Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[Cl:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=1.P(=O)(O)(O)O.O>ClC1C=CC=CC=1Cl.C1C2NC3C(=CC=CC=3)SC=2C=CC=1>[Cl:6][C:7]1[CH:8]=[C:9]([OH:13])[CH:10]=[C:11]2[C:12]=1[CH2:1][CH2:2][C:3]2([CH3:5])[CH3:4]
Reactant: C=CC(=C)C
Reactant: Oc1cccc(Cl)c1
Agent: O=P(O)(O)O
Agent: c1ccc2c(c1)Nc1ccccc1S2
Solvent: O
Solvent: Clc1ccccc1Cl
Product: CC1(C)CCc2c(Cl)cc(O)cc21
Reaction time: 8 h
Yield: 16.4 %

Procedure:
449 g of isoprene, stabilized with 1.35 g of phenothiazine, were added dropwise over the course of 5.5 hours to a solution of 771 g of m-chlorophenol, 77 g of 85% strength phosphoric acid and 6 ml of water in 1.44 liters of o-dichlorobenzene at 150° C. To complete the reaction, stirring was continued overnight at 150° C. After cooling, the acid phase was separated off and extracted by shaking with toluene. The combined organic phases were washed until neutral. Fractional distillation gives 194 g of 7-chloro-3,3-dimethyl-5-hydroxy-indane; boiling point 105°-110° C/0.5 mm Hg; melting point 86.5° - 87.5° C. ##STR38##
Reaction SMILES: [N+:1]([C:4]1[CH:19]=[CH:18][C:7]2[N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-:3])=[O:2].[CH3:20][CH2:21][Mg+].[Br-].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[CH2:20]([C:5]1[C:6]2[N:10]=[CH:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[C:7]=2[CH:18]=[CH:19][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:21]
Reactant: CC(C)(C)OC(=O)n1cnc2cc([N+](=O)[O-])ccc21
Reactant: CC[Mg+]
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Br-]
Solvent: C1CCOC1
Product: CCc1c([N+](=O)[O-])ccc2c1ncn2C(=O)OC(C)(C)C
Temperature: -15 °C
Reaction time: 2 h
Yield: 12.3 %

Procedure:
To a solution of tert-butyl 5-nitro-1H-benzo[d]imidazole-1-carboxylate (150 g, 0.56 mol) in dry THF (1500 mL) was added EtMgBr (3.0 Min THF, 1.12 mol, 2 equiv.) dropwise at −15° C. The reaction mixture was stirred at −15° C. for 2 h. A solution of DDQ (129 g, 1.12 mol, 2 equiv.) in THF (120 mL) was added at −15° C., then the reaction mixture was warmed to RT and the stirring was continued for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic layers were washed with brine and then (Na2SO4), filtered, and concentrated. The crude material was purified by SiO2 chromatography eluting with 10% EtOAc/hexane to afford tert-butyl 4-ethyl-5-nitro-1H-benzo[d]imidazole-1-carboxylate (20 g, 12% yield) as a yellow solid.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[N:22]=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[CH:20]2)=[CH:15][C:14]=1[CH2:13]3)=[O:11].[CH:27](=[O:29])[CH3:28].S(=O)(=O)(O)O.C(OO)(C)(C)C>O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[CH3:1][CH2:2][C@@:3]1([OH:26])[C:8](=[O:9])[O:7][CH2:6][C:5]2[C:10]([N:12]3[C:24](=[CH:25][C:4]1=2)[C:23]1[C:14](=[C:15]([C:27]([CH3:28])=[O:29])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:21]=2[N:22]=1)[CH2:13]3)=[O:11]
Reactant: CC=O
Reactant: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2cc3ccccc3nc2-1
Agent: [Fe+2]
Agent: CC(C)(C)OO
Agent: O=S(=O)(O)O
Solvent: O
Product: CC[C@@]1(O)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2C(C)=O
Yield: 75 %

