Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21]Cl)[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28]>CN(C)C=O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[N:20]=[C:19]([CH2:21][N:29]([CH2:30][CH3:31])[CH2:27][CH3:28])[O:18][N:17]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCNCC
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(CCl)n3)c2[C@@H]2CCCN12
Solvent: CN(C)C=O
Product: CCN(CC)Cc1nc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.1 %

Procedure:
A suspension of 1.85 g (4.74 mmol) of (S)-8-chloro-1-(5-chloromethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 30 ml of N,N-dimethylformamide was treated with 1.73 g (23.7 mmol) of diethylamine. After stirring at room temperature for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with methylene chloride/methanol 19:1 as the eluent. There were obtained 1.54 g (76%) of (S)-8-chloro-1-(5-diethylaminomethyl-1,2,4-oxadiazol-3-yl)-11,12,13,13a-tetrahydro-9H-imidazo-[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one as a pale yellow oil. A sample was recrystallized from ether and gave white crystals; m.p. 151°-153° and [α]D20 =+35.5° (MeOH, c=1%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O>[N:16]([C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][CH:3]=1)=[N+:17]=[N-:18]
Reactant: COC(=O)c1c(Cl)ccnc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N=[N+]=[N-])ccnc1C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred solution of methyl 4-chloro-2-(trifluoromethyl)nicotinate (9.75 g, 40.7 mmol) in DMF (300 mL) is added sodium azide (21.2 g, 326 mmol). The solution is warmed to 45° C. for 3 hours and then to 50° C. for 1 hour. The reaction is diluted with water (300 mL) and extracted with ether-pentane (1:1, ca. 1 L). The organic layer is back extracted with water (3×). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 9.50 g (95%) of the title compound as a brown oil: 1H NMR (400 MHz, CD3OD), 8.651 (d, 1H), 7.603 (d, 1H), 3.878 (s, 3H).
Reaction SMILES: [CH:1]([NH2:3])=O.[N+:4]([C:7]1[CH:8]=[C:9]([NH2:16])[C:10](=[CH:14][CH:15]=1)[C:11]([OH:13])=O)([O-:6])=[O:5]>O>[N+:4]([C:7]1[CH:8]=[C:9]2[C:10]([C:11]([OH:13])=[N:3][CH:1]=[N:16]2)=[CH:14][CH:15]=1)([O-:6])=[O:5]
Reactant: NC=O
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Temperature: 160 °C
Reaction time: 7 h
Yield: 86.1 %

Procedure:
A mixture of formamide (7.91 g, 176 mmol) and 4-nitroanthranilic acid (4.00 g, 22.0 mmol) was warmed to 160° C. and stirred for 7 h then cooled to RT and stirred overnight. The mixture was diluted with H2O (30 mL) and stirred overnight. The brown solid was collected by filtration and dried to yield 7-nitroquinazolin-4-ol (3.62 g, 86% yield). 1H NMR (300 MHz, DMSO-d6): 8.38-8.33 (m, 2H), 8.27-8.23 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([CH:21]=1)[C:18](O)=O>>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([Cl:22])=[C:17]([CH2:18][C:9]2[S:8][C:7]([C:5]3[S:6][C:2]([Cl:1])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)[CH:21]=1
Reactant: Clc1ccc(-c2cccs2)s1
Reactant: O=C(O)c1cc(Br)ccc1Cl
Product: Clc1ccc(-c2ccc(Cc3cc(Br)ccc3Cl)s2)s1

