Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([CH3:13])([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=1)[CH3:5].[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:14])[C:4]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][Br:15])=[CH:10][CH:11]=1)([CH3:5])[CH3:13]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)C(C)(C)c1ccc(C)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(C)(C)c1ccc(CBr)cc1
Reaction time: 5 h
Yield: 72 %

Procedure:
To a refluxing solution of 2-Methyl-2-p-tolyl-propionic acid methyl ester (892 mg, 4.64 mmol) and N-bromosuccinimide (826 mg, 4.64 mmol) in CCl4 (120 mL) is added 2,2′-Azobisisobutyronitrile (12 mg, 0.073 mmol). After 5 h, the reaction is concentrated and the residue is chromatographed (SiO2 120 g, 5% to 20% EtOAc/Hex) to yield the title compound (906 mg, 72%) 1H NMR (400 MHz, CDCl3) δ 7.38-7.28 (m, 4H), 4.48 (s, 2H), 3.65 (s, 3H), 1.57 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24](Br)[CH:25]=4)[N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[F:28][C:29]([F:58])([F:57])[C:30]1[C:34](B(O)O)=[CH:33][N:32]([C:38]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:31]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:34]5[C:30]([C:29]([F:57])([F:58])[F:28])=[N:31][N:32]([C:38]([C:45]6[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=6)([C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[C:39]6[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=6)[CH:33]=5)[CH:25]=4)[N:20]=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(F)cc1)C1CCN(c2ccnc3ccc(Br)cc23)CC1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1C(F)(F)F
Product: O=C(Nc1ccc(F)cc1)C1CCN(c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)CC1
Yield: 43.7 %

Procedure:
73 mg 1-(6-bromoquinolin-4-yl)piperidine-4-carboxylic acid (4-fluorophenyl)amide (compound in Production Example 457) and 94 mg 3-trifluoromethyl-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 31) were reacted in the same manner as in Example 9, to give 54 mg 1-[6-(3-trifluoromethyl-1-trityl-1H-pyrazol-4-yl)quinolin-4-yl]-piperidine-4-carboxylic acid (4-fluorophenyl)amide. This product was reacted in the same manner as in Example 67 to give 54 mg of the title compound as pale gray crystals.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH2:8])[O:4][N:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:31]=[CH:30][C:15]([CH2:16][C:17]2[S:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[C:18]=2[S:26](Cl)(=[O:28])=[O:27])=[CH:14][CH:13]=1>C1COCC1>[CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][S:26]([C:18]2[C:19]3[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=3[S:21][C:17]=2[CH2:16][C:15]2[CH:14]=[CH:13][C:12]([Cl:11])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[O:4][N:3]=1
Reactant: O=S(=O)(Cl)c1c(Cc2ccc(Cl)cc2)sc2ccccc12
Reactant: Cc1noc(N)c1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(NS(=O)(=O)c2c(Cc3ccc(Cl)cc3)sc3ccccc23)c1C

Procedure:
N-(3,4-dimethyl-5-isoxazolyl)-2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonamide was prepared by the method of Example 41 with 3,4-dimethyl-5-aminoisoxazole (1.2 mmoles, 1.4 g), NaH (3.0 mmoles, 73 mg), 2-(4-chlorobenzyl)-benzo[b]thiophene-3-sulfonylchloride (1.4 mmoles, 0.50 g) and THF (8 ml). Flash chromatography (50% ethyl acetate/hexanes) followed by recrystallization from methanol and water provided 1.04 g (27%) of a yellow solid, m.p. 100-102° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=[O:19])[NH:11][C:10]1=[O:20])=[O:4].[OH-].[Na+]>O.CO>[C:3]([C:5]1[CH:6]=[C:7]([CH:21]=[CH:22][CH:23]=1)[CH2:8][N:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](=[O:19])[NH:11][C:10]1=[O:20])([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc(Cn2c3c(c(=O)[nH]c2=O)CCCC3)c1
Yield: 82.1 %

Procedure:
A solution of 1-(3-methoxycarbonylbenzyl)-5,6,7,8-tetrahydroquinazoline-2,4(1H,3H)-dione (2.3 g, 7.3 mmol) and NaOH (0.59 g, 14.7 mmol) in water-methanol (40 mL and 40 mL) was refluxed for 4 h. After the removal of methanol, the solution was adjusted to pH=2-3 by 3N hydrochloric acid (a.q). The mixture was filtered and the solid was washed by water, and dried to give the title compound (1.8 g, 82% yield) as yellow solid. MS: m/z 301.3 [M+H]+.
Reaction SMILES: C([O:3][C:4]1[C:13]2[C:8](=[N:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])C.[CH2:20](Br)[CH3:21]>C1(C)C=CC=CC=1>[CH2:18]([O:17][C:15]([C:5]1[C:4](=[O:3])[C:13]2[C:8](=[N:9][C:10]([CH3:14])=[CH:11][CH:12]=2)[N:7]([CH2:20][CH3:21])[CH:6]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cnc2nc(C)ccc2c1OCC
Reactant: CCBr
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cn(CC)c2nc(C)ccc2c1=O
Temperature: 130 °C
Yield: 80 %

