Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][CH:9]([C:13]3[NH:18][C:17]4=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:20]=[N:21][C:16]4=[CH:15][N:14]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[O:30]C(C)=O.[ClH:34]>CO>[OH2:30].[ClH:34].[C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][CH:9]([C:13]3[NH:18][C:17]4=[C:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[CH:20]=[N:21][C:16]4=[CH:15][N:14]=3)[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(C)=O
Agent: Cl
Agent: c1ccc(-c2cnc3cnc(C4CCNC(c5ccccc5)C4)[nH]c2-3)cc1
Solvent: CO
Product: O

Procedure:
Using the method described in Example 30 by employing (1,2-diphenylvinyl)pyrrolidine (freshly prepared before use) (1.85 g, 7.43 mmol), 4,6-dichloro-5-nitropyrimidine (Aldrich Chemical Company) (1.40 g, 7.43 mmol), N,N-diisopropylethyl amine (Aldrich Chemical Company) (1.3 mL, 7.43 mmol), piperidine (1.2 mL, 11.9 mmol), NEt3 (Aldrich Chemical Company) (2.0 mL) and SnCl2 (Aldrich Chemical Company) (22 mL of a 2M solution in DMF). The residue was purified by flash chromatography on silica gel with 95:5 CHCl3:MeOH as elutant to give 258 mg (10%) of the free base as a brown colored sandy solid. 1H NMR (DMSO-d6; 400 MHz): δ 1.66 (br s, 6), 3.75 (br s, 4), 7.19 (t, 1, J=7.3), 7.29 (t, 2, J=7.7), 7.42-7.47 (m, 7), 8.30 (s, 1), 11.38 (s, 1). MS m/z: 355 (M+1). To a solution of 6,7-diphenyl-4-piperidylpyrrolo[3,2-d]pyrimidine (0.26 g, 0.73 mmol) in 4:1 EtOAc: MeOH (30 mL) was added 1M etheral HCl (Aldrich Chemical Company) (730 mL, 0.73 mmol). The precipitate was collected by filtration, washed with ether (3×15 mL) and dried under vacuum to give 258 mg (91%) of the title compound as a beige colored solid. Mp: 266-268.5° C. 1H NMR (DMSO-d6; 400 MHz): δ 1.73 (br s, 6), 4.09 (br s, 4), 7.29 (d, 2, J=6.7), 7.37-7.44 (m, 8), 8.50 (s, 1), 12.42 (s, 1), 14.15 (s, 1). MS m/z: 355 (M+1). Anal. Calcd for C23H22N4.HCl.0.25H2O: C, 69.92; H, 5.99; N, 14.18; Cl, 8.97. Found C, 69.92; H, 6.01; N, 13.86; Cl, 9.37.
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH2:14])=[CH:7][CH:6]=1)([O-])=O>CO.[Pd]>[ClH:1].[NH2:2][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH:11]2[NH2:14])=[CH:7][CH:6]=1
Reactant: NC1CCc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)C(N)CC2
Reaction time: 1 h

Procedure:
To a solution of 6-nitro-1-aminoindane hydrochloride (1.00 g, 4.66 mmol) in MeOH (100 ml) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 6-amino-1-aminoindane hydrochloride which was homogeneous by TLC and used immediately in the next step.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@H:21]([OH:33])[C@@H:22]([NH2:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[C:8]([O:12][C:13]([N:15]1[C@@H:20]([C@@H:21]([OH:33])[C@@H:22]([NH:32][C:1](=[O:3])[CH3:2])[CH2:23][C:24]2[CH:25]=[C:26]([F:31])[CH:27]=[C:28]([F:30])[CH:29]=2)[CH2:19][O:18][C@@H:17]([O:34][CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[C@@H:16]1[CH3:40])=[O:14])([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@H]1[C@H](OCC(C)(C)C)OC[C@H]([C@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)N1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H](O)[C@H]1CO[C@@H](OCC(C)(C)C)[C@H](C)N1C(=O)OC(C)(C)C
Yield: 90.8 %

