Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)([CH3:3])[CH3:2].[OH-].[Na+].Cl[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[CH:28][CH:27]=1.ICCCCCOC1C=CC(C#N)=CC=1>C(OC(=O)C)C.CN(C)C=O>[CH:1]([C:4]1[S:8][C:7]([CH3:9])=[N:6][C:5]=1[C:10]1[CH:11]=[CH:12][C:13]([O:16][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([C:30]#[N:31])=[CH:32][CH:33]=2)=[CH:14][CH:15]=1)([CH3:3])[CH3:2]
Reactant: N#Cc1ccc(OCCCCCCl)cc1
Reactant: Cc1nc(-c2ccc(O)cc2)c(C(C)C)s1
Agent: N#Cc1ccc(OCCCCCI)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc(OCCCCCOc3ccc(C#N)cc3)cc2)c(C(C)C)s1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
While 72.6 g of 4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)-phenol (6) prepared in Example 4 were added to 850 ml of dimethylformamide and stirred, 15.0 g of sodium hydroxide were added. The reaction temperature was gradually increased and stirring was continued at 50-55° C. for 30 min. Thereafter, 70.0 g of 4-(5-chloro-pentoxy)-benzonitrile (8), prepared in Example 5, or 95.3 g of 4-(5-iodo-pentoxy)-benzonitrile (9), prepared in Example 6, were added. The reaction temperature was gradually increased and stirring was continued at 80-90° C. for 3 hr. After the reaction was completed, the temperature was decreased to room temperature, and the resultant reaction mixture was added with 850 ml of ethylacetate, and then washed with water and brine. Subsequently, the ethylacetate layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residual solution was crystallized with ethylacetate and n-hexane, thus obtaining 114 g (yield: 90%) of a title compound as a light yellow solid through the reaction with the compound (8), or 119.6 g (yield: 94%) of a title compound as a light yellow solid through the reaction with the compound (9).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([C:13]#[C:14][CH:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[O:16][CH3:17])[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(OCC)(=O)C.O.[Pt](=O)=O>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][CH:15]([C:18]2[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=2)[O:16][CH3:17])[CH2:11][O:10][C:9]1([CH3:26])[CH3:25])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C#C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(CC[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of (S)-4-[3-(4-chloro-phenyl)-3-methoxy-prop-1-ynyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (2.50 g) in ethyl acetate (100 ml) at room temperature was added platinum(IV) oxide monohydrate (484 mg). The mixture was stirred under an atmosphere of hydrogen (1 atm) at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo to yield (S)-4-[3-(4-chloro-phenyl)-3-methoxy-propyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a light yellow oil (1.57 g, 62%); MS (ISP): 386.2 ([{37Cl}M+H]+), 384.2 ([{35Cl}M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=O)=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:19]([Cl:24])=[N:20][CH:21]=[CH:22][CH:23]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1.O>C1(C)C=CC=CC=1>[Cl:24][C:19]1[C:18]([NH:17][C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccncc1
Reactant: Nc1cccnc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Fc1ccc(C=C(Nc2cccnc2Cl)c2ccncc2)cc1
Reaction time: 24 h
Yield: 64 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone (5.20 g, 24 mmol) and 3-amino-2-chloropyridine (4.04 g, 31.4 mmol) in toluene (150 ml) was added p-toluenesulfonic acid monohydrate (457 mg. 2.4 mmol) and the reaction mixture was brought to reflux with Dean-Stark removal of the toluene/water azeotrope. After 24 h, toluene was removed in vacuo and the residue was resuspended in ethyl acetate. The precipitate was collected by vacuum filtration to give (2-chloropyridin-3-yl)-[2-(4-fluorophenyl)-1-(pyridin-4-yl)-vinyl]amine (5.0 g) as a tan solid. The filtrate was concentrated in vacuo and purified by flash column chromatography (50%-80% ethyl acetate:hexanes gradient) to give additional 1.50 g of product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH2:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[CH2:1]([O:8][C:9]1[C:18]2[O:17][CH2:16][CH2:15][O:14][C:13]=2[C:12]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCC(=O)Nc1ccc(OCc2ccccc2)c2c1OCCO2
Reaction time: 17 h