Procedure:
A mixture containing 1 g of ethyl 4-ethoxy-7-methyl-1,8-naphthyridine-3-carboxylate, 1.26 g of ethyl bromide and 20 ml of toluene was heated in a sealed tube at 130°C for 7 hours. The solvent was evaporated and the residue was worked up as above. There was obtained 0.8 g of ethyl-1-ethyl-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [Cl:1][S:2]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9])(=[O:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)Cl.[N+:20]([C:23]1[CH:24]=[C:25]([S:29]([CH2:32][CH2:33]O)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]>O>[N+:20]([C:23]1[CH:24]=[C:25]([S:29]([CH2:32][CH2:33][O:9][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:5]([S:2]([Cl:1])(=[O:4])=[O:3])[CH:6]=2)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)([O-:22])=[O:21]
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)CCO)c1
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=C(OCCS(=O)(=O)c1cccc([N+](=O)[O-])c1)c1cccc(S(=O)(=O)Cl)c1
Temperature: 70 °C

Procedure:
To solid 3-chlorosulfonylbenzoic acid (3.2 g, 14.4 mmol) was added solid PCl5 (3.0 g, 14.4 mmol) at room temperature with mixing. The mixture was heated to 70° C. forming a brown liquid that was heated for an additional 2 h. POCl3 side product was removed by vacuum distillation and the residual brown oil was dissolved in 15 mL of CH3CN, and then 2-(3-nitrobenzenesulfonyl)ethanol (2.8 g, 12.0 mmol) was added. The mixture was heated to reflux temperature for 36 h. Thereafter water was added and the mixture was extracted with CH2Cl2. The resulting oil was purified by short column chromatography (eluent: CH2Cl2 to 1% MeOH in CH2Cl2) to give a brown semisolid, which became a white solid by treatment with ether-EtOAc (yield 2.75 g (53%)).
Reaction SMILES: C1COCC1.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][C:22]([N:24]2[CH2:28][CH:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26](/[CH:35]=[N:36]/O)[CH2:25]2)=[O:23])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.C1N=CN(C(N2C=NC=C2)=O)C=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10](/[CH:20]=[CH:21]/[C:22]([N:24]2[CH2:28][CH:27]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH:26]([C:35]#[N:36])[CH2:25]2)=[O:23])[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1
Reactant: COc1cc(C=CC(=O)N2CC(/C=N/O)C(c3ccccc3)C2)ccc1-n1cnc(C)c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(=O)N2CC(C#N)C(c3ccccc3)C2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.6 %

Procedure:
To a THF (3 ml) solution of (E)-1-{3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}-4-phenylpyrrolidine-3-carbaldehyde oxime (17.8 mg) obtained in Example 359, CDI (32.4 mg) was added at room temperature, and heat-refluxing was carried out for 3 hours. After the reaction solution was allowed to be cooled to room temperature, ethyl acetate and saturated sodium bicarbonate solution were added to the reaction solution, and the organic layer was partitioned. After drying the obtained organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent: ethyl acetate methanol 10:1), and the 14.6 mg (86%) title compound was obtained. The physical properties of the compound are as follows.
Reaction SMILES: [CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:32])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][OH:31])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[CH3:33][S:34](Cl)(=[O:36])=[O:35].N1C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:17][C:18]([O:20][CH2:21][C:22](=[CH2:32])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][S:34]([CH3:33])(=[O:36])=[O:35])=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C=C(COCCCCCCO)COC(=O)OCCCCCCCCCCCCCCCC
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(COCCCCCCOS(C)(=O)=O)COC(=O)OCCCCCCCCCCCCCCCC
Reaction time: 2.5 h

