Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1.[N-:21]=[N+:22]=[N-:23].[Na+].C(OCC)(=O)C>CS(C)=O>[N:21]([C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])=[O:9])=[CH:4][CH:3]=1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(NCCc1ccc(Cl)cc1Cl)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: [N-]=[N+]=Nc1ccc(C(=O)NCCc2ccc(Cl)cc2Cl)cn1
Temperature: 100 °C

Procedure:
6-Chloro-N-[2-(2,4-dichlorophenyl)ethyl]pyridine-3-carboxamide (1 equivalent) and sodium azide (2.6 equivalents) were suspended in anhydrous DMSO (0.6 M) under nitrogen. The mixture was heated at 100° C. for four days. Ethyl acetate was added and the organic phase washed with water and brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness and the resultant residue dissolved in a 1:1 ethyl acetate/DCM mixture. This solution was purified by flash chromatography over silica (1:1 ethyl acetate/DCM). The fractions coeluting with the major band (Rf 0.53, eluent: 1:1 ethyl acetate/DCM) were combined and evaporated to dryness. The residue was recrystallized from acetonitrile to give 6-azido-N-[2-(2,4-dichlorophenyl)ethyl]-pyrid ine-3-carboxamide as pale yellow needles. LCMS (MH+) 336.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:9](=[O:10])[C:7]1=[O:8].[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>CN(C)C=O>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:9](=[O:10])[C:7]2=[O:8])[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1C(=O)N(CCCCBr)c2ccccc21
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1C(=O)N(CCCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)c2ccccc21
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29.7 %

Procedure:
A mixture of 1-(4-bromobutyl)isatin (5.64 g), 1-benzhydrylpiperazine (7.56 g) and triethylamine (3.0 g) in N,N-dimethylformamide (48 ml) was stirred for 30 minutes at 80° C. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography on silica gel (50 g) using chloroform as an eluent. The fractions containing the object compound were collected and evaporated. The remaining oil (3.25 g) was crystallized from diisopropyl ether, washed with diethyl ether, and then recrystallized from acetonitrile to give crystals of 1-[4-(4-benzhydryl-1-piperazinyl)butyl]isatin (2.69 g), mp. 127° to 129° C.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:22][C:23]([CH3:28])([CH3:27])[C:24](Cl)=[O:25]>C(Cl)Cl>[CH3:22][C:23]([CH3:28])([CH3:27])[C:24]([S:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH2:21][CH2:20][CH2:19][N:11]3[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:6][CH:7]=1)=[O:25]
Reactant: Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)Sc1ccc(-c2nc3n(c2-c2ccncc2)CCC3)cc1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
To 1.0 q (3.4 mmole) of 2-(4 mercaptophenyl)-3-(4-pyridyl)-6,7-dihydro [5H]pyrrolo[1,2-a]imidazole prepared as in Example 16 in 50ml methylene chloride at ° C. was added a solution of 0.3 q (3.7 mmole, 0.26 ml) trimethylacetyl chloride in 10 ml CH2Cl2 over a period of 10 minutes. The reaction was allowed to come to room temperature and was stirred for 30 minutes. The mixture was then diluted with methylene chloride and washed with N NaHCO3, saturated NaCl, treated with Na2SO4, stripped, then flash chromatographed on silica with methylene chloride containing 1% to 5% MeOH. The isolated material was recrystallized from ethyl acetate to give 0.43 g of the titled compound. 33.5% yield, mp 216-217.5 ° C. C22H23N3OS, Calculated, C: 70.00, H: 6.14, N: 1.13; Found, C: 70.01, H: 6.20, N: 10.99.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH2:5]([Mg]Br)[CH3:6].C(OCC)C.[CH2:14]([C@H:16]1[C:20](=[O:21])[CH2:19][CH2:18][N:17]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH3:15]>>[CH2:14]([C@H:16]1[C@@:20]([CH2:5][CH3:6])([OH:21])[CH2:19][CH2:18][N:17]1[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[CH3:15]
Reactant: CC[C@H]1C(=O)CCN1C(=O)OCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCOCC
Product: CC[C@@H]1N(C(=O)OCc2ccccc2)CC[C@@]1(O)CC