Procedure:
To a solution of 30 g of 5-benzyloxy-8-amino-1,4-benzodioxane (XX); code number 760 727, in 250 ml of chloroform and 21.3 ml of triethylamine, cooled to 0° C., 12.1 cm3 of propionyl chloride were slowly added. Then, it was stirred for 17 hours, washed with a solution of diluted hydrochloric acid, with water, with an aqueous solution of sodium bicarbonate, then with water, the organic phase was evaporated and the residue recrystallized in ethyl acetate.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].C([N:12]1[CH2:16][CH2:15][CH:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)[CH2:13]1)C1C=CC=CC=1.N1CCCC1>C(Cl)Cl>[CH3:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[O:17][CH:14]1[CH2:15][CH2:16][N:12]([C:1]([Cl:4])=[O:2])[CH2:13]1
Reactant: O=C(Cl)Cl
Reactant: Cc1cccc(OC2CCN(Cc3ccccc3)C2)c1
Solvent: ClCCl
Solvent: C1CCNC1
Product: Cc1cccc(OC2CCN(C(=O)Cl)C2)c1
Reaction time: 8 h
Yield: 68.3 %

Procedure:
To a stirred solution of 9.5 g (0.097 mole) of phosgene in 100 ml of methylene chloride under nitrogen gas was added dropwise 23.84 g (0.088 mole) of 1-benzyl-3-(3-methylphenoxy)pyrrolidine in 50 ml of methylene chloride. When the addition was complete, thin-layer chromatography showed no starting pyrrolidine remained. The reaction mixture was stirred overnight and concentrated in vacuo to give an oil. The oil was triturated with 30/60 petroleum ether to remove benzyl chloride. A white solid, 14.4 g of crude product was obtained. A portion was recrystallized from hexane.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]2[C:5]([C:6]([CH3:14])=[N:7][NH:8]2)=[CH:4][C:3]=1[Cl:15].[Cl:16][C:17]1[C:18]([N:23]2[C:27]([C:28](O)=O)=[CH:26][C:25]([C:31]([F:34])([F:33])[F:32])=[N:24]2)=[N:19][CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1.CS(Cl)(=O)=O>O1CCCC1>[Cl:15][C:3]1[CH:4]=[C:5]2[C:6]([CH3:14])=[N:7][NH:8][C:9]2=[C:10]2[C:2]=1[N:1]=[C:28]([C:27]1[N:23]([C:18]3[C:17]([Cl:16])=[CH:22][CH:21]=[CH:20][N:19]=3)[N:24]=[C:25]([C:31]([F:34])([F:32])[F:33])[CH:26]=1)[O:12][C:11]2=[O:13]
Reactant: O=C(O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Reactant: Cc1n[nH]c2c(C(=O)O)c(N)c(Cl)cc12
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: Cc1n[nH]c2c1cc(Cl)c1nc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)oc(=O)c12
Temperature: 0 °C
Reaction time: 48 h
Yield: 70.3 %

Procedure:
To a suspension of 540 mg (2.39 mmol) of 6-amino-5-chloro-3-methyl-1H-indazole-7-carboxylic acid in 22 mL of anhydrous tetrahydrofuran at 10° C., is added 698 mg (2.39 mmol) of 2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazole-3-carboxylic acid followed by 963 μL (11.97 mmol) of pyridine. Then the suspension is cooled to 0° C. and 748 μL (9.57 mmol) of methanesulfonyl chloride are added dropwise. The mixture is stirred at ambient temperature for 48 hours. Then the solvent is evaporated and the residue is taken-up with acetone. After filtration, the filtrate is evaporated in vacuo. The residue obtained is purified by flash chromatography (SiO2, heptane/ethyl acetate 1:2) and affords 810 mg (1.68 mmol, 70%) of the product as a solid; LC/MS:481/483 (M+H)+.
Reaction SMILES: CN(C)[C:3]([C:5]1[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:7][N:6]=1)=[O:4].C[Mg]Br.Cl.[O:21]1CC[CH2:23][CH2:22]1>C1(C)C=CC=CC=1>[C:10]1([C@@H:8]2[O:7][N:6]=[C:5]([C:3]([C:22](=[O:21])[CH3:23])=[O:4])[CH2:9]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: CN(C)C(=O)C1=NO[C@@H](c2ccccc2)C1
Agent: C[Mg]Br
Agent: Cl
Solvent: Cc1ccccc1
Product: CC(=O)C(=O)C1=NO[C@@H](c2ccccc2)C1
Temperature: -15 °C

