Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([Si:11]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[O:12][C@@H:13]1[C@@H:17]([CH2:18][O:19]C(C2C=CC=CC=2)(C2C=CC(OC)=CC=2)C2C=CC(OC)=CC=2)[O:16][C@@H:15]([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:14]1)([CH3:10])[CH3:9].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH:55]([Si:11]([CH:8]([CH3:10])[CH3:9])([CH:52]([CH3:54])[CH3:53])[O:12][C@@H:13]1[C@@H:17]([CH2:18][OH:19])[O:16][C@@H:15]([N:43]2[CH:51]=[C:49]([CH3:50])[C:47](=[O:48])[NH:46][C:44]2=[O:45])[CH2:14]1)([CH3:56])[CH3:57]
Reactant: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O[Si](C(C)C)(C(C)C)C(C)C)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1cn([C@H]2C[C@H](O[Si](C(C)C)(C(C)C)C(C)C)[C@@H](CO)O2)c(=O)[nH]c1=O
Yield: 94.2 %

Procedure:
1.6 ml of trifluoroacetic acid were added dropwise to a solution of 1.861 g (2.655 mmol) of 3'-O-triisopropylsilyl-5'-O-(4,4'-dimethoxytrityl)thymidine [prepared as described in step (a) above] in 80 ml of chloroform, whilst cooling in an ice bath and stirring. The resulting mixture was stirred for 10 minutes and then 2 ml of pyridine were added. The reaction mixture was washed twice, each time with 100 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 50 g of silica gel (70-230 mesh), using methylene chloride containing 4% by volume of methanol as the eluent, to give 0.9965 g (yield 94%) of the title compound.
Reaction SMILES: C([O:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([NH:13][C:14]([NH:16][C:17]2[C:18](=[O:37])[O:19][C:20]3[CH:33]=[C:32]4[CH2:34][CH2:35][CH2:36][C:31]4=[CH:30][C:21]=3[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])=[CH:7][C:6]=1[O:38][CH3:39])(=O)C.Cl>O1CCCC1>[OH:4][C:5]1[C:6]([O:38][CH3:39])=[CH:7][C:8]([NH:13][C:14]([NH:16][C:17]2[C:18](=[O:37])[O:19][C:20]3[CH:33]=[C:32]4[CH2:34][CH2:35][CH2:36][C:31]4=[CH:30][C:21]=3[C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])=[O:15])=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: COc1cc(NC(=O)Nc2c(-c3ccccc3C)c3cc4c(cc3oc2=O)CCC4)cc(OC)c1OC(C)=O
Agent: Cl
Solvent: C1CCOC1
Product: COc1cc(NC(=O)Nc2c(-c3ccccc3C)c3cc4c(cc3oc2=O)CCC4)cc(OC)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.6 %

Procedure:
To a solution of N-(4-acetoxy-3,5-dimethoxyphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-yl]urea (400 mg) in tetrahydrofuran (4 ml) was added 10% methanolic hydrochloride (4 ml). The mixture was stirred at room temperature for 8 hours and the solvent was then distilled off. The residue was diluted with water and extracted with ethyl acetate. The extract was washed with water, dried (MgSO4) and distilled to remove the solvent. To the residue was added ethanol to give crystals of N-(4-hydroxy-3,5-dimethoxyphenyl)-N'-[4-(2-methylphenyl)-2-oxo-2,6,7,8-tetrahydrocyclopenta[g][1]benzopyran-3-yl]urea (330 mg, 66.7%). Recrystallization from ethanol gave colorless needles, m.p. 176°-179° C.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:25])(=[O:5])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].Cl.[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37]Cl.O>CN(C)C=O>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[CH3:24])=[CH:13][CH:12]=[CH:11][C:10]=2[O:25][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)CCCCl
Reactant: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(=O)c1cnc2c(OCCCN(C)C)cccc2c1Nc1ccc(F)cc1C
Reaction time: 1 h
Yield: 10.9 %