Procedure:
3-Hexadecyloxycarbonyloxy-1-(6-hydroxyhexyloxy)-2-methylenepropane (from Preparation 51) (0.54 g) and methanesulfonyl chloride (0.20 g) were stirred in methylene chloride at 0° C. Pyridine (6 ml) was added and stirring continued for 15 minutes at 0° C. and for 2.5 hours at 22° C. Methylene chloride (10 ml) was added, and the organic phase was washed with water (3×15 ml), dried over magnesium sulfate, filtered and evaporated in vacuo to dryness. Purification was achieved by chromatography on silica gel 60 (70-230 mesh, 15 g) eluting with chloroform/ether/pentane 1:1:10 followed by chloroform/ether 1:1.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]1[CH2:10][CH2:9][C:8]2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]([O:17][CH3:18])=[C:14]([O:15][CH3:16])[C:7]=2[CH2:6][CH2:5]1.[OH:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:16][O:15][C:14]1[C:7]2[CH2:6][CH2:5][CH:4]([CH2:3][CH2:2][O:23][C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH2:10][CH2:9][C:8]=2[C:11]([O:21][CH3:22])=[C:12]([O:19][CH3:20])[C:13]=1[O:17][CH3:18]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCI)CC2
Reactant: Oc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1cccnc1)CC2
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.9 %

Procedure:
A mixture of 7-(2-iodoethyl)-1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cycloheptene (1.20 g), 3-hydroxypyridine (816 mg), and potassium carbonate (2.38 g) in DMF (12 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (ethyl acetate) and then with recrystallization from hexane-ethyl acetate to obtain the entitled compound (430 mg).
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[S:5][CH3:6])#[N:2].[CH2:9]([NH2:19])[C:10]1[CH:18]=[CH:17][C:16]2[O:15][CH2:14][O:13][C:12]=2[CH:11]=1>CO>[O:15]1[C:16]2[CH:17]=[CH:18][C:10]([CH2:9][NH:19][C:4](=[N:3][C:1]#[N:2])[S:5][CH3:6])=[CH:11][C:12]=2[O:13][CH2:14]1
Reactant: NCc1ccc2c(c1)OCO2
Reactant: CSC(=NC#N)SC
Solvent: CO
Product: CSC(=NC#N)NCc1ccc2c(c1)OCO2
Reaction time: 0.5 h
Yield: 88 %

Procedure:
1.6 g (10.94 mmol) of dimethyl cyanocarbonodithioimidate and 2.0 g (13.23 mmol) of piperonyl amine were dissolved in methyl alcohol, and then stirred for 30 minutes. After completion of the reaction, the produced solid was filtered, and then washed with water and methyl alcohol, thus obtaining 2.4 g (95% yield) of a desired compound of Formula 3.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([O:19]CC3C=CC=CC=3)=[O:18])[C:11]=2[CH:10]=[C:9]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)=O.CO>[C:1]([O:5][C:6]([N:8]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([C:17]([OH:19])=[O:18])[C:11]=2[CH:10]=[C:9]1[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cc2c(C(=O)OCc3ccccc3)cccc2n1C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: CCOC(=O)c1cc2c(C(=O)O)cccc2n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85 %

Procedure:
To a mixture of 10% palladium on charcoal (130 mg) in 5.0% formic acid-methanol (5.0 ml) was added a solution of benzyl 1-tert-butoxycarbonyl-2-ethoxycarbonylindole-4-carboxylate (130 mg) in 5.0% formic acid-methanol (5.0 ml). The mixture was stirred under nitrogen atmosphere at ambient temperature for 30 minutes. The resulting mixture was filtered through a bed of celite and the filtrate was evaporated in vacuo to give 1-tert-butoxycarbonyl-2-ethoxycarbonylindole-4-carboxylic acid (87 mg) as a white crystal.
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26](Cl)[C:21]=3[CH:20]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].[NH2:39][C:40]1[CH:45]=[CH:44][C:43]([OH:46])=[CH:42][C:41]=1[Cl:47]>O>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:35])([CH3:36])[CH3:34])[C:22]3[N:23]=[CH:24][N:25]=[C:26]([O:46][C:43]4[CH:44]=[CH:45][C:40]([NH2:39])=[C:41]([Cl:47])[CH:42]=4)[C:21]=3[CH:20]=2)=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Cl)ncnc21
Reactant: Nc1ccc(O)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(-c2ccc(OCc3ccccc3)cc2)cc2c(Oc3ccc(N)c(Cl)c3)ncnc21
Reaction time: 0.17 h