Procedure:
By an operation in the same manner as in Reference Example 3 and using cerium chloride (8.58 g), 3 mol/L ethylmagnesium bromide—diethyl ether solution (9.6 mL) and benzyl (2S)-2-ethyl-3-oxopyrrolidine-1-carboxylate (2.37 g), the title compound was obtained as colorless oil (yield: 2.19 g, yield: 82%).
Reaction SMILES: Cl.CN.[CH2:4]([N:6](CC)CC)C.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18](Cl)=[O:19])[CH:13]=1>C(Cl)Cl>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH:6][CH3:4])=[O:19])[CH:13]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: CCN(CC)CC
Agent: CN
Agent: Cl
Solvent: ClCCl
Product: CNC(=O)c1cc(Cl)ccn1
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a solution of methylamine hydrochloride (2.057 g, 30.5 mmol) and triethylamine (14.16 ml, 102 mmol) in DCM (30 ml) at 0° C., was added 4-chloropyridine-2-carbonyl chloride (3.575 g, 20.31 mmol) in DCM (20 ml). The resulting black suspension was allowed to reach room temperature and stirred overnight. The mixture was concentrated under reduced pressure and dissolved in ethyl acetate. Water was added and the layers were separated. The aqueous layer was extracted with ethyl acetate (3×), the combined organic layers were washed with water (3×) and brine, dried with Na2SO4 and concentrated under reduced pressure. The residue was purified with column chromatography (20-50% ethyl acetate in n-heptane) to give 2.04 gram of a yellow oil (10.64 mmol, 52%). MS (ESI) m/z=170.0 [M+1]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6]1.[C:16]([O-:19])(=[S:18])[CH3:17].[K+]>CC(C)=O>[C:16](=[O:19])([S:18][CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=[N:6]1)[CH3:17]
Reactant: CC([O-])=S
Reactant: ClCCCn1cc(-c2ccccc2)cn1
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)SCCCn1cc(-c2ccccc2)cn1
Yield: 88.6 %

Procedure:
0.23 g (1.04 mmol) 1-(3-chloroprop-1-yl)-4-phenyl-1H-pyrazole were dissolved in 6 ml acetone, potassium thioacetate (0.15 g, 1.3 mmol) was added and the mixture was heated to reflux during 16 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (hexane/ethyl acetate, gradient 9:1 to 7:3) to give 240 mg of the desired product as a yellow oil. MS (EI): 260.1 (M+). 1H-NMR (CDCl3): 2.19 (quint, 2H), 2.35 (s, 3H), 2.87 (t, 2H), 4.21 (t, 2H), 7.23 (m, 1H), 7.36 (m, 1H), 7.47 (m, 1H), 7.64 (s, 1H), 7.78 (s, 1H).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[N:6][CH:5]=1.[F:11][C:12]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:13]=1[C:14](O)=O.N>>[F:11][C:12]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:13]=1[C:14]1[O:1][N:2]=[C:3]([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[N:10]=1
Reactant: NC(=NO)c1cccnc1
Reactant: O=C(O)c1cc(F)ccc1F
Agent: N
Product: Fc1ccc(F)c(-c2nc(-c3cccnc3)no2)c1