Procedure:
Camptothecin (5 g, 14.36 mmol) was dissolved in trifluoroacetic acid/acetic acetic acid (60 mL; ratio, 1:1) and deionized water added (15 mL) along with freshly distilled acetaldehyde (20 mL; excess) followed by dropwise addition of concentrated sulfuric acid (5 mL) at 0° C. using an ice bath over a period of 15 minutes. To the above stirred reaction medium is then introduced a 70% aqueous solution of t-butylhydroperoxide (3 ml) followed by iron sulfate heptahydrate (7.8 g, 28 mmol) in 1 mL water. The reaction mixture was then stirred at 0° C. to 25° C. for an additional 24 hours. The reaction mixture was then diluted with water and extracted with diethyl ether (500 mL×1), chloroform (250 mL×1) and then n-butanol (250 mL ×4). The organic portions were extracted out using diethyl ether and chloroform and discarded as fractions lacking desired product, while the n-butanol portion was concentrated to dryness at 40° C. and the crude product was recrystallized from a 90% chloroform/methanol mixture to furnish 4.2 g of the title compound (75% yield).
Reaction SMILES: C(N)C1C=CC=CC=1.C(O)(=O)C.O1CC1COC1C2C3C(=CC=CC=3)NC=2C=CC=1.[CH3:31][O:32][C:33]1[C:38]([O:39][CH2:40][CH2:41][N:42]([CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]2[C:59]3[C:60]4[C:65]([NH:66][C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:64][CH:63]=[CH:62][CH:61]=4)CC2C=CC=CC=2)=[CH:37][CH:36]=[CH:35][CH:34]=1>C1OCCOC1>[CH3:31][O:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:38]=1[O:39][CH2:40][CH2:41][NH:42][CH2:50][CH:51]([OH:67])[CH2:52][O:53][C:54]1[CH:55]=[CH:56][CH:57]=[C:58]2[NH:66][C:65]3[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=3[C:59]=12
Reactant: COc1ccccc1OCCN(Cc1ccccc1)CC(O)COc1cccc2[nH]c3ccccc3c12
Agent: c1ccc2c(c1)[nH]c1cccc(OCC3CO3)c12
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: NCc1ccccc1
Product: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Reaction time: 8 h

Procedure:
To 5 ml dioxane 1.4 g (0.0054 moles) of anhydrous N-2-[2-(methoxy)-phenoxy]-ethyl]-benzylamine, 0.07 g (0.00125 moles) of acetic acid and 0.5 g (0.0021 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is heated to 70-75° C. for 24 hrs (TLC control for checking conversion to N-benzyl carvedilol). To this reaction mixture, a second lot of 0.07 g (0.00125 moles) of acetic acid and 0.5 g (0.0021 moles) of 4-(oxiranylmethoxy)-9H-carbazole are added and the reaction mixture is further heated to 70-75° C. for 24 hrs (TLC control for checking conversion to N-benzyl carvedilol). Dioxane is distilled off from the reaction mixture and to the concentrated reaction mixture 10 ml ethylacetate is added and subjected the reaction mass to hydrogenation. To this solution of N-benzyl carvedilol in ethylacetate, (0.14 g) of wet Pd/C catalyst (5% Pd content and 50% moisture content) is added. The reaction mixture is hydrogenated at 3.5-4.5 Kg/cm2 at temperature of 60-70° C. for a period of about 8 hours. The reaction mixture is filtered and the filtrate is washed with 12-15% v/v aqueous ammonia (1 volume w. r .t. to the carbazole). The product enriched organic layer is separated and concentrated to remove ethylacetate. To the resultant syrupy mass n-butanol (2 ml) is added and the solution is stirred for about 10 hours, the crystals separated by filtration, washed successively with n-butanol (1 ml) and toluene (1 ml) to obtain carvedilol (0.9 g). The product is recrystallized from 3 volumes of ethyl acetate to obtain carvedilol (0.75 g).
Reaction SMILES: [N:1]1([C:6]2[CH:40]=[CH:39][C:9]([CH2:10][C:11]3[C:12]([O:37]C)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)[OH:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[OH-].[Na+]>CO>[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH2:10][C:11]3[C:12]([OH:37])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)([OH:23])[C:24]3[N:28]([CH3:29])[CH:27]=[N:26][CH:25]=3)=[CH:16][CH:15]=4)=[CH:39][CH:40]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2nc(O)c(Cc3ccc(-n4cccn4)cc3)c(Cl)c2c1
Reaction time: 96 h

