Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[N:6]=1)(=[O:3])[CH3:2].[CH3:12][C:13]1([CH3:24])[O:18][C:17](=[O:19])[C:16](=[CH:20]OC)[C:15](=[O:23])[O:14]1>C(O)C>[C:1]([NH:4][C:5]1[N:6]=[C:7]([NH:11][CH:20]=[C:16]2[C:15](=[O:23])[O:14][C:13]([CH3:12])([CH3:24])[O:18][C:17]2=[O:19])[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc(N)n1
Reactant: COC=C1C(=O)OC(C)(C)OC1=O
Solvent: CCO
Product: CC(=O)Nc1cccc(NC=C2C(=O)OC(C)(C)OC2=O)n1
Yield: 22.4 %

Procedure:
A mixture of 2-acetamido-6-aminopyridine (2.9 g, 19 mmol), (Angew. chem. 1995, 107, 2589), and 2,2-dimethyl-5-methoxymethylene-1,3-dioxane-4,6-dione (4.28 g, 23 mmol), (Montatsh. Chem. 1967, 98, 564), in ethanol (75 ml) was stirred and heated at reflux for 5 hours. The mixture was allowed to cool and the precipitated product was collected by filtration and dried to give 5-((6-acetamido-2-pyridylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (1.3 g, 22%) as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25].I[CH3:27]>C1COCC1.[Ag]=O>[CH3:27][O:1][C@H:2]1[C@H:7]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:6]=[C:5]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][C:17]=2[N+:22]([O-:24])=[O:23])[CH2:4][C@@H:3]1[CH3:25]
Reactant: C[C@H]1CC(c2ccncc2[N+](=O)[O-])=C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: CI
Agent: O=[Ag]
Solvent: C1CCOC1
Product: CO[C@@H]1[C@@H](C)CC(c2ccncc2[N+](=O)[O-])=C[C@H]1NC(=O)OC(C)(C)C
Temperature: 45 °C
Reaction time: 10 h
Yield: 35 %

Procedure:
(+/−)-Tert-butyl (1R,5S,6R)-6-hydroxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enylcarbamate (1.0 equiv.) was suspended in iodomethane (100.0 equiv.). Silver oxide (6.0 equiv.) was added to the mixture and the reaction vessel was wrapped in foil (kept dark) and allowed to stir 45° C. for 10 hrs. The reaction was diluted with THF and filtered through a pad of celite. The celite cake was further washed with MeOH. The organics were concentrated and the crude was taken up in DCM, washed with NaHCO3(aq.), dried over Na2SO4, filtered and concentrated. The crude was loaded onto silica gel and purified via ISCO to yield (+/−)-tert-butyl ((1R,5S,6R)-6-methoxy-5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-en-1-yl)carbamate in 35% yield. LC/MS (m/z)=364.1 (MH+), Rt=0.89 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@@H:7]([OH:9])[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[Br:18][C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]1[CH2:8][C@H:7]([O:9][C:22]2[CH:23]=[CH:24][C:19]([Br:18])=[CH:20][CH:21]=2)[CH2:6][N:5]1[C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11]
Reactant: Oc1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](Oc2ccc(Br)cc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a solution of trans-1-(Boc)-4-hydroxy-L-proline methyl ester (0.5 g) (2 mmol), 4-bromophenol (0.52 g) (1.5 eq.) and Ph3P (0.78 g) (1.5 eq.) in 10 mL of dry THF at 0° C. was added DEAD (0.47 mL) in a minimal volume of THF. The reaction mixture was warmed to RT overnight. The solvent was removed in vacuo and the resulting residue suspended in ether. The solids were removed by filtration and the solvent evaporated under reduced pressure to afford after SiO2 chromatography (eluent: cyclohexane/EtOAc-9/1), cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester as a colorless oil (0.54 g). NMR (CDCl3, 200 MHz): 7.37 (2H, d), 6.70 (2H, d), 4.85 (1H, m), 4.37-4.6 (1H, m), 3.6-3.85 (5H, m), 2.35-2.50 (2H, m), 1.4-1.5(9H). To a solution cis-1-(Boc)-4-(4-bromo-phenoxy)-L-proline methyl ester (0.54 g) in 8 mL of DCM at 0° C. was added 2.5 mL of TFA. The reaction mixture was stirred at 0° C. for 1 h and warmed to RT for an additional hour. The solvents were evaporated in vacuo. The resulting residue was dissolved in water and the aqueous layer basified with aqueous NaHCO3 and extracted with EtOAc. The combined organic extracts were washed with water, dried over MgSO4, and the solvent was evaporated under reduced pressure to afford the titled compound as a colorless oil which solidified upon standing (0.39 g). NMR (CDCl3, 200 MHz): 7.35 (2H, d), 6.70 (2H, d), 4.8 (1H, m), 3.92 (1H, dd), 3.72 (3H, s), 3.35 (1H, d), 3.1 (1H, dd) 2.25-2.55 (2H, m).
Reaction SMILES: Br[C:2]1[CH:12]=[C:11]([O:13][CH3:14])[C:5]2[O:6][CH2:7][CH2:8][CH2:9][O:10][C:4]=2[C:3]=1[F:15].C([Li])CCC.[CH:21](N1CCOCC1)=[O:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[F:15][C:3]1[C:4]2[O:10][CH2:9][CH2:8][CH2:7][O:6][C:5]=2[C:11]([O:13][CH3:14])=[CH:12][C:2]=1[CH:21]=[O:22]
Reactant: O=CN1CCOCC1
Reactant: COc1cc(Br)c(F)c2c1OCCCO2
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)c(F)c2c1OCCCO2
Temperature: -72 °C
Reaction time: 0.5 h