Procedure:
Add acetic anhydride (0.084 ml, 0.89 mmol) to a solution of (2R,3S,5R)-5-[(1R,2S)-2-amino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2-(2,2-dimethylpropoxy)-3-methylmorpholine-4-carboxylic acid tert-butyl ester (400 mg, 0.85 mmol) in dry dichloromethane (9 mL). Add triethylamine (0.179 mL, 1.27 mmol), stir 1 hour at room temperature, concentrate and purify (silica gel cartridge chromatography, eluting with 1:1 hexanes:ethyl acetate) to give the title compound as a white solid (397 mg, 91%).
Reaction SMILES: FC1C=C(C2N=C(SC)N=C(N3CCOC[C@@H]3C)C=2)C=NC=1.Cl[C:24]1[N:29]=[C:28]([N:30]2[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]2[CH3:36])[CH:27]=[C:26]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1.[CH:43]1([NH:46][C:47](=[O:64])[NH:48][C:49]2[CH:54]=[CH:53][C:52](B3OC(C)(C)C(C)(C)O3)=[CH:51][CH:50]=2)[CH2:45][CH2:44]1>>[CH:43]1([NH:46][C:47]([NH:48][C:49]2[CH:54]=[CH:53][C:52]([C:24]3[N:29]=[C:28]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][C@@H:31]4[CH3:36])[CH:27]=[C:26]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[N:25]=3)=[CH:51][CH:50]=2)=[O:64])[CH2:45][CH2:44]1
Reactant: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: CSc1nc(-c2cncc(F)c2)cc(N2CCOC[C@@H]2C)n1
Product: C[C@H]1COCCN1c1cc(-c2ccccn2)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1

Procedure:
Method as described for intermediate 5 using (S)-4-(2-chloro-6-(pyridin-2-yl)pyrimidin-4-yl)-3-methylmorpholine (intermediate 21) and 4-(3-cyclopropylureido)phenyl boronic acid pinacol ester. Material was purified by prep HPLC (low pH) to afford a light orange solid.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:8]([C:9]([CH3:12])=[CH:10][CH:11]=1)=[N:7][C:6](=[O:13])[C:5]([CH3:15])([CH3:14])[CH:4]=2.Cl[CH2:17][C:18]([CH3:20])=[CH2:19].C(=O)([O-])[O-].[K+].[K+]>CCOCC>[CH3:19][C:18](=[CH2:17])[CH2:20][C:11]1[CH:10]=[C:9]([CH3:12])[C:8]2[C:3](=[CH:4][C:5]([CH3:15])([CH3:14])[C:6](=[O:13])[N:7]=2)[C:2]=1[OH:1]
Reactant: Cc1ccc(O)c2c1=NC(=O)C(C)(C)C=2
Reactant: C=C(C)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Product: C=C(C)Cc1cc(C)c2c(c1O)=CC(C)(C)C(=O)N=2
Yield: 54.9 %

Procedure:
Using 5-hydroxy-3,3,8-trimethylcarbostyril (1.99 g, 9.69 mmol), 3-chloro-2-methyl-1-propene (1.08 g, 12.0 mmol), and potassium carbonate (2.67 g, 19.38 mmol), the procedure of Reference Example 41 was followed (reaction and post-treatment) to obtain 2.43 g of a crude ether. The obtained crude (2.43 g) was allowed to react and post-treated in a manner similar to that Reference Example 47, followed by purifying by silica gel column chromatography(ether:hexane =1:1). As a result, 1.37 g of the title compound was obtained as a colorless solid (54.4%).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]#[C:5][CH2:6][CH3:7].Cl[C:10]1[N:15]=[CH:14][N:13]=[C:12]([O:16][CH:17]([CH3:22])[C:18]([CH3:21])([OH:20])[CH3:19])[CH:11]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:8][C:10]1[CH:11]=[C:12]([O:16][CH:17]([CH3:22])[C:18]([OH:20])([CH3:19])[CH3:21])[N:13]=[CH:14][N:15]=1)[C:4]#[C:5][CH2:6][CH3:7]
Reactant: CCC#CCO
Reactant: CC(Oc1cc(Cl)ncn1)C(C)(C)O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC#CCOc1cc(OC(C)C(C)(C)O)ncn1
Reaction time: 0.17 h

