Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[S].[NH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O>>[Br:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)/[CH:10]=[N:4]/[N:5]=[CH:10]/[C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([Br:6])[CH:8]=1
Reactant: O=Cc1cccc(Br)c1
Reactant: NN
Agent: [Na+]
Agent: [OH-]
Agent: [S]
Product: Brc1cccc(/C=N/N=C/c2cccc(Br)c2)c1
Temperature: 85 °C
Yield: 80.6 %

Procedure:
To a 250 mL 3-neck round-bottom flask equipped with condenser was added sodium hydroxide (6.2 g, 156 mmol), sulfur (5.0 g, 156 mmol), and hydrazine (5.0 g, 156 mmol). The mixture was stirred at reflux 85° C. for 2 hours. The solution was cooled to room temperature and treated dropwise via syringe with 3-bromobenzaldehyde (18 mL, 156 mmol). The precipitate was recovered by filtration, washed with water and dried in an oven to provide (1E,2E)-1,2-bis(3-bromobenzylidene)hydrazine (23 g, 40%). LCMS (M+H) 367.1 calc. for C14H, Br2N2 366.9. 1H NMR (400 MHz, CDCl3): δ ppm 7.30-7.35 (m, 2H) 7.59 (d, J=7.82 Hz, 2H) 7.70-7.73 (d, 2H) 8.03 (s, 2H) 8.56 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13](OC)=[O:14])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[CH2:13][OH:14])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cnoc1-c1ccc(F)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnoc1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To a solution of methyl 5-(4-fluorophenyl)isoxazole-4-carboxylate (7.06 g) in tetrahydrofuran (50 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-fluorophenyl)-4-isoxazolylmethanol (6.35 g, yield 90%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 41–42° C.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([N:7]=[C:8]=[O:9])=[CH:3][CH:4]=[CH:5][CH:6]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH2:15].CCCCCCC>C1(C)C=CC=CC=1>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][NH:15][C:8]([NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[CH3:10])=[O:9]
Reactant: NCc1ccccc1F
Reactant: Cc1ccccc1N=C=O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1ccccc1NC(=O)NCc1ccccc1F

Procedure:
ortho-Tolylisocyanate (4.95 ml) was added to a solution of 2-fluorobenzylamine (4.56 ml) in toluene (50 ml) under an atmosphere of nitrogen at 5° C. to produce rapid formation of a white solid. Heptane was added, the solid broken up and filtered off to afford 1-(2-fluorobenzyl)-3-(2-methylphenyl)urea (9.5 g) as a white solid. The urea (8 g) and cyanoacetic acid (2.9 g) were ground together and heated in acetic anhydride (15 ml) to 80° C. After cooling the reaction mixture to room temperature, diethyl ether was added and washed with water. The separated ether phase was dried over magnesium sulphate, filtered and evaporated in vacuo to give a crude solid residue (8.9 g). This residue was redissolved in dichloromethane (120 ml), triethylamine (5.7 ml) added and the mixture stirred at room temperature for 3 days. Filtration of the precipitate yielded the desired uracil as a white solid (2.6 g).
Reaction SMILES: C([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[C:8]([Cl:16])[N:7]=1)(C)(C)C>C(O)=O.O>[Cl:16][C:8]1[NH:7][C:6](=[O:5])[C:15]2[C:10]([CH:9]=1)=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CC(C)(C)Oc1nc(Cl)cc2ccccc12
Solvent: O=CO
Solvent: O
Product: O=c1[nH]c(Cl)cc2ccccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.8 %