Procedure:
3-Butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (3.38 g, 10 mmol) and potassium t-butoxide (3.05 g, 25 mmol) were dissolved in dimethyl formamide (30 ml), warmed to 70° and 3-dimethylaminopropyl chloride hydrochloride (1.90 g, 12 mmol) added. The mixture was stirred for 1 hour at 80° then a further portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) added, and stirring continued overnight. A third portion of potassium t-butoxide (2.44 g, 20 mmol) and 3-dimethylaminopropyl chloride hydrochloride (1.58 g, 10 mmol) was added and the temperature raised to 85° . After a further 5 hours the mixture was poured into water, extracted with ether and the ether extracts dried and evaporated. Chromatography (silica gel, 4-6% methanolic ammmonia in dichloromethane) and recrystallisation from ethyl acetate gave 3-butyryl-4-(4-fluoro-2-methylphenyl-amino)-8-(3-dimethylaminopropoxy)quinoline (0.46 g, 11%), m.p. 99°-100°.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[C:6](=[S:12])[NH:5][C:4](=[O:13])[C:3]=1[NH:14][CH3:15].[CH:16](O)=O>>[CH2:8]([N:7]1[C:2]2[N:1]=[CH:15][N:14]([CH3:16])[C:3]=2[C:4](=[O:13])[NH:5][C:6]1=[S:12])[CH:9]([CH3:11])[CH3:10]
Reactant: CNc1c(N)n(CC(C)C)c(=S)[nH]c1=O
Reactant: O=CO
Product: CC(C)Cn1c(=S)[nH]c(=O)c2c1ncn2C
Temperature: 85 °C
Yield: 74 %

Procedure:
6-Amino-1-isobutyl-5-methylamino-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (0.11 g, 0.48 mmol) was dissolved in formic acid (1 mL) and heated at 85° C. for 1 h. The excess of formic acid was evaporated off under reduced pressure. 10% Sodium hydroxide solution (2 mL) was added and the solution was heated at 85° C. for 20 minutes. Water was added and the pH was adjusted to 4 with dilute acetic acid, upon which a white solid precipitated. The white solid was collected by filtration, washed with water and dried to yield the title compound (85 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9](OCO)[CH:8]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[S:7][C:6]=2[C:18]=1[Cl:19].B(F)(F)F.C[CH2:25][O:26]CC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:26][CH3:25])=[CH:4][C:5]2[CH:9]=[C:8]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[S:7][C:6]=2[C:18]=1[Cl:19]
Reactant: OCOC1c2ccc(Cl)c(Cl)c2SC1C1CCCC1
Reactant: CCOCC
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc2cc(C3CCCC3)sc2c(Cl)c1Cl
Reaction time: 8 h

Procedure:
A mixture of 2.5 g of 6,7-dichloro-2-cyclopentyl-2,3-dihydro-3-hydroxymethoxybenzo[b]thiophene and 10 ml of glacial acetic acid containing 5 ml of boron trifluoride etherate is warmed on a steam bath for 15 minutes and allowed to stand overnight. The mixture is poured into a chilled solution of dilute sodium hydroxide and the organic material is extracted into ether. Washing with water, followed by drying over anhydrous magnesium sulfate and evaporation in vacuo, gives 2.0 g of wax-like crystals. Recrystallization from ether-hexane gives 1.8 g of 6,7-dichloro-2-cyclopentyl-5-methoxybenzo-[b]thiophene as fine needles, mp 59.5°-60°.
Reaction SMILES: [C:1]1([C:7]2[N:8]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[C:9]([CH2:12][CH2:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:30]=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[C:1]1([C:7]2[N:8]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH2:30])=[O:24])=[CH:21][CH:20]=3)[C:9]([CH2:12][CH2:13][C:14]3[NH:18][N:17]=[N:16][N:15]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccc(-n2c(CCc3nnn[nH]3)ccc2-c2ccccc2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: NC(=O)c1ccc(-n2c(CCc3nnn[nH]3)ccc2-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a stirred solution of 4-{2-phenyl-5-[2-(1h-tetrazol-5-yl)-ethyl]-pyrrol-1-yl}-benzoic acid (0.37 mmol, 1.0 eq.) in DMF(10 ml) were added EDCI (1.48 mmol, 4.0 eq), HOBt hydrate (1.48 mmol, 4.0 eq.), and DIEA (diisopropylethylamine, 2.96 mmol, 8.0 eq.). The resulting mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM (75 mL) and 10% citric acid (50 mL). The organic layer was washed with saturated NaHCO3 (75 mL). The saturated NaHCO3 was acidified with 1M HCl and extracted with DCM (2×100 mL). The organic layer was dried (MgSO4) and the solvent removed in vacuo. The crude material was purified by prep HPLC to give product as a white solid, 30% yield.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:3]=1.[C:20]([N:24]1[C:28]([NH2:29])=[CH:27][C:26]([CH3:30])=[N:25]1)([CH3:23])([CH3:22])[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:20]([N:24]1[C:28]([NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:3]=2)=[CH:27][C:26]([CH3:30])=[N:25]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=c1c2ccccc2c(Br)nn1-c1ccc(Cl)cc1
Reactant: Cc1cc(N)n(C(C)(C)C)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nn(-c3ccc(Cl)cc3)c(=O)c3ccccc23)n(C(C)(C)C)n1