Procedure:
A solution of (5R)-4,5-dihydro-N,N-dimethyl-5-phenyl-3-isoxazole-carboxamide (i.e. the product of Example 12, Step D) (3.5 g, 16.0 mmol) in a mixture of tetrahydrofuran (5 mL) and toluene (10 mL) was cooled to −15° C., and methyl magnesium bromide (3.0 M solution in tetrahydrofuran, 8.8 mL, 26.4 mmol) was added over 1 h at −15° C. Then the reaction mixture was poured over a mixture of 20 g of concentrated hydrochloric acid and 80 g of ice, and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (100 mL), and the combined extract was washed with brine (40 mL) and concentrated under reduced pressure to give 3.2 g of 1-[(5R)-4,5-dihydro-5-phenyl-3-isoxazoyl]ethanone.
Reaction SMILES: [Cl:1][O-:2].[Cl-].[Ca+2:4].[Cl-].Cl[O-].[Ca+2].Cl[O-].[Cl:11]([O-])(=O)=[O:12].[Ca+2].[Cl:16]([O-])(=O)=[O:17]>>[OH2:12].[OH2:17].[Cl-:11].[Ca+2:4].[Cl-:16].[OH2:2].[OH2:12].[OH2:12].[OH2:12].[Cl-:1].[Ca+2:4].[Cl-:11].[OH2:12].[OH2:12].[OH2:12].[OH2:12].[OH2:12].[OH2:12].[Cl-:11].[Ca+2:4].[Cl-:11]
Reactant: [O-]Cl
Reactant: [O-][Cl+2]([O-])[O-]
Agent: [Ca+2]
Agent: [Cl-]
Product: O

Procedure:
In the flow diagram represented in FIG. 1, an aqueous filtrate from a hemibasic hypochlorite or dibasic hypochlorite process comprised of calcium chloride, calcium hypochlorite, and minor amounts of calcium chlorate is fed through line 7 to blender 8 where it is blended with calcium chlorate mother liquor fed to blender 8 through line 33. The blended solution passes through line 9 to first evaporative crystallizer 12. Crystallizer 12 is operated under vacuum and temperature conditions which produce crystalline calcium chloride dihydrate, calcium chloride tetrahydrate, or calcium chloride hexahydrate or mixtures thereof. The crystalline calcium chloride hydrate is separated from a first mother liquor and recovered through line 13. The first mother liquor is fed through line 29 to second evaporative crystallizer 30. Second evaporative crystallizer 30 is operated under vacuum and temperature conditions which will produce anhydrous crystalline calcium chlorate or crystalline calcium chlorate dihydrate or mixtures thereof. Crystals of the calcium chlorate product are separated from a second mother liquor and recovered through line 31. The second mother liquor is fed to blender 8 through line 33.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=2[C:6]=1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:8].[C:22]([N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37](O)=[O:38])(=[O:33])=[O:32])[CH2:27][CH2:26]1)(=[O:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CC(N(C)C)=O>[C:22]([N:25]1[CH2:30][CH2:29][N:28]([S:31]([C:34]2[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=2)[C:37]([NH:1][C:2]2[S:3][C:4]3[CH2:21][CH2:20][CH2:19][CH2:18][C:5]=3[C:6]=2[C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:8])=[O:38])(=[O:32])=[O:33])[CH2:27][CH2:26]1)(=[O:24])[CH3:23]
Reactant: COc1ccc(NC(=O)c2c(N)sc3c2CCCC3)cc1
Reactant: CC(=O)N1CCN(S(=O)(=O)c2cccc(C(=O)O)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2c(NC(=O)c3cccc(S(=O)(=O)N4CCN(C(C)=O)CC4)c3)sc3c2CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
A mixture of 10.6 mg of 2-amino-N-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide, 10.9 mg of 3-(4-acetyl-piperazine-1-sulfonyl)benzoic acid, 16.0 mg of HATU, 0.012 mL of N,N-diisopropylethylamine, and 1 mL of DMA was stirred at room temperature overnight. The reaction mixture was separated by the addition of chloroform and water, and then the organic layer was concentrated under reduced pressure. The obtained residue was purified by preparative high performance liquid chromatography (methanol-0.1% aqueous formic acid solution) to obtain 5.2 mg of 2-({3-[(4-acetylpiperazin-1-yl)sulfonyl]benzoyl}amino)-N-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1-benzothiophene-3-carboxamide.
Reaction SMILES: [CH2:1]1[N:9]2[C:10]3[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=3[N:12]=[CH:13][C:7]3=[C:8]2[C:3](=[CH:4][CH:5]=[CH:6]3)[CH2:2]1.[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[NH4+].[OH-]>O1CCCC1.CCOCC>[C:18]1([CH:13]2[NH:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]3[CH2:1][CH2:2][C:3]4=[CH:4][CH:5]=[CH:6][C:7]2=[C:8]34)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: C1=Nc2ccccc2N2CCc3cccc1c32
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc(C2Nc3ccccc3N3CCc4cccc2c43)cc1
Temperature: 0 °C

