Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:20].CI.[C:28](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:3]=1[CH2:4][N:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18][CH3:19])=[O:17])=[CH:11][CH:12]=2)[N:7]([CH3:28])[C:6]1=[O:20]
Reactant: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(=O)n(Cc3ccc(Cl)cc3Cl)c(=O)n(C)c2c1
Yield: 94.3 %

Procedure:
A mixture of 3-(2,4-dichlorobenzyl)-7-(methoxycarbonyl)-2,4-(1H,3H)-quinazolinedione (2.30 g), methyl iodide (2.13 g) and potassium carbonate (2.07 g) in acetone (30 ml) was heated under reflux for 2 hr. After cooling, the reaction mixture was concentrated, and the residue was washed with water (60 ml) and methyl t-butyl ether (20 ml) and dried to give the objective compound (2.25 g) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[N:6][C:7]=1[C:8]#[N:9].C(Cl)Cl.[C:31](O)([C:33](F)(F)F)=O>CN1C(=O)CCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C@@H:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18][CH2:17]2)=[O:14])=[N:6][C:7]=1[C:8]1[NH:3][C:2]([C@H:31]2[CH2:33][CH2:4][CH2:5][NH:6][CH2:7]2)=[N:1][N:9]=1
Reactant: N#Cc1nc(-c2cccc(C(=O)N[C@H]3CCc4ccccc43)c2)cnc1N
Reactant: O=C(O)C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: Nc1ncc(-c2cccc(C(=O)N[C@H]3CCc4ccccc43)c2)nc1-c1nnc([C@H]2CCCNC2)[nH]1

Procedure:
A solution of 3-(5-amino-6-cyanopyrazine-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzamide (2.4 g, 6.6 mmol) and 1,1-dimethyl (3S)-3-(hydrazinocarbonyl)piperidine-1-carboxylate (2.4 g, 10.1 mmol) in NMP (3 mL) was heated to 180-200° C. for 1 h. The solvent was removed under reduced pressure. The residue obtained was stirred with CH2Cl2/TFA (20% v/v)) for 30 min., concentrated and purified by hplc. The compound was converted to the hydrochloride salt using a 4 M solution of HCl in dioxane to afford 3-(5-amino-6-{5-[(3S)-piperidin-3-yl]-4H-1,2,4-triazol-3-yl}pyrazin-2-yl)-N-[(1S)-2,3-dihydro-1H-inden-1-yl]benzamide: 1H NMR (400 MHz; CD3OD): 8.65 (s, 1H); 8.6 (d, 1H); 7.6 (t, 1H); 7.7-7.8 (m, 4H); 5.7 (t, 1H); 3.75-3.4 (m, 4H); 3.8-3.36 (m, 3H); 3.35-2.8 (m, 3H); 2.6 (m, 1H); 2.4 (m, 2H); 2.1-2.0(m, 4H); 1.3 (t, 3H); MS (EI) for C27H28N8O: 481 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[CH2:17]([N:21]1[C:25](=[O:26])[CH:24]=[CH:23][C:22]1=[O:27])[CH2:18][CH2:19][CH3:20]>C(N(CC)CC)C>[CH2:17]([N:21]1[C:25](=[O:26])[CH2:24][CH:23]([S:11][C:9]2[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=2)[C:22]1=[O:27])[CH2:18][CH2:19][CH3:20]
Reactant: CCCCN1C(=O)C=CC1=O
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Product: CCCCN1C(=O)CC(Sc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)C1=O

