Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18].C1N=CN(C(N2C=NC=C2)=O)C=1>C1COCC1>[CH3:1][O:5][C:6]([CH:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:13]1)=[O:7]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)C1CCC(C(=O)O)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)C1CCC(C(=O)OC)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Cyclohexane-1,4-dicarboxylic acid mono-t-butyl ester (26.9 mmol, 5.0 g) and N,N′-carbonyldiimidazole (33.6 mmol, 5.44 g) in anhydrous THF (80 mL) were stirred 16 h at room temperature under argon. In a separate, sealed and argon-flushed flask, LiHMDS (1.0 M in THF, 56.5 ml) was added to 40 mL anhydrous THF stirring at −78° C. To this solution was added dropwise anhydrous ethyl acetate (57.8 mmol, 5.65 mL). This solution was allowed to stir at −78° C. for 1 hour prior to dropwise addition of original CDI/acid solution that had been stirring overnight. The reaction mixture was allowed to stir and warm to room temperature overnight. The reaction was then quenched with saturated NH4Cl(aq) (200 mL) and extracted with Et2O (100×2). The combined organics were then washed with water, saturated brine, and dried over Na2SO4. The solvent was removed in vacuo and the crude residue (8.5 g) was used in the next step without further purification.
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[CH3:21])[C:13](=[O:22])[NH:12][C:11]1=[O:23])(C)(C)C.Cl>O1CCOCC1>[OH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:15]=[C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[CH3:21])[C:13](=[O:22])[NH:12][C:11]1=[O:23]
Reactant: Cc1ccsc1-c1cn(CCCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccsc1-c1cn(CCCO)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.6 %

Procedure:
A solution of 1-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 27, 73 mg, 0.2 mmol) in dioxane (8 mL) was cooled at 0° C. and then 4N HCl in dioxane (0.5 mL) was added. The mixture was stirred for 1 hour at room temperature and then the solvent was evaporated. The crude was purified by trituration with diisopropylether to afford the title compound as a white solid (36 mg, 72% yield).
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][C:11]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].CN([CH:27]=[O:28])C.[NH4+].[Cl-]>>[CH2:12]([C:11]1[CH:10]=[CH:9][S:8][C:7]=1[CH:27]=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CN(C)C=O
Reactant: CCCCCCCCCCCCc1ccsc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Product: CCCCCCCCCCCCc1ccsc1C=O
Temperature: 25 °C
Yield: 87 %

Procedure:
A solution of n-Butyllithium (1.6M in hexanes, 8 mL, 12.67 mmol) was added dropwise at −78° C. under N2 to a stirred solution of 2-bromo-3-dodecylthiophene (10) (4 g, 12.07 mmol in 96 mL of ether). During the whole addition, the reaction temperature was kept at −78° C. At this temperature, DMF (1.4 mL, 18.11 mmol) was slowly added and the mixture was allowed to warm to room temperature. The mixture was poured into a 1 M aqueous solution of NH4Cl and extracted with CH2Cl2. The organic layer was washed with water, dried over Na2SO4, and evaporated under reduced pressure. The residue was passed through a short column (silica gel, hexane/ethylacetate, 9:1) to give a light yellow liquid compound 11 in 87% yield. 1H-NMR (DCM-d2, 400 MHz) ppm 0.88 (t, 3H, J=6.8 Hz) ppm 1.27 (m, 18H) ppm 1.67 (td, 2H, J=7.6 Hz, J=15.1 Hz) ppm 2.96 (t, 2H) ppm 7.04 (d, 1H, J=5.0 Hz) ppm 7.66 (d, 1H, J=5.0 Hz) ppm 10.04 (s, 1H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[OH:7][C@@:8]([CH3:16])([C:12]([F:15])([F:14])[F:13])[C:9](O)=[O:10].[Cl:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH2:20].C(OCC)(=O)C>ClCCl.CN(C=O)C>[Cl:17][C:18]1[CH:24]=[C:23]([S:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:22]=[CH:21][C:19]=1[NH:20][C:9](=[O:10])[C@:8]([OH:7])([CH3:16])[C:12]([F:15])([F:14])[F:13]
Reactant: C[C@@](O)(C(=O)O)C(F)(F)F
Reactant: Nc1ccc(Sc2ccccc2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@](O)(C(=O)Nc1ccc(Sc2ccccc2)cc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.1 %

Procedure:
Oxalyl chloride (0.063 ml) was added to a stirred suspension of (R)-(+)-2-hydroxy-2-methyl-3,3,3-trifluoropropanoic acid (Method 9) (0.106 g) in dichloromethane (2 ml) containing DMF (1 drop). The mixture was stirred at ambient temperature for 90 minutes and was then added to a solution of 2-chloro-4-phenylthioaniline (Method 11) (0.143 g) in dichloromethane (4 ml) and stirred a further 3 hours. Ethyl acetate (30 ml) was added and the mixture was washed with water (2×30 ml) and brine then dried. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 15% ethyl acetate/hexane to give the title compound (0.153 g) as a gum. NMR: 1.57 (s, 3H), 7.26-7.41 (m, 6H), 7.44 (d, 1H), 7.82 (s, 1H), 7.95 (d, 1H), 9.74 (s, 1H); MS: 374 (M−H)−.