Procedure:
0.5 g (2.12 mmol) of 1-t-butoxy-3-chloroisoquinoline from example 16.3 was dissolved in 5.0 ml of formic acid and stirred at room temperature for 20 h. The solution was then diluted with 10 ml of H2O, and the precipitated solid was filtered off through a glass frit, washed with 10 ml of H2O/formic acid (2:1) and dried under high vacuum. 0.30 g (1.67 mmol, 78.8%) of 3-chloroisoquinolin-1(2H)-one was obtained. The combined aqueous phases were concentrated to dryness under reduced pressure and the resulting solid was purified by column chromatography (5:1 dichloromethane/ethyl acetate), whereupon a further 0.040 g (0.22 mmol, 10.4%) of 3-chloroisoquinolin-1(2H)-one was obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:14])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:13])=[CH:7]/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11].S(=O)(=O)(O)O>C(Cl)Cl>[CH3:13][C:6]1[CH2:5][CH2:4][CH2:3][C:2]([CH3:14])([CH3:1])[C:7]=1/[CH:8]=[CH:9]/[C:10]([CH3:12])=[O:11]
Reactant: CC(=O)/C=C/C=C(\C)CCC=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(=O)/C=C/C1=C(C)CCCC1(C)C
Yield: 98 %

Procedure:
The procedure was carried out exactly as described in Example 9, except that the solution of 600 g of a 96% pure pseudoionone in 1,200 ml of methylene chloride, and the 1,000 ml of sulfuric acid, were introduced simultaneously into the reactor in the course of 5 minutes instead of 10 minutes. The distillation gave 490 g of a 98% pure β-ionone, corresponding to a yield of β-ionone of 83.4% of theory.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=4)[N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].Br[C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>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].C1(C)C=CC=CC=1>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[N:16]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=4)[N:15]=[CH:14][CH:13]=3)=[CH:9][CH:10]=2)[N:5]([C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[N:4]=1)[CH3:2]
Reactant: CCc1n[nH]c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Reactant: Brc1ncccn1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CCc1nn(-c2ncccn2)c2cc(-c3ccnn3-c3ccc(S(C)(=O)=O)cc3)ccc12
Reaction time: 0.33 h
Yield: 67.5 %

Procedure:
A mixture of 3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1H-indazole (50 mg, 0.14 mmol), tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol), 2-bromopyrimidine (26 mg, 0.16 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (16 mg, 0.03 mmol), sodium tert-butoxide (19.7 mg, 0.21 mmol) and toluene (2.3 mL) was subjected to microwave irradiation (300 watts, 140° C.) for 300 seconds in a 10 mL sealed tube. The solvent was removed and the crude product absorbed onto silica gel. The residue was purified by column chromatography using as eluent 10% ethyl acetate in hexanes for 10 minutes, then a gradient to 50% ethyl acetate in hexanes at 20 minutes, then 50% for 5 minutes, then 100% at 35 minutes to provide 42 mg (70%) of 3-ethyl-6-{1-[4-(methylsulfonyl)phenyl]-1H-pyrazol-5-yl}-1-pyrimidin-2-yl-1H-indazole. LC/MS (EI) tR 3.82 (Method C), m/z 445.1 (M++1), 1H NMR (CDCl3) δ 1.5 (t, 3H); 3.0 (s, 3H); 3.1 (q, 2H); 6.6 (s, 1H); 7.1 (d, 2H); 7.6 (d, 2H); 7.7 (d, 1H); 7.8 (d, 1H); 7.9 (m, 2H); 8.7 (m, 3H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[O:18]1[CH:22]=[CH:21][N:20]=[C:19]1[CH2:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:28][C:27]3[CH:26]=[CH:25][C:24]([CH2:23][C:19]4[O:18][CH:22]=[CH:21][N:20]=4)=[CH:30][CH:29]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: Nc1ccc(Cc2ncco2)cc1
Product: Clc1cccc(-c2nc3c(c(Nc4ccc(Cc5ncco5)cc4)n2)CCC3)c1
Yield: 38.1 %