Procedure:
To a solution of 548 mg of 7-bromo-6-fluoro-9-methoxy-3,4-dihydro-2H-benzo[b][1,4]dioxepine in 15 ml of THF there was added dropwise 0.81 ml of n-butyllithium (2.55 M, hexane solution) at −70° C. under a nitrogen atmosphere. After stirring at −72° C. for 30 minutes, 0.3 ml of N-formylmorpholine was added and the temperature was raised from −78° C. to 0° C. over a period of 30 minutes. Saturated aqueous ammonium chloride was added to the reaction mixture, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (239 mg) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([Cl:22])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:32])[C:10](=[O:14])[O:9]2)=[CH:6][CH:7]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: O=c1[nH]c(=O)n(-c2ccc(Cl)cc2)o1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(Cl)cccc1Cl)n1c(=O)on(-c2ccc(Cl)cc2)c1=O
Reaction time: 72 h

Procedure:
2-(4-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (3.8 grams; 0.018 mole), toluene (50 ml) and triethylamine (2.8 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Dichlorobenzoyl chloride (4.19 grams) dissolved in toluene (10 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 3 days. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate, is filtered and is stripped of solvent under reduced pressure. The residue is washed with a hexane-ether mixture to yield a brown solid. This solid is recrystallized from a benzene-hexane mixture to yield the desired product 2-(4-chlorophenyl)-4-(2,6-dichlorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione having a melting point of 112° to 116°C.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[NH:4][C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C)C=O.C(OCC)(=O)C>[CH2:19]([N:7]1[C:6]2[C:5](=[O:11])[NH:4][C:3](=[O:12])[N:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]cnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methylxanthine (2.882 g) was suspended in N,N-dimethylformamide (40 ml), and potassium carbonate (3 g) and benzyl bromide (2.5 ml) was added thereto. The reaction mixture was stirred at room temperature overnight, diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The deposited crystals were collected by filtration and washed with ethyl acetate to give 3.18 g of the title compound.
Reaction SMILES: N[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].N([O-])=O.[Na+].[ClH:16]>O1CCOCC1.O>[Cl:16][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: Cl
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc(O)c1Cl
Temperature: 70 °C
Reaction time: 0.25 h