Procedure:
To a mixture of (3-(4-(1H-pyrazol-1-yl)benzyl)-4-chloro-2-methoxyquinolin-6-yl)(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanol (0.32 g, 0.561 mmol, Example 33A) in methanol (1.5 mL) was added 6.6 M aqueous HCl (5 mL). The resulting solution was stirred for 4 days, cooled in an ice bath and aqueous NaOH (3 M) added dropwise to a basic pH. The crude product was isolated by filtration then chromatographed (10% MeOH in DCM, gradient) to provide the product, 1H NMR (400 MHz, DMSO-d6) δ ppm 12.23 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 7.85 (s, 1H), 7.58-7.77 (m, 4H), 7.32-7.48 (m, 6H), 7.28 (d, J=9.1 Hz, 2H), 6.97 (s, 1H), 6.51 (d, J=2.0 Hz, 1H), 6.12 (s, 1H), 4.11 (s, 2H), 3.32 (s, 3H); MS (ESI) 556.
Reaction SMILES: C[O:2][C:3](=[O:43])[C@@H:4]([NH:20][C:21](=[O:42])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[NH:29][S:30]([C:33]1[C:38]2=[N:39][S:40][N:41]=[C:37]2[CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1.N1SN=C2C(S(NC3C=C(Cl)C=CC=3C(O)=O)(=O)=O)=CC=CC=12.COC(=O)[C@@H](N)C(C1C=CC(Cl)=CC=1)C1C=CC(Cl)=CC=1>>[N:41]1[S:40][N:39]=[C:38]2[C:33]([S:30]([NH:29][C:23]3[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=3[C:21]([NH:20][C@@H:4]([CH:5]([C:6]3[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=3)[C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:3]([OH:43])=[O:2])=[O:42])(=[O:31])=[O:32])=[CH:34][CH:35]=[CH:36][C:37]=12
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: COC(=O)[C@@H](N)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=C(O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Product: O=C(N[C@H](C(=O)O)C(c1ccc(Cl)cc1)c1ccc(Cl)cc1)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Yield: 94 %