Procedure:
Following General Procedure B2, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.075 g, 0.28 mmol) was reacted with 4-(oxazol-2-ylmethyl)aniline (0.074 g, 0.42 mmol) to afford the title compound (0.043 g, 58%) as an off-white solid. MW=402.88. 1H NMR (DMSO-d6, 300 MHz) δ 8.88 (s, 1H), 8.30-8.19 (m, 2H), 8.03 (d, J=0.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.56-7.50 (m, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.15 (d, J=0.8 Hz, 1H), 4.13 (s, 2H), 2.90 (q, J=7.6 Hz, 4H), 2.20-2.04 (m, 2H); APCI MS m/z 403 [M+H]+.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].COCCO[AlH2-]OCCOC.[Na+].[CH:27]([NH:29][CH:30]([CH3:43])[CH2:31][C:32]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=2)[CH2:35][CH2:34][CH2:33]1)=O.Cl>C1(C)C=CC=CC=1.CCOCC>[ClH:42].[CH3:27][NH:29][CH:30]([CH3:43])[CH2:31][C:32]1([C:36]2[CH:37]=[CH:38][C:39]([Cl:42])=[CH:40][CH:41]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: CC(CC1(c2ccc(Cl)cc2)CCC1)NC=O
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CNC(C)CC1(c2ccc(Cl)cc2)CCC1

Procedure:
A 70% solution of sodium bis(2-methoxyethoxy) aluminum hydride in toluene (sold under the trade mark Red-al) (35 ml) was added dropwise to a solution of N-formyl-2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine prepared as described in Example 6 (5 g) in dry ether (110 ml) with cooling to maintain the temperature at less than 10° C. The temperature was allowed to rise to about 25° C. and then the mixture was heated under reflux for two hours. The reaction mixture was poured into a mixture of crushed ice and concentrated hydrochloric acid. The resulting mixture was washed with ether, basified with aqueous sodium hydroxide and extracted with ether. The ether extract was washed with brine, dried and evaporated to give a liquid which was dissolved in petroleum ether (b.p. 40°-60° C.). Hydrogen chloride gas was bubbled through the solution to precipitate a solid which was recrystallised from propan-2-ol to give N-methyl-2-[1-(4-chlorophenyl)cyclobutyl]-1-methylethylamine hydrochloride (Formula I R1, R 2 =H; R3 =H; R4 =Me; R5 =4-Cl; R6 =H; R7 =Me and R8 =H) (m.p. 192°-194° C.).
Reaction SMILES: [N:1]1([CH:6]([F:17])[C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])=O)[CH:5]=[N:4][CH:3]=[N:2]1.[C:18](=O)([O-])[O-].[K+].[K+].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[C:7]([CH:6]([F:17])[N:1]1[CH:5]=[N:4][CH:3]=[N:2]1)=[CH2:18]
Reactant: O=C(c1ccc(F)cc1F)C(F)n1cncn1
Reactant: O=C([O-])[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C(c1ccc(F)cc1F)C(F)n1cncn1

Procedure:
2-(1H-1,2,4-Triazol-1-yl)-2,2',4'-trifluoroacetophenone (10 g), anhydrous potassium carbonate (7.3 g), and methyltriphenylphosphonium bromide (15.5 g) were heated under reflux for 16 hours in 1,4-dioxan (250 ml), to which water (1.0 g) had been added.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9][C:10](=[O:12])[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[N:14]1([CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:18]=[CH:17][N:16]=[CH:15]1>>[F:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:11][C:10](=[O:12])[N:23]([CH2:22][CH2:21][CH2:20][CH2:19][N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)[C:7]2=[O:9]
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Reactant: NCCCCn1ccnc1
Product: O=c1[nH]c2ccc(F)cc2c(=O)n1CCCCn1ccnc1

Procedure:
When 5-fluoroisatoic anhydride and 1H-imidazole 1-butanamine are reacted by the procedure of example 24, this compound is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][NH2:10].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21](=[O:20])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][NH:10]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1ccc(F)cc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccc(F)cc2F)c1=O
Yield: 66.6 %