Procedure:
After adding 12 ml of dimethylsulfoxide to the 6-(4-benzyloxyphenyl)-4-chloro-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidine synthesized in Production Example 153-4, 141 mg (1.5 equivalents) of sodium hydride (60% dispersion, Aldrich) and 507 mg (1.5 equivalents) of 4-amino-3-chlorophenol were added while stirring, and stirring was then continued at room temperature for 10 minutes and then at 135-140° C. for 4 hours. The mixture was returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate:tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 1.20 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3]S(I)(C)(C)=O.[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]=[O:14]>CS(C)=O>[CH3:9][O:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH:13]1[CH2:3][O:14]1
Reactant: CS(C)(C)(=O)I
Reactant: COc1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COc1ccccc1C1CO1
Temperature: 40 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Into a 1000-mL 3-necked round-bottom flask was placed DMSO (400 mL) and sodium hydride (7 g, 175.00 mmol, 1.19 equiv, 60%). This was followed by the addition of S,S-dimethylmethanesulfinyl iodide (38 g, 172.67 mmol, 1.18 equiv). The mixture was stirred for 1 h at 40° C. To this was added a solution of 2-methoxybenzaldehyde (20 g, 146.90 mmol, 1.00 equiv) in DMSO (100 mL) dropwise with stirring at 15° C. The resulting solution was stirred for 1 h at room temperature. The reaction was then quenched by the addition of 400 mL of NH4Cl (aq.). The resulting solution was extracted with 1000 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 1000 mL of H2O. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. Purification afforded 14 g (63%) of 2-(2-methoxyphenyl)oxirane as a yellow oil.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([CH3:19])[C:10]([C:14]([O:16]CC)=O)=[N:11]2)=[CH:6][CH:5]=1.[C:20](#[N:22])[CH3:21].O>C1(C)C=CC=CC=1>[F:3][C:4]1[CH:13]=[C:12]2[C:7]([N:8]=[C:9]([CH3:19])[C:10]([C:14](=[O:16])[CH2:21][C:20]#[N:22])=[N:11]2)=[CH:6][CH:5]=1
Reactant: CC#N
Reactant: CCOC(=O)c1nc2cc(F)ccc2nc1C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1nc2ccc(F)cc2nc1C(=O)CC#N
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil, 12.0 g, 300 mmol) in toluene (450 mL) was added a solution of ethyl 7-fluoro-3-methylquinoxaline 2-carboxylate (35.1 g, 150 mmol) and acetonitrile (19.6 mL, 375 mmol) in toluene (40 mL) dropwise over 35 min at 85° C. After being stirred for 5 min at the same temperature, the reaction mixture was cooled to 0° C., and then added water (175 mL). The aqueous layer was separated and the organic layer was extracted with 1N aqueous sodium hydroxide (200 mL). The combined aqueous layer was acidified to pH 2 with conc. Hydrochloric acid (45.0 mL) at 0° C., and the resulting precipitate was collected and washed with water (150 mL). The solid was dissolved with chloroform (1000 mL) and water (500 mL). The aqueous layer was extracted with chloroform (300 mL). The combined organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate was concentrated in vacuo. The residue was triturated with ethanol to give 3-(7-fluoro-3-methylquinoxalin-2-yl)-3-oxopropanenitrile. MS (APCI): m/z 230 (M+H).
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:15][CH2:16][CH2:17][CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:23].[NH2:26][C:27]1[S:28][CH:29]=[C:30]([CH2:36][O:37][CH2:38][O:39][CH3:40])[C:31]=1[S:32]([NH2:35])(=[O:34])=[O:33]>C1(C)C=CC=CC=1>[CH2:15]([C:12]1([CH2:19][CH2:20][CH2:21][CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:23])=[C:4]([C:3]2[NH:26][C:27]3[S:28][CH:29]=[C:30]([CH2:36][O:37][CH2:38][O:39][CH3:40])[C:31]=3[S:32](=[O:33])(=[O:34])[N:35]=2)[C:13]1=[O:14])[CH2:16][CH2:17][CH3:18]
Reactant: COCOCc1csc(N)c1S(N)(=O)=O
Reactant: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: CCCCC1(CCCC)C(=O)C(C2=NS(=O)(=O)c3c(COCOC)csc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A mixture of the product of Example 5C (66 mg, 0.18 mmol) and the product of Example 10E (44 mg, 0.18 mmol) in toluene (10 mL) was stirred at reflux for 2 h, cooled to 25° C. and concentration in vacuo. The residue was chromatographed on silica gel, eluting with ethyl acetate in hexane to give the title compound (54 mg, 58%). 1H NMR (300 MHz, CDCl3): δ 16.44 (s, 1 H), 15.03, 14.86 (two s, 1 H), 8.27 (m, 1 H), 7.69 (m, 1 H), 7.49 (t, J=7.17 Hz, 1 H), 7.26 (m, 1 H), 7.08 (s, 1 H), 4.84 (s, 2 H), 4.80 (s, 2 H), 3.45 (s, 3 H), 2.33 (m, 2 H), 1.95 (m, 2 H), 1.13 (m, 4 H), 0.86 (m, 2 H), 0.69 (m, 6 H), 0.56 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]([F:30])([F:29])[CH:17]([NH2:28])[CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([O:9][CH3:10])[C:3]=1[S:11]([NH:28][CH:17]([CH2:18][C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:21][CH:20]=1)[C:16]([F:15])([F:29])[F:30])(=[O:13])=[O:12]