Procedure:
2-Amino-3-nitrophenol 1b1 (5 g; 32.4 mmol) was dissolved in concentrated HCl (75 mL) and 1,4-dioxane (14.7 mL). The mixture was heated to 70° C. until most of the solids were in solution. The reaction mixture was cooled to 0° C. (ice bath), and sodium nitrite (2.23 g; 32.3 mmol) in H2O (5.4 mL) was added over a period of 3 hours to the brown solution. The temperature was maintained below 10° C. during the addition and the stirring was continued for an additional 15 min. at 0° C. This diazonium intermediate was poured into a solution of Cu(I)Cl (3.8 g; 38.9 mmol) in H2O (18.5 mL) and conc. HCl (18.5 mL) at 0° C. The reaction was stirred for 15 min. at 0° C., warmed to 60° C., and stirred for an additional 15 min. The reaction mixture was then brought to room temperature, and left to stir overnight. The reaction mixture was transferred to a separatory funnel and extracted with ether (3×150 mL). The organic layers were combined, washed with brine (1×), dried (Na2SO4), filtered and concentrated to afford the crude product (5.83 g) as a red-brown oil. The crude material was purified by flash column chromatography (1:25 ultra pure silica gel, 230-400 mesh, 40-60 mm, 60 angstroms; 3:1 hexane/EtOAc as the solvent) to afford pure 2-chloro-3-nitrophenol 1c1 (48%; 2.7 g) as an orange solid. MS 171.8 (MH)+: Homogeneity by HPLC (TFA) @ 220 nm: 96%.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14](O)=[O:15])(=[O:5])=[O:4].S(Cl)([Cl:21])=O>C(Cl)(Cl)Cl>[F:1][C:2]([F:18])([F:17])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][C:14]([Cl:21])=[O:15])(=[O:5])=[O:4]
Reactant: O=C(O)Cc1ccccc1NS(=O)(=O)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C(Cl)Cc1ccccc1NS(=O)(=O)C(F)(F)F
Yield: 71.4 %

Procedure:
To a solution of 10 g of o-(trifluoromethanesulfonamido)phenylacetic acid in 100 ml of chloroform, there were dropwise added 8.4 g of thionyl chloride. After completion of the addition, the resultant mixture was heated and refluxed until the evolution of the gas stopped. Concentration of the reaction mixture gave a solid substance, which was recrystallized from toluene to give 7.6 g of o-(trifluoromethanesulfonamido)phenylacetyl chloride. M.P. 94°-95° C.
Reaction SMILES: O=[C:2]1CN[C:5](=[O:8])[CH2:4][NH:3]1.C=O.[OH:11][PH:12]([OH:14])=[O:13].P(Cl)(Cl)Cl.[OH:19]P(O)=O>C(O)(=O)C>[P:12]([CH2:2][NH:3][CH2:4][C:5]([OH:8])=[O:19])([OH:14])([OH:11])=[O:13]
Reactant: O=[PH](O)O
Reactant: O=C1CNC(=O)CN1
Agent: C=O
Solvent: ClP(Cl)Cl
Solvent: CC(=O)O
Product: O=C(O)CNCP(=O)(O)O

Procedure:
The sequence of reactions in Reaction Scheme 9a is comparable to those set forth in Reaction Scheme 9 except that N-acetylglycine XVIII is deacylated to form 2,5-diketopiperazine XXX. 2,5-diketopiperazine XXX is then reacted with formaldehyde and H3PO3 PCl3 or other H3PO3 source to produce N-(phosphonomethyl)glycine I and acetic acid. Acetic acid which is produced in the hydrolysis step can be reacted with ammonia to generate acetamide for the carboxymethylation step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][CH:10]([CH2:13][NH2:14])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26])([O-:17])=[O:16]>>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][CH:10]([CH2:13][NH:14][C:25]([NH:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N+:15]([O-:17])=[O:16])=[O:26])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Reactant: NCC1CCN(c2ccncc2)CC1
Product: O=C(NCC1CCN(c2ccncc2)CC1)Nc1ccccc1[N+](=O)[O-]
Yield: 63.8 %