Procedure:
The title compound was prepared according to the procedure of Example 8 using N′-hydroxynicotinimidamide (Aldrich) and 2,5-difluorobenzoic acid (Aldrich). 1H NMR (300 MHz, CD3OD) δ 7.41-7.56 (m, 2 H), 7.65 (ddd, J=7.9, 5.0, 1.0 Hz, 1 H), 7.98-8.04 (m, 1 H), 8.57 (dt, J=8.0, 1.9 Hz, 1 H), 8.75 (dd, J=5.2, 1.6 Hz, 1 H), 9.31 (dd, J=2.0, 0.8 Hz, 1 H); MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[S:14])=[CH:4][CH:3]=1.C(C(CC)(CC)C([O-])([O-])[O-])C.[C:26]([O:29][C:30](=O)[CH3:31])(=O)[CH3:27]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[C:11](=[C:26]([O:29][CH2:30][CH3:31])[CH3:27])[S:10][C:9]2=[S:14])=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C1CSC(=S)N1c1ccc(Cl)cc1
Agent: CCC(CC)(CC)C([O-])([O-])[O-]
Product: CCOC(C)=C1SC(=S)N(c2ccc(Cl)cc2)C1=O

Procedure:
A mixture of 50 g. (0.2 m.) of the above-prepared rhodanine and 140 g. (0.86 m.) of triethylorthoacetate in 350 ml. of acetic anhydride is refluxed for four hours. The cooled reaction solution is filtered and the product is washed with 100 ml. of 70% aqueous acetic acid to yield 3-(4'-chlorophenyl)-5-(1'-ethoxyethylidene)-rhodanine, m.p. 168°-171°C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH2:9][CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:23])[F:24])[CH:16]=2)[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCN(Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1cc(C2=CCN(Cc3ccccc3)CC2)ccc1Cl

Procedure:
1-Benzyl-4-(4-chloro-3-trifluoromethyl-phenyl)-piperidine-4-ol (1.5 g) was dissolved trifluoroacetic acid (35 ml) and refluxed for 24 hours and then CH2Cl2 (200 ml) was added. The phases were separated and then the organic phase was washed with two portions of 10%-Na2CO3, dried (MgSO4), filtered and evaporated to dryness. Yield 1.5 g. MS m/z (relative intensity, 70 eV) 351 (M+, 27), 172 (9), 92 (11), 91 (bp), 65 (21).
Reaction SMILES: C([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[S:27]1[CH:31]=[CH:30][CH:29]=[C:28]1B(O)O.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[CH3:9][C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH:18][C:19]2[N:20]=[CH:21][C:22]([C:28]3[S:27][CH:31]=[CH:30][CH:29]=3)=[CH:23][N:24]=2)[N:15]=1)([CH3:8])[C:6]([OH:5])=[O:26]
Reactant: OB(O)c1cccs1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCNc2ncc(Br)cn2)cs1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Sc1nc(CCNc2ncc(-c3cccs3)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 162-1 and 2-thiopheneboronic acid as starting materials and by an operation similar to that of Example 162-2 was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, and the obtained solid was triturate and washed with hexane-ethyl acetate to give the title compound as a white solid.
Reaction SMILES: C(O)CCCC.[CH3:7][N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.Cl.CS[C:17]1[N:23]2[CH:24]=[CH:25][N:26]=[C:22]2[CH2:21][C:20]2[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=2[N:18]=1.[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35]>C(O)(C)C>[C:31]([OH:38])(=[O:37])/[CH:32]=[CH:33]\[C:34]([OH:36])=[O:35].[CH3:7][N:8]1[CH2:13][CH2:12][N:11]([C:17]2[N:23]3[CH:24]=[CH:25][N:26]=[C:22]3[CH2:21][C:20]3[CH:27]=[CH:28][CH:29]=[CH:30][C:19]=3[N:18]=2)[CH2:10][CH2:9]1
Reactant: CN1CCNCC1
Reactant: CSC1=Nc2ccccc2Cc2nccn21
Agent: Cl
Agent: O=C(O)/C=C\C(=O)O
Solvent: CCCCCO
Solvent: CC(C)O
Product: CN1CCN(C2=Nc3ccccc3Cc3nccn32)CC1