Procedure:
2-(5-Chloro-2-thienyl)thiophene and 5-bromo-2-chlorobenzoic acid were treated in a manner similar to Reference Example 5 to give the target compound.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:5])C.[OH-].[Li+]>CO>[N:15]1[C:16]2[C:11](=[CH:10][C:9]([C@@H:7]3[CH2:8][C@H:6]3[C:4]([OH:5])=[O:3])=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1ccc2ncccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)[C@@H]1C[C@H]1c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
To a solution of trans 2-quinolin-6-yl-cyclopropanecarboxylic acid ethyl ester (125 mg, 0.523 mmol) in methanol (2 mL) was added 4 M aqueous solution of lithium hydroxide (0.65 mL, 2.62 mmol). The reaction mixture was stirred at room temperature for 3 h then it was concentrated in vacuo, diluted with water, and treated with 1 N aqueous hydrochloric acid until pH 4-5. The resulting precipitate was filtered, washed with water, and dried in vacuo to provide 102 mg of product as a white solid. 1H NMR 500 MHz (DMSO) δ 1.50 (m, 2H), 1.96 (m, 1H), 2.60 (m, 1H), 7.50 (dd, 1H), 7.57 (dd, 1H), 7.78 (d, 1H), 7.93 (d, 1H), 8.26 (dd, 1H), 8.83 (dd, 1H); MS (m/z) 214 [M+H+]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[N:9][C:10]2[CH:15]=[C:14]([C:16]([CH3:24])([CH3:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:13]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:11]=2O)=[C:4]([N+:35]([O-])=O)[CH:3]=1.[N+](C1C=CC=CC=1N=NC1C=C(C(C)(C)C2C=CC=CC=2)C=C(C(C)(C)C2C=CC=CC=2)C=1O)([O-])=[O:39]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][N:9]([C:10]3[CH:11]=[C:12]([C:25]([CH3:33])([CH3:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=4[OH:39])[CH:13]=[C:14]([C:16]([CH3:23])([CH3:24])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:15]=3)[N:35]=[C:4]2[CH:3]=1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Reactant: CC(C)(c1ccccc1)c1cc(N=Nc2ccccc2[N+](=O)[O-])c(O)c(C(C)(C)c2ccccc2)c1
Product: CC(C)(c1ccccc1)c1cc(-n2nc3ccc(Cl)cc3n2)cc(C(C)(C)c2ccccc2O)c1
Yield: 70 %

Procedure:
When, using the general procedure of example 3, the amount of 4-chloro-2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl)azobenzene was substituted for 2-nitro-2'-hydroxy-3',5'-di-(α,α-dimethylbenzyl)azobenzene, the above-named compound was prepared in a yield of 70.0% as light tan crystalls melting at 160°-161° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(#N)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:24]#[C:23][Si:20]([CH3:22])([CH3:21])[CH3:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccc(OCc2ccccc2)cc1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1ccc(OCc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A resealable tube was charged with 1-benzyloxy-4-iodobenzene 100 (5.00 g, 16.1 mmol), acetonitrile (80 mL), and triethylamine (10 mL). Dichlorobis(triphenylphosphine)palladium (II) (0.733 g, 1.05 mmol), copper (I) iodide (0.200 g, 1.05 mmol), and (trimethylsilyl)acetylene (2.06 g, 2.96 mL, 20.9 mmol) were added. The system was purged with argon, the tube was sealed, and the mixture stirred at 60° C. for 17 h. The reaction mixture was filtered twice through a pad of Celite along with ethyl acetate. The filtrate was concentrated to afford (4-benzyloxy-phenylethynyl)trimethylsilane (101) as an orange brown solid which was used without purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:17]([O-])([O-:19])=[O:18].[Na+].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(Cl)Cl>[N+:17]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:9])[C:11]=1[OH:16])([O-:19])=[O:18]
Reactant: O=C(Nc1ccccc1)c1ccccc1O
Reactant: O=[N+]([O-])[O-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1ccccc1)c1cccc([N+](=O)[O-])c1O
Reaction time: 24 h
Yield: 42.1 %

Procedure:
2-Phenylaminocarbonylphenol (5.00 g, 23 mmol) was dissolved in methylene chloride(40 mL) followed by the addition of sodium nitrate (2.20 g, 25.5 mmol). The addition of sulfuric acid (30 mL/3 M) was then made, followed by addition of a catalytic amount of sodium nitrite. The mixture was allowed to stir. After 24 hours, the reaction mixture was diluted with methylene chloride and extracted with water. THe organic layer was dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4%MeOH/CH2Cl2) gave the desired product(2.50 g, 42%). 1H NMR (CD3COCD3): δ 8.15 (d,1H), 8.09 (d,1H), 7.51 (d, 1H), 7.30 (d, 1H), 7.10 (t, 1H), 7.01 (t, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14][CH3:15])([CH3:4])([CH3:3])[CH3:2].[CH2:16](I)C>>[C:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[O:14][CH2:15][CH3:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: COc1cc(C(=O)O)ccc1C(C)(C)C
Product: CCOc1cc(C(=O)O)ccc1C(C)(C)C

