction, the temperature of reaction solution was raised to about 60° C. and the reaction was continued at the temperature for 2 hours. Thereafter, the reaction mixture was cooled and filtered to remove the sodium chloride generated as the byproduct. The obtained filtrate was distilled under reduced pressure to recover the solvent. Therefore, 34 g (0.09 mol) of 4,6-bis(diallylamino)-2-chloro-1,3,5-triazine was obtained.
Reaction SMILES: [NH2:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6].[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]1[O:22][C:21](=[O:23])[C:20]2([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[N:19]=1.O>CN(C)C=O>[S:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[CH:11]=[C:10]1[C:18]([NH:19][C:20]1([C:21]([NH:1][C@H:2]([CH2:7][OH:8])[CH2:3][CH2:4][S:5][CH3:6])=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]
Reactant: O=C1OC(c2cc3ccccc3s2)=NC12CCCCC2
Reactant: CSCC[C@H](N)CO
Solvent: O
Solvent: CN(C)C=O
Product: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Reaction time: 8 h
Yield: 98.1 %

Procedure:
284 mg (2.1 mmol) of L-methioninol was added to a solution of 500 mg (1.75 mmol) of 2-(2-benzothienyl)-3-oxa-1-azaspiro[4.5]dec-1-en-4-one in 3 ml of N,N-dimethylformamide, and the mixture was stirred overnight. Water was slowly added and the precipitated crystal was collected by filtration. The obtained crystal was dried under reduced pressure to obtain 722 mg (98%) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:15])([CH3:14])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1.[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22]Cl)#[N:18].N1C=CC=CC=1>C(Cl)Cl>[C:17]([CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]#[N:27])[S:22][N:2]([CH3:1])[C:3](=[O:16])[O:4][C:5]1[C:13]2[O:12][C:11]([CH3:14])([CH3:15])[CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)#[N:18]
Reactant: CNC(=O)Oc1cccc2c1OC(C)(C)C2
Reactant: N#CCCN(CCC#N)SCl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(SN(CCC#N)CCC#N)C(=O)Oc1cccc2c1OC(C)(C)C2
Reaction time: 20 h

Procedure:
4.4 g (0.02 mole) of 2,3-dihydro-2,2-dimethylbenzofuran-7-yl N-methyl-carbamate, 3.8 g (0.02 mole) of bis(cyanoethyl)aminosulfenyl chloride obtained in Example 31, and 4.7 g (0.06 mole) of pyridine were dissolved in 35 ml of methylene chloride, and the resulting solution was stirred for 20 hours at 25° to 30° C. After completion of the reaction, the reaction solution was washed successively with water, diluted hydrochloric acid and water. The methylene chloride layer was dried over sodium sulfate and concentrated under reduced pressure to obtain an oily product which was almost entirely composed of the desired product although containing small amounts of the starting materials and impurities. Yield: 6.2 g (82.7%).
Reaction SMILES: O.[OH-].[Li+].[C:4]([N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH2:19][C:20]([NH:22][C@@H:23]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:24](=[O:31])[C:25]([O:27]C(C)C)=[O:26])=[O:21])[C:9](=[O:39])[C@H:8]1[CH:40]([CH3:42])[CH3:41])(=[O:6])[CH3:5]>CO>[C:4]([N:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:10]([CH2:19][C:20]([NH:22][C@@H:23]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:24](=[O:31])[C:25]([OH:27])=[O:26])=[O:21])[C:9](=[O:39])[C@H:8]1[CH:40]([CH3:42])[CH3:41])(=[O:6])[CH3:5]
Reactant: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C(=O)OC(C)C)C(=O)[C@H]1C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=O)N1C=C(c2ccccc2)N(CC(=O)N[C@@H](Cc2ccccc2)C(=O)C(=O)O)C(=O)[C@H]1C(C)C
Reaction time: 1 h
Yield: 96.6 %

Procedure:
Water (0.45 ml) and a 1 N aqueous lithium hydroxide solution (55 μl) are added to a solution of isopropyl (3S)-3-{(3R)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-2-oxo-4-phenylbutyrate (24.5 mg, Compound No. 2-2) in methanol (0.5 ml), and the mixture is stirred for one hour. The reaction mixture is concentrated under reduced pressure, and 1 N hydrochloric acid is added to the concentrate to acidify the system. The whole is extracted with ethyl acetate, and the extract is washed with water and a saturated aqueous sodium hydrogencarbonate solution successively and dried over magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (21.8 mg).