Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([CH2:5][CH2:6][C@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[O:4].C(CC(=O)C)(=O)C.[CH2:19]([N:21](CC)CC)[CH3:20].C(N)C.C(O)=O>CO.CC(O)C>[NH2:11][C@H:7]([C:8]([OH:10])=[O:9])[CH2:6][CH2:5][C:3]([NH:21][CH2:19][CH3:20])=[O:4]
Reactant: CCN(CC)CC
Reactant: COC(=O)CC[C@H](N)C(=O)O
Agent: CCN
Solvent: O=CO
Solvent: CO
Solvent: CC(C)O
Product: CCNC(=O)CC[C@H](N)C(=O)O
Temperature: 60 °C
Reaction time: 1 h
Yield: 81.9 %

Procedure:
First, 20.0 g (0.124 mol) of L-glutamic acid-γ-methyl ester was suspended in 20 g of methanol. To this, 13.7 g (0.137 mol) of acetylacetone and 12.5 g (0.124 mol) of triethylamine were added. The mixture was stirred at 60° C. for one hour. Subsequently, 80 g (1.24 mol) of 70% ethylamine was added to the mixture. After the mixture was allowed to react for 6 hours, excessive ethylamine was distilled away under reduced pressure. To this, 11.4 g (0.246 mol) of formic acid and 120 mL of 2-propanol (IPA) were added. The crystal precipitated was filtrated by suction and washed with 20 mL of IPA to obtain wet matter. The wet matter was dried under reduced pressure to obtain 17.7 g of theanine as a white crystal substance (yield: 82%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2Br)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>O1CCOCC1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=2[C:37]2[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=2)[N:11]2[CH2:25][CH2:26][N:27]([CH:30]([CH3:32])[CH3:31])[C:28](=[O:29])[C:10]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: CC(C)N1CCn2c(Cc3ccc(Cl)cc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)N1CCn2c(Cc3ccc(Cl)cc3-c3ccc(F)cc3)nc(=O)c(OCc3ccccc3)c2C1=O
Temperature: 80 °C
Yield: 44.2 %

Procedure:
Into a sealed tube was placed a stirred solution of 9-benzyloxy-6-(2-bromo-4-chlorobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (380) (70 mg, 0.136 mmol) in dioxane (3 mL). 4-Fluorophenyl boronic acid (18.99 mg, 0.14 mmol) and a 1N solution of potassium carbonate [(56.244 mg, 0.407 mmol) in 0.82 mL water] were added at room temperature and the reaction mixture was purged for 30 min with argon. To the reaction Pd(triphenyl phosphine)4 (15.676 mg, 0.014 mmol) was added under argon, followed by 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (11.138 mg, 0.027 mmol). The reaction mixture was further degassed for another 10 min, then heated to 80° C. for 30 min (monitored by LC-MS). The reaction mixture was filtered through a pad of celite. The filtrate was diluted with water (5 mL) and extracted with ethyl acetate (2×20 mL). The combined extracts were dried and concentrated. The resulting crude product was purified by column chromatography (using amine bound silica gel) to get 9-benzyloxy-6-(5-chloro-4′-fluoro-biphenyl-2-ylmethyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (385) (32 mg, 44.34%) as an off-white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CC[N:13]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.NCC(N[C@H](B1O[C@@H]2C[C@@H]3C[C@H]([C@]2(C)O1)C3(C)C)CC(C)C)=O>C(Cl)Cl>[C:4]([NH2:13])(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(O)c1ccccc1Br
Reactant: CCN=C=NCCCN(C)C
Agent: CC(C)C[C@H](NC(=O)CN)B1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: NC(=O)c1ccccc1
Reaction time: 2 h
Yield: 292.9 %