Procedure:
(S)-2-[2-(Benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester. The title compound (48 mg, 94%) was obtained from 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chlorobenzoic acid and (S)-2-amino-3,3-bis-(4-chloro-phenyl)-propionic acid methyl ester as in Example 1, Part C. 1H NMR (500 MHz, CDCl3): 11.28 (s, 1H), 8.37 (dd, J=7.0, 1.0, 1H), 8.22 (dd, J=8.8, 1.0, 1H), 7.72 (dd, J=8.8, 7.1, 1H), 7.68 (d, J=1.9, 1H), 7.32-7.28 (m, 4H), 7.20-7.15 (m, 4H), 6.96 (d, J=8.5, 1H), 6.87 (dd, J=8.4, 2.0, 1H), 6.21 (br d, J=8.8, 1H), 5.50 (t, J=8.5, 1H), 4.48 (d, J=8.3, 1H), 3.63 (s, 3H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([O:11][CH3:12])[CH:5]=1)[CH:2]=[CH2:3].[OH-].[Na+].[CH2:15](Cl)[CH:16]=[CH2:17]>C(O)CC>[CH2:17]([C:8]1[CH:9]=[C:4]([CH2:1][CH:2]=[CH2:3])[CH:5]=[C:6]([O:11][CH3:12])[C:7]=1[OH:10])[CH:16]=[CH2:15]
Reactant: C=CCCl
Reactant: C=CCc1ccc(O)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Product: C=CCc1cc(CC=C)c(O)c(OC)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To the solution of 162.4 g (1 mol) of 4-allyl-2-methoxyphenol (Eugenol) in 500 ml of 1-propanol heated to 70° C., 40 g (1 mol) of NaOH pellets are added and the mixture is stirred at 90° C. until NaOH is dissolved. The solution is cooled to 70° C. and 95.6 g (1.25 mol) of allyl chloride are added dropwise. After that, the reaction mixture is refluxed at 90° C. for 3 hours, then filtered, and propanol distilled off. 500 ml of toluene are added to the residue and the obtained solution is washed with 10% NaOH in water. The toluene-water mixture is distilled off and 6.5 g of LiCl and 1.6 g of Na2CO3 are added. The reaction mixture is heated to 130° C. under vacuum and kept at this temperature for 1 hour, then filtered and distilled under vacuum. The product 2,4-diallyl-6-methoxyphenol is off-white, low viscosity liquid (viscosity is 7 cPs at 25° C.) having a boiling point of 109°-112° C. (2-3 mm Hg), the structure is confirmed by IR and NMR Data. Yield is 163 g (80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].Cl>N1CCCCC1.N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5](/[CH:6]=[CH:14]/[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1ccc(/C=C/C(=O)O)cc1OC
Temperature: 120 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of 3,4-dimethoxybenzaldehyde (5.0 g, 30 mmol) and malonic acid (4.7 g, 45 mmol) in a mixture of piperidine (0.5 mL) and pyridine (15 mL) was heated to 120° C. and stirred overnight. The mixture was cooled to rt and acidified with conc. HCl. The resulting precipitate was filtered and washed with water to give (E)-3-(3,4-dimethoxyphenyl)-2-propenoic acid (5.1 g, 81%) as a pale brown solid; δH (400 MHz, DMSO-d6) 3.78 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 6.42 (d, J=16.0 Hz, 1H, CH═CHCO2H), 6.96 (d, J5,6=8.0 Hz, 1H, H5), 7.19 (d, J5,6=8.0 Hz, 1H, H6), 7.30 (s, 1H, H2), 7.51 (d, J=16.0 Hz, 1H, CH═CHCO2H).
Reaction SMILES: C1C[O:4][CH2:3]C1.C(N1C=CN=C1)(N1C=CN=C1)=O.[Cl:18][C:19]1[C:28]([NH2:29])=[C:27]([NH:30][C@@H:31]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH3:32])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.O>N1C=CC=CC=1>[Cl:18][C:19]1[C:28]2[N:29]=[C:3]([OH:4])[N:30]([C@@H:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:32])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: C[C@@H](Nc1c(N)c(Cl)nc2ccccc12)c1ccccc1
Reactant: C1CCOC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](c1ccccc1)n1c(O)nc2c(Cl)nc3ccccc3c21
Temperature: 90 °C
Reaction time: 8 h

Procedure:
THF (100 mL) and 1,1′-carbonyldiimidazole (8.1 g, 50.5 mmol) were sequentially added to a solution of 2-chloro-N4-[(1R)-1-phenylethyl]quinoline-3,4-diamine (10.0 g, 33.6 mmol) in pyridine (100 mL), and the reaction was heated at 90° C. overnight. An analysis by LC/MS indicated the presence of starting material, and additional 1,1′-carbonyldiimidazole (6 equivalents) was added in portions as heating at 90° C. was continued for a second day. The reaction was cooled to approximately 0° C., and water (300 mL) was added. The mixture was stirred overnight. A precipitate was present and was isolated by filtration and washed with water and diethyl ether to provide 6.67 g of 4-chloro-1-[(1R)-1-phenylethyl]-1H-imidazo[4,5-c]quinolin-2-ol. A small portion of the product was triturated with hot acetonitrile, isolated by filtration, washed with cold acetonitrile and diethyl ether, and dried under vacuum to provide a white solid with the following analytical data, mp 227-229° C.
Reaction SMILES: [CH2:1]([C:4]([C:6]1[N:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[O:8][N:7]=1)=[O:5])[CH2:2][CH3:3].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C(O)(C)C>[OH:5][CH:4]([C:6]1[N:10]=[C:9]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[O:8][N:7]=1)[CH2:1][CH2:2][CH3:3]
Reactant: CCCC(=O)c1noc(COc2ccc(Cl)cc2Cl)n1
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(C)O
Product: CCCC(O)c1noc(COc2ccc(Cl)cc2Cl)n1
Yield: 53.5 %