Procedure:
The procedure of Example 1 is repeated using 11.92 grams 2,6-di-tert-butyl-4-mercaptophenol, 7.66 grams N-n-butylmaleimide, and 0.5 grams triethylamine. The residue is purified by dry column chromatography to give a white solid, m.p. 80°-85° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-]>CCO.O.[Fe]>[NH2:17][C:14]1[CH:13]=[CH:12][C:11]([CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)NCCc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCc1ccc(N)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A mixture of (tert-butoxy)-N-[2-(4-nitrophenyl)ethyl]-carboxamide (570 mg, 2.15 mmol, Step A), iron powder (602 mg, 10.75 mmol) and NH4Cl (82 mg, 1.5 mmol) in EtOH (6 mL) and H2O (6 ml) was stirred for 4 h at 80° C. Filtration and concentration gave the crude compound, which was used in next step without further purification.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[NH:10]2)[CH3:4].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>CN(C=O)C>[CH2:3]([C:5]1[N:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[C:11]2[C:6]=1[CH:7]=[CH:8][C:9](=[O:17])[N:10]2[CH2:25][C:24]1[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=1)[CH3:4]
Reactant: CCc1cc2[nH]c(=O)ccc2c(CC)n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc2c(ccc(=O)n2Cc2ccc([N+](=O)[O-])cc2)c(CC)n1
Yield: 61.7 %

Procedure:
Sodium hydride (50% dispersion in oil; 0.2 g) was added to a stirred suspension of 5,7-diethyl-1,6-naphthyridin-2(1H)-one (1.0 g) in DMF (10 ml) under an atmosphere of argon. The mixture was stirred until effervescence ceased and 4-nitrobenzyl bromide (1.1 g) was added. The mixture was then stirred for 16 hours. The mixture was then poured into water (50 ml) and extracted twice with ethyl acetate. The combined extracts were washed with saturated sodium chloride solution, dried (MgSO4) and solvent was removed by evaporation to give an oil. The oil was purified by flash chromatography, eluting with ethyl acetate/dichloromethane (1:4 v/v) to give 5,7-diethyl-1-(4-nitrobenzyl)-1,6-naphthyridin-2(1H)-one (B) as a solid (1.03 g); m.p. 105°-106° C.; NMR (CDCl3): 1.22(t, 3H), 1.36(t, 3H), 2.77(q, 2H), 3.11(q, 2H), 5.57(s, 2H), 6.69(s, 1H), 6.77(d, 1H), 7.38(d, 2H), 8.03(d, 1H), 8.19(d, 2H); mass spectrum (CI, ammonia): 338 (M+H)+ ; microanalysis, found: C, 67.0; H, 5.7; N, 12.4%; C19H19N3O3 requires: C, 67.6; H, 5.7; N, 12.5%.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=O)[CH:15](O)O)=[N:6]1.S([O:27][C:28]1[NH:32][N:31]=[C:30]([NH2:33])[C:29]=1[NH2:34])(O)(=O)=O>C(O)(=O)C>[F:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[CH:15]=[N:34][C:29]3[C:30](=[N:31][NH:32][C:28]=3[OH:27])[N:33]=2)=[N:6]1
Reactant: Nc1n[nH]c(OS(=O)(=O)O)c1N
Reactant: O=C(c1nn(Cc2ccccc2F)c2ncccc12)C(O)O
Solvent: CC(=O)O
Product: Oc1[nH]nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.4 %