Procedure:
To a solution of 2-bromobenzoic acid (0.124 g, 0.62 mmol) in DCM (2.25 mL) were added EDCI (0.119 g, 0.62 mmol), HOBt (0.084 g, 0.62 mmol), N-methyl morpholine (0.185 mL, 1.68 mmol) and 2-amino-N-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}acetamide (0.2 g, 0.56 mmol). The reaction mixture was allowed to stir for 2 h and was concentrated. The residue was diluted with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography to give 2-bromo-N-[2-{(1R)-3-methyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]butyl}amino)-2-oxoethyl]benzamide (0.22 g, 78%).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:15][CH2:14][O:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:16]([NH:18][C:19](=[O:37])[C:20]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[C:23]([CH3:35])=[C:22]([F:36])[CH:21]=1)[CH3:17].C(=O)([O-])O.[Na+]>C(O)(C)C.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>[CH2:16]([NH:18][C:19](=[O:37])[C:20]1[CH:25]=[C:24]([C:2]2[CH:10]=[C:9]3[C:5]([C:6]([CH:11]4[CH2:15][CH2:14][O:13][CH2:12]4)=[N:7][NH:8]3)=[CH:4][CH:3]=2)[C:23]([CH3:35])=[C:22]([F:36])[CH:21]=1)[CH3:17]
Reactant: Brc1ccc2c(C3CCOC3)n[nH]c2c1
Reactant: CCNC(=O)c1cc(F)c(C)c(B2OC(C)(C)C(C)(C)O2)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: [Na+]
Solvent: CC(C)O
Product: CCNC(=O)c1cc(F)c(C)c(-c2ccc3c(C4CCOC4)n[nH]c3c2)c1
Temperature: 150 °C
Reaction time: 0.25 h
Yield: 38.1 %

Procedure:
A mixture of 6-bromo-3-(tetrahydro-3-furanyl)-1H-indazole (Intermediate 9, 84 mg) N-ethyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (Intermediate 5, 97 mg) aqueous sodium hydrogen carbonate (1M, 630 μL) and tetrakis(triphenylphosphine)palladium (7 mg) in isopropanol (4 ml) in a sealed vial was stirred at 150° C. for 15 min in a microwave oven. The solvent was removed under vacuum and the residue purified by chromatography on a silica column eluting with cyclohexane:ethyl acetate (50:50 to 0:100) to give the title compound as a white solid (44 mg).
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2].[Cl:16]N1C(=O)N(Cl)C(=O)N(Cl)C1=O>CN(C)C=O>[CH:1]([NH:3][C:4]1[S:5][C:6]([Cl:16])=[C:7]([C:9](=[O:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:8]=1)=[O:2]
Reactant: CCOC(=O)C(=O)c1csc(NC=O)n1
Reactant: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: CCOC(=O)C(=O)c1csc(=NC=O)[nH]1
Solvent: CN(C)C=O
Product: CCOC(=O)C(=O)c1nc(NC=O)sc1Cl
Temperature: 60 °C

Procedure:
A suspension of ethyl 2-(2-formylamino-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2formylimino-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (6.9 g.) in dimethylformamide (40 ml.) was heated at 60° C. to produce a solution, and to the solution was dropwise added a solution of trichloroisocyanuric acid (2.8 g.) in dimethylformamide (10 ml.) over 15 minutes at the same temperature with stirring and then the mixture was further stirred for 1 hours at the same temperature. After the reaction, the reaction mixture was poured into ice-water (400 g.). The precipitates were collected by filtration, washed with water and then dried to give ethyl 2-(2-formylamino-5-chloro-1,3-thiazol-4-yl)glyoxylate, which can be represented as ethyl 2-(2-formylimino-5-chloro-2,3-dihydro-1,3-thiazol-4-yl)glyoxylate, (7.1 g.), mp. 151° to 153° C. The remaining filtrate was extracted with ethyl acetate, and the extract was washed with water and then dried over magnesium sulfate. The solvent was distilled off from the extract to give further the same object compound (0.75 g.).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[C:6]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)=[C:5]2[Cl:25].C1COCC1.C([Li])CCC.[CH3:36][C:37]1[C:42]([CH:43]=[O:44])=[CH:41][CH:40]=[C:39]([CH3:45])[N:38]=1>CC(C)=O.CCCCCC>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:43]([C:42]3[C:37]([CH3:36])=[N:38][C:39]([CH3:45])=[CH:40][CH:41]=3)[OH:44])[CH:3]=2)[N:8]=[C:7]([O:12][CH3:13])[C:6]=1[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1
Reactant: Cc1ccc(C=O)c(C)n1
Reactant: COc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)cc1
Temperature: -70 °C
Reaction time: 0.02 h