Procedure:
In 3 ml of tetrahydrofuran was suspended 0.17 g of sodium hydride (60% in oil), to which 0.4 ml of a solution containing 0.17 g of 2-pentyn-1-ol was added dropwise at 0° C., followed by stirring for 10 minutes. To this was added dropwise 0.4 ml of tetrahydrofuran containing 0.37 g of 3-(6-chloro-4-pyrimidyloxy)-2-methyl-2-butanol dissolved therein, followed by stirring at the same temperature for 1 hour and at room temperature for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, which was extracted three times with t-butyl methyl ether. The combined organic layers were washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.33 g of 4-(2-pentynyloxy)-6-(2-hydroxy-1,2-dimethylpropyloxy)pyrimidine.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[NH2:23][OH:24].C[O-].[Na+]>CO>[OH:24][NH:23][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10](=[O:20])[CH2:11]/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)CCCCCNC(=O)CC=Cc1ccccc1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(CCCCCNC(=O)C/C=C/c1ccccc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
(Method J7) To a mixture of 6-(4-phenyl-but-3-enoylamino)-hexanoic acid methyl ester (3/57) (100 mg, 0.35 mmol) and hydroxylamine hydrochloride (96 mg, 1.38 mmol) in methanol (1 ml) the 3.43 N solution of sodium methylate (0.61 ml, 2.1 mmol) in methanol was added. The mixture was stirred for 1 hour at room temperature, diluted with saturated NaH2PO4 (10 ml), and extracted with ethyl acetate (2×20 ml). The organic extracts were combined, washed with brine, and dried (Na2SO4). The solvent was evaporated and the residue was crystallized from ethyl acetate to give the title product, yield 66%. M.p. 127-128° C. (from ethyl acetate). 1H NMR (DMSO-d6, HMDSO), δ: 1.07-1.68 (m, 6H); 1.78-2.06 (m, 2H); 2.03 (t, 2H, J=6.6 Hz); 2.85-3.18 (m, 4H); 6.30 (dd, 1H, J=16.1 and 6.0 Hz); 6.48 (d, 1H, J=16.1 Hz); 7.14-7.53 (m, 5H); 7.85 (t, 1H, J=5.8 Hz); 8.63 (br s, 1H); 10.32 (br s, 1H). HPLC analysis on Zorbax SB-C18 column: impurities 2% (column size 4.6×150 mm; mobile phase 0.1% H3PO4, gradient from 50:50 to 90:10; detector UV 254 nm; sample concentration 0.75 mg/ml, flow rate 1.5 ml/min). Anal. Calcd for C16H22N2O3: C, 66.19; H, 7.64; N, 9.65. Found: C, 66.19; H, 7.69; N, 9.67.
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:6][C:5]=1[F:42].O.[OH-].[Li+]>C1COCC1.O>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([C@@:17]2([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:40])([CH3:41])[CH3:39])[NH:15][C@@H:14]([C:12]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[C:5]([F:42])[CH:6]=3)=[O:13])[C@@H:18]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=2[F:26])=[C:30]([F:36])[CH:31]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)c(F)c2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Yield: 97.4 %

Procedure:
In a manner similar to the method described in Example 380, rac-4-({[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid methyl ester (80.3 mg, 0.127 mmol) in THF (9 ml) was reacted with lithium hydroxide hydrate (37.6 mg, 0.896 mmol) in water (4.5 mL) to give rac-4-({[(2R,3S,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-2-fluoro-benzoic acid as a white lyophilized solid (76.5 mg, 97%). HRMS (ES+) m/z Calcd C31H28Cl2F3N3O3+H [(M+H): 618.1533. Found: 618.1533.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]([C:9]1[N:10](C(OC(C)(C)C)=O)[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)([CH3:8])[CH3:7])=[O:5])[CH3:2]>ClCCl.C(O)(C(F)(F)F)=O>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:17]=[C:9]1[C:6]([CH3:7])([CH3:8])[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)C(C)(C)c1cc2ccccc2n1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C(C)(C)c1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.2 %

Procedure:
tert-Butyl 2-(2-(ethoxycarbonyl)propan-2-yl)-1H-indole-1-carboxylate (22.9 g, 69.1 mmol) was dissolved in dichloromethane (200 mL) before TFA (70 mL) was added. The mixture was stirred for 5 h at room temperature. The mixture was evaporated to dryness, taken up in dichloromethane and washed with saturated sodium bicarbonate solution, water, and brine. The product was purified by column chromatography on silica gel (0-20% EtOAc in hexane) to give ethyl 2-(1H-indol-2-yl)-2-methylpropanoate (12.5 g, 78%).
Reaction SMILES: ClN1C(=O)CCC1=O.[CH:9]1([CH:12]=[N:13][OH:14])[CH2:11][CH2:10]1.[CH3:15][C:16]1[CH:17]=[C:18]([C:29]2[N:33]=[C:32]([CH3:34])[O:31][N:30]=2)[CH:19]=[C:20]([CH3:28])[C:21]=1[O:22][CH2:23][CH2:24][CH2:25][C:26]#[CH:27].C(N(CC)CC)C>CN(C)C=O.N1C=CC=CC=1>[CH:9]1([C:12]2[CH:27]=[C:26]([CH2:25][CH2:24][CH2:23][O:22][C:21]3[C:16]([CH3:15])=[CH:17][C:18]([C:29]4[N:33]=[C:32]([CH3:34])[O:31][N:30]=4)=[CH:19][C:20]=3[CH3:28])[O:14][N:13]=2)[CH2:11][CH2:10]1
Reactant: ON=CC1CC1
Reactant: C#CCCCOc1c(C)cc(-c2noc(C)n2)cc1C
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cc(C)c(OCCCc3cc(C4CC4)no3)c(C)c2)no1