Procedure:
500 mg (1.291 mmol) of the compound from example 68A were admixed with 7 ml of acetic acid and 273 mg (1.291 mmol) of 3,4-diamino-1H-pyrazol-5-ol sulfate. The mixture was stirred at RT for 16 h and then concentrated on a rotary evaporator. Water and ethyl acetate were added, and the mixture was stirred. The organic phase was removed and extracted once with a 1N sodium hydroxide solution, dried over sodium sulfate and concentrated on a rotary evaporator. The residue was purified by preparative HPLC (eluent: water/acetonitrile/water with 1% trifluoroacetic acid, ratio 80:15:5). 142 mg of the title compound were obtained (29% of theory).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1)[CH3:2].[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].N1C=CN=C1.O>CN(C)C=O>[Si:20]([O:19][C:11]1[C:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[C:14]([C:15]([F:17])([F:18])[F:16])[NH:13][N:12]=1)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(Cc2c(O[Si](C)(C)C(C)(C)C)n[nH]c2C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
15.0 g (55.6 mmol) of 1,2-dihydro-4-((4-ethylphenyl)methyl)-5-(trifluoromethyl)-3H-pyrazol-3-one (4) (prepared by the method described in J. Med. Chem 1996, 39, 3920-3928) was dissolved in 150 ml of dimethylformamide, and cooled to 0° C. Then, 9.3 g (61.1 mmol) of t-butyl dimethylsilyl chloride was added to the above solution in small portions, and thereafter 4.2 g (61.1 mmol) of imidazole was added in small portions. The temperature of the resultant mixture was returned to room temperature and the mixture was stirred for 3 hours. After the addition of water to the reaction mixture, the reaction mixture was extracted with ethyl acetate twice. The resultant organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate and concentrated, to give 21.4 g (55.6 mmol) of the intended compound (100% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([I:9])=[CH:4][N:3]=1.[S-:10][C:11]#[N:12].[K+].C(O)=O>O>[Cl:1][C:2]1[N:7]=[C:6]([S:10][C:11]#[N:12])[C:5]([I:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(I)c(Cl)n1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O=CO
Solvent: O
Product: N#CSc1nc(Cl)ncc1I
Temperature: 20 °C
Reaction time: 3 h
Yield: 75.2 %

Procedure:
Into a 300-ml four-necked flask fitted with a thermometer and a stirrer were charged 35.0 g of 2,4-dichloro-5-iodopyrimidine, 15.0 g of potassium thiocyanate, and 150 ml of formic acid. This reaction mixture was stirred at room temperature (20° C.) for 3 hours. After completion of the reaction, the reaction mixture was poured into a large volume of water and the resulting precipitate was filtered off and dried to obtain crude crystals. Then, these crystals were recrystallized from toluene to obtain 28.5 g (75.4% yield) of 2-chloro-5-iodo-4-thiocyanopyrimidine, m.p. 185°-186.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[C:21]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)(=[O:23])[CH3:22]>>[C:21]([N:24]1[CH2:29][CH2:28][N:27]([C:18](=[O:20])[CH2:17][C:4]2[C:5]3[C:6](=[C:7]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=4)[O:8][N:9]=3)[CH:16]=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH2:25]1)(=[O:23])[CH3:22]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: CC(=O)N1CCN(C(=O)Cc2cc(Cl)cc3c(-c4ccccc4)onc23)CC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with N-acetylpiperazine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.O.O.[F-].[K+].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:2]3[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=3[CH3:8])[CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: Cc1[nH]c(=O)[nH]c(=O)c1Br
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1[nH]c(=O)[nH]c(=O)c1N1CCN(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Yield: 18.9 %

Procedure:
A mixture of 20.50 g (0.100 mole) of 5-bromo-6-methyl-2,4(1H, 3H)pyrimidinedione, 26.96 g (0.100 mole of 1-(4-chlorophenyl)-piperazine, 10.35 g (0.110 mole) of potassium fluoride dihydrate and 41.40 g (0.300 mole) of potassium carbonate in 200 ml of dimethylsulfoxide was heated at 80° for 72 hours. The reaction mixture was cooled and poured into 1 l of ice water. The solid was collected, washed with water, and recrystallized from ethanol to give 6.05 g of the product as a dull yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([N+:13]([O-])=O)[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]>CCO>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:18])[C:6]=1[C:7]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:8]=1[O:16][CH3:17]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1c(Cl)cnn1C
Solvent: CCO
Product: COc1ccc(N)cc1-c1c(Cl)cnn1C
Temperature: 75 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
4-Chloro-5-(2-methoxy-5-nitro-phenyl)-1-methyl-1H-pyrazole (2.27 g, 8.5 mmol) was dissolved in dry EtOH (150 mL) and heated to 75° C. The heated solution was then treated with Sn(II) chloride dihydrate (9.6 g, 42.5 mmol) and stirred at 75° C. After three hours, the reaction was found to be complete by TLC and LCMS. The solvent was removed under reduced pressure. The residue was subsequently diluted with EtOAc (100 mL) and 1N NaOH, neutralizing the reaction to a pH of approximately 6 or 7. The mix was then filtered through celite. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was then purified by flash chromatography (Biotage, SiO2, Hexanes/EtOAc gradient elution) to afford 1.73 g (86%) of 3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine as a light brown solid. LCMS m/z (%)=240 (M+H37Cl, 37), 238 (M+H35Cl, 100). 1H NMR (400 MHz, CDCl3) δ: 7.48 (s, 1H), 6.87 (d, J=8, 1H), 6.81 (dd, J1=8, J2=4, 1H), 6.63 (d, J=4, 1H), 3.72 (s, 3H), 3.70 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]([CH:17]=O)=[CH:13][CH:12]=1>>[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:17]([C:10]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]=1[CH3:1])[C:14]1[CH:15]=[CH:16][C:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:12][CH:13]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: Cc1cc2ccccc2[nH]1
Product: Cc1[nH]c2ccccc2c1C(c1ccc(-c2ccccc2)cc1)c1c(C)[nH]c2ccccc12