Procedure:
200 mg 4-Bromo-2-(4-chloro-phenyl)-2H-phthalazin-1-one (prepared as described in Method R), 91 mg 1-tert.-butyl-3-methyl-1H-pyrazol-5-ylamine, 310 mg cesium carbonate, 21 mg 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and 16.4 mg tris-(dibenzylideneacetone)-dipalladium in 2 ml dry dioxane were stirred under nitrogen at 100 C for 18 hrs. The solvent was removed under vacuum and the residue stirred with 50 ml water. The crude product was isolated by filtration, washed with water and purified by chromatography on silica, eluting sequentially with heptane, dichloromethane and finally dichloromethane/methanol 60:1. Yield 180 mg (74%) of the title product.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([OH:20])=O)[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.Cl.[N:24]1([CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[N:24]1([CH2:31][CH2:32][N:33]2[CH2:34][CH2:35][CH:36]([NH:39][C:18]([C:12]3[NH:13][C:14]4[C:10]([CH:11]=3)=[C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:17]=[CH:16][CH:15]=4)=[O:20])[CH2:37][CH2:38]2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccccc3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-Benzyloxy-1H-indole-2-carboxylic acid and amine 5.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:28]=1[C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30]>>[CH:32]1([NH:31][C:29]([C:28]2[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:27]=2[CH2:26][NH:25][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:20])[CH3:21])=[O:24])=[O:30])[CH2:33][CH2:34]1
Reactant: NCc1ccc(F)cc1C(=O)NC1CC1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1C(=O)NC1CC1)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 40, 2-(aminomethyl)-N-cyclopropyl-5-fluorobenzamide. LC/MS m/z 521 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:11])[S:3]([N:6]1[CH:10]=[CH:9][CH:8]=[N:7]1)(=[O:5])=[O:4].C([Li])CCC.[Br:17]C(Cl)(Cl)C(Cl)(Cl)Br>O1CCCC1>[Br:17][C:8]1[CH:9]=[CH:10][N:6]([S:3]([N:2]([CH3:11])[CH3:1])(=[O:4])=[O:5])[N:7]=1
Reactant: CN(C)S(=O)(=O)n1cccn1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1ccc(Br)n1
Reaction time: 0.25 h
Yield: 89.4 %

Procedure:
To a solution of N-dimethylsulfamoylpyrazole (44.0 g, 0.251 mol) in dry tetrahydrofuran (500 mL) at −78° C. was added dropwise a solution of n-butyllithium (2.5 M in hexane, 105.5 mL, 0.264 mol) while maintaining the temperature below −60° C. A thick solid formed during the addition. Upon completion of the addition the reaction mixture was maintained for an additional 15 minutes, after which time a solution of 1,2-dibromo-tetrachloroethane (90 g, 0.276 mol) in tetrahydrofuran (150 mL) was added dropwise while maintaining the temperature below −70° C. The reaction mixture turned a clear orange; stirring was continued for an additional 15 minutes. The −78° C. bath was removed and the reaction was quenched with water (600 mL). The reaction mixture was extracted with methylene chloride (4×), and the organic extracts were dried over magnesium sulfate and concentrated. The crude product was further purified by chromatography on silica gel using methylene chloride-hexane (50:50) as eluent to afford the title product as a clear colorless oil (57.04 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:10](=[S:13])[NH:11][N:12]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C[O-].[Na+].Cl>CO.O>[Cl:1][C:2]1[C:3]2[N:12]([NH:11][C:10](=[S:13])[N:4]=2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)c2n[nH]c(=S)n12
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ncc(Cl)c2nc(=S)[nH]n12
Temperature: 25 °C
Yield: 77.5 %