Reaction SMILES: Cl.[CH3:2][C:3]1([OH:8])[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].[C:15]1([CH:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[C:15]1([CH:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:5]2[CH2:6][CH2:7][C:3]([CH3:2])([OH:8])[CH2:4]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CC1(O)CCNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1(O)CCN(C(c2ccccc2)c2ccccc2)C1
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a reaction flask were added 3-methylpyrrolidin-3-ol hydrochloride (1 g, 7.2 mmol), anhydrous potassium carbonate (2.5 g, 18 mmol) and acetonitrile (50 L). To the resulting mixture was slowly added a solution of diphenylbromomethane (1.78 g, 7.2 mmol) in acetonitrile dropwisely at 85° C. The reaction was conducted for 12 hours. After the completion of reaction monitored by TLC, the resulting mixture was evaporated under reduced pressure to remove acetonitrile. To the residue was added a mixed solution of dichloromethane and water for extraction. The organic phase was dried over anhydrous sodium sulfate and evaporated to remove the solvent to produce a crude product. The crude product was purified by column chromatography (silica gel column, eluted with petroleum ether:ethyl acetate=30:1 (volumetric ratio)) to produce 1-(diphenylmethyl)-3-methylpyrrolidin-3-ol (1 g) in a yield of 52.0%.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C.C1(C)C=CC=CC=1.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>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([C:27]4[CH:28]=[CH:29][C:24]([C:23]([F:34])([F:33])[F:22])=[CH:25][CH:26]=4)[CH:10]=3)[CH:6]=[CH:7]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc(Cn2ccc3ccc(Br)cc32)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(Cn2ccc3ccc(-c4ccc(C(F)(F)F)cc4)cc32)cc1
Yield: 67.3 %

Procedure:
Following the procedure described in Step 2 of Example 5, 6-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (0.490 g, 1.43 mmol) was coupled to 4-trifluoromethylbenzeneboronic acid (0.300 g, 1.58 mmol), using tetrakis(triphenylphosphine)palladium (0.0560 g, 0.0484 mmol) and sodium carbonate (0.615 g, 5.80 mmol) in water (2.8 mL), ethanol (1.4 mL) and toluene (10 mL). Purification by flash chromatography using hexane as an eluant afforded 1-[4-(tert-butyl)benzyl]-6-[4-(trifluoromethyl)phenyl]-1-H-indole as a white solid (0.392 g, 67%), mp 134-135° C. 1HNMR (200 MHz, DMSO-d6): δ 7.85 (d, 3H, J=7.7 Hz), 7.75 (d, 2H, J=7.7 Hz), 7.65 (d, 1H, J=7.7 Hz), 7.55 (d, 1H, J=4.1 Hz), 7.25-7.4 (m, 3H), 7.15 (d, 2H, J=7.7 Hz), 6.5 (d, 1H, J=2.6 Hz), 5.45 (s, 2H), and 1.2 ppm (s, 9H).
