Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[OH:4].[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34]([NH:1][CH:2]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)[CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[F:11])[OH:4])=[O:35])=[CH:26][CH:25]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccccc1F)c1ccc(F)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(2-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in acetonitrile (20 ml) were added 4-fluoronaphthalenecarboxylic acid (274 mg, 1.44 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (412 mg, 2.15 mmol) and 1-hydroxy-1H-benzotriazole (221 mg, 1.44 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1). Recrystallization from ethyl acetate-hexane gave the title compound (465 mg, 67%).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[N:25]=[CH:26][C:27]2[C:32]([CH3:33])=[C:31]([CH:34]([OH:36])[CH3:35])[N:30]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[C:28]=2[N:29]=1.ClC1N=CC2C=C(C(=O)C)N(C(CC)CC)C=2N=1>>[Cl:23][C:24]1[N:25]=[CH:26][C:27]2[C:32]([CH3:33])=[C:31]([C:34](=[O:36])[CH3:35])[N:30]([CH:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[C:28]=2[N:29]=1
Reactant: Cc1c(C(C)O)n(C2CCCC2)c2nc(Cl)ncc12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CCC(CC)n1c(C(C)=O)cc2cnc(Cl)nc21
Product: CC(=O)c1c(C)c2cnc(Cl)nc2n1C1CCCC1

Procedure:
1-(2-Chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-ethanone is prepared by Dess-Martin periodinane oxidation of 1-(2-Chloro-7-cyclopentyl-5-methyl-7H-pyrrolo[2,3-d]pyrimidin-6-yl)-ethanol using a procedure similar to that described for 1-[2-chloro-7-(1-ethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-yl]-ethanone in the synthesis of Example 376. [M+H]+=278.03.
Reaction SMILES: C1C2N(C(=O)CC2)C(=O)C1.O[N:12]=[C:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:15][C:16](O)=[O:17]>>[O:17]=[C:16]1[NH:12][CH:13]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[CH2:14][CH2:15]1
Reactant: O=C(O)CCC(CCC(=O)O)=NO
Agent: O=C1CCC2CCC(=O)N12
Product: O=C(O)CCC1CCC(=O)N1

Procedure:
In accordance with the present invention an improved process for preparing dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione comprises the steps of first catalytically hydrogenating a mono(lower alkyl) ester of 4-(hydroxyimino)heptanedioic acid in the presence of a tertiary lower alkyl amine to produce 5-oxo-2-pyrrolidinepropanoic acid, and thereafter heating the 5-oxo-2-pyrrolidinepropanoic acid in the presence of a cyclizing agent to form dihydro-1H-pyrrolizine-3,5-(2H,6H)-dione.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:26]([CH3:28])([CH3:27])[C:25](=[O:29])[NH:24][C:4]=2[N:5]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][C:13](Cl)=[CH:14][CH:15]=3)[C:10]([CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])=[N:9]2)[N:7]=1>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:2]1[C:3]2[C:26]([CH3:27])([CH3:28])[C:25](=[O:29])[NH:24][C:4]=2[N:5]=[C:6]([N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([CH2:18][CH2:19][C:20]([F:22])([F:21])[F:23])=[N:9]2)[N:7]=1
Reactant: CC1(C)C(=O)Nc2nc(-n3nc(CCC(F)(F)F)c4cc(Cl)ccc43)nc(N)c21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC1(C)C(=O)Nc2nc(-n3nc(CCC(F)(F)F)c4ccccc43)nc(N)c21

Procedure:
The compound of Example 1 (9 mg, 0.02 mmol) and palladium hydroxide on carbon (20 wt %, 15 mg) in MeOH (ca 10 mL) were stirred under a hydrogen atmosphere (balloon). After stirring for several hours the solution was filtered through celite and concentrated. The residue was purified by preparative TLC using 5% MeOH/DCM as the eluent to give the indicated compound. 1H NMR (500 MHz, DMSO-d6): δ 11.08 (s, 1H); 8.82 (d, J=8.5 Hz, 1H); 7.89 (d, J=8.0 Hz, 1H); 7.53 (t, J=7.8 Hz, 1H); 7.31 (t, J=7.5 Hz, 1H); 6.94 (s, 2H); 3.28-3.21 (m, 2H); 2.89-2.77 (m, 2H); 1.35 (s, 6H). LC4 rt=3.42 min, m/z=391 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][N:12]([CH:28]3[C:37]4[N:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH2:31][CH2:30][CH2:29]3)[CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.O.NN>C(O)C.C(OCC)C>[F:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][N:12]([CH:28]3[C:37]4[N:36]=[CH:35][CH:34]=[CH:33][C:32]=4[CH2:31][CH2:30][CH2:29]3)[CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c(F)cccc2[nH]1)C1CCCc2cccnc21
Agent: NN
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: NCCCCN(Cc1nc2c(F)cccc2[nH]1)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 45.6 %