Procedure:
A stirred mixture of 2.1 g of 1,2-dihydroindolo[1,7-ab][1,5]benzodiazepine in 16 ml of dry tetrahydrofuran is cooled under N2 to 0°-5° C., then treated dropwise with 9.4 ml of a 2.8 molar solution of phenyl magnesium bromide in ether at such a rate as to keep the reaction temperature below 10° C. When the addition is complete, the reaction mixture is refluxed for 3 hours, cooled and then poured into 100 ml ice-water containing 10 ml of concentrated HCl. The resultant mixture is made alkaline with NH4OH and extracted with methylenechloride. The organic phase is separated, washed with brine, dried over Na2SO4 and concentrated to give 6-phenyl-1,2,6,7-tetrahydroindolo[1,7-ab][1,5]benzodiazepine, m.p. 161°-164° C.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Cl[CH2:6][C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>C(O)C>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]12[CH2:9][CH2:10][CH2:11][CH:7]1[CH2:6][S:3][C:2]([NH2:4])=[N:1]2
Reactant: NC(N)=S
Reactant: Fc1ccccc1C1=C(CCl)CCC1
Solvent: CCO
Product: NC1=NC2(c3ccccc3F)CCCC2CS1
Temperature: 25 °C

Procedure:
Thiourea (2.60 g) was added to a solution of 1-(2-chloromethylcyclopent-1-enyl)-2-fluorobenzene obtained in Preparation Example 3-(4) (7.20 g) in ethanol (100 mL), and the mixture was stirred with heating under reflux for five hours. The reaction solution was cooled to room temperature and the solvent was evaporated under reduced pressure. The residual syrup was washed with heptane, followed by drying under reduced pressure. Trifluoroacetic acid (50.0 mL) and trifluoromethanesulfonic acid (10.0 mL) were added to the residue in an ice bath. Then, the reaction mixture was warmed to room temperature and stirred for four days. The reaction solution was poured into ice, diluted with ether and then neutralized with sodium bicarbonate, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain a residue. The residue was purified by NH-silica gel column chromatography to obtain the title compound (4.98 g).
Reaction SMILES: C1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=C1NCCc2c(-c3ccc(F)c(Cl)c3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (300 mg, 1.13 mmol) and 3-chloro-4-fluorophenylboronic acid (217 mg, 1.24 mmol) were coupled to yield 2-(3-chloro, 4-fluoro-phenyl)-1,3,4,5-tetrahydro-azepino[5,4,3-cd]indol-6-one, 217 mg (61%), as a pale-yellow solid. mp 234-235° C.; 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.39 (m, 2H), 7.24 (app t, 1H, J=7.8 Hz), 7.57 (dd, 1H, J=8.1, 0.9 Hz), 7.61 (m, 2H), 7.69 (dd, 1H, J=7.5, 0.9 Hz), 7.85 (dd, 1H, J=7.2, 2.1 Hz), 8.10 (br t, 1H), 11.68 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H13ClFN2O. 315.0700, Found: 315.0704; Anal. (C17H12ClFN2O.1.0 H2O.0.5 MeOH) C, H, N.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[C:18]([F:26])[CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:28][NH2:29]>C(O)C>[CH2:1]([C:8]1[CH:13]=[C:12]([CH3:14])[N:11]=[C:10]([NH:15][C:16]2[CH:25]=[CH:24][C:19]([C:20]([NH:28][NH2:29])=[O:21])=[C:18]([F:26])[CH:17]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Nc2nc(C)cc(Cc3ccccc3)n2)cc1F
Reactant: NN
Solvent: CCO
Solvent: O
Product: Cc1cc(Cc2ccccc2)nc(Nc2ccc(C(=O)NN)c(F)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 81.8 %