Reaction SMILES: CCO.[OH-].[K+].[F:6][C:7]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=[CH:11][C:10]([NH2:25])=[C:9]([NH2:26])[CH:8]=1.[C:27](=S)=[S:28]>C(O)(=O)C.O>[C:16]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][C:13]([C:12]2[C:7]([F:6])=[CH:8][C:9]3[NH:26][C:27](=[S:28])[NH:25][C:10]=3[CH:11]=2)=[CH:18][CH:17]=1
Reactant: Nc1cc(F)c(-c2ccc(-c3ccccc3)cc2)cc1N
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: Fc1cc2[nH]c(=S)[nH]c2cc1-c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of EtOH (20 mL), H2O (4 mL) and KOH (593 mg, 11 mmol) was added compound 13-3 (2.46 g, 8.8 mmol). CS2 (0.65 mL, 11 mmol) was then added and the suspension was heated to reflux for 2 h. The reaction mixture was cooled to 25° C., then 40 mL of H2O and 0.8 mL of acetic acid were added resulting in a tan precipitate. The precipitate was collected by vacuum filtration resulting in title compound 13-4, which required no further purification.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[C:6]([CH2:8][C:9]([OH:11])=O)[O:5][N:4]=1.[CH2:12]([C@H:19]1[CH2:23][NH:22][C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([C@H:19]1[CH2:23][N:22]([C:9](=[O:11])[CH2:8][C:6]2[O:5][N:4]=[C:3]([CH3:2])[CH:7]=2)[C@H:21]([C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)=[CH:29][CH:28]=2)=[O:25])[CH2:20]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Reactant: Cc1cc(CC(=O)O)on1
Agent: Cl
Product: Cc1cc(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)on1
Yield: 29.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3-methylisoxazol-5-yl)acetic acid hydrochloride and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 32, (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)-1-(2-(3-methylisoxazol-5-yl)acetyl)pyrrolidine-2-carboxamide (9 mg, 29.2%). 1H-NMR (400 MHz, DMSO-D6): σ 9.97 (s, 1H), 7.54 (d, 2H), 7.27 (t, 2H), 7.19 (m, 4H), 6.67 (m, 4H), 6.20 (d, 1H), 4.48 (1H), 3.88 (m, 3H), 2.66 (m, 4H), 2.15 (s, 3H), 1.91 (m, 2H). MS (EI) for C30H28FN3O4: 514.6 (MH+).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[C:8]2[C:3]=1[CH:4]=[C:5]([CH3:15])[N:6]=[CH:7]2.O.NN>C(O)C.[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][CH:2]=[C:3]2[C:8]=1[CH:7]=[N:6][C:5]([CH3:15])=[CH:4]2
Reactant: Cc1cc2c(Br)ccc([N+](=O)[O-])c2cn1
Agent: [Pd]
Agent: NN
Solvent: O
Solvent: CCO
Product: Cc1cc2cccc(N)c2cn1
Yield: 68.8 %

Procedure:
A catalyst consisting of palladium-on-carbon (3/97 by weight; 5 g) is added to a solution of 5-bromo-3-methyl-8-nitroisoquinoline (10.8 g) in ethanol (200 cc). The suspension is stirred, whilst heating to the reflux temperature under a nitrogen atmosphere, and hydrazine hydrate (25 cc) is added dropwise in the course of 30 minutes. The mixture is then heated under reflux for a further 2 hours. The suspension is filtered hot through diatomaceous silica and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. The residue is dissolved in 0.5 N aqueous hydrochloric acid (200 cc) and the resulting solution is extracted with methylene chloride (2×50 cc). The aqueous phase is then rendered alkaline to pH 10 by addition of sodium hydroxide and is extracted with methylene chloride (3×150 cc). The organic extracts are combined, washed with water, dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. to yield 8-amino-3-methylisoquinoline (4.4 g), which is a beige solid, m.p.=175° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([N:8]([C@H:10]2[CH2:15][CH2:14][C@H:13](C3C=CC(CNC)=CC=3)[CH2:12][CH2:11]2)[CH3:9])=[O:7])=[CH:4][CH:3]=1.Cl[CH2:28][C:29]([NH2:31])=[O:30]>>[NH2:31][C:29]([CH2:28][C:3]1[CH:2]=[CH:26][C:25]([C@H:13]2[CH2:14][CH2:15][C@H:10]([N:8]([C:6](=[O:7])[C:5]3[CH:25]=[CH:26][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH3:9])[CH2:11][CH2:12]2)=[C:5]([CH2:6][NH:8][CH3:9])[CH:4]=1)=[O:30]