Procedure:
To a stirred solution of 2-{4-[(4-fluoro-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (86 mg, 0.173 mmol) in ethanol (2.0 mL) was added hydrazine hydrate (0.05 mL, 1.03 mmol) and the mixture stirred at room temperature for 20 hours. The mixture was then diluted with diethyl ether, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude yellow oil. The oil was purified by flash chromatography (1.75 cm ID, 12 g silica, 25:1:1 CH2Cl2: MeOH: NH4OH) to give pure N1-(4-fluoro-1H-benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (29 mg, 46%). 1H NMR (CDCl3) δ 1.28-1.47 (m, 4H), 1.63-1.77 (m, 1H), 1.85-2.09 (m, 2H), 2.15-2.25 (m, 1H), 2.46-2.60 (m, 3H), 2.65-2.76 (m, 2H), 2.79-2.91 (m, 1H), 4.01-4.18 (m, 3H), 6.89 (dd, 1H, J=10.3, 8.0 Hz), 7.05-7.11 (m, 1H), 7.12-7.18 (m, 1H), 7.35 (d, 1H, J=7.8 Hz), 7.43 (d, 1H, J=7.9 Hz), 8.59 (d, 1H, J=4.4 Hz).
Reaction SMILES: C([O:8][C:9](=[O:42])[C@@H:10]([NH:23][C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][CH2:28][N:27]1[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1)(=[O:34])=[O:33])=[O:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][F:22])=[CH:14][CH:13]=1)C1C=CC=CC=1>[Pd].C(O)C>[F:41][C:37]1[CH:36]=[C:35]([S:32]([N:27]2[CH2:28][CH2:29][CH2:30][CH2:31][C@H:26]2[C:24]([NH:23][C@@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][F:22])=[CH:14][CH:13]=2)[C:9]([OH:42])=[O:8])=[O:25])(=[O:34])=[O:33])[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Agent: [Pd]
Solvent: CCO
Product: O=C(O)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Reaction time: 3 h
Yield: 65.7 %

Procedure:
To a mixture of (S)-2-{[(S)-1-(3-fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-fluoro-propoxy)-phenyl]-propionic acid benzyl ester (1.9 g, 3.1 mmol) (compound 18a), ethanol (50 mL), and 10% Pd on carbon was hydrogenated at 30 psi for 3 h. The suspension was filtered through Celite®, washed with dichloromethane and the filtrate concentrated. The resulting oil was chromatographed (dichloromethane/methanol, 9/1) on silica gel to provide 1.04 g (64.7%) of the title compound as a white powder.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([OH:13])=[CH:11][CH:10]=[C:9]([S:14](=[O:21])(=[O:20])[NH:15][CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:11][CH:10]=[C:9]([S:14](=[O:20])(=[O:21])[NH:15][CH2:16][C:17]([OH:19])=[O:18])[C:7]=2[CH:8]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc2c(S(=O)(=O)NCC(=O)O)ccc(O)c2o1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cc2c(S(=O)(=O)NCC(=O)O)ccc(OCc3ccccc3)c2o1
Yield: 56.1 %