Procedure:
Using a similar procedure to that described for Example 48, Part A, 1-(4-pyridyl)piperidine-4-methylamine (1.34 g, 7.01 mmol) and 2-nitrophenyl isocyanate (1.21 g, 7.40 mmol) yielded 1.59 g (64%) of the title compound.
Reaction SMILES: [CH:1](=[C:3]1/[CH2:4][CH2:5][C@@H:6]2[C@:11]/1([CH3:12])[CH2:10][CH2:9][CH2:8][C@@H:7]2[OH:13])\[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].N1C=CC=CC=1>CCOCC>[C:14]([O:13][C@H:7]1[CH2:8][CH2:9][CH2:10][C@@:11]2([CH3:12])[C@H:6]1[CH2:5][CH2:4]/[C:3]/2=[CH:1]/[CH3:2])(=[O:16])[CH3:15]
Reactant: CC(=O)OC(C)=O
Reactant: C/C=C1/CC[C@H]2[C@@H](O)CCC[C@]12C
Solvent: c1ccncc1
Solvent: CCOCC
Product: C/C=C1/CC[C@H]2[C@@H](OC(C)=O)CCC[C@]12C
Yield: 91 %

Procedure:
A solution of indenol 9 (100.5 g, 0.56 mmol), 6 mL of acetic anhydride and 5 mL of pyridine was stirred for 16 hr at rt. The reaction mixture was diluted with ether (80 mL), washed with 10% HCl (50 mL×4), saturated aqueous NaHCO3, dried over anhydrous MgSO4 and concentrated in vacuo. Purification by chromatography (5% EtOAc/hexane) gave 112.8 mg (91%) of compound 10 as a colorless oil. 1H NMR (400 MHz, CDCl3) δ 5.20 (br d, J=2.4 Hz, IH), 5.08 (qt, J=7.2, 2.0 Hz, 1H), 2.33 (m, 2H), 2.18 (m,1H), 1.80 (m, 2H) 2.04 (s, 3H), 1.65 (dt, J=7.2, 2.4 Hz, 3H), 1.55 (m, 6H),1.08 (s, 3H); MS, m/z (70 eV, EI) 343 (M-tert-Bu+, 100%); HRMS Calcd. 343.1761 for C20H40O4 Si2 -tert-Bu+, found 313.1108.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.CCCCCC.[Li]CCCC.[C:33]1([N:39]=[C:40]=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)C>[C:33]1([NH:39][C:40]([C:2]2[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=3)[N:3]=2)=[O:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C=Nc1ccccc1
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)Nc2ccccc2)c1
Reaction time: 0.17 h

Procedure:
0.8 g (0.0022 mol) of 2-bromo-4-dimethylamino-6-{3-(trifluoromethyl)phenoxy} pyridine was dissolved in about 15 ml of diethyl ether. While cooling the solution in a dry ice-acetone bath in an argon atmosphere, 1.5 ml of a 1.6M-hexane solution of BuLi (0.0022×1.1 mol) was added to the solution, followed by stirring the solution for about 10 minutes. After 0.60 g (0.0022×2.3 mol) of phenyl isocyanate dissolved in about 5 ml of diethyl ether was added to the reaction solution, the solution was removed from the bath and stirred at room temperature for about 30 minutes. The reaction solution was mixed with about 5 ml of a 1.2N-aqueous hydrochloric acid solution, and then distributed in ethyl acetate-water, followed by washing with saturated sodium bicarbonate water and saturated brine. The organic phase of the obtained solution was dried with anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (eluting solution: ethyl acetate/hexane) to separate a main fraction therefrom. The fraction was concentrated and then precipitated with hexane, thereby obtaining an aimed product.
Reaction SMILES: C(Cl)Cl.Br[C:5]1[N:10]=[C:9]([NH:11][C:12]2[CH:16]=[C:15]([C@@H:17]3[CH2:19][C@H:18]3[CH3:20])[NH:14][N:13]=2)[C:8]([Cl:21])=[CH:7][N:6]=1.[C:22]([NH:26][S:27]([C:30]1[S:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])=[O:28])([CH3:25])([CH3:24])[CH3:23]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:22]([NH:26][S:27]([C:30]1[S:34][C:33]([C:5]2[N:10]=[C:9]([NH:11][C:12]3[CH:16]=[C:15]([C@@H:17]4[CH2:19][C@H:18]4[CH3:20])[NH:14][N:13]=3)[C:8]([Cl:21])=[CH:7][N:6]=2)=[CH:32][CH:31]=1)(=[O:28])=[O:29])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(B(O)O)s1
Reactant: C[C@@H]1C[C@H]1c1cc(Nc2nc(Br)ncc2Cl)n[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@H]1C[C@H]1c1cc(Nc2nc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)ncc2Cl)n[nH]1
Temperature: 90 °C
Yield: 63.2 %