Procedure:
Amyl alcohol (5100 ml) and 918.35 g (9.17 moles) of N-methylpiperazine were charged into a 12 liter 3-necked reaction flask fitted with a Dean-Stark adapter. The solution was stirred under nitrogen atmosphere and 989 ml of 10N ethanolic hydrogen chloride solution were added rapidly. The reaction mixture was heated to reflux and the distillate was collected in the Dean-Stark adapter. When the temperature of the reaction mixture reached 131° the Dean-Stark adapter was removed and an additional 918.35 g (9.17 moles) of N-methylpiperazine followed by 1045.0 g (4.56 moles) of 5-methylthio-11H-imidazo[1,2-c][1,3]benzodiazepine were added. The mixture was heated at reflux under nitrogen atmosphere for 20 hours. Amyl alcohol was then removed under reduced pressure at a water bath temperature of 80°. The viscous residual oil was dissolved in 10,000 ml of dichloromethane, washed with 3×4,000 ml of 4N sodium hydroxide and 6×4,000 ml of water. The dichloromethane solution was then extracted with 3×2,000 ml of 6N hydrochloric acid. The aqueous solution was back washed with 2×2,000 ml of dichloromethane, treated with 100 g of activated carbon and filtered. The clear filtrate was adjusted to pH 9-10 with 1,500 ml of ammonium hydroxide solution (29%). The oil which separated was extracted with 3×4,000 ml of dichloromethane, the extracts were dried over 1,000 g of sodium sulfate and the solvent removed at reduced pressure with a water bath temperature of 60°. An oil was obtained which rapidly solidified and after drying further (5 mm Hg/40°) yielded crude product, m.p. 113°-120°. The crude product was dissolved in 8,000 ml of hot (60°-70°) isopropanol. The solution was decolorized with 200 g of activated carbon and filtered. To this solution was added a solution of 760.7 g (8.28 moles) of maleic acid in 2,500 ml of warm (30°) isopropanol and the maleate salt began to precipitate. The suspension was stirred overnight at ambient temperature to complete crystallization and the solid was collected by filtration. The product was washed with 3×500 ml of cold isopropanol and dried (0.5 mm/50°). This was recrystallized from ethanol, the resulting product was washed first with ethanol and then with ether and then dried to give 5-(4-methyl-1-piperazinyl)-11H-imidazo[1,2-c][1,3]benzodiazepine monomaleate, m.p. 204°-205° (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][NH:8][CH2:7]2)([O-:3])=[O:2].C(N(C(C)C)CC)(C)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][N:8]([C:30]([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31])[CH2:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CNC2
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1Cc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-nitroisoindoline (1.16 g, 7.79 mmol) in CH2Cl2 (100 mL), was added diisopropylethylamine (2.7 mL, 15.6 mmol) followed by benzylchloroformate (1.2 mL, 8.56 mmol). The mixture was stirred at room temperature under N2 for 1 h. The reaction mixture was diluted with CH2Cl2 and washed with 1N HCl. The organic layer was dried (Na2SO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel to provide benzyl 5-nitro-1,3-dihydro-2H-isoindole-2-carboxylate. LCMS calc.=321.1; found=320.8 (M+Na)+. 1H NMR (500 MHz, CDCl3): δ 8.22-8.14 (m, 2H); 7.49-7.37 (m, 6H); 5.27 (s, 2H); 4.89 (s, 2H); 4.87 (s, 2H).
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.[CH2:9]([C:11](=[CH2:14])[CH:12]=O)[CH3:10].[NH2:15][C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>C(O)(C)C>[CH2:9]([C:11]1[CH:12]=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N:15][CH:14]=1)[CH3:10]
Reactant: CCOC(=O)C=C(N)C(=O)OCC
Reactant: C=C(C=O)CC
Agent: O=C(O)/C=C\C(=O)O
Solvent: CC(C)O
Product: CCOC(=O)c1cc(CC)cnc1C(=O)OCC
Temperature: 70 °C
Yield: 37.3 %