Procedure:
Following a procedure similar to that described in Example 2(b) and using 0.52 g N-chlorosuccinimide in 5 mls dimethylformamide, two drops of pyridine, 0.33 g cyclopropanecarboxaldehyde oxime from part (a) above in 10 mls dimethylformamide, 0.53 g 3-[3,5-dimethyl-4-(3-ethinylpropoxy)phenyl]-5-methyl-1,2,4-oxadiazole prepared by a procedure similar to that described in Example 1(b), and 0.40 g triethylamine in 20 mls dimethylformamide, there was obtained after chroamtography (MPLC, silica gel; 20:80 ethyl acetate/hexane) and recrystallization (methyl alcohol) 0.312 g of the title compound, m.p. 50.5°-51° C.
Reaction SMILES: I[C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1.[C:27]([C:29]1[N:33]([CH3:34])[CH:32]=[N:31][CH:30]=1)#[CH:28]>>[CH3:34][N:33]1[C:29]([C:27]#[C:28][C:2]2[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=2[CH2:4][O:5][NH:6][C:7](=[O:22])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH:14][CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[CH:30][N:31]=[CH:32]1
Reactant: C#Cc1cncn1C
Reactant: O=C(NOCc1ccccc1I)c1ccccc1NCc1ccncc1
Product: Cn1cncc1C#Cc1ccccc1CONC(=O)c1ccccc1NCc1ccncc1

Procedure:
Starring materials: N-(2-Iodo-benzyloxy)-2-[(pyridin-4-ylmethyl)-amino]-benzamide (see Example 360) and 5-ethynyl-1-methyl-1-H-imidazole (Aldrich).
Reaction SMILES: C(Cl)CCl.[O:5]([C:12]1[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:31][NH:32][CH3:33].C1C=CC2N(O)N=NC=2C=1.O.C(N(CC)CC)C>CN(C=O)C>[CH3:33][N:32]([CH2:31][C:23]1[N:22]([CH3:21])[C:30]2[C:25]([CH:24]=1)=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14](=[O:16])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=1[O:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCc1cc2ccccc2n1C
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1cc2ccccc2n1C)C(=O)c1ccccc1Oc1ccccc1
Reaction time: 16.5 h
Yield: 106.2 %

Procedure:
EDC (230 mg, 1.2 mmole) was added to a solution of 2-phenoxybenzoic acid (214.2 mg, 1.0 mmole), 1-methyl-2-(methylaminomethyl)indole (209.1 mg, 1.2 mmole), HOBt.H2O (162.2 mg, 1.2 mmole), and triethylamine (0.35 mL, 2.5 mmole) in DMF (5 mL) at RT. After 16.5 hr, the reaction was concentrated, and the residue was reconcentrated from xylenes/CHCl3 to remove residual DMF. Flash chromatography on silica gel (40% EtOAc/hexanes) gave the title compound (393.5 mg, quantitative) as a nearly colorless, very viscous oil: 1H NMR (360 MHz, CDCl3) indicated an approximately 5:1 mixture of amide rotamers; for the major rotamer: δ 7.56 (d, J=7.9 Hz, 1H), 6.98-7.50 (m, 9H), 6.95 (d, J=7.6 Hz, 2H), 6.87 (d, J=7.5 Hz, 1H), 6.49 (s, 1H), 4.40-5.40 (m, 2H), 3.62 (s, 3H), 2.84 (s, 3H); for the minor rotamer: δ 6.80-7.50 (m, 13H), 6.47 (s, 1H), 4.40-5.40 (m, 2H), 3.56 (s, 3H), 2.98 (s, 3H); MS (ES) m/e 371 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH:19]([C:22]1[O:23][C:24]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:25]([C:27](O)=[O:28])[N:26]=1)([CH3:21])[CH3:20]>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:27]([C:25]3[N:26]=[C:22]([CH:19]([CH3:21])[CH3:20])[O:23][C:24]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:28])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: CC(C)c1nc(C(=O)O)c(-c2ccccc2)o1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C(C)C)oc3-c3ccccc3)n2)o1