Procedure:
To a 100 mL flask containing 6-bromo-4-chloro-2-methoxy-3-(4-(trifluoromethyl)benzyl)quinoline (2.5 g, 5.8 mmol, Intermediate 12: step d) was added THF (55 mL) at room temperature which resulted in a colorless homogeneous mixture. The solution was cooled to −70° C. (the solution remained homogeneous) and then n-butyllithium (2.5 M in hexanes, 2.6 mL, 6.5 mmol) was added dropwise. The color of the solution became a reddish-brown color. After 1 minute, (2,6-dimethylpyridine-3-carboxaldehyde (1.01 g, 7.5 mmol in 2 mL THF) was introduced and the color of the mixture became a light greenish-yellow color. After 15 minutes, HPLC and TLC (50% acetone-hexane) indicated that the reaction was complete. The mixture was allowed to warm to −20° C. over 40 minutes at which time the reaction was quenched with aqueous NH4Cl solution. The reaction was diluted further with water and extracted with EtOAc (3×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to provide an orange foam. The crude product was chromatographed on silica gel (10% acetone-hexane increasing to 30% acetone) to afford the title compound as a light yellow foam.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36].O>CN(C)C(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1)=[O:36]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Reactant: O=C(Cl)CCl
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (948 mg, 2.14 mmol) produced in Example D25(iii) in N,N-dimethylacetamide (20 mL) was added chloroacetyl chloride (425 μL, 5.34 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water (60 mL), and the mixture was extracted with ethyl acetate (30 mL, 15 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (778 mg, 71%) as a white solid.
Reaction SMILES: [C:1]1([C:7]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:8][CH2:9][CH2:10][C:11]([NH2:13])=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.C(=O)(O)[O-].[Na+].C(OCC)(=O)C>CS(O)(=O)=O>[C:1]1([C:7]2([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[NH:13][C:11](=[O:12])[CH2:10][CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NC(=O)CCC=C(Cc1ccccc1)c1ccccc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: CCOC(C)=O
Product: O=C1CCCC(Cc2ccccc2)(c2ccccc2)N1
Temperature: 0 °C
Yield: 55 %

Procedure:
5,6-Diphenyl-4-hexenamide (30 g) from step (d) was added to a stirred solution of phosphorous pentoxide (25 g) in methanesulfonic acid (250 mL) at 100°-110° C. The reaction was stirred for several minutes; then the reaction mixture was poured slowly into an ice-cooled mixture of saturated aqueous sodium bicarbonate and ethyl acetate. The mixture was extracted with ethyl acetate and the ethyl acetate layer was separated, washed with aq. NaHCO3, water and brine and dried (MgSO4). Concentration of the solvent to dryness afforded the crude amide which was purified by chromatography on silica gel and elution with 75% ethyl acetate: hexane to give the title compound as a solid (16.5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:17].[NH2:18][C:19]1[C:23]([C:24]#[N:25])=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:20]3[N:21]=[CH:22][C:23]([C:24]#[N:25])=[C:19]3[N:18]=2)=[CH:4][C:3]=1[CH3:17]
Reactant: N#Cc1c[nH]nc1N
Reactant: Cc1cc(C(=O)CC(=O)C(F)(F)F)ccc1Cl
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#N)c3n2)ccc1Cl
Yield: 38 %

Procedure:
Reaction of 1-(4-chloro-3-methyl-phenyl)-4,4,4-trifluoro-butane-1,3-dione (264 mg, 1.0 mmol), prepared from commercially available 4-chloro-3-methyl-acetophenone according to general procedure A, and 3-amino-4-cyano-pyrazole (108 mg, 1.0 mmol) according to general procedure B yielded the title compound as an off-white solid (128 mg, 38%). MS (ISP) 337.1 [(M+H)+]; mp 216° C.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:14]=[CH:15][N:16]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=2.[CH:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([NH:23][C:2]2[C:3]3[N:4]([CH:14]=[CH:15][N:16]=3)[C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([Cl:12])=[C:7]([Cl:13])[CH:6]=3)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: Clc1cc2nc(Cl)c3nccn3c2cc1Cl
Reactant: NC1CCCCC1
Product: Clc1cc2nc(NC3CCCCC3)c3nccn3c2cc1Cl

Procedure:
By reacting 4,7,8-trichloroimidazo[1,2-a]quinoxaline example 22 with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-cyclohexylamino-7,8-dichloroimidazo[1,2-a] quinoxalin m.p. (DSC)=162.3° C.(onset); IR (KBr): 3332, 2929, 1587, 1550 cm-1 ; 1H-NMR (CDCl3): δ7.8 (2H,m), 7.7 (1H,s), 7.55 (1H,d, J=2 Hz), 6.2 (1H,d), 4.4 (1H,m), 2.3÷1.2 (10H,m); UV (EtOH): λmax =234, 274, 292, 304, 330, 345 nm. Elementary analysis for C16H16Cl2N4 (m.w. 344.25): calcd. C 55.82, H 4.98, N 16.28%; found C 55.83, H 5.00, N 16.31%.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][CH:17]=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[N:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: OC[C@@H]1CC[C@H]2CNCCN2C1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@@H]1CC[C@H]2CN(c3ncccn3)CCN2C1
Temperature: 90 °C
Yield: 88.4 %