Procedure:
Isopropyl alcohol 150 ml and maleic acid 30.7 g (0 264 mol) were placed in 200 ml four-neck flask equipped with a reflux condenser. After heating the content to 70° C., a mixture of 22.2 g (0.264 mol) of 2-ethyl-2-propenal and 32.9 g (0.176 mol) of ethyl β-amino-β-ethoxycarbonylacrylate were added dropwise thereto with air-bubbling and refluxed for 10 hours. After removal of isopropyl alcohol, 100 ml of water was added thereto and the reaction mixture was neutralized with sodium carbonate. Oil layer was separated and concentrated under reduced pressure to obtain 16.5 g of 5-ethyl-2,3-diethoxycarbonylpyridine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:12]2[C:13]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:14]=3[S:15][C:16]=2[NH2:17])=O)=[CH:6][CH:5]=1.[CH:24]1([C:27](=[O:32])[CH2:28][C:29](=O)[CH3:30])[CH2:26][CH2:25]1>C(O)(=O)C.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:12]3[C:13]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:14]=4[S:15][C:16]=3[N:17]=[C:29]([CH3:30])[C:28]=2[C:27]([CH:24]2[CH2:26][CH2:25]2)=[O:32])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)c2c(N)sc3c2CCCCC3)cc1
Reactant: CC(=O)CC(=O)C1CC1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2c(C(=O)C3CC3)c(C)nc3sc4c(c23)CCCCC4)cc1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 43.7 %

Procedure:
To a stirred solution of 20 mg (0.06 mmol) 4-(2-Amino-5,6,7,8-tetrahydro-4H-cyclohepta[b]thiophene-3-carbonyl)-benzoic acid methyl ester in 1 ml acetic acid was added 10 mg (0.06 mmol) of 1-cyclopropyl-butane-1,3-dione and one drop of sulfuric acid. The mixture was then stirred at 100° C. for 10 minutes in a microwave and then concentrated in vacuo. Preparative HPLC (30% CH3CN/H20) afforded 11 mg (44%) 4-(3-cyclopropanecarbonyl-2-methyl-6,7,8,9-tetrahydro-5H-10-thia-1-aza-benzo[a]azulen-4-yl)-benzoic acid methyl ester as a light yellow solid. ES-MS m/e (%): 420 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([CH:6]=[O:7])=[C:4]([CH3:11])[CH:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1.[CH2:23](O)[CH2:24][CH2:25][OH:26].CCCCCC>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([CH:6]2[O:26][CH2:25][CH2:24][CH2:23][O:7]2)=[C:8]([CH3:10])[CH:9]=1
Reactant: OCCCO
Reactant: Cc1cc(Br)cc(C)c1C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: Cc1cc(Br)cc(C)c1C1OCCCO1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-bromo-2,6-dimethylbenzaldehyde (2.51 g, 12 mmol), 4-methyl-benzenesulfonic acid (0.20 g, 1.2 mmol), and propane-1,3-diol (1.2 mL, 16 mmol) in toluene (200 mL) was heated under nitrogen at 140° C. for 16 h, using a Dean-Stark trap to remove water. The reaction solution was then cooled to 25° C., diluted with EtOAc (200 mL), and sequentially washed with saturated aqueous sodium bicarbonate solution (100 mL) and brine (100 mL). The organic layer was separated, dried over MgSO4, filtered, and concentrated in vacuo to provide a yellow-brown oil. Hexane (200 mL) was added to the oil, and the resulting mixture was stirred vigorously for 10 min, resulting in the precipitation of a solid. This solid was collected by vacuum filtration, washed with hexanes (100 mL), and dried in vacuo to provide 2-(4-bromo-2,6-dimethylphenyl)-1,3-dioxane as a tan solid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:4]([O:5][CH3:6])[CH:3]=1.[NH:13]1[CH2:19][C:17](=[O:18])[NH:16][C:14]1=[O:15].C([O-])(=O)C.[Na+]>C(OC(=O)C)(=O)C>[CH3:6][O:5][C:4]1[CH:3]=[C:2]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:1]=[C:19]1[NH:13][C:14](=[O:15])[NH:16][C:17]1=[O:18]
Reactant: COc1ccc(C=O)cc1OC
Reactant: O=C1CNC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc(C=C2NC(=O)NC2=O)cc1OC