Procedure:
Following general procedure B followed by C, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 2-isopropyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.08 min; [M+H]+=419.3.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([O:28]CC)=O)[C:8]2=[O:31])[CH2:3][CH2:2]1.[CH3:33][NH2:34]>>[CH:1]1([NH:4][C:5](=[O:32])[CH2:6][N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([CH2:17][C:18]4[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=4)[CH:15]=3)[C:10]([OH:25])=[C:9]([C:26]([NH:34][CH3:33])=[O:28])[C:8]2=[O:31])[CH2:3][CH2:2]1
Reactant: CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O
Product: CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)NC2CC2)c1=O

Procedure:
This compound was prepared from ethyl 1-[2-(cyclopropylamino)-2-oxoethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and methanolic methylamine employing methods similar to those described in Example 245. The crude material was triturated with a mixture of MeOH and 1N HCl to afford the product as a white solid: 1H NMR (d6-DMSO) δ 9.99 (1H, d, J=5 Hz), 8.53 (1H, s), 8.23 (1H, d, J=4 Hz), 7.74 (1H, s), 7.32 (2H, dd, J=8.6, 5.7 Hz), 7.11 (2H, t, J˜9 Hz), 4.79 (2H, s), 4.13 (2H, s), 2.88 (3H, d, J=5 Hz), 2.57 (1H, m), 0.59 (2H, m), 0.34 (2H, m); HRMS calcd for C22H21FN4O4+H+: 425.1625. Found: 425.1623.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:8][C:9]1=[C:10]([Br:16])[C:11]([O:13][C:14]1=O)=[O:12]>CC(O)=O>[C:2]1([N:1]2[C:14](=[O:13])[C:9]([Br:8])=[C:10]([Br:16])[C:11]2=[O:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1OC(=O)C(Br)=C1Br
Reactant: Nc1ccccc1
Solvent: CC(=O)O
Product: O=C1C(Br)=C(Br)C(=O)N1c1ccccc1
Temperature: 130 °C
Reaction time: 1.5 h
Yield: 63.7 %

Procedure:
Aniline (72 μL, 0.788 mmol) was added to a solution of dibromomaleic anhydride (200 mg, 0.788 mmol) in AcOH (10 mL). The mixture was stirred for 3 h at RT and at 130° C. for 90 mins. After cooling, the mixture was concentrated to dryness and traces of AcOH removed by azeotrope with toluene. The tan residue was purified using silica flash chromatography (5% EtOAc/95% petroleum ether) to yield the desired compound as a pale yellow solid (166 mg, 60%). δH (600 MHz, CDCl3) 7.48 (m, 2H, ArH), 7.41 (tt, 1H, J=7.4 and 1.1 Hz, ArH), 7.33 (m, 2H, ArH); δC (150 MHz, CDCl3) 163.0, 131.0, 130.0, 129.5, 128.8, 126.2.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[O:11][C:12]([NH:14][C:15]([CH3:29])([C:26](O)=[O:27])[CH2:16][C:17]1[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=1)=[O:13])[CH2:8]2.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.Cl.[N:64]1[CH:69]=[CH:68][N:67]=[CH:66][C:65]=1[CH2:70][CH2:71][NH2:72]>C(OCC)(=O)C.O>[NH:19]1[C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([CH2:16][C:15]([NH:14][C:12](=[O:13])[O:11][CH:2]2[CH:1]3[CH2:10][CH:5]4[CH2:6][CH:7]([CH2:9][CH:3]2[CH2:4]4)[CH2:8]3)([CH3:29])[C:26](=[O:27])[NH:72][CH2:71][CH2:70][C:65]2[CH:66]=[N:67][CH:68]=[CH:69][N:64]=2)=[CH:18]1
Reactant: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)O
Reactant: NCCc1cnccn1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(Cc1c[nH]c2ccccc12)(NC(=O)OC1C2CC3CC(C2)CC1C3)C(=O)NCCc1cnccn1
Reaction time: 1.75 h
Yield: 63.2 %