Reactant: CNCc1ccc([C@H]2CC[C@H](N(C)C(=O)c3ccc(Cl)cc3)CC2)cc1
Reactant: NC(=O)CCl
Product: CNCc1cc(CC(N)=O)ccc1[C@H]1CC[C@H](N(C)C(=O)c2ccc(Cl)cc2)CC1

Procedure:
from trans-N-(4-chlorobenzoyl)-N-methyl-4-(4-methylaminomethylphenyl)cyclohexylamine and chloroacetamide. Melting point: 138°-140° C.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[C:7]([NH:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][O:30]1.CC(C)=O>CN(C)C=O>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][CH2:27][CH2:26][N:16]1[CH2:17][CH2:18][CH:13]([NH:12][C:7]2[CH:8]=[CH:9][CH:10]=[C:11]3[C:6]=2[CH:5]=[CH:4][N:3]=[CH:2]3)[CH2:14][CH2:15]1
Reactant: c1cc(NC2CCNCC2)c2ccncc2c1
Reactant: BrCCOC1CCCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: c1cc(NC2CCN(CCOC3CCCCO3)CC2)c2ccncc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A suspension of the compound of Example 20 (70 mg) and potassium carbonate (142 mg, Kokusan Chemical) in N,N-dimethylformamide (1.5 ml) was added with 2-(2-bromoethoxy)tetrahydro-2H-pyran (254 μl, Aldrich) and stirred at room temperature for 48 hours. The reaction mixture was added with acetone (10 ml), and insoluble matters were separated by filtration. Then, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=6:1) to obtain the title compound (40 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].Br.[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36](=[O:51])[N:37]([CH:45]3[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]3)[C:38](=[O:44])[N:39]2[CH2:42][CH3:43])=[CH:34][C:33]=1[N+:52]([O-:54])=[O:53].Cl[C:56]1[C:65]2[C:60](=[CH:61][C:62]([O:68][CH3:69])=[C:63]([O:66][CH3:67])[CH:64]=2)[N:59]=[CH:58][N:57]=1.C(N(CC)CC)C>CO.O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:26])[N:7]([CH:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].[Cl:31][C:32]1[CH:41]=[C:40]2[C:35]([C:36](=[O:51])[N:37]([CH:45]3[CH2:50][CH2:49][N:48]([C:56]4[C:65]5[C:60](=[CH:61][C:62]([O:68][CH3:69])=[C:63]([O:66][CH3:67])[CH:64]=5)[N:59]=[CH:58][N:57]=4)[CH2:47][CH2:46]3)[C:38](=[O:44])[N:39]2[CH2:42][CH3:43])=[CH:34][C:33]=1[N+:52]([O-:54])=[O:53]
Reactant: CCn1c(=O)n(C2CCNCC2)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Br
Agent: CCOC(=O)N1CCC(n2c(=O)c3cc([N+](=O)[O-])c(Cl)cc3n(CC)c2=O)CC1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CO
Product: CCn1c(=O)n(C2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)c(=O)c2cc([N+](=O)[O-])c(Cl)cc21
Temperature: 25 °C

Procedure:
The procedure similar to that described in Example 15 was repeated, except that 200.0 mg (0.47 mmol) of 7-chloro-3-(1-ethoxycarbonyl-4-piperidinyl)-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxoquinazoline (Compound t ) was used in place of Compound a, whereby 150.6 mg of crude 7-chloro-1-ethyl-1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)quinazoline hydrobromide was obtained. The product (145.0 mg, 0.31 mmol) was suspended in 10 ml of methanol, and 70 mg (0.31 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 0.11 ml (0.78 mmol) of triethylamine were added thereto, followed by heating under reflux for 1 hour. After the reaction mixture was cooled to room temperature, water was added, and the precipitated crystals were collected by filtration, washed successively with water, methanol, and ether, and dried. Recrystallization of the resulting crude crystals from methanol/water gave 144.6 mg (yield from Compound t: 60%) of Compound 36 as pale yellow crystals.