Procedure:
A mixture of the 7-hydroxy compound (1.8 g) obtained in Example 28 (Compound No. 28), K2CO3 (1.6 g) and benzylbromide (2.9 g) in DMF was stirred at 80° C. for 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate, which was purified by a silica-gel column chromatography to give 1.3 g of 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-benzyloxybenzofuran as yellow crystals. After the obtained product was added to 20 ml of 2N-NaOH aqueous solution and the mixture was stirred for 30 minutes, the resultant was acidified to form precipitate, which was recrystallized with ethanol to give 0.4 g of 2-acetyl-4-(N-carboxymethylsulfamoyl)-7-benzyloxybenzofuran. The physical constants are shown in Table 4.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:21](Cl)=[O:22])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2].[NH3:40]>ClCCl>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:14]=2)[C@H:9]([N:20]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[C:21]([NH2:40])=[O:22])[CH2:8][C@@H:7]1[CH3:39])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(=O)Cl)C[C@@H]1C
Reactant: N
Solvent: ClCCl
Product: CCOC(=O)N1c2ccc(C(F)(F)F)cc2[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(N)=O)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
cis-4-[(3,5-Bis-trifluoromethyl-benzyl)-chlorocarbonyl-amino]-2-methyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester. (Example 50A) (125 mg) was dissolved in dichloromethane (4 mL), and cooled in an ice water bath as gasous ammonia was condensed into the solution. After stirring overnight at room temperature, the reaction mixture was quenched with 10 mL of 1N HCl and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with 10 mL saturated sodium bicarbonate, 10 mL of brine, dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel chromatography using 0-50% ethyl acetate/hexanes as eluent afforded the title product (0.091 g, 76%). MS m/z 563 (M+ +1); 1H NMR (CDCl3) δ 1.18 (Me, d, 3H, J=5.9 Hz), 1.2-1.4 (m, 4H), 2.1-2.2 (m, 1H), 4.1-4.3 (m, 3H), 4.3-4.5 (m, 1H), 4.9 (bs, 2H), 5.0-5.3 (m, 3H), 7.20 (C5, s, 1H), 7.5 (d, 1H), 7.6 (d, 1H), 7.75 (s, 2H), 7.8 (s, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=O)[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1(C)C(C)=CC=CC=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:29]>C(OCC)(=O)C>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[S:29])[NH:9][N:10]2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=c1[nH]n(-c2ccccc2)c2cc([N+](=O)[O-])ccc12
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc2c(=S)[nH]n(-c3ccccc3)c2c1
Temperature: 25 °C

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed 6-nitro-1-phenyl-1,2-dihydroindazol-3-one (15 g, 58.82 mmol, 1.00 equiv), xylene (150 mL), P2S5 (52.2 g, 235.14 mmol). The resulting solution was heated to reflux for 40 min in an oil bath. The resulting mixture was then cooled to 25° C. The resulting solution was diluted with ethyl acetate (50 mL). The solids were filtered out to yield 6-nitro-1-phenyl-1,2-dihydroindazole-3-thione as a yellow solid. MS: 272 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:14]2=[N:15][C:16]3[C:17](=[C:18]([CH:22]=[O:23])[CH:19]=[CH:20][CH:21]=3)[N:13]2[CH2:12][CH2:11][CH2:10]1.[CH:24]1([Mg]Br)[CH2:26][CH2:25]1>O1CCCC1>[CH:24]1([CH:22]([C:18]2[C:17]3[N:13]4[CH2:12][CH2:11][CH2:10][N:9]([C:3]5[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=5[Cl:1])[C:14]4=[N:15][C:16]=3[CH:21]=[CH:20][CH:19]=2)[OH:23])[CH2:26][CH2:25]1
Reactant: Br[Mg]C1CC1
Reactant: O=Cc1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: C1CCOC1
Product: OC(c1cccc2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C1CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
To a solution of 1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (3.00 g, 8.67 mmol) in tetrahydrofuran (25 mL) was added dropwise cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 11.6 mL, 11.6 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 h. The reaction was quenched by methanol, and the mixture was neutralized with aqueous saturated ammonium chloride, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-60% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol to give the title compound as a colorless crystal (1.71 g, 4.40 mmol, 76%).
Reaction SMILES: O[CH2:2][C:3]1[CH:16]=[N:15][C:6]2[C:7]3[N:8]([CH:12]=[CH:13][CH:14]=3)[C:9](=[O:11])[NH:10][C:5]=2[CH:4]=1.[F:17][C:18]1[CH:19]=[C:20]([CH:26]=[CH:27][C:28]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)[C:21]([NH:23][CH2:24][CH3:25])=[O:22].[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C>C(#N)CC>[CH2:24]([NH:23][C:21](=[O:22])[C:20]1[CH:26]=[CH:27][C:28]([N:29]2[CH2:34][CH2:33][N:32]([CH2:2][C:3]3[CH:16]=[N:15][C:6]4[C:7]5[N:8]([CH:12]=[CH:13][CH:14]=5)[C:9](=[O:11])[NH:10][C:5]=4[CH:4]=3)[CH2:31][CH2:30]2)=[C:18]([F:17])[CH:19]=1)[CH3:25]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)c(F)c1
Reactant: O=c1[nH]c2cc(CO)cnc2c2cccn12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)[nH]c(=O)n3cccc43)CC2)c(F)c1
Temperature: 95 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a suspension of 3-(hydroxymethyl)pyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-6(5H)-one (47.50 mg, 0.221 mmol), 3-fluoro-N-ethyl-4-(piperazin-1-yl)benzamide (69.3 mg, 0.276 mmol) and (cyanomethyl)trimethylphosphonium iodide (86 mg, 0.353 mmol) in Propiononitrile (Volume: 1.00 mL) was added N-ethyl-N-isopropylpropan-2-amine (0.192 mL, 1.104 mmol) at 23° C. The reaction was stirred at 95° C. for 15 hr. The suspension was cooled to 23° C., concentrated via rotary evaporation, re-constituted in ACN (2.0 mL), stirred for 15 min, filtered, rinsed with ACN (3×1 mL) and dried in vacuo. The crude solid was re-suspended in ACN (2.0 mL), heated to reflux, cooled to 23° C., filtered, rinsed with ACN (3×2.0 mL) to provide N-ethyl-3-fluoro-4-(4-((6-oxo-5,6-dihydropyrido[2,3-e]pyrrolo[1,2-c]pyrimidin-3-yl)methyl)piperazin-1-yl)benzamide (0.069 g, 0.221 mmol, 70.1% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.20 Hz, 3 H) 2.54-2.64 (m, 4 H) 3.07-3.17 (m, 4 H) 3.21-3.28 (m, 2 H) 3.63 (s, 2 H) 6.71-6.76 (m, 1 H) 7.01-7.10 (m, 2 H) 7.55-7.64 (m, 3 H) 7.67 (dd, J=3.03, 1.52 Hz, 1 H) 8.32 (t, J=5.43 Hz, 1 H) 8.36 (d, J=1.77 Hz, 1 H) 11.58 (br. s., 1 H). ESI-MS: m/z 449.4 (M+H)+. mp=262.7-267.4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[S:23][C:22]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:24])[C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:24][C:18]1[C:17]2[CH:16]=[C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])[S:23][C:22]=2[CH:21]=[CH:20][N:19]=1
Reactant: Clc1nccc2sc(Br)cc12
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2cc3c(Cl)nccc3s2)C1=O
Yield: 22.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 100 mg, 0.5643 mmol) was reacted with 2-bromo-4-chloro-thieno[3,2-c]pyridine (141.3 mg, 0.5643 mmol), 1,4-dioxane (20 mL), copper iodide (10.75 mg, 0.05643 mmol), trans-1,2-diamino cyclohexane (19.38 mg, 0.1693 mmol) and potassium phosphate (299 mg, 1.4108 mmol) to afford the crude product. Purification by column chromatography on silica gel (2% MeOH in CHCl3) afforded 43 mg of the product (22.16% yield).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19](=O)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:19]1/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(C=Cc1ccccc1)Nc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccccc1I
Product: Clc1ccccc1-n1c(/C=C/c2ccccc2)nc2ccccc21
Yield: 21.2 %