Procedure:
In the same manner as in Reference Example 63 and using (2,4-difluorophenyl)hydrazine•hydrochloride (5.1 g, 28 mmol), water (100 mL), potassium carbonate (8.6 g, 62 mmol) and diethyl ethoxymethylenemalonate (7.4 g, 34 mmol) as starting materials, the title compound (5.0 g, 66%) was obtained as a pale-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[H-].[Na+].[CH3:23][N:24]([CH2:26][CH2:27]Cl)[CH3:25].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33]>CN(C)C=O.O>[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]\[C:32]([OH:34])=[O:33].[CH3:23][N:24]([CH3:25])[CH2:26][CH2:27][S:20][C:11]1[CH2:10][N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: CN(C)CCCl
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Agent: O=C(O)/C=C\C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCSC1=Nc2ccc(Cl)cc2C(c2ccccc2Cl)=NC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 6.4 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in 50 ml of anhydrous dimethylformamide is added under ice cooling with stirring 1.2 g of sodium hydride (50% oily suspension), and the resulting mixture is stirred at room temperature for 20 minutes. To the mixture is added dropwise 6.6 g of N,N-dimethyl-2-chloroethylamine over a period of 10 minutes, followed by stirring at room temperature for 1 hour. The reaction mixture is poured into iced water and then extracted with chloroform. The extract is water washed and dried over magnesium sulfate, and the solvent is distilled off. An oily product obtained as the residue is subjected to column chromatography on alumina and eluted from the column with benzene. The eluate is concentrated to obtain a crude 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The crude product thus obtained is treated, according to usual procedure, with maleic acid and then recrystallized from an anhydrous isopropyl alcohol-acetone mixture to obtain 4.8 g of 2-(2-dimethylaminoethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine maleate, m.p. 140°-142° C.
Reaction SMILES: [OH:1][CH:2]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)=[CH2:10])[C:3]([O:5]C(C)C)=[O:4].[K].O>C(O)(C)C>[CH3:10][CH:9]([C:11]1[CH:12]=[CH:13][C:14]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:15][CH:16]=1)[C:2](=[O:1])[C:3]([OH:5])=[O:4]
Reactant: C=C(c1ccc(C2CCCCC2)cc1)C(O)C(=O)OC(C)C
Agent: [K]
Solvent: CC(C)O
Solvent: O
Product: CC(C(=O)C(=O)O)c1ccc(C2CCCCC2)cc1
Yield: 83 %

Procedure:
3.0 Grams of isopropyl 2-hydroxy-3-(4-cyclohexylphenyl)-3-butenoate was dissolved in 50 ml of anhydrous isopropyl alcohol. Separately, 1.1 g of metalic potassium was dissolved in 100 ml of anhydrous isopropyl alcohol. The two solutions thus prepared were combined together, and the combined solution was refluxed for 20 minutes. To the solution was then added 2 ml of water, and the mixture was further refluxed for 5 minutes. Thereafter, the isopropyl alcohol was removed from the mixture by distillation under reduced pressure. The residue was charged with water, and insoluble matter was removed therefrom by extraction with ethyl acetate. The extraction mother liquor was acidified with hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was successively washed with water and saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. The ethyl acetate was removed by distillation under reduced pressure to obtain crude crystals. The crude crystals were recrystallized from benzene-hexane to obtain 2.15 g of 3-methyl-3-(4-cyclohexylphenyl)-pyruvic acid, m.p. 100.6°-102.5° C. The yield was 83%.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]3[N:25]=[N:26][C:27]4[CH:33]=[C:32]([C:34]5[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=5[Cl:41])[CH:31]=[C:30]([CH3:42])[C:28]=4[N:29]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[OH:49][C:43]([C:45]([F:48])([F:47])[F:46])=[O:44].[Cl:40][C:39]1[CH:38]=[CH:37][CH:36]=[C:35]([Cl:41])[C:34]=1[C:32]1[CH:31]=[C:30]([CH3:42])[C:28]2[N:29]=[C:24]([NH:23][C:20]3[CH:19]=[CH:18][C:17]([S:14]([N:11]4[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]4)(=[O:16])=[O:15])=[CH:22][CH:21]=3)[N:25]=[N:26][C:27]=2[CH:33]=1
Reactant: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2c(Cl)cccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)N4CCNCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 86.8 %