Procedure:
The compound Bis(2-methylindol-3-yl)-(1,1′-biphenyl-4-yl)methane was prepared following procedure A, starting from 2-methyl indole and 4-biphenyl carboxaldehyde. LC: Tr 2.71 min, MS: 427 (M+H)+
Reaction SMILES: [CH3:1][C@H:2]([O:11][C:12]1[CH:13]=[C:14](/[CH:18]=[CH:19]/[CH2:20][N:21]2[CH:25]=[CH:24][CH:23]=[C:22]2[C:26]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[O:27])[CH:15]=[CH:16][CH:17]=1)[C:3](N1CCOCC1)=[O:4].[OH-:35].[Li+]>O1CCCC1.CO>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]([C:22]2[N:21]([CH2:20]/[CH:19]=[CH:18]/[C:14]3[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=3)[O:11][C@@H:2]([CH3:1])[C:3]([OH:4])=[O:35])[CH:25]=[CH:24][CH:23]=2)=[O:27])=[CH:29][CH:30]=1
Reactant: [OH-]
Reactant: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)N3CCOCC3)c2)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)c2cccn2C/C=C/c2cccc(O[C@@H](C)C(=O)O)c2)cc1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of (4-methylphenyl)(1-allyl-1H-pyrrol-1-yl)methanone (47.31 g, 210 mmol) in dimethylformamide (650 ml) were added 4-[(2S)-2-(3-iodophenoxy)propanoyl]morpholine (72.24 g, 200 mmol), sodium hydrogencarbonate (33.60 g, 400 mmol), benzyltriethylammonium chloride (45.56 g, 200 mmol) and palladium acetate (2.245 g, 10.0 mmol), and the mixture was stirred for 6 hours at 50–55° C. After the mixture was allowed to cool to room temperature, thereto was added water (1 L) and the mixture was extracted with toluene/ethyl acetate (1/2) twice (1 L and 0.5 L). The organic layer was washed with an aqueous 10% potassium hydrogensulfate solution three times and then water and an aqueous saturated sodium chloride solution. The organic layer was dried over magnesium sulfate. After addition of charcoal, the organic layer was filtered with Celite. The solvent was removed under reduced pressure to give {1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrol-2-yl}(4-methylphenyl)methanone (about 10 g). To a solution of {1-[(2E)-3-(3-{[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]oxy}phenyl)prop-2-enyl]-1H-pyrrol-2-yl}(4-methylphenyl)methanone (about 100 g) in tetrahydrofuran (350 ml) and methanol (350 ml) was added an aqueous 2N lithium hydroxide solution (500 ml) and the mixture was stirred for 5 hours at 70° C. The reaction mixture was concentrated, followed by addition of water. The mixture was acidified (pH 2–3) with 1N hydrochloric acid. The solution was extracted with toluene/ethyl acetate (1/2)(1 L×2) and dried over anhydrous magnesium sulfate. The solvent was removed and the residue was dried to give (2S)-2-(3-{(1E)-3-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]prop-1-enyl}phenoxy)propionic acid (about 90 g).
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:18])CO)[CH:13]=1>O>[Br:7][C:8]1[C:9](=[O:31])[C:10]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:11]([C:19]([O:21][CH3:22])=[O:20])[N:12]([CH2:14][CH:15]([OH:2])[OH:18])[CH:13]=1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)CO
Agent: [Na+]
Solvent: O
Product: COC(=O)c1c(OCc2ccccc2)c(=O)c(Br)cn1CC(O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.5 %