Procedure:
The title compound was prepared with the analogous procedure described in example 7 (one pot reaction) using 1-iodo-2-nitrobenzene (124.5 mg, 0.5 mmol) and N-(2-chloro-phenyl)-3-phenylacrylamide (154 mg, 0.6 mmol) as starting materials to yield the title compound as a solid (35 mg, 21%). 1H NMR (DMSO) δ 6.73 (d, 1 H), 7.03 (d, 1H), 7.31 (t, 1H), 7.39 (m, 4H), 7.58 (d, 2 H), 7.70 (m, 1H), 7.75 (m, 1H), 7.79 (m, 2H), 7.88 (dd, 2H). [M+H+]: 331.08.
Reaction SMILES: [CH2:1]1[CH2:6]CC(N=C=NC2CCCCC2)C[CH2:2]1.[C:16]([O:20][C:21]([NH:23][CH2:24][C:25]([C:27]1[CH:37]=[CH:36][C:30]([O:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:29][CH:28]=1)=[O:26])=[O:22])([CH3:19])([CH3:18])[CH3:17].CC(O)C>CCOC(C)=O.CN(C1C=CN=CC=1)C>[CH:1]([O:34][C:33](=[O:35])[CH2:32][O:31][C:30]1[CH:29]=[CH:28][C:27]([C:25](=[O:26])[CH2:24][NH:23][C:21]([O:20][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:22])=[CH:37][CH:36]=1)([CH3:6])[CH3:2]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)OC(=O)COc1ccc(C(=O)CNC(=O)OC(C)(C)C)cc1
Reaction time: 2 h