Procedure:
A mixture of 2.52 g (14.8 mmol) of (7R,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 1), 1.70 g (14.8 mmol) of 2-chloropyrimidine and 6.91 g (65.2 mmol) of sodium carbonate in 150 mL of water was heated at 90° C. for 16 h.; then cooled and extracted with chloroform (3×). The organic layer was dried (magnesium sulfate), filtered and evaporated to give 3.25 g (89%) of the title compound which was used without purification in subsequent reactions.
Reaction SMILES: [C:1]([O:5][P:6]([C:13]([F:64])([F:63])[C:14]1[CH:62]=[CH:61][C:17]([CH2:18][C:19]([C:49]2[CH:60]=[CH:59][C:52]([C:53]([O:55][CH:56]([CH3:58])[CH3:57])=[O:54])=[CH:51][CH:50]=2)([C:40](=[O:48])[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:20]/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][C:26]([C:29]([P:32]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:33])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.[Pd]>[C:9]([O:8][P:6]([C:13]([F:64])([F:63])[C:14]1[CH:62]=[CH:61][C:17]([CH2:18][C:19]([C:49]2[CH:60]=[CH:59][C:52]([C:53]([O:55][CH:56]([CH3:57])[CH3:58])=[O:54])=[CH:51][CH:50]=2)([C:40](=[O:48])[C:41]2[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=2)[CH2:20][CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]([P:32]([O:37][CH2:38][CH3:39])([O:34][CH2:35][CH3:36])=[O:33])([F:31])[F:30])=[CH:25][CH:24]=2)=[CH:16][CH:15]=1)([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: CCOP(=O)(OCC)C(F)(F)c1ccc(/C=C/CC(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)(C(=O)c2ccc(F)cc2)c2ccc(C(=O)OC(C)C)cc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(F)(F)c1ccc(CCCC(Cc2ccc(C(F)(F)P(=O)(OC(C)(C)C)OC(C)(C)C)cc2)(C(=O)c2ccc(F)cc2)c2ccc(C(=O)OC(C)C)cc2)cc1

Procedure:
To a solution of isopropyl 4-[(E)-1-{4-[[di(tert-butoxy)phosphoryl](difluro)methyl]benzyl}-4-{4-[(diethoxyphosphoryl)(difluoro)methyl]phenyl}-1-(4-fluorobenzoyl)-3-butenyl]benzoate in ethyl acetate was added palladium on charcoal. The mixture ws then hydrogenated on a Parr apparatus at 50 psi. The reaction mixture was filtered and evaporated to give 0.02 g of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([O:20]C(C)(C)C)=[O:19])[CH:13]=[CH:12][CH:11]=3)[S:9][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>>[CH3:1][C:2]1[CH:27]=[CH:26][C:5]2[C:6](=[O:25])[N:7]=[C:8]([C:10]3[N:15]=[C:14]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:13]=[CH:12][CH:11]=3)[S:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(=O)nc(-c3cccc(CCC(=O)OC(C)(C)C)n3)sc2c1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(=O)nc(-c3cccc(CCC(=O)O)n3)sc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.1 %

Procedure:
A mixture of tert-butyl 3-[6-(7-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]propanoate (0.40 g, 1.0 mmol) obtained in Example 175 and trifluoroacetic acid (5.0 ml) was stirred at 0° C. for 2 hrs. The reaction mixture was concentrated under reduced pressure and combined with diisopropyl ether to precipitate crystals, which were collected by filtration and dried to give the titled compound (0.33 g, 97%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:13](=[O:18])[CH2:12]1.C1(C)C=CC=CC=1.CS(C)=O>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:15]([CH2:16][CH:11]([CH3:10])[CH2:12][C:13]([OH:18])=[O:14])=[O:17])=[N:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)nc1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: CS(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cn1
Yield: 14.5 %