Procedure:
A mixture of methyl 4-(4-benzyl-6-methyl-pyrimidin-2-ylamino)-2-fluoro-benzoate (420 mg, 1.20 mmol) and hydrazine monohydrate (1.4 mL, 28.8 mmol) in ethanol (9 mL) was stirred at 90° C. for 6 h. After cooling to 20° C., a white precipitate was formed which was isolated by filtration to afford the title compound (345 mg, 82%) as white solid. Mp 191-193° C.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](=O)[C:8](OCC)=[O:9])=[CH:4][CH:3]=1.[Br:14][C:15]1[CH:16]=[CH:17][C:18]([OH:23])=[C:19]([CH:22]=1)[CH:20]=[O:21]>O.C(O)(=O)C.[Cl-].[Cl-].[Cl-].[Ti+3]>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[O:23][C:8](=[O:9])[C:7]([C:5]3[S:6][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:20]([OH:21])[C:19]=2[CH:22]=1
Reactant: CCOC(=O)C(=O)c1ccc(Br)s1
Reactant: O=Cc1cc(Br)ccc1O
Agent: [Ti+3]
Agent: [Cl-]
Solvent: CC(=O)O
Solvent: O
Product: O=c1oc2ccc(Br)cc2c(O)c1-c1ccc(Br)s1
Temperature: 4 °C
Reaction time: 8 h

Procedure:
A solution of titanium trichloride (7.71 g) in water (50 ml) was added to a solution of ethyl (5-bromo-2-thienyl)glyoxylate (5.0 g) and 5-bromo-2-hydroxybenzaldehyde (4.36 g) in dry acetic acid (50 ml) with stirring at 4° C. and the mixture was stirred for 11/2 hours. It was extracted with ethyl acetate and the extract was washed with water, brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was dissolved in toluene and p-toluenesulfonic acid (2.5 g) was added and the mixture heated under reflux for 21/2 hours. It was allowed to stand at room temperature overnight and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 6-bromo-3-(5-bromo-2-thienyl)-4-hydroxy-2H-1-benzopyran-2-one, m.p. 234-6° C. (compound 27)
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[H-].[Na+].[C:8]([NH:11][CH2:12][CH:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][C:21](F)=[C:20]([F:25])[CH:19]=2)[CH2:14]1)(=[O:10])[CH3:9]>CN(C)C=O>[F:25][C:20]1[CH:19]=[C:18]([C:15]2[CH2:14][CH:13]([CH2:12][NH:11][C:8](=[O:10])[CH3:9])[O:17][N:16]=2)[CH:23]=[CH:22][C:21]=1[N:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: c1cc[nH]c1
Reactant: CC(=O)NCC1CC(c2ccc(F)c(F)c2)=NO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)NCC1CC(c2ccc(-n3cccc3)c(F)c2)=NO1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 58 %

Procedure:
Pyrrole (0.299 ml) is dissolved in 7 ml dimethylformamide in a 25 ml one neck round bottom flask under nitrogen. The solution is cooled to 0° C., is treated with 60% sodium hydride (132 mg) and the mixture is stirred 20 minutes at room temperature. The solution is treated with (-)-5-(acetamidomethyl)-3-(3,4-difluorophenyl)-isoxazoline (Step 1, Example 11) (763 mg), and the reaction is stirred 2 hours at 50-60° C. The reaction is cooled, the dimethylformamide is removed under a stream of nitrogen, and the residue is washed with water followed by diethyl ether and is dried to give an off-white solid. The crude material is chromatographed over 25 g silica gel (230-400 mesh), eluting with 5% methanol/dichloromethane while collecting 5 ml fractions. Fractions 13-30 are combined and concentrated to give 520 mg (58%) of the title compound as a white solid, mp 176-177° C., [α]25D -73° (c 0.75).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9](O)=[O:10])[CH3:2].C(Cl)[Cl:16].C(Cl)(=O)C(Cl)=O>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[O:7][CH2:8][C:9]([Cl:16])=[O:10])[CH3:2]
Reactant: CCOc1cccc(OCC(=O)O)c1
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: CCOc1cccc(OCC(=O)Cl)c1
Reaction time: 8 h