Procedure:
Prepared in a similar manner to that described for 4-tert-butyl-3-methoxybenzoic acid (J. Org. Chem. (1961) 26,1732), replacing methyl iodide with ethyl iodide.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:19][C@@H:20]3[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]3[O:22][C:23](=[O:25])[CH3:24])=[N:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1.[C:43](=O)([O-])[O-].[K+].[K+].IC>O1CCCC1>[CH3:43][N:13]1[C:14]([C:15]([F:18])([F:17])[F:16])=[C:10]([CH2:9][C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[C:11]([O:19][C@@H:20]2[O:37][C@H:36]([CH2:38][O:39][C:40](=[O:42])[CH3:41])[C@@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]([O:27][C:28](=[O:30])[CH3:29])[C@H:21]2[O:22][C:23](=[O:25])[CH3:24])=[N:12]1
Reactant: O=C([O-])[O-]
Reactant: CSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C(F)(F)F)cc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)nn(C)c2C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
A suspension of 4-[(4-metylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole (30 mg), potassium carbonate (8.0 mg) and iodomethane (8.2 mg) in tetrahydrofuran (1 mL) was stirred at 75° C. overnight. The reaction mixture was filtered through celite®, and the solvent of the filtrate was removed under reduced pressure. The residue was purified by preparative thin layer chromatography (developing solvent: dichloromethane/ethyl acetate=5/1) to give 1-methyl-4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethylpyrazole (13 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].[C:10]([NH:18][C:19]1[NH:23][N:22]=[C:21]([S:24](Cl)(=[O:26])=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>N1C=CC=CC=1>[C:10]([NH:18][C:19]1[NH:23][N:22]=[C:21]([S:24]([NH:4][C:3]2[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=2[Cl:9])(=[O:26])=[O:25])[N:20]=1)(=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Nc1nc(S(=O)(=O)Cl)n[nH]1)c1ccccc1
Reactant: Nc1c(Cl)cccc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1nc(S(=O)(=O)Nc2c(Cl)cccc2Cl)n[nH]1)c1ccccc1
Yield: 49.5 %

Procedure:
A small flask equipped with a magnetic stirrer and protected from the atmosphere by a drying tube was charged with 8.1 g (0.05 mole) of 2,6-dichloroaniline, 20 ml of dry pyridine and then 14.4 g (0.05 mole) of dry 5-benzoylamino-3-chlorosulfonyl-1,2,4-triazole was added over about 1 minute with vigorous stirring. After the exotherm had subsided somewhat, the mixture was heated with an oil bath maintained at 100°-106° C. for 3 hours with stirring. The mixture was next concentrated under reduced pressure on a rotary evaporator to remove the bulk of the pyridine (80° C./1 mm) and then taken up in a mixture of 25 ml of concentrated aqueous ammonia, 125 ml of water and 100 ml of methylene chloride. After cooling and filtration to remove the insoluble material, the methylene chloride phase was removed and the pH of the aqueous phase was adjusted to 2.5 with hydrochloric acid. The precipitate that formed was collected by filtration, washed with water, and dried to obtain 10.2 g (50 percent of theory) of the title sulfonamide. A sample purified by recrystallization from acetonitrile melted at 321°-322° (dec.). The carbon nmr spectrum was consistent with the assigned structure, having absorptions at 159.2, 149.7, 165.6, 135.9, 130.8, 128.9, 130.0, 132.8, 128.0, 128.1, and 131.7 ppm.
Reaction SMILES: [BH4-].[Li+].C[Si](C)(C)Cl.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([NH:19][C:20]1[N:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=[C:24]2[CH:23]=[C:22]([C:35]2[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=2)[CH:21]=1)=O.CO>O1CCCC1>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][NH:19][C:20]1[N:25]2[N:26]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[N:28]=[C:24]2[CH:23]=[C:22]([C:35]2[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=2)[CH:21]=1
Reactant: COc1ccccc1CC(=O)Nc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1CCNc1cc(-c2ccncc2)cc2nc(-c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
To 10 ml of a 1 molar solution of lithiumborohydride in tetrahydrofuran were added 2.17 g (0.02 mol) trimethylchlorosilane. After stirring for one hour at room temperature the suspension was added dropwise to a suspension of 0.11 g (0.25 mol) 2-(2-methoxy-phenyl)-N-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-acetamide and the mixture heated for 18 hours at 50° C. Then 5 ml methanol were slowly added, the solvents were distilled off and the residue taken up in ethylacetate. The solution was washed with aqueous sodiumhydroxide and with water, dried with sodiumsulfate and evaporated. Recrystallisation from ethanol yielded 0.10 g (94%) [2-(2-methoxy-phenyl)-ethyl]-(2-phenyl-7-pyridin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-5-yl)-amine as beige crystals. MS m/e(%):422 (M+H+, 100).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1.Br[C:27]1[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]([C:33]#[N:34])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1
Reactant: N#Cc1cc(Br)ccn1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccn(C)n2)n1
Product: Cc1cc(-c2ccnc(C#N)c2)cc(C(=O)Nc2ccn(C)n2)n1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-2-cyanopyridine instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=319.2 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([OH:37])(=[S:36])[CH3:35].[F:38][C:39]1[CH:44]=[CH:43][C:42]([CH2:45][CH:46](O)[C:47]([O:49][CH:50]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])=[CH:41][CH:40]=1>O1CCCC1>[C:34]([S:36][CH:46]([CH2:45][C:42]1[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=1)[C:47]([O:49][CH:50]([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)=[O:48])(=[O:37])[CH3:35]
Reactant: CC(O)=S
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(O)Cc1ccc(F)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)SC(Cc1ccc(F)cc1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 76 %