Procedure:
4-{4-[7-(2,6-dichloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-benzenesulfonyl}-piperazine-1-carboxylic acid tert-butyl ester (0.0696 g, 0.111 mmol, 1 equiv) was diluted with DCM (5 mL) and treated with TFA (0.051 mL, 0.664 mmol, 6 equiv). The resulting red solution was stirred at ambient temperature for 6 hours. Additional 6 equivalents of TFA were then added and the reaction was stirred for 12 hours. The solvents were then evaporated and the resulting solids collected and dried to yield a yellow powder (0.062 g, 99% yield). MS (ESI+): m/z=528.9, LC retention time: 2.70 min. 1H NMR (DMSO-d6): δ 2.72 (s, 3H), 3.13 (m, 4H), 3.22 (m, 4H), 7.53 (m, 1H), 7.68 (d, J=8.2 Hz, 2H), 7.81 (d, J=1.6 Hz, 1H), 7.84 (d, J=8.7 Hz, 2H), 8.20 (d, J=1.7 Hz, 1H), 8.32 (d, J=8.8 Hz, 2H), 8.62 (bs, 2H), 11.53 (s, 1H).
Reaction SMILES: [S:1]1[C:5]2[CH2:6][CH2:7][CH2:8][O:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](O)=[C:12]([CH2:17][CH2:18][CH3:19])[CH:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Br:26][CH2:27][CH2:28][CH2:29]Br.O>CN(C=O)C>[Br:26][CH2:27][CH2:28][CH2:29][C:13]1[CH:14]=[CH:15][C:10]([C:2]2[S:1][C:5]3[CH2:6][CH2:7][CH2:8][O:9][C:4]=3[N:3]=2)=[CH:11][C:12]=1[CH2:17][CH2:18][CH3:19]
Reactant: BrCCCBr
Reactant: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1cc(-c2nc3c(s2)CCCO3)ccc1CCCBr
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-6,7-dihydro-5H-pyrano[2,3-d][1,3]thiazol-2-yl)-2-propylphenol (560 mg, 2.02 mmol) (Example 505) in DMF (5 mL) were added Cs2CO3 (0.99 g, 3.03 mmol) and 1,3-dibromopropane (0.72 mL, 7.07 mmol). The reaction mixture was stirred at rt for 18 h. Water was added, and the aqueous phase was extracted with Et2O. The combined organic phases were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (9:1 hexanes/EtOAc) to give the title compound was a white solid (121 mg, 15%). 1H NMR (400 MHz, CDCl3) 7.68 (d, 1H), 7.65 (dd, 1H), 6.82 (d, 1H), 4.30 (t, 2H), 4.12 (t, 2H), 3.62 (t, 2H), 2.78 (t, 2H), 2.61 (t, 2H), 2.34 (quintet, 2H), 2.11-2.03 (m, 2H), 1.63 (hex, 2H), 0.96 (t, 3H); LC-MS: RT=4.05 min, (M+H)+ 396.3.
Reaction SMILES: [Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[Cl:1][C:2](=[CH2:13])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: C=C(Cl)COc1ccc(C#N)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: C=C(Cl)COc1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.2 %

Procedure:
1 36 g of lithium aluminum hydride was suspended in 50 ml of diethyl ether, and a solution of 7.0 g of 4-(2-chloro-2-propeneoxy)benzonitrile in 40 ml of diethyl ether was added dropwise. After the addition, the mixture was stirred at room temperature for 30 minutes and then 10 ml of water was added dropwise for 30 minutes. The insoluble matter was removed by filtration. The ether layer was dried and diethyl ether was evaporated under reduced pressure to give 6.7 g of the desired 4-(2-chloro-2-propeneoxy)benzylamine as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>N1C=CC=CC=1>[C:8]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)(=[O:10])[CH3:9]
Reactant: Nc1ccccn1
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(S(=O)(=O)Nc2ccccn2)cc1