Procedure:
0.316 g of 3-propylcarbonyl-5-[(2,4-dichlorophenoxy)methyl]-1,2,4-oxadiazole and 0.20 g of aluminum isopropoxide were added to 10 ml of isopropanol. The mixture was heated to reflux for 48 hours. After evaporation of isopropanol, water was added to the residue. The aqueous solution was extracted with ethylacetate. After evaporation of ethylacetate, the residue was purified by column chromatography(hexane: ethylacetate=3:2) to provide 0.17 g of the desired product(yield: 54.0%).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[C:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1>[OH-].C(C([NH3+])(CC1C=CC=CC=1)CC1C=CC=CC=1)C1C=CC=CC=1.C(O)C.CC(C=C)=O>[CH:11]1[C:12]2[C:13](=[C:15]3[CH2:20][CH2:19][N:18]([CH2:3][CH2:4][C:5](=[O:6])[CH3:14])[CH2:17][CH2:16]3)[C:14]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[O:6][C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc2c(c1)Oc1ccccc1C2=C1CCNCC1
Agent: C=CC(C)=O
Agent: [NH3+]C(Cc1ccccc1)(Cc1ccccc1)Cc1ccccc1
Agent: [OH-]
Solvent: CCO
Product: CC(=O)CCN1CCC(=C2c3ccccc3Oc3ccccc32)CC1
Reaction time: 4 h

Procedure:
One drop of tribenzylmethyl ammonium hydroxide is added to a solution of 7 g of 4-(9-xanthenylidene)-piperidine in 70 cc of ethanol, 4.38 cc of methylvinylketone are then added dropwise, and stirring is effected at 50° for 4 hours. The reaction mixture is then concentrated by evaporation in a vacuum, the residue is dissolved in chloroform, extraction is effected with water, and after drying over magnesium sulphate, concentration is effected by evaporation. The partially crystalline residue is triturated with ether/petroleum ether 1:1 and recrystallized from ethanol. M.P. of the title compound 111°-112°.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[CH:11]=2)[S:6][CH:7]=1)[CH3:2].[C:17](OC1C=CC(Cl)=C(Cl)C=1Cl)(=[O:22])[CH2:18][C:19]([O-])=[O:20]>C1(C)C(C)=CC=CC=1>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]3[C:19](=[O:20])[CH:18]=[C:17]([OH:22])[N:16]=[C:12]3[CH:11]=2)[S:6][CH:7]=1)[CH3:2]
Reactant: CCc1csc(CCc2ccnc(N)c2)n1
Reactant: O=C([O-])CC(=O)Oc1ccc(Cl)c(Cl)c1Cl
Solvent: Cc1ccccc1C
Product: CCc1csc(CCc2ccn3c(=O)cc(O)nc3c2)n1
Temperature: 140 °C
Reaction time: 3 h
Yield: 21.9 %

Procedure:
4-[2-(4-Ethyl-1,3-thiazol-2-yl)ethyl]-2-pyridinamine (480 mg, 2.044 mmol) dissolved in xylene (10 ml) was added with trichlorophenyl malonate (1 g, 2.160 mmol) and refluxed by heating at 140° C. The reaction solution was stirred for 3 hours and returned to room temperature. The solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform→chloroform:methanol=80:1→50:1→5:1) to obtain 135 mg (22%) of orange crystals.
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:9]C1C=CC=CC=1)[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]>O1CCOCC1.S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH:5]=[CH2:6]
Reactant: C=CC(C)(C)C(=CCl)Oc1ccccc1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=CC(C)(C)C(=O)CCl
Yield: 71.6 %