Procedure:
Triphenylphosphine (3.99 g, 15.2 mmol) was dissolved in dry tetrahydrofuran (78 ml), followed by cooling to 0° C. under cooling with ice. Further, diisopropyl azodicarboxylate (DIAD (2.99 ml, 15.2 mmol)) was dropped thereinto under stirring. Thirty minutes thereafter, a solution of a mixture of thioacetic acid (1.25 ml, 17.8 mmol) with diphenylmethyl 3-(4-fluorophenyl)lactate (4.0 g, 11.4 mmol) obtained in the Synthesis Example F-1 in dry tetrahydrofuran (45 ml) was dropped thereinto. The mixture was allowed to react at 0° C. for 3 hours. Then the ice bath was removed and the reaction mixture was warmed to room temperature and allowed to react at this temperature overnight. Next, this reaction mixture was concentrated under reduced pressure. The residue thus obtained was separated by silica gel column chromatography (hexane:ethyl acetate=6:1) to thereby give a crude product (4.7 g). This crude product was recrystallized from diisopropyl ether and hexane (20 ml-30 ml). The solid thus precipitated was removed by filtration and the filtrate was concentrated under reduced pressure to thereby give the title compound (3.54 g, 76%) as an oily product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC(=O)[S:10][N:9]=2)=[CH:4][CH:3]=1.[C:14]([C:17]#[N:18])(=[O:16])[CH3:15]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:18]=[C:17]([C:14](=[O:16])[CH3:15])[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=c1oc(-c2ccc(F)cc2)ns1
Reactant: CC(=O)C#N
Solvent: Cc1ccccc1
Product: CC(=O)c1nc(-c2ccc(F)cc2)ns1
Reaction time: 3 h