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-].[CH:23]1([NH:29][C:30]2[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][C:31]=2[N+:40]([O-:42])=[O:41])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.O1CCOCC1.C(OCC)(=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([NH:39][S:36]([C:33]3[CH:34]=[CH:35][C:30]([NH:29][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)=[C:31]([N+:40]([O-:42])=[O:41])[CH:32]=3)(=[O:38])=[O:37])=[O:17])=[CH:13][CH:12]=2)[CH2:9][CH2:10]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(NC2CCCCC2)c([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(C2CCC(C(C)(C)C)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)C1CCC(c2ccc(C(=O)NS(=O)(=O)c3ccc(NC4CCCCC4)c([N+](=O)[O-])c3)cc2)CC1
Reaction time: 3 h

Procedure:
A mixture of Example 5C (55 mg, 0.20 mmol) and 1M LiOH (0.3 mL) in TBF (2 mL) was heated to 50° C., stirred for 3 hours, concentrated, dissolved in DMF (0.5 mL), and treated with a mixture of Example 3A (60 mg 0.20 mmol), EDCI (96 mg, 0.50 mmol), and DMAP (10 mg) in dioxane (2.0 mL). The mixture was stirred for 16 hours, diluted with ethyl acetate (50 mL), washed sequentially with 1M HCl (5 mL), water (5 mL), and brine (5 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel, with 50% ethyl acetate/hexanes to provide a ˜2:1 mixture of diastereomers. MS (ESI(−)) m/e 540 (M−H)−; 1H NMR (400 MHz, DMSO-d6) δ 8.63 (2d, 1H total), 8.33 (2d, 1H total), 7.95 (m, 1H), 7.82 and 7.78 (2d, 2H total), 7.45 (m, 1H), 7.30 (m, 2H), 3.71 (m, 1H), 2.28-0.95 (m, 20H), 0.86 and 0.75 (2s, 9H total).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1.CO[CH:15](OC)[N:16]([CH3:18])[CH3:17]>>[CH3:1][C:2]([CH3:12])([CH3:11])[C:3](=[O:10])[C:4]([N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)=[CH:15][N:16]([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)Cn1ccnc1
Reactant: COC(OC)N(C)C
Product: CN(C)C=C(C(=O)C(C)(C)C)n1ccnc1
Yield: 90.4 %

Procedure:
41.6 g (0.25 mol) of 3,3-dimethyl-1-(imidazol-1-yl)-butan-2-one and 35.7 g (0.3 mol) of dimethylformamide dimethyl acetal were heated under reflux for 5 hours. The excess acetal was then distilled off. The oil which remained crystallized on cooling. 50 g (90.5% of theory) of 4,4-dimethyl-1-dimethylamino-2-(imidazol-1-yl)-pent-1-en-3-one of melting point 45°-50° C. were obtained. ##STR16##
Reaction SMILES: CC1(C)CCCC(C)(C)N1[Mg]Cl.[Cl-].[Li+].[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[S:25][C:24]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[CH:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=[CH:33][C:32]=1[CH:41]=[O:42]>C1COCC1.ClCCl>[OH:42][CH:41]([C:32]1[CH:33]=[CH:34][C:35]2[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=1)[C:23]1[CH:22]=[C:21]([C:18]2[CH:17]=[CH:16][N:15]=[CH:20][CH:19]=2)[S:25][C:24]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc(-c2ccncc2)s1
Agent: CC1(C)CCCC(C)(C)N1[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)c1sc(-c2ccncc2)cc1C(O)c1ccc2ccccc2c1
Temperature: -25 °C
Yield: 49 %

Procedure:
A dry, nitrogen flushed flask, equipped with a stirbar and septum, was charged with 2,2,6,6-tetramethylpiperidinylmagnesium chloride.lithium chloride in tetrahydrofuran (1.0M, 1.21 mL, 1.21 mmol). The flask was cooled to −25° C. and a solution of ethyl 5-pyridin-4-ylthiophene-2-carboxylate (0.257 g, 1.10 mmol) in tetrahydrofuran (1.0 mL, 12 mmol) was added dropwise with stirring. The resulting dark reddish orange solution was stirred at −25° C. for 30 minutes. 2-Naphthalenecarboxaldehyde (0.172 g, 1.10 mmol) was then added dropwise (as a solution in 1.5 ml THF)—the reaction mixture became purple. The reaction was stirred at −25° for 5 minutes, then the cooling bath was removed and the reaction was allowed to warm to room temperature with stirring. An aliquot was removed from the reaction and quenched into sat. NH4Cl solution, then extracted with ethyl acetate. A LCMS of this extract indicated that all starting material had been consumed and that the major peak had correct mass for the desired product. The reaction was quenched by the slow dropwise addition of a saturated ammonium chloride solution (5 ml). The resulting yellow-orange mixture was transferred to a separatory funnel and diluted further with water and ethyl acetate. The organic layer was separated and the aqueous layer was further extracted with ethyl acetate. The extracts were combined, washed with saline, dried, and evaporated to leave crude product as an orange oil which was dissolved in minimal dichloromethane then was purified by column chromatography on silica gel (gradient 100% DCM to 5% MeOH in ethyl acetate) to afford product 210 mg (49% yield) as a white foam. LC/MS (FA) ES+ 390. 1H NMR (400 MHz, DMSO) δ 8.63-8.58 (dd, J=4.6, 1.6 Hz, 2H), 8.04-8.00 (s, 1H), 8.00-7.96 (s, 1H), 7.87-7.81 (d, J=8.7 Hz, 3H), 7.76-7.71 (dd, J=4.6, 1.7 Hz, 2H), 7.62-7.58 (d, J=1.6 Hz, 1H), 7.50-7.45 (t, J=3.0 Hz, 2H), 6.74-6.69 (d, J=4.2 Hz, 1H), 6.33-6.28 (d, J=4.2 Hz, 1H), 4.37-4.31 (dd, J=7.1, 4.3 Hz, 2H), 1.35-1.27 (t, J=7.1 Hz, 3H).
Reaction SMILES: CCN=C=NCCCN(C)C.[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28](=[O:31])[CH2:29][NH2:30].CCOCC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]1[C:22]([NH:30][CH2:29][C:28]([O:27][CH3:26])=[O:31])=[O:24]
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: COC(=O)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: COC(=O)CNC(=O)c1cc2ccccc2n1C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
DMAP (1.222 g, 0.01 mol) and EDAC (2.680 g, 0.014 mol) were added as solids to a solution of 1-methylindole-2-carboxylic acid (1.752 g, 0.01 mol) and glycine methyl ester hydrochloride (1.256 g, 0.01 mol) in methylene chloride (30 mL) and DMP (5 mL) under a nitrogen atmosphere at 0° C. Stirring was continued for 1 hour at 0° C. and then for 3 hours at room temperature. The reaction mixture was partitioned with ethyl acetate and 5% KHSO4 solution and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate solution was washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) solution and brine, dried over sodium sulfate, and concentrated to give a purple powder as crude product. Trituration of the powder with ether afforded the title product (1.734 mg, 70%). TLC: (methanol/methylene chloride 1:9): Rf=0.61, 1H NMR (CDCl3): δ7.65 (dt, J=8.0, 1.1, 1H), 7.41-7.31 (m, 2H), 7.16 (dd, J=6.6, 1.4, 1H) 6.96 (d, J=0.5, 1H), 6.67 (bs, 1H), 4.25 (d, J=5.2, 2H), 4.05 (s, 3H), 3.82 (s, 3H).