Procedure:
It was previously reported by Deulofeu and Mendivelzua, Z. physiol, Chem. 219, 233 (1933) that the condensation of veratraldehyde (3,4-dimethoxybenzaldehyde) with hydantoin in acetic anhydride in the presence of fused anhydrous sodium acetate gave 5-(3',4'-dimethoxybenzal) hydantoin. We have now found, however, that this reaction leads to the formation of a corresponding acetylated product.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)N)=[CH:5][CH:4]=1.CO[CH:24](OC)[CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>>[F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:13]3[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:25]([CH2:26][CH2:27][NH:28][CH3:29])=[CH:24]2)=[CH:5][CH:4]=1
Reactant: CNCCCC(OC)OC
Reactant: Cc1ccc(N(N)CCc2ccc(C(F)(F)F)nc2)cc1
Product: CNCCc1cn(CCc2ccc(C(F)(F)F)nc2)c2ccc(C)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-p-tolylhydrazine (Example 2) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].C(=O)([O-])[O-].[K+].[K+].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20].O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[S:9]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:11])=[O:10]
Reactant: CC(C)(C)N
Reactant: O=S(=O)(Cl)c1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1c(Br)cccc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
A solution of 2,6-dibromobenzenesulfonyl chloride (4.7 g, 14.0 mmol) in tetrahydrofuran (20 mL) was treated with potassium carbonate (5.8 g, 42 mmol) and t-butyl amine (1.2 g, 16.8 mmol). The resulting mixture was stirred at ambient temperature over 18 h then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford 2,6-dibromo-N-(1,1-dimethylethyl)benzenesulfonamide (4.5 g, 87%) as the white solid, which was used without further purification. 1H NMR (CD3OD): δ1.22 (s, 9H), 7.22 (t, 1H), 7.85 (d, 2H).
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20](Br)[N:21]=2)[N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH2:34]([N:36]1[CH:40]=[C:39](B2OC(C)(C)C(C)(C)O2)[CH:38]=[N:37]1)[CH3:35].C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]([CH3:33])([CH3:32])[C@@H:3]([NH:11][C:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:39]3[CH:38]=[N:37][N:36]([CH2:34][CH3:35])[CH:40]=3)[N:21]=2)[N:16]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[CH:15]=1)=[O:13])[C:4]([N:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)(C)[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: CCn1cc(-c2cnc3c(n2)c(C(=O)N[C@@H](C(=O)N2CCCC2)C(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Temperature: 90 °C
Yield: 75.2 %

Procedure:
In a pressure tube 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide (162 mg, 0.30 mmol) and 1-ethyl-1H-pyrazole-4-boronic acid pinacol ester (80 mg, 0.36 mmol) were dissolved in DME (3.0 mL). Aqueous K2CO3 (2.0 M, 0.45 mL, 0.90 mmol) and Pd(PPh3)4 (17 mg, 0.015 mmol) were added and the mixture degassed with a gentle stream of N2 for 15 min. The vial was then sealed and heated at 90° C. for 6 h. The reaction mixture was cooled to room temperature, quenched with H2O and extracted with EtOAc. The organic extracts were washed with brine, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (20-100% EtOAc/hexane) to afford 125 mg (75%) of 2-(1-ethyl-1H-pyrazol-4-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2,2-dimethyl-1-(pyrrolidine-1-carbonyl)-propyl]-amide as a light brown foam.