Procedure:
The mixture of Pd(dppf)Cl2.CH2Cl2 (74 mg, 0.09 mmol, 0.15 eq.), 2-bromo-5-chloro-N-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-yl)pyrimidin-4-amine (200 mg, 0.61 mmol, 1.0 eq), 5-(N-tert-butylsulfamoyl)thiophen-2-ylboronic acid (192 mg, 0.73 mmol, 1.2 equiv.) and saturate Ka2CO3 (5 mL) in dioxane (10 mL) was heated to 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to rt, and extracted with THF. The combined layers were purified by silica gel chromatography (EtOAc/Petroleum ether from 10:1 to 2:1) to afford compound N-tert-butyl-5-(5-chloro-4-(5-(trans-2-methylcyclopropyl)-1H-pyrazol-3-ylamino)pyrimidin-2-yl)thiophene-2-sulfonamide (180 mg, 63%).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[C:10]1([C:16]2[N:17]=[CH:18][NH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1>[NH:1]1[CH:5]=[C:4]([S:6]([N:19]2[CH:20]=[C:16]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:17]=[CH:18]2)(=[O:8])=[O:7])[N:3]=[CH:2]1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1c[nH]cn1)n1cnc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.4 %

Procedure:
A round bottom flask equipped with a magnetic stirrer, reflux condenser and nitrogen inlet was charged with 8.35 g of imidazole- 4-sulfonylchloride and 300 ml or THF. The solution was treated with 14.5 g of 4-phenylimidazole in one portion and the resulting solution stirred 18 hours at room temperature. The precipitate was filtered and the filtrate concentrated at reduced pressure. The solids were triturated with water, filtered, rinsed and dried at high vacuum over NaOH; then dissolved in hot ethyl acetate, treated with charcoal, filtered and concentrated to 600 ml. Hexane was added and induced crystallization. The product was filtered, rinsed and dried giving 12.02 g of white crystals in two crops of 1-(4-imidazolylsulfonyl)-4-phenylimidazole, mp 204.5-206; λmaxnujol 3.13 (NH), 7.27 (SO2N) and 8.61 μ (SO2N). NMR (DMSO, d6) 750-840 Hz, m, 1H; 495 Hz, t, J = 1Hz, 2H; 466-484 Hz, m, 4 H; 435-438 Hz, m, 3H.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[F:24][C:25]([F:42])([F:41])[C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38]CO)[CH2:34][CH2:33]2)[CH:29]=[CH:30][CH:31]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:14]=3[C:15]([O:17][CH2:18][CH2:38][N:35]3[CH2:34][CH2:33][N:32]([C:28]4[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:42])([F:24])[F:41])[CH:27]=4)[CH2:37][CH2:36]3)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Reactant: OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1
Product: O=C(OCCN1CCN(c2cccc(C(F)(F)F)c2)CC1)c1cc(F)ccc1Nc1ccnc2cc(Cl)ccc12
Yield: 6.1 %

Procedure:
Using the procedure of Example 3, 4 g of the ester of Example 1 and 3.316 g of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethanol were reacted to obtain 6.88 g of a raw oily product. 500 mg of the said product were crystallized from isopropyl ether to obtain 425 mg of 2-[4-(3-trifluoromethylphenyl)-piperazin-1-yl]-ethyl 2-(7-chloro-4-quinolinylamino)-5-fluoro-benzoate melting at 113° C.
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([N+:11]([O-])=O)[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH:3][CH3:4].[H][H]>[Pd]>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:8]=[CH:9][CH:10]=1)[NH2:11])[CH2:2][CH2:3][CH3:4]
Reactant: CC=CCc1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Product: CCCCc1cccc(N)c1
Yield: 89.4 %