Procedure:
4.44 g (20 mmols) of 1-chloro-3,3-dimethyl-2-phenoxy-1,4-pentadiene are warmed to 100° C. in 20 ml of dioxane and 10 ml of 50% sulphuric acid, during the course of 6 hours. The working-up according to Example B1(a) yields 2.1 g of 1-chloro-3,3-dimethyl-pent-4-en-2-one, which are 72% of theory.
Reaction SMILES: [CH:1]([NH:3][C@@H:4]1[C:15](=[O:16])[N:6]2[C@@H:7]([C:12]([O-:14])=[O:13])[C:8]([CH3:11])([CH3:10])[S:9][C@H:5]12)=[O:2].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CN(C)C=O>[CH:1]([NH:3][C@@H:4]1[C:15](=[O:16])[N:6]2[C@@H:7]([C:12]([O:14][CH2:25][C:24]3[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)=[O:13])[C:8]([CH3:11])([CH3:10])[S:9][C@H:5]12)=[O:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CC1(C)S[C@@H]2[C@H](NC=O)C(=O)N2[C@H]1C(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)S[C@@H]2[C@H](NC=O)C(=O)N2[C@H]1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reaction time: 4 h

Procedure:
A mixture of sodium (3S,5R,6R)-6-formamido-2,2-dimethylpenam-3-carboxylate (15.0109 g., 56.4 mmole) and p-nitrobenzyl bromide (12.16805 g., 56.3 mmole) in N,N-dimethylformamide (250 ml.) was stirred for 4 hours at +20°to +25°, after which time all the solid had dissolved. The solvent was removed by evaporation and the residual paste was suspended in ethyl acetate (100 ml.) and washed with brine. The aqueous layer was washed with ethyl acetate (150 ml.) and the combined organic layers washed with water (5 × 250 ml.), passed through phase-separating paper and evaporated to a pale-yellow foam. Chromatography on kieselgel G (600 g.) in benzene-ethyl acetate (1:1) gave p-nitrobenzyl (3S,5R,6R)-6-formamido-2,2-dimethylpenam-3-carboxylate which crystallised from ether-ethyl acetate (3:1) as a white solid (8.73 g., 23 mmole, 41%); m.p. 129° to 132°; [α]D + 190°; λmax. 262 (ε 10,170); νmax. 3420 (NH), 2880 (HCO), 1788 (azetidin-2-one), 1750 (CO2R), 1695 and 1505 (CONH), 1528 and 1346 (Ar-NO2), 841 cm.-1 (para-disubstituted aromatic ring); τ 1.73, 2.43 (2H, AB-q, J 8.5 Hz, p-nitrophenyl), 1.75 (1H, s, HCO), 3.37 (1H, d, J 9 Hz, NH), 4.21 (1H, dd, J 9 and 4.5 Hz, C6 -H), 4.42 (1H, d, J 4.5 Hz, C5 -H), 4.68 (2H, s, NO2C6H4CH2), 5.46 (1H, s, C3 -H), 8.36 (3H, s) and 8.54 (3H, s) (C[CH3 ]2). (Found : C, 50.5; H, 4.6; N, 11.1; S, 8.5.C16H17N3O6S (379.4) requires C, 50.7; H, 4.6; N, 11.1; S, 8.4%).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:10]([CH3:11])[CH2:9][CH:8]=[C:7]([C:12]2[NH:16][N:15]=[N:14][N:13]=2)[CH2:6]1)([OH:3])=[O:2].[CH:17](I)([CH3:19])[CH3:18]>>[CH:17]([N:14]1[N:15]=[N:16][C:12]([C:7]2[CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH:10]([CH3:11])[CH2:9][CH:8]=2)=[N:13]1)([CH3:19])[CH3:18]
Reactant: CC1CC=C(c2nnn[nH]2)CN1CC(=O)O
Reactant: CC(C)I
Product: CC1CC=C(c2nnn(C(C)C)n2)CN1CC(=O)O