Procedure:
A 250 mL flask fitted with a stir-bar, addition funnel, and an Ar inlet was charged with 3-ethoxyphenoxyacetic acid (13.0 g, 66.3 mmol) from above, CH2Cl2 (80 mL), and DMF (0.2 mL). To the resultant solution was added oxalyl chloride (2M in CH2Cl2, 41.4 mL, 82.8 mmol) over 30 min. The solution was stirred overnight then concentrated in vacuo to give 14.4 g of 47a as an oil/solid mix (100%). HPLC analysis (15:10:75 H2O:A1:MeOH) showed a purity of 95% with a retention time of 4.5 min.
Reaction SMILES: [CH3:1][C:2]([OH:6])([C:4]#[CH:5])[CH3:3].Br[C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1.C(N(CC)CC)C>CN(C=O)C.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>[CH3:1][C:2]([OH:6])([C:4]#[C:5][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1)[CH3:3]
Reactant: C#CC(C)(C)O
Reactant: CC1(C)OB(c2ccc(Br)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)C#Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1

Procedure:
2-Methyl-but-3-yn-2-ol (24 ml; 247 mmol), 2-(4-bromo-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (8.7 g; 30.85 mmol) (J.Organomet. Chem. 2006, 691(26), 5725), Pd(PPh3)2Cl2 (4.33 g; 6.17 mol) Cul (1.17 g; 6.17 mmol) in DMF (140 ml) and triethylamine (60 ml) are heated to 110° C. for 20 minutes. The reaction mixture is evaporated to dryness and the residue taken up in hexanes/acetone (85:15), filtered and the filtrate purified via chromatography ((SiO2; hexaneslacetone 85:15) to deliver the target compound as light-brown crystals. 1H-NMR (400 MHz; DMSO-d6): 7.65 (d, 2H); 7.40 (d, 2H); 5.51 (s, 1H); 1.48 (s, 6H); 1.31 (s, 12H). MS (m/z) ES+: 269 (100).
Reaction SMILES: Cl.[CH3:2][N:3]1[N:7]=[C:6]([NH2:8])[CH:5]=[N:4]1.C[O:10][C:11]([C:13]1[CH:23]=[C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[CH:27][CH:26]=2)[C:16]2[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=2[CH:14]=1)=O>>[CH3:2][N:3]1[N:7]=[C:6]([NH:8][C:11]([C:13]2[CH:23]=[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([C:31]#[N:32])=[CH:29][CH:30]=3)[C:16]3[CH2:17][C:18]([CH3:21])([CH3:20])[O:19][C:15]=3[CH:14]=2)=[O:10])[CH:5]=[N:4]1
Reactant: Cn1ncc(N)n1
Reactant: COC(=O)c1cc(Oc2ccc(C#N)cc2)c2c(c1)OC(C)(C)C2
Agent: Cl
Product: Cn1ncc(NC(=O)c2cc(Oc3ccc(C#N)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Example 1, from 2-methyl-2H-1,2,3-triazol-4-amine hydrochloride (533 mg, 1.78 mmol) and 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid methyl ester (187a) (128 mg, 0.396 mmol) to give a white solid (130 mg, 84% yield). 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1 H) 8.07 (s, 1 H) 7.62 (d, J=8.59 Hz, 2 H) 7.09 (d, J=10.36 Hz, 2 H) 7.02 (d, J=8.59 Hz, 2 H) 4.07 (s, 3 H) 2.88 (s, 2 H) 1.49 (s, 6 H); LCMS for C21H19N5O3 m/z 390.20 (M+H+).