Procedure:
Treatment of 3-nitrobenzaldehyde (8.2 g) with propyltriphenyl phosphonium bromide (25 g) and n-butyllithium in hexane (64.9 mmol), as described in Example 1a, gave 3-(2-butenyl)nitrobenzene (9.3 g), δ (360 MHz, CDCl3) 1.1 (3H, t, CH3), 2.4 (2H, m, CH2CH3). 5.8 (1H, m, =CH--CH2), 6.3 (1H, m, CH=CH2), 7.2 to 8.0 (4H, m, ArH). Treatment of the above 3-(2-butenyl)nitrobenzene (9.3 g) with hydrogen and palladium on carbon (10%, 0.93 g) as described in Example 1a, gave 3-butylaniline (7.0 g), δ (60 MHz, CDCl2) 0.9 (3H, t, CH3), 1.4 (4H, m, CH2CH2CH3), 2.5 (2H, t, ARCH2), 3.4 (2H, bs, NH2 ) and 6.2 to 7.0 (4H, m, ArH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][NH2:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1.[Cl:21][CH2:22][C:23](Cl)=O.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:23]([CH2:22][Cl:21])=[N:13][N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[C:6]=2[CH:20]=1
Reactant: NNC1=Nc2ccc(Br)cc2C(c2ccccn2)=NC1
Reactant: O=C(Cl)CCl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: ClCc1nnc2n1-c1ccc(Br)cc1C(c1ccccn1)=NC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
15 g. of 7-bromo-5-(2-pyridyl)-3H-1,4-benzodiazepin-2-yl hydrazine (obtained as in Preparation 2) is slowly added to 150 ml. of acetic acid with external cooling. A solution of 6 g. of chloroacetyl chloride in 75 ml. of acetic acid is then added during about ten minutes, the solution is stirred at room temperature for about 1.5 hours and 4 g. of sodium acetate added with additional stirring for about 30 minutes, the mixture then being refluxed for about 3.25 hours. This mixture is cooled, poured into ice water and concentrated to a small volume, then diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The extract is dried over anhydrous magnesium sulfate, concentrated and the residue chromatographed on 1 kg. column of silica gel with 1% methanol -- 99% chloroform. The product obtained from the column is crystallized from ethyl acetate to give pure 8-bromo-1-(chloromethyl)-6-(2-pyridyl)-4H-s-triazolo-[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:9](Cl)=[O:10])[CH2:8][CH2:7][CH2:6]1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH:5]1([C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:10])[CH2:8][CH2:7][CH2:6]1
Reactant: O=C(Cl)C1CCC1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)C1CCC1
Temperature: 25 °C

Procedure:
In a 5-L round bottomed flask equipped with an overhead stirrer and a pressure equalizing additional funnel was placed 1500 mL of benzene and 1150 g (8.65 mole) of anhydrous aluminum chloride. The reaction vessel was cooled in an ice-salt bath. To this mixture was added very carefully over a 1.5 hour period 920 g (7.7 mole) of cyclobutanecarbonyl chloride. Following the addition, the cooling bath was removed and the mixture allowed to warm to room temperature overnight and cautiously poured onto ice. The phases were separated and the aqueous layer extracted three times with ethyl acetate. The organic layers were combined washed three times with saturated sodium bicarbonate three times with water, and once with brine. The solution was dried over anhydrous magnesium sulfate and the solvent removed under reduced pressure. The residue was distilled to give 1126 g of phenyl cyclobutyl ketone, bp 97°-102° C. at 0.1 mm Hg. NMR (CDCl3) 1.8-2.6 (m, 6 H), 4.0 (q, 1 H), 7.4-7.6 (m, 3 H), 7.8-8.0 (m, 2 H); IR (neat film) 2950, 1675, 1450, 1350, 1225, 960, and 700 cm-1.