Procedure:
A solution of 6-aminonicotinonitrile (100.0 mg, 0.839 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (118 mg, 0.923 mmol) in a mixed solvent of toluene (3 mL) and DMSO (0.3 mL) was stirred at 120° C. for 24 hr. To the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate (4×30 mL). The organic layer was washed with water, and dried, and the solvent was evaporated under reduced pressure. The obtained solid was washed with 50% dichloromethane/hexane solution to give 4-(5-cyanopyridin-2-ylcarbamoyl)-3-methylbutyric acid (30 mg, 14.49%) as a pale-yellow powder.
Reaction SMILES: C(OCC)(=O)C.[Cl:7][C:8]([Cl:32])([Cl:31])[CH2:9][O:10][C:11]([NH:13][C@H:14]([C:28]([OH:30])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])=[O:12].O[N:34]1[C:38](=[O:39])[CH2:37][CH2:36][C:35]1=[O:40].[K+].[Br-]>CCO>[Cl:7][C:8]([Cl:31])([Cl:32])[CH2:9][O:10][C:11]([NH:13][C@H:14]([C:28]([O:30][CH:36]1[CH2:37][C:38](=[O:39])[NH:34][C:35]1=[O:40])=[O:29])[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([O:22][CH2:23][C:24]([Cl:27])([Cl:26])[Cl:25])=[O:21])=[O:12]
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(NCCCC[C@H](NC(=O)OCC(Cl)(Cl)Cl)C(=O)O)OCC(Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CC(OC(=O)[C@H](CCCCNC(=O)OCC(Cl)(Cl)Cl)NC(=O)OCC(Cl)(Cl)Cl)C(=O)N1

Procedure:
In a manner similar to Example 2A, utilizing anhydrous ethyl acetate as the solvent, N,N'-bis-trichloroethoxycarbonyl-L-lysine is reacted with N-hydroxy succinimide to obtain the above named compound; [α]D26 -19.6° (EtOH); νmax (KBr) 1820, 1785, 1715 cm-1.
Reaction SMILES: [Li+].[OH-].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:24][CH:23]([CH2:25][C:26]([O:28]C)=[O:27])[C:22](=[O:30])[N:21]([CH3:31])[CH2:20][C:19]=2[CH:32]=1>O1CCOCC1.O>[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]=1[CH2:12][NH:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]2[NH:24][CH:23]([CH2:25][C:26]([OH:28])=[O:27])[C:22](=[O:30])[N:21]([CH3:31])[CH2:20][C:19]=2[CH:32]=1
Reactant: COC(=O)CC1Nc2ccc(CNCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CN1Cc2cc(CNCc3nc4ccccc4[nH]3)ccc2NC(CC(=O)O)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.3 %

Procedure:
LiOH (14.6 mg, 0.34 mmol) was added at RT to a solution of methyl (±)-7-[[[(2-benzimidazolyl)methyl]amino]methyl]-4-methyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine-2-acetate (133 mg, 0.31 mmol) in dioxane (3 mL) and H2O (1 mL). The reaction mixture was stirred at RT overnight then the organic solvent was removed in vacuo. The aqueous residue was acidified with 1M HCl solution (0.38 mL) to obtain a white solid which was purified by ODS chromatography (10% acetonitrile/H2O-0.1% TFA) to afford the title compound (65 mg, 51%): 1H NMR (DMSO-d6, 400 MHz) δ 2.51 (m, 1H), 2.73 (m, 1H), 2.91 (s, 3H), 3.69 (bs, 2H), 3.76 (d, J=16.6 Hz, 1H), 3.97 (br s, 2H), 4.97 (m, 1H), 4.45 (d, J=16.6 Hz, 1H), 5.77 (m, 1H), 6.52 (d, J=8.1 Hz, 1H), 6.97 (s, 1H), 7.02 (d, J=8.1 Hz, 1H), 7.20 (m, 2H), 7.52 (m, 2H); MS (ES) m/e 394 (M+H)+. Anal. Calcd. for C21H23N5O3.2 CF3CO2H.H2O: C, 46.95; H, 4.26; N, 10.95. Found: C, 46.81; H, 4.00; N, 10.84.
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1.[CH2:15](Cl)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:15]([O:1][C:2]1[C:3]([OH:14])=[CH:4][C:5]2[C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:13]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1CCCCc2cc(O)c(O)cc21
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C1CCCCc2cc(OCc3ccccc3)c(O)cc21
Temperature: 50 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
A mixture of 2,3-dihydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (10 g), benzyl chloride (8 g), anhydrous potassium carbonate (9 g) and acetone (200 ml) is stirred at 50° C. for two hours. The reaction mixture is cooled and filtered off. The filtrate is concentrated under reduced pressure. The concentrate is dissolved in ethyl acetate. The organic layer is washed with water, dried and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent, hexane:ethyl acetate:methylene chloride=3:1:1) to afford 2-benzyloxy-3-hydroxy-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-one (8.8 g). This product is recrystallized from ethyl acetate-hexane to give colorless needles, m.p. 127°-128° C.