Reactant: COc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Reactant: NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cc(Cl)c1S(=O)(=O)NC(Cc1c[nH]c2ccccc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
To a solution of 50 mg (0.18 mmol) of 2,4-dichloro-6-methoxybenzenesulfonyl chloride in 4 mL of pyridine was added 42 mg (0.19 mmol) of 2,2,2-trifluoro-1-(1H-indol-3-ylmethyl)ethylamine. The mixture stirred for 6 hours at room temperature and was then diluted with 10 mL of ethyl acetate and washed with four 30 mL portions of 10% acetic acid, two 30 mL portions of saturated aqueous sodium bicarbonate solution, and brine, dried over sodium sulfate, decanted and concentrated in vacuo. The crude material was purified by filtering through a pad of silica eluting with ether. The material from the pad was dissolved in ether, and precipitated by slow evaporation which afforded 50 mg (57%) of the title compound as a bright yellow powder. MS: m/z 467 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][C:13]([O:15][CH3:16])=[O:14].[H-].[Na+].[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH2:12][C:13]([O:15][CH3:16])=[O:14])=[CH:7]2)=[O:25])=[CH:22][CH:21]=1
Reactant: COC(=O)Cc1c[nH]c2ccc(OC)cc12
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1cn(C(=O)c2ccc(Cl)cc2)c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methyl 2-(5-methoxy-1H-indol-3-yl)acetate (60 mg, 0.27 mmol) and NaH (8 mg, 0.33 mmol) were stirred in anhydrous DMF (1 mL) at 0° C. under argon for 30 min, at which time 4-chlorobenzoyl chloride (57 mg, 0.33 mmol) was added. The reaction mixture was stirred overnight at room temperature and was then poured into cold water (2 mL). The organic compound was immediately extracted with dichloromethane (2×2 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified on silica (ethyl acetate/hexane gradient) and recrystallized from hexane. Yield: 18 mg (18%). C19H16ClNO4, Mr=357.79; 1H NMR (400 MHz, DMSO-d6) d: 3.61 (s, 3H), 3.78 (s, 2H), 3.81 (s, 3H), 7.00 (dd, J=2.4/9.0 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.35 (s, 1H), 7.65-7.77 (m, 4H), 8.17 (d, J=8.8 Hz, 1H); LCMS (ESI) tR: 2.81 min (>99%, ELSD), m/z: 358.0 [M+1]+.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[C:2]([NH2:4])=[O:3].[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18]([OH:25])=[C:19]([C:22](=O)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]>CO>[C:12]([C:15]1[C:16](=[O:26])[O:17][C:18](=[O:25])[C:19](=[C:22]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([NH:1][C:2]([NH2:4])=[O:3])=[CH:6][CH:7]=2)[CH3:23])[C:20]=1[OH:21])(=[O:14])[CH3:13]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: NC(=O)Nc1ccc(N)cc1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(NC(N)=O)cc2)C(=O)OC1=O

Procedure:
A solution of 1.5 g. (0.01 m.) of p-ureidoaniline in 50 ml. of methanol is added to a solution of 2.1 g. (0.01 m.) of 3,5-diacetyl-4,6-dihydroxy 2H-pyran-2-one in 150 ml. of methanol. A solid is formed immediately and the mixture is refluxed for 12 hours. The filtered solid is recrystallized to give 5-acetyl-4-hydroxy-3-[1-(p-ureidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 250°-253° C.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[C:10]([Cl:12])[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)=[O:4].[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(#N)C>[Cl:12][C:10]1[N:9]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Reactant: C1CCNCC1
Solvent: CC#N
Product: O=C(CN1CCCCC1)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 1.5 h

Procedure:
2-Bromo-N-(6-chloro-2-phenylpyrimidin-4-yl)acetamide (28 mg) was dissolved in acetonitrile (2 ml) and piperidine added (23 μl in 500 μl acetonitrile). The mixture was left to stir for 1.5 hr after which time the solvent was removed in vacuo. Purification using a short silica plug, eluting with a mixture of ethyl acetate and petroleum ether (1:1 v/v) furnished the title compound (25 mg).