Procedure:
A room temperature solution of 0.40 g (1.01 mmol) of 2-adamantyloxycarbonyl-α-methyl-DL-tryptophan and 0.15 g (1.11 mmol) of 1-hydroxybenzotriazole hydrate in 15 mL of anhydrous ethyl acetate under N2 atmosphere was treated with 0.23 g (1.11 mmol) of 1,3-dicyclohexylcarbodiimide in one portion. The reaction was stirred for 1.75 hours and treated with 0.12 g (1.22 mmol) of triethylamine and 0.17 g (1.07 mmol) of 2-pyrazineethaneamine hydrochloride. The reaction as stirred for 1.75 hours and filtered. The filtrate was washed with aqueous 1M citric acid (2×15 mL), saturated aqueous NaHCO3 (2×15 mL), and saturated aqueous NaCl (15 mL), dried over Na2SO4, and concentrated in vacuo. The residue was treated with 1,2-dimethoxyethane (5 mL), allowed to stand at 0°-5° C. for 16 hours, filtered, and concentrated in vacuo. Chromatography (flash, SiO2, 230-400 mesh, 0.5% triethylamine/10% isopropanol/ethyl acetate eluant, 15×2.5 cm) gave a clear oil upon solvent removal. The residue was dissolved in methanol (10 mL) and water (1 mL) and concentrated in vacuo until a solid formed. The solid was suspended in water, filtered, and dried to give 0.32 g (63%) of the desired product as a white solid; mp 97°-101° C.; 1H NMR (CDCl3) δ1.4-2.0 (17H, m), 2.87 (2H, m), 3.29 (1H, d, J 15 Hz), 3.46 (1H, d, J 15 Hz), 3.62 (2H, m), 4.74 (1H, br s), 5.23 (1H, br s), 6.95 (2H, br s), 7.0-7.2 (2H, m), 7.33 (1H, d, J 8 Hz), 7.58 (1H, d, J 8 Hz), 8.20 (1H, br s), 8.37 (2H, s), 8.38 (1H, s).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-:3])=[O:2].Cl.Cl[CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:17][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O.[I-].[K+]>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:13][C:14]1[N:15]=[C:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[S:17][CH:18]=1)([O-:3])=[O:2]
Reactant: ClCc1csc(-c2ccccc2)n1
Reactant: O=[N+]([O-])c1ccccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccccc1OCc1csc(-c2ccccc2)n1
Yield: 66.8 %

Procedure:
To a solution of 10.7 g (0.08 mol) of 2-nitrophenol in 500 ml of acetone are added 19.0 g (0.08 mol) of 4-chloromethyl-2-phenylthiazole hydrochloride, 26.3 g (0.08 mol) of cesium carbonate, and 0.5 g of potassium iodide, and the slurry is heated to reflux for 20 hours. The mixture is filtered, and the filtrate is concentrated in vacuo to obtain a crystalline residue. Recrystallization from ethanol gives 16.7 g (67%) of crystals, m.p. 95° C.
Reaction SMILES: IC1C=CC(C(N2CCN(C3C(C)=CC(C)=C(C)N=3)CC2)=O)=CC=1.COC1C=CC(CN2CC(C)NC2=O)=CC=1.COC1C=CC(C[N:48]2[CH2:52][CH:51]([CH3:53])[N:50]([C:54]3[CH:59]=[CH:58][C:57]([C:60]([N:62]4[CH2:67][CH2:66][N:65]([C:68]5[C:73]([CH3:74])=[CH:72][C:71]([CH3:75])=[C:70]([CH3:76])[N:69]=5)[CH2:64][CH2:63]4)=[O:61])=[CH:56][CH:55]=3)[C:49]2=[O:77])=CC=1>>[CH3:53][CH:51]1[N:50]([C:54]2[CH:55]=[CH:56][C:57]([C:60]([N:62]3[CH2:63][CH2:64][N:65]([C:68]4[C:73]([CH3:74])=[CH:72][C:71]([CH3:75])=[C:70]([CH3:76])[N:69]=4)[CH2:66][CH2:67]3)=[O:61])=[CH:58][CH:59]=2)[C:49](=[O:77])[NH:48][CH2:52]1
Reactant: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5nc(C)c(C)cc5C)CC4)cc3)C2=O)cc1
Agent: COc1ccc(CN2CC(C)NC2=O)cc1
Agent: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)NCC4C)cc3)CC2)nc1C

Procedure:
Using (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (174 mg) described in Preparation Example 120 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (106 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 506, the title compound (135 mg) was obtained via 1-(4-methoxybenzyl)-4-methyl-3-{4-[4-(3,5,6-trimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}imidazolidin-2-one.