Procedure:
8-Chloro-5-methoxy-1,2,4-triazolo[4,3-c]-pyrimidine-3(2H)-thione (0.215 g, 1.00 mmol) was mixed with 2.0 g of dry methanol and to this mixture was added, in increments with stirring at ambient temperature, 0.26 g (1.2 mmol) of commercial 25 percent sodium methoxide in methanol. After a 35-min reaction period, the mixture was acidified with aqueous hydrochloric acid and diluted with water. The precipitate that formed was recovered by filtration and dried to obtain 0.168 g of the title compound in 97 percent purity as determined by HPLC (76 percent of theory) as a cream colored solid. The compound can be recrystallized from a mixture of methanol and water; it decomposes, but does not melt up to 250° C.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][O:17][C:18]([C:20]1[N:24]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]([CH3:35])(O)[C:26]2([CH3:37])[CH3:36])[CH:23]=[N:22][CH:21]=1)=[O:19]>N1C=CC=CC=1>[CH3:16][O:17][C:18]([C:20]1[N:24]([CH:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27](=[CH2:35])[C:26]2([CH3:37])[CH3:36])[CH:23]=[N:22][CH:21]=1)=[O:19]
Reactant: COC(=O)c1cncn1C1c2ccccc2C(C)(O)C1(C)C
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: C=C1c2ccccc2C(n2cncc2C(=O)OC)C1(C)C
Yield: 51.1 %

Procedure:
1.7 ml of trifluoromethanesulfonic acid anhydride are added dropwise at a temperature of -15° C. to a solution of 2.5 g of 1-(2,2,3-trimethyl-3-hydroxyindan-1-yl)-5-imidazolecarboxylic acid methyl ester in 20 ml of pyridine. After a reaction period of 10 minutes the mixture is concentrated by evaporation in vacuo and the residue is chromatographed on silica gel using an ether/methylene chloride mixture (1:1). 1.2 g of 1-(2,2-dimethyl-3-methylideneindan-1-yl)-5-imidazolecarboxylic acid methyl ester are obtained in the form of brownish colourless crystals having a melting point of 125°-126° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23].[Cl:25][CH:26]([Cl:30])[C:27]([OH:29])=[O:28]>C(OCC)(=O)C.CCCCCCC>[Cl:25][C:26]([Cl:30])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]([CH3:21])[CH3:20])=[CH:17][CH:16]=[CH:15][C:14]=1[CH:22]([CH3:24])[CH3:23])[C:27]([OH:29])=[O:28]
Reactant: O=C(O)C(Cl)Cl
Reactant: CC(C)c1cccc(C(C)C)c1OCCCCCCCCCCBr
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc(C(C)C)c1OCCCCCCCCCCC(Cl)(Cl)C(=O)O
Yield: 52.8 %

Procedure:
7.95 g (20.0 mmol) 81 was reacted with 10.3 g (80.0 mmol) dichloroacetic acid as in example 9. Flash chromatography (ethyl acetate/heptane 1:10) yielded 4.7 g (53%) 29 as a light coloured oil.
Reaction SMILES: [CH:1]1([C:4](=[O:27])[CH2:5][C:6]([C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.[CH:28](OCC)(OCC)[O:29][CH2:30][CH3:31].C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:27])[C:5](=[CH:28][O:29][CH2:30][CH3:31])[C:6]([C:8]2[C:13](=[O:14])[N:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CCOC(OCC)OCC
Reactant: O=C(CC(=O)C1CC1)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1cnc(-c2ccccc2)n(-c2ccccc2)c1=O)C(=O)C1CC1
Temperature: 110 °C

Procedure:
A suspension of 1-cyclopropyl-3-(1,6-dihydro-6-oxo-1,2-diphenyl-5-pyrimidinyl)-1,3-propanedione (i.e. the product from Example 6, Step A) (165 mg, 0.46 mmol), triethyl orthoformate (0.23 mL, 1.4 mmol), and acetic anhydride (0.92 mL) was heated at 110° C. under a nitrogen atmosphere for 4 h. The residue was dissolved in toluene (5 mL) and the resulting solution was concentrated under reduced pressure at 50° C. The residue was re-dissolved in toluene (5 mL) and the resulting solution was concentrated at 50° C. to give 181 mg of the title compound as a brown oil that was used in the next step without further purification. 1H NMR analysis showed the product to contain a mixture of Z- and E-olefin isomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=O)=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1>C(O)C.N1CCCCC1>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:32]=[C:31]([CH3:33])[NH:30][C:29]=2[CH:34]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[O:27])[CH:22]=[CH:21][N:20]=[N:19]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Reactant: Cc1cc(C(=O)NCCn2ccnn2)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCn2ccnn2)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 74.2 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 2-formyl-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide (64.8 mg, 0.25 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 2-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-methyl-1H-pyrrole-3-carboxylic acid (2-[1,2,3]triazol-1-yl-ethyl)-amide as a yellow solid (96 mg, 74%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[CH:7]=O)([O-:3])=[O:2].[NH2:15][C:16]1[CH:34]=[CH:33][CH:32]=[CH:31][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([CH2:29][CH3:30])[CH3:28])=[CH:23][CH:22]=1)=[O:19]>CCO>[CH:27]([C:24]1[CH:25]=[CH:26][C:21]([N:20]2[C:18](=[O:19])[C:17]3[C:16](=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:15]=[C:7]2[C:6]2[CH:9]=[CH:10][C:11]([N+:12]([O-:14])=[O:13])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[CH:22][CH:23]=1)([CH2:29][CH3:30])[CH3:28]
Reactant: O=Cc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1
Reactant: CCC(C)c1ccc(NC(=O)c2ccccc2N)cc1
Solvent: CCO
Product: CCC(C)c1ccc(-n2c(-c3ccc([N+](=O)[O-])c([N+](=O)[O-])c3)nc3ccccc3c2=O)cc1
Yield: 48.9 %