Procedure:
The title compound was prepared from 28 (5 g, 0.022 mol) as described in Example 5, using isopropyl iodide instead of methyl iodide. Yield: 3.23 g (0.012 mol, 55%) as an oil.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[O:13][CH:14]=[CH:15][N:16]=1.[OH-].[Na+]>C(O)(=O)C.[Fe]>[CH3:1][N:2]([CH3:17])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:12]1[O:13][CH:14]=[CH:15][N:16]=1
Reactant: CN(C)c1ccc([N+](=O)[O-])cc1-c1ncco1
Agent: [Fe]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CN(C)c1ccc(N)cc1-c1ncco1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.8 %

Procedure:
Iron powder (0.15 g, 2.574 mmol) was added to a solution of dimethyl-(4-nitro-2-oxazol-2-yl-phenyl)-amine (200 mg, 0.86 mmol) in acetic acid (3 ml) and stirred overnight at room temperature. The reaction mixture was poured into ice water and basified with dilute sodium hydroxide solution and then filtered. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water, then brine and dried. Evaporation to dryness gave N1,N1-dimethyl-2-oxazol-2-yl-benzene-1,4-diamine (150 mg, 88.2%) as oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[N:8][CH:9]=1)([O-])=O>CO.[Pd]>[CH2:14]([N:10]([CH2:11][CH2:12][CH3:13])[C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][N:8]=1)[CH2:15][CH3:16]
Reactant: CCCN(CCC)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CCCN(CCC)c1ccc(N)cn1
Yield: 61.6 %

Procedure:
A solution of (5-nitro-pyridin-2-yl)-dipropylamine (630 mg, 2.82 mmol) in methanol (10 ml) was hydrogenated over 10% Pd—C (130 mg) at room temperature and atmospheric pressure until no further gas absorption occurred. The reaction mixture was filtered over celite and the filtrate was concentrated to an oil. Purification by column chromatography over silica gel using 0-20% ethyl acetate in pet ether yielded N2,N2-dipropyl-pyridine-2,5-diamine (336 mg, 46.5%) as oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1OS(C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)(=O)=O)=[O:5])[CH3:2].[Br:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[C:36]([F:41])[CH:35]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]>[CH2:1]([O:3][C:4]([C:6]1[N:14]([CH3:15])[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:38][C:37]1[CH:39]=[CH:40][C:34]([Br:33])=[CH:35][C:36]=1[F:41])=[O:5])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: CCOC(=O)c1c(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c2cnccc2n1C
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(Nc2ccc(Br)cc2F)c2cnccc2n1C
Temperature: 25 °C
Yield: 33.9 %

Procedure:
A degassed solution of 1-methyl-3-(nonafluorobutane-1-sulfonyloxy)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (800 mg, 1.58 mmol), 4-bromo-2-fluoroaniline (360 mg, 1.89 mmol), Pd2dba3 (144 mg, 0.16 mmol), Xantphos (182 mg, 0.32 mmol) and DBU (538 μl, 3.79 mmol) in toluene (8 ml) was subjected to microwave irradiation at 120° C. for 5 minutes. The reaction mixture was cooled to ambient temperature then diluted with ethyl acetate (100 ml). The resultant solution was washed with water (50 ml), dried over sodium sulfate and concentrated in vacuo to give a solid residue. The solid residue was purified by flash chromatography (Si-PPC, pentane:ethyl acetate, gradient 100:0 to 60:40) to afford the title compound as a yellow solid (210 mg, 34%). LCMS (method B): RT=2.33 min, M+H=392/394.