Procedure:
In still a further embodiment, 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone may be prepared according to the methodology and reagents of Scheme 16A. In this embodiment, a 1,3,4-oxathiazol-2-one ring fragment is generated and subsequently converted to a 1,2,4-thiadiazole ring fragment during the preparation of 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone. Specifically, 4-fluoro-benzamide is reacted with chlorocarbonylsulfenyl chloride to provide 5-(4-fluoro-phenyl)-1,3,4-oxathiazol-2-one. In one embodiment, the reaction is performed in toluene. In another embodiment, the reaction is performed at elevated temperatures of about 80° C. for about 3 hours. 5-(4-Fluorophenyl)-1,3,4-oxathiazol-2-one is then reacted with acetyl cyanide to provide 1-(3-(4-fluorophenyl)-1,2,4-thiadiazol-5-yl)-ethanone. In one embodiment, this reaction is performed in 1,2-dichlorobenzene. In another embodiment, this reaction is performed at elevated temperatures of about 160° C. for about 20 hours. 1-(3-(4-Fluorophenyl)-1,2,4-thiadiazol-5-yl)ethanone is then converted to a compound of Formula (I-A) by the methods described herein, such as Scheme 1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH3:23])[C:9]2[CH:22]=[CH:21][C:12]3[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=1)[NH2:29]>CN(C=O)C>[CH3:24][N:25]([CH3:33])[C:26]1[CH:27]=[C:28]([NH:29][C:2]2[N:7]=[C:6]([N:8]([CH3:23])[C:9]3[CH:22]=[CH:21][C:12]4[C:13]([C:17]([NH:19][CH3:20])=[O:18])=[C:14]([CH3:16])[O:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)c1cccc(N)c1
Reactant: CNC(=O)c1c(C)oc2cc(N(C)c3ccnc(Cl)n3)ccc12
Solvent: CN(C)C=O
Product: CNC(=O)c1c(C)oc2cc(N(C)c3ccnc(Nc4cccc(N(C)C)c4)n3)ccc12
Temperature: 60 °C
Reaction time: 5 h
Yield: 78 %

Procedure:
6-((2-chloropyrimidin-4-yl)(methyl)amino)-N,2-dimethylbenzofuran-3-carboxamide (0.1 mmol) and 3-dimethylaminoaniline (0.1 mmol) were dissolved in 0.5 ml DMF. To this was added p-TsOH monohydrate (0.2 mmol). The reaction mixture was stirred at 60° C. for 5 hours, and subjected to extraction with EtOAc. Then water was added and the mixture was subjected to extraction with ethyl acetate. The organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4, and concentrated. The resulting residue was purified by column chromatography to provide the title product in a yield of 78%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1.[H-].[Na+].Br[CH2:17][CH2:18][O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[Si:20]([O:19][CH2:18][CH2:17][N:8]1[C:7]2[CH:13]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=2[O:11][CH2:10][C:9]1=[O:12])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: COc1ccc2c(c1)NC(=O)CO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)N(CCO[Si](C)(C)C(C)(C)C)C(=O)CO2
Temperature: 70 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 48) (800 mg, 4.5 mmol) in DMF (16 mL) was added sodium hydride (60% in mineral oil, 260 mg, 6.5 mmol). After 20 minutes, (2-bromoethoxy)(tert-butyl)dimethylsilane (1.4 mL, 6.5 mmol) was added and it was heated to 70° C. in the microwave for 40 minutes. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (100 mL). The aqueous phase was extracted with ethyl acetate (4×50 mL). The combined organic phases were washed with water (6×250 mL), dried over magnesium sulfate and concentrated at reduced pressure to afford the product as a yellow oil which was used without further purification. (1.38 g, 91%).
Reaction SMILES: C([O:3][C:4](=O)[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:21][N:22]=1
Reactant: NN
Reactant: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc(Br)cc21
Solvent: CCO
Solvent: O
Product: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a mixture of (R)-2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (75.2 g, 219 mmol) in EtOH (800 mL) was added hydrazine hydrate (98%, 21.9 g, 438 mmol) and the mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×80 mL) to give 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (6 g, 9%) as a yellow solid. The filtrate was concentrated to give 70 g of crude product, which was purified by chromatography on silica gel (eluting with 10-25% EtOAc in petroleum ether) to give a second batch of (R)-6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (45.9 g, 71%) as a yellow solid. 1H NMR (400 MHz, CDCl3): δ 8.53 (brs, 1H), 7.10 (d, J=8.4 Hz, 1H), 7.03 (s, 1H), 6.89 (d, J=8.4 Hz, 1H), 4.69-4.52 (m, 3H), 1.52 (d, J=6.8 Hz, 3H). SFC (Table 1, Method 32) Rt=6.075 min.; [α]D20=−314.92 (C=0.002 g/mL in methanol).