Procedure:
A reactor was charged with sodium periodate (1.67 kg, 7.8 mol) and 44 L of deionized water. To the agitated mixture was added 8.5 kg of ice. This was stirred until all the ice melted and the mixture temperature was 1.4° C. To this was added methyl 5-bromo-1-(2,3-dihydroxypropyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 19 (2.73 kg, 6.62 mol) via a powder addition funnel. The mixture was allowed to warm to rt and the slurry was stirred for 16 h. A sample was monitored by 1H NMR and showed the disappearance of starting material. The mixture was filtered and the cake washed with 20 kg of deionized water. This was repeated until a negative starch/iodide paper result was obtained (4×20 L washes). The solids were dried in a vacuum oven at 45-55° C. to provide methyl 5-bromo-1-(2,2-dihydroxyethyl)-4-oxo-3-[(phenylmethyl)oxy]-1,4-dihydro-2-pyridinecarboxylate 20 (2.176 kg, 88%) as a mixture with the corresponding aldehyde form 21. Purity was determined to be 99.5% by HPLC. 1H NMR (300 MHz, acetone-d6) δ 8.12 (s, 1H), 7.49-7.30 (m, 5H), 5.56 (dd, J=6.0, 2.4 Hz, 1H), 5.23 (m, 1H), 5.20 (s, 2H), 3.97 (d, J=5.1 Hz, 2H), 3.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([CH3:19])[CH:13]=2)=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)C(O)=O.[OH2:20]>>[F:18][CH:15]1[C:14]([CH3:19])=[CH:13][C:12]2[C:3]3[C:2](=[CH:10][C:9]([F:11])=[CH:8][CH:4]=3)[CH2:1][C:17]=2[C:16]1=[O:20]
Reactant: Cc1cc(-c2c(C)cc(F)cc2C(=O)O)ccc1F
Reactant: O
Product: CC1=CC2=C(Cc3cc(F)ccc32)C(=O)C1F
Temperature: 180 °C
Yield: 33 %

Procedure:
A stirred mixture of methyl 2-(3-methyl-4-fluorophenyl)-5-fluorobenzoic acid (6.5 g, 26.2 mmol) and polyphosphoric acid (30 g) was heated at 180° C. for 2 h. After the mixture had cooled to 80° C., it was poured into water (200 mL), and extracted with ethyl acetate. The combined extracts were washed with brine, dried over MgSO4, treated with charcoal, and concentrated. Chromatography on silica gel using 20% toluene in hexane provided 2 g (33%) of the desired ketone.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([N:24]=[C:25]=[O:26])=[O:23])[N:15]=1>ClCCl>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[O:18][N:17]=[C:16]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][CH:29]=2)[C:22]([NH:24][C:25]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:26])=[O:23])[N:15]=1
Reactant: C1COCCN1
Reactant: O=C=NC(=O)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Solvent: ClCCl
Product: O=C(NC(=O)N1CCOCC1)c1cccc(-c2noc(-c3ccccc3F)n2)c1
Yield: 96.6 %