Procedure:
A solution of 13.4 g. of 2-aminopyridine in 300 ml. of pyridine is treated with 31.0 g. of 4-acetylbenzenesulfonyl chloride and the solution is stirred at room temperature for 6 hours. The solution is poured into 1 l. of cold water and the resulting precipitate of 4-acetyl-N-(2-pyridyl)benzenesulfonamide is collected by filtration, washed with water and dried; m.p. 201°-202° C. after crystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]3[CH:17]1[CH2:25][C:26]([OH:28])=O)(=[O:15])=[O:14])[CH:7]=[CH:6]2.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:62][NH:63][CH:64]1[CH2:73][CH2:72][C:71]2[C:66](=[CH:67][CH:68]=[C:69]([CH2:74][N:75]3[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]3)[CH:70]=2)[CH2:65]1>C1COCC1.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([S:13]([N:16]1[CH2:21][CH2:20][N:19]3[CH:22]=[CH:23][CH:24]=[C:18]3[CH:17]1[CH2:25][C:26]([N:63]([CH3:62])[CH:64]1[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([CH2:74][N:75]4[CH2:80][CH2:79][CH2:78][CH2:77][CH2:76]4)[CH:70]=3)[CH2:65]1)=[O:28])(=[O:15])=[O:14])[CH:7]=[CH:6]2
Reactant: CNC1CCc2cc(CN3CCCCC3)ccc2C1
Reactant: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)O)ccc2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2cc(S(=O)(=O)N3CCn4cccc4C3CC(=O)N(C)C3CCc4cc(CN5CCCCC5)ccc4C3)ccc2c1
Reaction time: 0.25 h
Yield: 47 %

Procedure:
To a solution of 2-(2-(6-methoxynaphthalen-2-ylsulfonyl)-1,2,3,4-tetrahydropyrrolo-[1,2-a]pyrazin-1-yl)acetic acid (S2) (200 mg, 0.5 mmol, 1.0 eq.) in THF (6 ml) were added DIPEA (300 μl, 2.0 mmol, 4.0 eq.) and HATU (190 mg, 0.5 mmol, 1.0 eq.) at 0° C. and the resulting mixture was stirred for 15 min at same temperature. A solution of N-methyl-6-(piperidin-1-ylmethyl)-1,2,3,4-tetrahydronaphthalen-2-amine (A51) (0.6 mmol, 1.2 eq.) in THF (4 ml) was added to the reaction mixture and it was allowed to stir at RT for 16 h. The reaction mixture was diluted with ethyl acetate (30 ml) and washed with sat. NH4Cl solution (20 ml), sat. NaHCO3 solution (20 ml), water (20 ml) and brine (20 ml). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the crude product which was purified by column chromatography (silica gel; 2-4% MeOH/DCM) to yield the desired product as a white solid. Yield: 47% (150 mg, 0.234 mmol); MS, Rt=3.7 min; m/z=641.1 [MH]+
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C.C(Cl)CCl>CN(C)C1C=CN=CC=1>[CH3:18][O:17][N:16]([CH3:15])[C:9](=[O:11])[CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1ccccc1CC(=O)O
Reactant: CNOC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2-methylphenyl)acetic acid in dry methylene chloride (16.7 g, 108.4 mmol) under nitrogen atmosphere was added N,O-dimethylhydroxylamine (13.8 g, 141.5 mmol), triethylamine (20 mL, 143.8 mmol), 4-dimethylaminopyridine (DMAP, 14.2 g, 119.3 mmol) and EDC (27 g, 140.6 mmol). The reaction mixture was stirred at RT for 2 hr then transferred to a separation funnel. The mixture was washed consecutively with 2 N aq. HCl, brine, saturated aq. NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and the solvent evaporated under vacuum to give 21 g of the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ: 7.20 (4H, m), 3.80 (2H, s), 3.65 (2H, s), 3.65 (3H, s), 2.34 (3H, m).