Procedure:
Anhydrous CuCl2 (0.370 g, 2.70 mmol) and 3,4-dinitrobenzaldehyde (0.270 g, 1.38 mmol) were added to a solution of 2-amino-N-(4-sec-butylphenyl)benzamide (0.370 g, 1.38 mmol) in anhydrous EtOH (20 mL). After heating to reflux temperature for 3 hours, the mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with H2O, then brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel, eluting with 10% to 60% EtOAc in heptane, afforded 3-(4-sec-butylphenyl)-2-(3,4-dinitrophenyl)quinazolin-4(3H)-one (0.300 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].[CH3:13]O>OS(O)(=O)=O>[CH3:13][O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)nc(OC)c1
Temperature: 65 °C
Reaction time: 20 h

Procedure:
To a suspension of 2-chloro-6-methoxy-isonicotinic acid (2.00 g, 10.7 mmol) in methanol (100 mL), H2SO4 (2 mL) is added. The mixture is stirred at 65° C. for 20 h. The solution is cooled to rt. A precipitate forms. The solid material is collected, washed with methanol and dried to give 2-chloro-6-methoxy-isonicotinic acid methyl ester (1.66 g) as a white solid; LC-MS: tR=1.29 min; [M+1]+=202.00.
Reaction SMILES: C([N:4]1[C:8]2[CH:9]=[C:10]([C:12](OC)=[O:13])[S:11][C:7]=2[CH:6]=[N:5]1)(=O)C.[BH4-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3].[NH4+].[Cl-]>CO>[NH:4]1[C:8]2[CH:9]=[C:10]([CH2:12][OH:13])[S:11][C:7]=2[CH:6]=[N:5]1
Reactant: COC(=O)c1cc2c(cnn2C(C)=O)s1
Agent: [Al+3]
Agent: [BH4-]
Agent: [Cl-]
Solvent: CO
Product: OCc1cc2[nH]ncc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of methyl 1-acetyl-1H-thieno[3,2-c]pyrazole-5-carboxylate (F-5) (4.5 g, 20.0 mmol) in MeOH (30 mL) was slowly added NaBH4 (836 mg, 22.0 mmol). The mixture was stirred at room temperature for 30 mins, and then concentrated. The residue was dissolved in anhydrous THF (80 mL) and then LiAlH4 (1.5 g, 40.0 mmol) was slowly added at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Aqueous NH4Cl solution was added dropwise to quench the reaction. The resulting mixture was filtered, and the filtrate was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give the title compound (2.9 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:23])([F:22])[F:21])[C:6]([C:24]([OH:26])=[O:25])=[CH:5]2.[OH-].[Na+:28]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([CH3:19])[CH:13]=3)[CH:11]=1)[O:8][CH:7]([C:20]([F:22])([F:23])[F:21])[C:6]([C:24]([O-:26])=[O:25])=[CH:5]2.[Na+:28]
Reactant: Cc1cc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)O)=C3)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2cc(Cl)cc3c2OC(C(F)(F)F)C(C(=O)[O-])=C3)ccc1Cl

Procedure:
A solution of 6-chloro-8-(4-chloro-3-methylphenyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid 31.5 mg (0.078 mmole) in 2.0 mL of ethanol was treated with 0.775 mL of 0.1008N NaOH. The resultant mixture was lyophilized to provide a quantitative yield of a yellow solid: 1H NMR (CD3OD/400 MHz) 2.39 (s, 3H), 5.77 (q, 1H, J=6.8 Hz), 7.25-7.28 (m, 1H), 7.34 (d, 1H, J=2.4 Hz), 7.37-7.40 (m, 3H), 7.79 (s, 1H).