Procedure:
Morpholine (114 μL; 1.30 mmol, 2.0 eq.) is added to a solution of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoyl isocyanate (Compound A4, 200 mg, 0.65 mmol) in anhydrous dichloromethane (4.0 mL) under nitrogen, and the reaction mixture is heated to reflux for 18 h. The resulting slurry is filtered and recrystallized from the minimum amount of dichloromethane in hexanes to afford 249 mg (97%) of morpholine-4-carboxylic acid 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoylamide (Compound 25) as a white powder: mp 190-194° C.; 1H NMR (300 MHz, DMSO-d6) δ 3.05 (t, J=5.1 Hz, 2H), 3.46 (d, J=4.5 Hz, 2H), 3.61 (m, 2H), 3.76 (t, J=5.1 Hz, 2H), 7.46-7.90 (m, 4H), 7.59 (d, J=8.1 Hz, 1H), 8.22-8.29 (m, 2H), 8.53 (d, J=1.5 Hz, 1 H), 9.20 (br s, 1H); MS m/z 397.15, calcd for C20H17FN4O4 (MH+) 397.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([OH:21])(=[O:20])[C:14]([CH2:16][C:17](O)=[O:18])=[CH2:15]>O>[O:18]=[C:17]1[N:1]([C:2]2[CH:3]=[CH:4][C:5]3[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=3[CH:12]=2)[CH2:15][CH:14]([C:13]([OH:21])=[O:20])[CH2:16]1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: O
Product: O=C1COc2ccc(N3CC(C(=O)O)CC3=O)cc2N1
Yield: 95.6 %

Procedure:
A mixture of 6-amino-2H-1,4-benzoxazin-3(4H)-one (4.93 g, 30.0 mmol), itaconic acid (4.06 g, 31.2 mmol) and water (80 ml) was heated under reflux overnight. The reaction solution was cooled, and the insoluble material was collected by filtration and washed with water and diethyl ether. The filtrate was dried at 50° C. under reduced pressure to yield 7.92 g (96%) of the title compound in the form of a brownish solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@H:17]([N:19]1C(=O)C2C(=CC=CC=2)C1=O)[CH3:18])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:19][C@H:17]([CH3:18])[CH2:16][N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: C[C@H](CN(Cc1ccccc1)C(=O)OC(C)(C)C)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: C[C@@H](N)CN(Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 12 h
Yield: 78.9 %

Procedure:
278 mg of (R)-tert-butyl benzyl{2-(1,3-dioxoisoindolin-2-yl)propyl}carbamate was dissolved in 5 mL of methanol. To the solution, 1 mL of hydrazine hydrate was added, and the mixture was stirred at 80° C. for 12 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. A 10% aqueous potassium hydroxide solution was added thereto, followed by extraction with dichloromethane (40 mL×3). The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (dichloromethane:methanol=2:1) to obtain 147 mg of the title compound as a colorless oil (79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12](I)[CH:11]=1)=[O:9].[CH2:18]([N:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[CH3:27])[CH2:19][C:20]#[CH:21]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][C:20]([CH2:19][CH2:18][N:22]3[CH2:26][CH2:25][CH2:24][C@H:23]3[CH3:27])=[CH:21][C:12]=2[CH:11]=1)=[O:9]
Reactant: O=C(c1ccc(O)c(I)c1)c1ccccc1F
Reactant: C#CCCN1CCC[C@H]1C
Product: C[C@@H]1CCCN1CCc1cc2cc(C(=O)c3ccccc3F)ccc2o1

Procedure:
The product from Example 70A and a 0.1M solution of the product from Example 68B were processed as described in Example 68C to provide the title compound. 1HNMR (300 MHz, CD3OD) δ 1.28 (d, 3H, J=6.1 Hz), 1.59 (m, 1H), 1.93 (m, 2H), 2.10-2.78 (m, 2H), 2.93 (m, 2H), 3.18 (m, 2H), 3.45 (m, 2H), 6.76 (s, 1H), 7.21-7.38 (m, 2H), 7-50-7.67 (m, 3H), 7.79 (d, 1H, J=8.9 Hz), 7.99 (s, 1H); MS (ESI) m/z 352.1 (M+H)+.