Procedure:
A solution of DCC (2.06 g; 10 mmol) in EtOAc (10 ml) was added with stirring, at 0° C. to a mixture of the compound of example 1f (2.78 g; 9 mmol) and propane-2-ol (2 ml) in EtOAc (20 ml). DMAP (1.1 g; 9 mmol) was added after 10 min and stirring continued for 2 h at 0° C. The reaction mixture was stored in a freezer overnight. The precipitated DCU was filtered and the filtrate was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 5% CH3CN in CHCl3) to obtain the title compound. Yield, 3.0 g (94.9%); mp, 62-64° C. (EtOAc-PE 60-80° C.); analysis: C18H25NO6 requires C, 61.53; H, 7.17; N, 3.99; found: C, 61.94; H, 7.19; N, 3.95%.
Reaction SMILES: CC[O:3][C:4]([C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[C:10]=1[C:17]([NH2:19])=[O:18])=[O:7])=[O:5].[OH-].[Na+]>O>[CH3:16][O:15][C:11]1[C:10]([C:17]([NH2:19])=[O:18])=[C:9]([NH:8][C:6]([C:4]([OH:5])=[O:3])=[O:7])[CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)Nc1cccc(OC)c1C(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cccc(NC(=O)C(=O)O)c1C(N)=O

Procedure:
2'-Carbamoyl-3'-methoxyoxanilic acid ethyl ester (1.33 g., 0.005 mole) is stirred in 50 ml. water, and 5.0 ml. of N NaOH is slowly added, giving a solution. After 1/2 hour the solution is filtered, and the filtrate is acidified to pH 2 with N HCl, giving 0.71 g. of the title compound, m.p. 214°-215° C., after crystallization from ethanol.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.O1CCOCC1.[OH-].[Na+].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.[Pt].Cl.C1COCC1.O>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[C:18]([OH:20])=[O:19])=[O:2])([CH3:7])([CH3:5])[CH3:6]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCc1ccccc1)C(=O)O
Agent: [Pt]
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CCC1CCCCC1)C(=O)O
Temperature: 70 °C
Reaction time: 8 h
Yield: 105.1 %

Procedure:
To a solution of Boc-homophenylalanine (3.00 g, 10.8 mmol) in CH2Cl2 at room temperature was added a solution of 4N HCl in dioxane (20 mL, 80 mmol), and mixture stirred overnight. Solvents concentrated, and white powder that resulted was reduced under high pressure (4 atm. H2) using platinum/HCl. The white solid that resulted from the reduction was mixed with aqueous 4N NaOH (30 mL), water (30 mL), and THF (50 mL) at room temperature, and to this was added di-t-butyl dicarbonate (3.5 g, 16 mmol). Reaction heated at 70° C. overnight. Reaction cooled to 0° C., and an aqueous solution of 3N HCl added until the pH reached 6. Product extracted out with CHCl3, and extracts dried with Na2SO4, filtered, and concentrated in vacuo to produce a white solid (3.24 g, 106%). m/e (DCI) 286 (MH+)
Reaction SMILES: [NH2:1][C:2]1[N:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:3]=1[C:4](N(OC)C)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([Li])=[CH:19][CH:18]=1.IC1C=CC(OC)=CC=1>>[NH2:1][C:2]1[C:3]([C:4]([C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:5])=[CH:10][CH:11]=[C:12]([Cl:14])[N:13]=1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1N
Reactant: [Li]c1ccc(OC)cc1
Agent: COc1ccc(I)cc1
Product: COc1ccc(C(=O)c2ccc(Cl)nc2N)cc1

Procedure:
The title compound was prepared from 2-Amino-6-chloro-N-methoxy-N-methyl-nicotinamide (Example 3) and 4-methoxyphenyllithium freshly prepared from 4-iodoanisole (Aldrich) using the procedure described in Example 7. HRMS, observed: 262.0512, Calcd for M+: 262.0509.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([OH:30])[C:26]([F:29])([F:28])[F:27].CC([O-])(C)C.[K+]>C1COCC1.O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:20])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:30][CH2:25][C:26]([F:29])([F:28])[F:27])/[N:7]([CH2:21][CH2:22][CH2:23][CH3:24])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1F
Reactant: OCC(F)(F)F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.6 %

Procedure:
A mixture of the product from Example 75A (537 mg, 1.45 mmol), trifluoroethanol (87 μL, 2.18 mmol) and potassium 2-methylpropan-2-olate (2.18 mL, 2.18 mmol) in THF (10 mL) was stirred at room temperature for 3 hrs. The mixture was diluted with water and extracted with EtOAc. The organic extract was dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280 ™ (SiO2, 0-50% Hexane in ethyl acetate) to afford 258 mg (40%) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 0.99 (t, J=7.32 Hz, 3H) 1.36 (s, 9H) 1.40 (dd, J=7.63 Hz, 2H) 1.82 (m, 2H) 4.19 (t, J=7.32 Hz, 2H) 4.48 (q, J=8.54 Hz, 2H) 6.65 (s, 1H) 7.02 (d, J=8.54 Hz, 1H) 8.03 (d, J=2.75 Hz, 1H). MS (DCI/NH4) m/z 449 (M+H)+.